Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:7][C:8]2([C:21]([OH:23])=O)[CH2:20][CH:11]3[CH2:12][N:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:14][CH:10]3[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC)=O.[N-:37]=[N+:38]=[N-:39].[Na+]>CC(C)=O.O>[CH:1]1([CH2:7][C:8]2([C:21]([N:37]=[N+:38]=[N-:39])=[O:23])[CH2:20][CH:11]3[CH2:12][N:13]([C:15](=[O:19])[N:16]([CH3:17])[CH3:18])[CH2:14][CH:10]3[CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)C(=O)N1CC2CC(CC3CCCCC3)(C(=O)O)CC2C1
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CC2CC(CC3CCCCC3)(C(=O)N=[N+]=[N-])CC2C1
Yield: 97.6 %

Procedure:
Upon cooling by an ice-water bath, 5-cyclohexylmethyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carboxylic acid 15c (0.75 g, 2.33 mmol) was dissolved in 20 mL of acetone with stirring followed by dropwise addition of triethylamine (0.36 mL, 2.56 mmol) and a solution of 2 mL of ethyl chloroformate (0.25 mL, 2.56 mmol) in acetone. The reaction mixture was stirred for 15 minutes and a solution of 2 mL of sodium azide (0.303 g, 4.66 mmol) in water was added. The reaction mixture was reacted for another 30 minutes at 0° C.˜5° C. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was concentrated to remove acetone and diluted with 10 mL of water. The mixture was extracted with ethyl acetate (10 mL×5). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound 5-cyclohexylmethyl-2-dimethylcarbamoyl-octahydro-cyclopenta[c]pyrrole-5-carbonyl azide 15d (0.79 g) as a yellow oil which was directly used in the next step.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1.[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25].C(O)C.N1CCCCC1>C(O)(=O)C>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=[C:23]3[S:19][C:20](=[O:25])[NH:21][C:22]3=[O:24])=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(CCOc2ccc(C=O)cc2)n1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1cccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)n1
Temperature: 0 °C

Procedure:
A mixture of 4-[2-(6-methyl-2-pyridyl)ethoxy]benzaldehyde (1.21 g), 2,4-thiazolidinedione (0.59 g), ethanol (50 ml) and piperidine (0.33 g) was heated under reflux for 16 hours. The reaction mixture was poured into ice-water and acidified with acetic acid. The resulting crystals were collected by filtration to give 5-{4-[2-(6-methyl-2-pyridyl)ethoxy]benzylidene}-2,4-thiazolidinedione. Yield: 1.34 g (78.5%). Recrystallization from methanol gave pale yellow prisms. m.p.: 180.5°-182° C.
Reaction SMILES: [OH:1]N1C(=O)CCC1=O.[CH2:9]1[CH2:14][CH2:13][CH:12]([N:15]=[C:16]=[N:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:11][CH2:10]1>C(#N)C>[C:16]([NH:15][CH:12]1[CH2:11][CH2:10][CH2:9][CH2:14][CH2:13]1)([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:1]
Reactant: O=C1CCC(=O)N1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC#N
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
Ligand A (150 mg; 0.4 mmol), N-hydroxysuccinimide (60 mg; 0.522 mmol) and DCC (101 mg; 0.49 mmol) were stirred in 4 ml of acetonitrile at room temperature for 2 hours. Dicyclohexylurea formed was removed by filtration and rinsed with about I ml of acetonitrile.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:8]([NH:10][CH2:11][C:12]([O:14]C)=O)=[O:9])=[N:4][CH:5]=[CH:6][N:7]=1.[NH3:16].Cl>CO.O>[NH2:16][C:12](=[O:14])[CH2:11][NH:10][C:8]([C:3]1[C:2]([OH:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:9]
Reactant: COC(=O)CNC(=O)c1nccnc1O
Reactant: N
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=O)CNC(=O)c1nccnc1O
Reaction time: 1 h

