Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[C:9]([CH2:14][CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:11][CH2:12][CH3:13])=[O:10]>C1(C)C=CC=CC=1>[CH2:12]([O:11][C:9](=[O:10])[CH:14]([CH3:15])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH3:13]
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccn1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)Cc1ccccn1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 2-pyridinecarboxaldehyde (0.96 mL, 10 mmol, 1.0 eq.) in toluene (17 mL) was added a solution of (carbethoxyethylidene)triphenylphosphorane (6.50 g, 16.1 mmol, 1.6 eq.) in toluene (24 mL). The resulting mixture was stirred at 80° C. for 18 hours. The solvent was removed in vacuo. The residue was suspended in a minimum amount of water and DCM was added. The product was extracted with 5% HCl soln. The aq. phase was cooled down to 0° C. and was basified with solid K2CO3. The product was then extracted with DCM (2×) and the comb. org. layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flashmaster (column: 100 g, flow: 45 mL/min, 45 fractions of 45 mL, Heptane 100% to Heptane+25% AcOEt). To a solution of the resulting α,β-unsaturated ester in THF (21 mL) under N2, palladium on activated carbon (10 wt. %, 33 mg) was added. The flask was carefully evacuated and refilled with H2 (3×). The black suspension was stirred at 45° C. under an H2-atmosphere for 18 hours. The black suspension was filtered through Celite. The Celite was rinsed with THF. The filtrate was concentrated in vacuo. The residue was purified by flashmaster (column: 25 g, flow: 30 mL/min, 30 fractions of 30 mL, Heptane 100% to Heptane+AcOEt 30%) to yield (±)-2-methyl-3-pyridin-2-yl-propionic acid ethyl ester as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[NH2:10])[CH3:2].C[Al](C)C.CO[C:17](=O)[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1>ClC(Cl)C.C1(C)C=CC=CC=1>[CH2:1]([N:3]1[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=[C:17]1[CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[C:24]1[N:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[CH3:2]
Reactant: COC(=O)Cn1ccnc1-c1ncccn1
Reactant: CCNc1ccncc1N
Agent: C[Al](C)C
Solvent: CC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCn1c(Cn2ccnc2-c2ncccn2)nc2cnccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
To a solution of N4-ethyl-pyridine-3,4-diamine (Justus Liebigs Ann. Chem. (1935) 518, 274, 287) (125 mg, 0.9 mmol) in dichloroethane (10 mL) is added a solution of AlMe3 in toluene (2M, 1.37 mL) dropwise under nitrogen. After addition, the mixture is stirred at room temperature for one hour and (2-pyrimidin-2-yl-imidazol-1-yl)-acetic acid methyl ester (100 mg, 0.45 mmol) is added in one portion. The reaction mixture is heated with stirring at 80° C. for 2 days. After cooled, the mixture is quenched with 5 mL of water, 2 drops of 5 N NaOH and extracted with CH2Cl2 (10 mL×5). The combined organic extracts are dried over Na2SO4, and concentrated. The residue is dissolved in 10 mL of acetic acid and the resulting mixture is heated at 100° C. overnight. After removal of acetic acid under vacuum, the residue is basified with saturated NaHCO3 solution and extracted with CH2Cl2 (10 mL×5). The combined organic extracts are dried over Na2SO4, and concentrated. The residue is purified on a silica gel column with 10:1 CH2Cl2/MeOH as eluent to yield the title compound (40 mg). 1H NMR (CDCl3) δ: 9.09 (s, 1H), 8.85 (d, 2H), 8.46 (d, 1H), 7.26-7.30 (m, 3H), 7.16 (1H), 6.39 (s, 2H), 4.25 (q, 2H), 1.15 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[F:8].[N+:10]([O-])([O-:12])=[O:11].[NH4+].FC(F)(F)C(O)=O.[OH-].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]=1[F:8]
Reactant: Cc1ccc(F)c(F)c1
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(F)c(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 38 %