Procedure:
In 4 mL of methanol is suspended 0.19 g of methyl 2-{[(3-hydroxy-2-pyrazinyl)carbonyl]-amino}acetate. The suspension is saturated with ammonia by introducing gaseous ammonia thereinto under ice-cooling for 30 minutes. The resulting mixture is stirred at the same temperature as above for 1 hour and then at ambient temperature for 15 hours. The solvent is distilled off under reduced pressure. The residue thus obtained is dissolved in a mixture of 4 mL of water and 1 mL of methanol. To the resulting solution is added 0.9 mL of 1 mol/L hydrochloric acid. The deposited crystals are collected by filtration to obtain 0.16 g of N2-(2-amino-2-oxoethyl)-3-hydroxy-2-pyrazinecarboxamide.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].C1([C@@H](O)CN2CCCC2)C=CC=CC=1.NO>CO>[CH3:1][N:2]([CH3:12])[CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: CN(C)CC(O)c1ccccc1
Agent: NO
Agent: O[C@@H](CN1CCCC1)c1ccccc1
Solvent: CO
Product: CN(C)C[C@H](O)c1ccccc1

Procedure:
Racemic 2-dimethylamino-1-phenyl ethanol was cleaved in accordance with the 2-pyrrolidinyl-1-phenyl ethanol (see example 6) using 16.5 g of crude amino alcohol as described in example 8. The yield of oily (R)-2-dimethyl-amino-1-phenyl ethanol with a [αD20] value of −45.5° (methanol) was 8.9 g.
Reaction SMILES: C(O[C:4](=[O:9])[CH2:5][C:6](=O)[CH3:7])C.[C:10]1([CH3:23])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([NH:19][C:20]([NH2:22])=[NH:21])=[NH:18]>C(O)C>[CH3:7][C:6]1[N:21]=[C:20]([NH:19][C:17]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:23])=[NH:18])[NH:22][C:4](=[O:9])[CH:5]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: Cc1ccccc1NC(=N)NC(=N)N
Solvent: CCO
Product: Cc1cc(=O)[nH]c(NC(=N)Nc2ccccc2C)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
In a 50 milliliter round-bottom flask, 3-oxobutyric acid ethyl ester (2.6 grams, 0.020 mol; obtained from Aldrich Chemical Co., Milwaukee, Wis.) was added at room temperature to a solution of 1-(o-tolyl)biguanide (3.8 grams, 0.020 mol; obtained from Aldrich Chemical Co.) in anhydrous ethanol (20 milliliters). The mixture was heated at reflux and stirred for 4 hours. After a few minutes, all the components dissolved. Cooling the resulting yellow solution mixture to room temperature gave a colorless precipitate. The precipitate was isolated by filtration and thoroughly washed with cold ethanol (0° C.). The solid was then recrystallized from anhydrous ethanol, recovered by filtration, and dried under reduced pressure to give the targeted N-(4-methyl-6-oxo-1,6-dihydropyrimidin-2-yl)-N′-o-tolylguanidine as a colorless solid (3.50 grams, 68 percent yield): mp=260° C.; Exact mass calculated for C13H15N5O=257.1277. Measured Low. Resolution Mass Spectrum (MAB/LR/N2)=257.1.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].P(=O)([O-])[O-].C([Li])CCC.[CH:17]1([C:27](OC)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1.CCCCCC.C(O)(=O)C>[O:28]=[C:27]([CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)C1CCCCCCCCC1
Agent: O=[PH]([O-])[O-]
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C1CCCCCCCCC1)OC
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 49.6 g (0.40 mole) dimethyl methylphosphonate (Aldrich) in 500 ml dry tetrahydrofuran is cooled to -78° in a dry nitrogen atmosphere. To the stirred phosphonate solution is added 188 ml of 2.34 M n-butyllithium in hexane solution (Alfa Inorganics, Inc.) dropwise over a period of 18 minutes at such a rate that the reaction temperature never rises above -65°. After an additional 5 minutes stirring at -78°, 25.6 g (0.20 mole) methyl cyclodecanecarboxylate is added dropwise at a rate that keeps the reaction temperature less than -70° (20 minutes). After 1.0 hour at -78° the reaction mixture is allowed to warm to ambient temperature, neutralized with 25 ml acetic acid and rotary evaporated to a white gel. The gelatinous material is taken up in 75 ml water, the aqueous phase extracted with 100 ml portions of chloroform (3x), the combined organic extracts are backwashed (50 cc H2O), dried (MgSO4), and concentrated (water aspirator) to a crude residue and distilled to give dimethyl 2-oxo-2-cyclodecylethylphosphonate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:9])=[N:7][CH:8]=1)#[N:2].II.CS(C)=[O:14]>>[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=1)=[O:14]
Reactant: Cc1ccc(C#N)cn1
Reactant: CS(C)=O
Agent: II
Product: N#Cc1ccc(C=O)nc1
Temperature: 150 °C