Procedure:
3,4-Difluorotoluene (9.00 g, 70.3 mmol), ammonium nitrate (6.75 g, 84.3 mmol) and trifluoroacetic acid (25 ml) were stirred at ambient temperature for 18 h. The resulting solution was made basic to pH>10 with 5 N sodium hydroxide and, after cooling to ambient temperature, extracted with diethyl ether (3×40 ml). The combined organic layers were washed with brine (40 ml) and dried over anhydrous sodium sulfate. The filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography, eluting with hexanes/ethyl acetate (9:1), to afford 3,4-difluoro-5-nitrotoluene (4.63 g, 40%) as a light yellow oil. 1H-NMR δ (400 MHz, CDCl3) 7.94 (1H, dd, J=9.9, 7.3 Hz), 7.17 (1H, dd, J=10.3, 7.6 Hz), 2.61 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=2[N:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.[Cu]>[Cl:1][C:2]1[N:7]=[C:6]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]2[CH2:9][CH2:10][CH2:11][C:4]=2[N:3]=1
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Reactant: Oc1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1nc2c(c(Oc3ccccc3)n1)CCC2
Temperature: 27.5 °C
Reaction time: 13 h
Yield: 52.4 %

Procedure:
A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (0.45 g, 2.4 mmol), phenol (0.28 g, 3 mmol), cesium carbonate (0.97 g, 3 mmol) and copper powder (0.01 g) in anhydrous dimethylformamide (5 mL) was stirred at about 20 to 35° C. for 6 to 20 hours. The reaction was quenched by addition of water. The organics were extracted with EtOAc and the combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude was purified by column chromatography (silica gel) to afford the title compound as a white solid (0.31 g, 54%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)=[CH:5][CH:4]=[N:3]1.[NH2:15][CH:16]([C:29]([CH3:37])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30])[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[O:28]=[C:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:26](=[O:27])[N:18]1[CH2:17][CH:16]([NH:15][C:12]([C:9]1[CH:8]=[C:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[S:11][CH:10]=1)=[O:14])[C:29]([CH3:30])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:37]
Reactant: CC(C)(c1ccccc1)C(N)CN1C(=O)c2ccccc2C1=O
Reactant: Cn1nccc1-c1cc(C(=O)O)cs1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1nccc1-c1cc(C(=O)NC(CN2C(=O)c3ccccc3C2=O)C(C)(C)c2ccccc2)cs1
Reaction time: 16 h
Yield: 29.6 %

Procedure:
To a heterogeneous mixture of 5-(1-methyl-1H-pyrazol-5-yl)-3-thiophenecarboxylic acid (155 mg, 0.74 mmol), 2-(2-amino-3-methyl-3-phenylbutyl)-1H-isoindole-1,3(2H)-dione (200 mg, 0.65 mmol)[from Preparation 4] and PyBrOP (426 mg, 0.91 mmol) in CHCl3 (10 mL) at 25° C. was added diisopropylethyl amine (0.5 mL, 2.9 mmol) dropwise. After 16 h, the mixture was adsorbed onto silica and the mixture purified via column chromatography (silica, 35-50% EtOAc/Hex) affording the title compound (96 mg, 26%) as a white solid: LC-MS (ES) m/z=499 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][CH:4]([C:8]([NH:10][CH2:11][C:12]2[C:17]([CH3:18])=[N:16][CH:15]=[CH:14][N:13]=2)=O)[CH2:3]1.N.C(OCC)(=O)C.CO>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CO>[CH3:1][N:2]1[CH2:3][CH:4]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:17]([CH3:18])[C:12]3=[CH:11][N:10]=2)[CH2:5][C:6]1=[O:7]
Reactant: Cc1nccnc1CNC(=O)C1CC(=O)N(C)C1
Agent: CS(=O)(=O)O
Agent: N
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nccn2c(C3CC(=O)N(C)C3)ncc12
Temperature: 60 °C
Reaction time: 18 h
Yield: 108.8 %