Procedure:
A mixture of 5-cyano-2-methylpyridine (400 mg, 3.38 mmol) and iodine (0.8 g, 3.15 mmol) in DMSO (2 mL) was heated to 150° C. under nitrogen for 20 min. The reaction mixture was cooled to room temperature and quenched with 10% aqueous NaHCO3 solution. The organic product was extracted with EtOAc and the combined extracts were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to get the crude 6-formylnicotinonitrile (400 mg), which was carried through without further purification. 6-Formylnicotinonitrile (400 mg, 3.03 mmol) was dissolved in 1,2-dichloroethane (5 mL) and cooled to 0° C. A solution of tert-butyl 2-methylpiperazine-1-carboxylate (606 mg, 3.03 mmol) in 1,2-dichloroethane (5 mL), followed by sodium triacetoxyborohydride (1.1 g, 5.4 mmol) were added and the reaction mixture was allowed to warm up to room temperature and further stirred for 8 h. The reaction mixture was quenched with 10% aqueous NaHCO3 solution and the product was extracted with EtOAc.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:39]=[CH:38][C:12]([C:13]([O:28][CH2:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[C:33]#[N:34])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1.O.CO>C(OCC)C>[CH3:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([O:28][CH2:29][C:30]2[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=2)[CH2:33][NH2:34])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:39][CH:38]=2)=[CH:19][CH:18]=1
Reactant: COc1ccc(C(OCc2cccc(C#N)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: COc1ccc(C(OCc2cccc(CN)c2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 66.6 %

Procedure:
To a suspension of LiAlH4 (238 mg, 6.28 mmol) in diethyl ether (30 mL), which was stirred and cooled with ice, was added dropwise a solution of 3-(4,4′-dimethoxytrityloxymethyl)benzonitrile (4) (0.86 g, 1.98 mmol) in diethyl ether (90 mL). The mixture was stirred for 16 hours at a room temperature under Ar atmosphere. TLC was used to confirm there was no starting material in the reaction mixture. Then, to the mixture were added water (1.2 mL) and MeOH (7.2 mL) and stirred for additional 30 minutes. Then, a formed salt was removed by suction filtration. The filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3:MeOH=100:1) to give 3-(4,4′-dimethoxytrityloxymethyl)benzylamine (5) (0.58 g, 69%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[F:23]>CCOC(C)=O>[F:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(N2CCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
To a solution of pyrrolidine (0.78 g, 11 mmol) in EtOAc (15 mL) and Et3N (1.52 g, 15 mmol) was added 1,2-difluoro-4-nitrobenzene (1.59 g, 10 mmol) in an ice bath. The mixture was stirred at rt overnight and filtered. The filter cake was washed with water and dried to give the title compound as a yellow solid (1.60 g, 76%).
Reaction SMILES: [C:1]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][C:16](=O)[NH2:17])(=[O:12])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[C:1]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][C:16]#[N:17])(=[O:12])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#CC[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Reaction time: 24 h
Yield: 32.3 %

Procedure:
To a mixture of 0.198 g (0.69 mmol) of N-quinaldoyl-L-asparagine and 0.24 ml (1.38 mmol) of N,N-diisopropylethylamine in 1 ml of chloroform was added 0.146 g (0.71 mmol) of dicyclohexylcarbodiimide. The reaction mixture was stirred for 24 hr. at room terperature, then partitioned between 10ml of 5% sodium bicarbonate and 10 ml of ether. The aqueous phase was acidified to pH2 and the acid was taken up by extraction with chloroform (3×10ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to give 0.101 g of crude product. This was recrystallized from a small portion of methylene chloride to give 0.06 g of the title compound melting at 144°-146° C.; NMR (5% DMSO-d6 in CDCl3): 3.22 (d, 2H, ala CH2); 4.95 (m, 1H, ala CH); 7.2-8.57 (m, 7H, aromatic, OH); 9.19(d, 1H, NH).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:15]([F:18])([F:17])[F:16])([O-])=O>C(O)C.[Pd]>[N:10]1([C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([C:15]([F:16])([F:17])[F:18])[CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCCC2)cc1C(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCCC2)cc1C(F)(F)F
Reaction time: 16 h
Yield: 97.2 %