Procedure:
1-Methyl-N-((3-methylpyrazin-2-yl)methyl)-5-oxopyrrolidine-3-carboxamide (330 mg, 1.329 mmol) was dissolved in Eaton's reagent (2 ml) and the reaction mixture was stirred at 60° C. for 18 hour. Then the reaction mixture was poured into an ice-bath and basified with 7N ammonia in methanol (20 ml). The resulting mixture was extrated with chloroform/iso-propanol (9/1) five times. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue (280 mg) was stripped with toluene twice and with dichloromethane twice. An additional crop (53 mg) was obtained by extraction of the water layer with chloroform/iso-propanol (9/1) twice and drying and concentrating as described before. In total 333 mg of crude 1-methyl-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)pyrrolidin-2-one was obtained which was used in the next reaction without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1[C:15]([CH:20]1[CH2:22][CH2:21]1)([C:17]#[C:18][CH3:19])[OH:16].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>C1COCC1>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:23](=[O:24])[O:16][C:15]([CH:20]4[CH2:22][CH2:21]4)([C:17]#[C:18][CH3:19])[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: CC#CC(O)(c1cc(-c2cccc(Cl)c2)ccc1N)C1CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC#CC1(C2CC2)OC(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
A mixture of 1-(4-amino-3′-chloro-biphenyl-3-yl)-1-cyclopropyl-1-propynyl-methanol (0.02 g, 0.064 mmol) and 1,1′-carbonyldiimidazole (0.016 g, 0.096 mmol) in dry THF (10 mL) was stirred under a blanket of nitrogen for 10 minutes. Upon completion of the reaction, the THF was removed and the residue purified via flash chromatography (silica gel, 40% ethyl acetate/hexane) to give 6-(3-chlorophenyl)-4-cyclopropyl-4-prop-1-ynyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (0.014 g, 56%) as a light yellow solid: mp 178-179° C.; 1H-NMR (DMSO-d6) δ10.6 (s, 1H), 7.68 (m, 2H), 7.64 (bs, 1H), 7.59 (d, 1H, J=7.72 Hz), 7.49 (t, 1H, J=7.82 Hz), 7.42 (d, 1H, J=7.95 Hz), 7.02 (d, 1H, J=8.0 Hz), 1.86 (s, 3H), 1.66 (m, 1H), 0.82 (m, 1H), 0.66 (m, 3H); MS (ESI) m/z 336 ([M−H]−, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)[CH:6]=[CH:5]2.[Li]CCCC.Cl[Ge:26]([CH3:29])([CH3:28])[CH3:27]>C1COCC1>[CH3:19][C:14]1[CH:13]=[C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Ge:26]([CH3:29])([CH3:28])[CH3:27])[CH:3]=3)[N:8]=2)[CH:17]=[C:16]([CH3:18])[CH:15]=1
Reactant: C[Ge](C)(C)Cl
Reactant: Cc1cc(C)cc(-c2ccc3cc(Br)ccc3n2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2ccc3cc([Ge](C)(C)C)ccc3n2)c1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
6-Bromo-2-(3,5-dimethylphenyl)quinoline (6.0 g, 19.2 mmol) and 150 mL anhydrous THF were added in a dry 2-necked round bottom flask and cooled down to −78° C. 8.46 mL BuLi (2.5 M in hexane) was added dropwise. The solution was stirred for 45 minutes at −78° C. and 2.83 mL (23.06 mmol) of chlorotrimethylgermane was slowly added with a syringe. The solution was stirred for overnight. The reaction mixture was purified by column 5% ethyl acetate in hexane and distillation. ˜4.1 g white slide was obtained after recrystallization from hexane. GC-MS confirmed the desired product.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][NH:3]1.[H-].[Na+].[CH2:9](Br)[C:10]#[CH:11].C(=O)(O)[O-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:11]([N:3]1[C:2](=[O:1])[CH2:6][S:5][CH2:4]1)[C:10]#[CH:9]
Reactant: O=C1CSCN1
Reactant: C#CCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCN1CSCC1=O
Reaction time: 0.5 h

Procedure:
To a stirred solution of 10.3 g of 4-oxothiazolidine in 500 ml of anhydrous dimethylformamide under N2 was added 6.0 g of sodium hydride (50% in oil). After 30 min., 15 ml of a solution of 80% propargyl bromide in toluene was added and the mixture was allowed to stir for another hour. The mixture was then poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The combined organic fractions were washed twice with water, then once with brine, dried (MgSO4), filtered and concentrated. The residue was distilled at 0.1/mm Hg, 95°-98° C., to provide 9.248 g of 3-propargyl-4-oxothiazolidine as an oil which solidified upon refrigeration, mp 29°-31°.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=[C:10]([C:11]([O:13]C)=O)[C:4]=2[O:3]1.[CH2:19]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH2:32])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(O)COCCO>[CH2:19]([N:26]1[CH2:30][CH2:29][CH2:28][CH:27]1[CH2:31][NH:32][C:11]([C:10]1[C:4]2[O:3][CH:2]([CH3:1])[CH2:6][C:5]=2[CH:7]=[C:8]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:9]=1)=[O:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc(S(N)(=O)=O)cc2c1OC(C)C2
Reactant: NCC1CCCN1Cc1ccccc1
Solvent: O
Solvent: OCCOCCO
Product: CC1Cc2cc(S(N)(=O)=O)cc(C(=O)NCC3CCCN3Cc3ccccc3)c2O1
Temperature: 25 °C
Reaction time: 30.5 h

Procedure:
A suspension of 4.0 g of methyl 2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxylate and 3.37 g of 1-benzyl-2-aminomethyl-pyrrolidine in 15 ml of diethylene glycol is heated at 120°-130° C. and stirred for 30-31 hours. The reaction solution is cooled to room temperature, poured into 150-200 ml of water, and extracted with ethyl acetate three times. The ethyl acetate extract is washed with water followed by sodium chloride saturated water. The product is dried over magnesium sulfate and the solvent is distilled off under diminished pressure. The resulting residue is recrystallized from isopropanol by the use of decolorizing charcoal to give crystals of N-(1-benzyl-2-pyrrolidinylmethyl)-2-methyl-5-sulfamoyl-2,3-dihydrobenzofuran-7-carboxamide, m.p. 161°-167° C.
Reaction SMILES: C(O[C:4](=[O:15])[C@H:5]([CH2:11][CH:12]([CH3:14])[CH3:13])[NH:6][CH2:7][CH:8]([CH3:10])[CH3:9])C.[CH3:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]=[C:27]=[S:28]>>[CH3:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=1[N:26]=[C:27]1[N:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[C@@H:5]([CH2:11][CH:12]([CH3:13])[CH3:14])[C:4](=[O:15])[S:28]1
Reactant: CCOC(=O)[C@H](CC(C)C)NCC(C)C
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC(=O)[C@H](CC(C)C)N1CC(C)C

Procedure:
N-Isobutylleucine ethyl ester was reacted with 2-methyl-4-nitrophenyl isothiocyanate according to Method C11a to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidin-5-one.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Fc1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)c(F)c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2,4-difluoro-phenylboronic acid to give [1-(2,4-difluoro-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 323(MH+).
Reaction SMILES: [CH3:1][C:2]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10](=[O:11])[C:9]2[C:4](=[CH:5][C:6]([O:14]C)=[C:7]([Cl:13])[C:8]=2[Cl:12])[C:3]1=[O:16].Cl.N1C=CC=CC=1>O>[CH3:1][C:2]1([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10](=[O:11])[C:9]2[C:4](=[CH:5][C:6]([OH:14])=[C:7]([Cl:13])[C:8]=2[Cl:12])[C:3]1=[O:16]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC1(c2ccccc2)C(=O)c2cc(O)c(Cl)c(Cl)c2C1=O
Temperature: 175 °C