Procedure:
To a flask charged with 10% Pd/C (50 mg) under inert atmosphere was added a solution of 1-(4-nitro-3-(trifluoromethyl)phenyl)pyrrolidine (350 mg, 1.34 mmol) in ethanol. The reaction was stirred under H2 atmosphere for 16 h, then filtered and dried down to provide 4-(pyrrolidin-1-yl)-2-(trifluoromethyl)aniline (300 mg, 97% yield). M+H m/z 231.3. 1H NMR (400.0 MHz, DMSO-d6) δ 6.84 (d, J=8.8 Hz, 1H), 6.72 (dd, J=2.5, 8.8 Hz, 1H), 6.53 (d, J=2.7 Hz, 1H), 4.74 (s, 2H), 3.18 (m, 4H), 1.99-1.95 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:19])=[O:18])=[CH:13][CH:12]=2)[N:7]([CH3:21])[CH:6]=1)=[O:4].[OH:22]O>CC(O)=O>[Cl:1][CH2:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=[O:20])[C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:19])(=[O:22])=[O:18])=[CH:13][CH:12]=2)[N:7]([CH3:21])[CH:6]=1)=[O:4]
Reactant: Cn1cc(C(=O)CCl)cc1C(=O)c1ccc(S(C)=O)cc1
Reactant: OO
Solvent: CC(=O)O
Product: Cn1cc(C(=O)CCl)cc1C(=O)c1ccc(S(C)(=O)=O)cc1
Reaction time: 144 h
Yield: 30 %

Procedure:
A mixture of 2.5 g (0.0074 mole) of 2-chloro-1-[1-methyl-5-(4-(methylsulfinyl)benzoyl]-1H-pyrrol-3-yl]-ethanone, 20 mL of HOAc, and 1.7 mL of 30% H2O2 was stirred for 6 days. The solid was filtered off to give 0.75 g (30%) of 2-chloro-1-[1-methyl-5-(4-(methylsulfonyl)benzoyl]-1H-pyrrol-3-yl]-ethanone. HNMR (CDCl3) δ8.1 (s, 2H); 8.0 (s, 2H); 7.7 (ar, 1H); 7.1 (ar, 1H); 4.4 (s, 2H); 4.1 (s, 3H); 3.1 (s, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[OH:12])=O.C(C1C=CC(C(O)=O)=CC=1O)#N.[N+](CC)([O-])=O.[NH2:30][C@@H:31]([C:34]([OH:36])=[O:35])[CH2:32][SH:33]>C([O-])(=O)C.[Na+].C(O)(=O)C>[OH:12][C:4]1[CH:5]=[C:6]([C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:3]=1[C:1]1[S:33][CH2:32][C@H:31]([C:34]([OH:36])=[O:35])[N:30]=1
Reactant: N[C@H](CS)C(=O)O
Reactant: O=Cc1ccc(C(=O)O)cc1O
Agent: CC(=O)[O-]
Agent: N#Cc1ccc(C(=O)O)cc1O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC[N+](=O)[O-]
Product: O=C(O)c1ccc(C2=N[C@@H](C(=O)O)CS2)c(O)c1

Procedure:
The key step of the synthesis of (S)-4,5-dihydro-2-(2-hydroxy-3-methoxyphenyl)-4-thiazolecarboxylic acid (6) was cyclocondensation of D-cysteine with 2-hydroxy-3-methoxybenzonitrile. The cyano intermediate was obtained from o-vanillin by treatment with nitroethane in sodium acetate and acetic acid. (S)-4,5-Dihydro-2-(2-hydroxy-4-carboxyphenyl)-4-thiazolecarboxylic acid (7) was synthesized by a similar reaction sequence. 4-Formyl-3-hydroxybenzoic acid was converted to 4-cyano-3-hydroxybenzoic acid using nitroethane in sodium acetate and acetic acid; cyclization with D-cysteine completed the synthesis of dicarboxylic acid chelator 7.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:7]1[C:15]2[C:14]([F:16])=[CH:13][N:12]=[CH:11][C:10]=2[C:9]([I:17])=[CH:8]1)([CH3:6])[CH3:5].CC(C[AlH]CC(C)C)C>C1COCC1>[F:16][C:14]1[C:15]2[N:7]([C:4]([CH3:5])([CH3:6])[CH2:3][OH:2])[CH:8]=[C:9]([I:17])[C:10]=2[CH:11]=[N:12][CH:13]=1
Reactant: COC(=O)C(C)(C)n1cc(I)c2cncc(F)c21
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC(C)(CO)n1cc(I)c2cncc(F)c21
Reaction time: 2 h
Yield: 65 %

Procedure:
2-(7-Fluoro-3-iodo-pyrrolo[3,2-c]pyridin-1-yl)-2-methyl-propionic acid methyl ester (Preparation 71, 500 mg, 1.38 mmol) was taken in dry THF (3 mL) and DIBAL-H (25% solution in toluene, 2 mL, 3.03 mmol) was added drop wise at 0° C. and stirred at the same temperature for 2 hours. The reaction was quenched with MeOH, water, 2N HCl at 0° C. and stirred for 15 minutes before being diluted with EtOAc and water. The organic layer was separated and washed with brine, dried over sodium sulphate and evaporated in vacuo to obtain the title compound (65%) that was used in the next step directly without any further purification.
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.Cl[C:23]1[N:24]=[C:25]([C:33]2[CH:54]=[CH:53][C:36]([O:37][CH2:38][CH2:39][CH:40]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]3)=[C:35]([C:55]([F:58])([F:57])[F:56])[CH:34]=2)[C:26]2[CH:31]=[CH:30][N:29]([CH3:32])[C:27]=2[N:28]=1.CCOC(C)=O.C[C:66]([N:68](C)C)=O>[Zn].[C-]#N.[Zn+2].[C-]#N.FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O>[C:66]([C:23]1[N:24]=[C:25]([C:33]2[CH:54]=[CH:53][C:36]([O:37][CH2:38][CH2:39][CH:40]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]3)=[C:35]([C:55]([F:58])([F:57])[F:56])[CH:34]=2)[C:26]2[CH:31]=[CH:30][N:29]([CH3:32])[C:27]=2[N:28]=1)#[N:68]
Reactant: CC(=O)N(C)C
Reactant: Cn1ccc2c(-c3ccc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)nc(Cl)nc21
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: O=C([O-])C(F)(F)F
Solvent: CCOC(C)=O
Product: Cn1ccc2c(-c3ccc(OCCC4CCN(C(=O)OC(C)(C)C)CC4)c(C(F)(F)F)c3)nc(C#N)nc21
Temperature: 110 °C
Reaction time: 5 h

Procedure:
Zinc (29 mg), 2-(di-tert-butylphosphino)biphenyl (59 mg), zinc cyanide (63 mg), and palladium (II) trifluoroacetate (30 mg) were added to a solution of tert-butyl 4-{2-[4-(2-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(trifluoromethyl)phenoxy]ethyl}piperidine-1-carboxylate (480 mg) in DMAc (10 mL) at room temperature in an argon atmosphere, and the mixture was stirred at 110° C. for 5 hours. After the reaction mixture was cooled to room temperature, EtOAc was added thereto, followed by stirring, and the insoluble material was separated by filtration using Celite. This filtrate was washed with a saturated aqueous NaHCO3 solution, water, and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=9:1 to 1:1), whereby tert-butyl 4-{2-[4-(2-cyano-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-(trifluoromethyl)phenoxy]ethyl}piperidine-1-carboxylate (236 mg) was obtained as a light yellow solid.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:31]=[N:32][C:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:45]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[O:46])[CH:43]=3)[C:38]([CH2:53][OH:54])=[CH:37]2)=[N:34][CH:35]=1>ClCCl>[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[CH:35]=[N:34][C:33]([N:36]2[C:44]3[C:39](=[CH:40][CH:41]=[C:42]([C:45]([N:47]4[CH2:52][CH2:51][O:50][CH2:49][CH2:48]4)=[O:46])[CH:43]=3)[C:38]([CH:53]=[O:54])=[CH:37]2)=[N:32][CH:31]=1
Reactant: O=C(c1ccc2c(CO)cn(-c3ncc(-c4ccccc4F)cn3)c2c1)N1CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Dess Martin periodinane (235 mg, 0.556 mmol, 1.5 eq) was added to the product of 27d) (160 mg, 0.370 mmol, 1.0 eq) in dichloromethane (10 mL) at 0° C. The mixture was stirred for 2 h at room temperature, and then filtered through a pad of celite. The filter was rinsed with dichloromethane and the filtrate was dried over sodium sulfate, and evaporated. White solid. Yield: 140 mg. Mass spectroscopy: m/z: [M+H]+=430.9
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@@H:4]1[CH2:8][C@H:7]([C:9]([OH:11])=O)[CH2:6][N:5]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[C:46]1([CH:52]2[CH2:54][CH:53]2[NH2:55])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>O1CCOCC1.C(Cl)Cl>[CH3:1][O:2][C:3]([CH:4]1[CH2:8][CH:7]([C:9](=[O:11])[NH:55][CH:53]2[CH2:54][CH:52]2[C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:6][N:5]1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:22]
Reactant: NC1CC1c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](C(=O)O)CN1C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C1CC(C(=O)NC2CC2c2ccccc2)CN1C(=O)OCc1ccccc1
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
To a stirred solution of cis-N-(benzyloxycarbonyl)-4-carboxy-proline methyl ester (615 mg, 2 mmol) and HOSu (173 mg, 3 mmol) in 1,4-dioxane (2 mL) was added a solution of DCC (454 mg, 2.2 mmol) in CH2Cl2 (2 mL). After 10 min at room temperature, 2-phenylcyclopropylamine (266 mg, 2 mmol) in CH2Cl2 (1 mL) was added with stirring. After 16 h, the resulting N,N′-dicyclohexylurea was removed by filtration. The filtrate was washed with saturated aqueous NaHCO3 (5 mL), 1 N aqueous citric acid (5 mL), water (5 mL), dried over MgSO4 and concentrated. The residue was purified by a silica gel column using hexane/EtOAc (6:4) as eluant to yield the desired compound as a colorless oil (633 mg, 75%).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Br[CH2:15][CH2:16][CH:17]=[CH2:18]>CN(C=O)C>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:18][CH2:17][CH:16]=[CH2:15])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: C=CCCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCC(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
A mixture of sodium hydride (60% in mineral oil, 435 mg, 10.87 mmol, 1.1 eq) in DMF (20 mL) was treated dropwise with diethyl malonate (1.5 mL, 9.88 mmol, 1.0 eq). The reaction mixture was then cooled to 0° C. and 4-bromo-1-butene (1.0 mL, 9.88 mmol, 1 eq) was added dropwise. The reaction mixture was warmed to rt, stirred for 3 days and then partitioned between ether and water. The layers were separated, the aqueous layer was extracted with ether (2×50 mL) and the combined organic phases were washed with water (2×) and brine, dried over MgSO4 and concentrated. Column chromatography (SiO2, 5% ether/heptane) gave C8.1 (1.51 g, 71% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 5.77 (m, 1H), 5.00 (m, 2H), 4.13 (q, J=7.1 Hz, 4H), 3.43 (t, J=7.4 Hz, 1H), 2.02 (m, 2H), 1.84 (m, 2H), 1.17 (t, J=7.1 Hz, 6H).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:17]([O-])=O)=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3]>[Ni].C(O)C>[CH2:20]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([NH2:17])=[C:10]([O:15][CH3:16])[CH:11]=2)[CH2:6]1)[CH2:21][CH3:22]
Reactant: CCCN(CCC)C1CCc2cc(OC)c([N+](=O)[O-])cc2C1
Agent: [Ni]
Solvent: CCO
Product: CCCN(CCC)C1CCc2cc(OC)c(N)cc2C1

Procedure:
9 g of the 2-dipropylamino-6-methoxy-7-nitro-1,2,3,4-tetrahydronaphthalene obtained in accordance with Example 1(b) are introduced into 200 ml of ethanol, together with 1 g of Raney nickel. At ambient temperature, hydrogenation is carried out under pressure until the absorption has stopped. After evaporation of the solvent, an oil remains which is shown to oxidise fairly readily in air.