Procedure:
A stirred mixture of 2-methyl-2-phenyl-4,5-dichloro-6-methoxyindan-1,3-dione (5.01 g., 0.015 mole) and pyridine hydrochloride (50 g.) is heated at 175°C. for 1 hour, then poured into water (500 ml.) to give 2-methyl-2-phenyl-4,5-dichloro-6-hydroxyindan-1,3-dione.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[N:3]=1.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24]>CC#N.C(O)(C(F)(F)F)=O>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([C:4]2[N:3]=[C:2]([NH:20][CH2:21][CH2:22][CH2:23][OH:24])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=2)=[CH:13][CH:14]=1)[CH3:19]
Reactant: NCCCO
Reactant: CCc1ccc(-c2ccc(C(F)(F)F)c(Cl)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCc1ccc(-c2ccc(C(F)(F)F)c(NCCCO)n2)cc1
Yield: 51.8 %

Procedure:
To a solution of 2-chloro-6-(4-ethylphenyl)-3-(trifluoromethyl)pyridine (Example 315, 0.36 g, 1.25 mmol) and 3-amino-1-propanol (0.38 g, 5.00 mmol) in CH3CN (2 mL), TFA (0.5 mL) was added. The mixture was stirred at reflux for 18 h, and then concentrated under reduced pressure. The product (0.21 g, 52%) was isolated after silica gel flash chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3OD) δ 7.95 (d, 2H), 7.72 (d, 1H), 7.27 (d, 2H), 7.10 (d, 1H), 3.72 (t, 2H), 3.66 (t, 2H), 2.69 (q, 2H), 1.90 (q, 2H), 1.27 (t, 3H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]2[CH2:13]4)[CH2:17]3)=[O:9])[CH2:4]1.Cl[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>>[CH:25]([O:24][C:22]([NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:12]3[CH2:13][CH:14]4[CH2:15][CH:16]([CH2:17][CH:18]2[CH2:19]4)[CH2:20]3)=[O:9])[CH2:4]1)=[O:23])([CH3:27])[CH3:26]
Reactant: N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Reactant: CC(C)OC(=O)Cl
Agent: Cl
Product: CC(C)OC(=O)N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1

Procedure:
The title compound was prepared from (R)-2-adamantyl 3-aminopyrrolidine-1-carboxylate HCl salt and isopropyl chloroformate following a procedure analogous to that described in Example 3 Step 2. LC-MS Method 1 tR=1.98 min, m/z=351; 1H NMR (CDCl3) 1.24 (d, 6H), 1.57 (d, 2H), 1.70-2.00 (13H), 2.18 (m, 1H), 3.16 (1H), 3.49 (m, 2H), 3.69 (m, 1H), 4.24 (m, 1H), 4.74 (1H), 4.82 (s, 1H), 4.93 (m, 1H)
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:35][C@H:36]([C:49]([O:51]C(C)(C)C)=[O:50])[CH2:37][CH2:38][CH2:39][CH2:40][NH:41]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1>>[NH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH:36]([NH:35][C:16]([C:14]1[CH:13]=[CH:12][C:11]2[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]([C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[C:24]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:23]=[CH:22]4)=[N:9][C:10]=2[CH:15]=1)=[O:17])[C:49]([OH:51])=[O:50]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NCCCCC(NC(=O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)ccc3c1)n2C1CCCCC1)C(=O)O
Yield: 15 %

Procedure:
Compound 232 was synthesized from Compound 201 as described for Compound 235, except H-Lys(Boc)-OtBu was used instead of L-5-hydroxytryptophane. In the 3rd step the protected intermediate was treated with a mixture of TFA-anisol 8:2 for 2 hours then the product was precipitated with ether and purified on RP-HPLC. Yield 15%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9]C(OC(C)(C)C)=O)=[CH:4][C:3]=1[F:17].[Cl:18][C:19]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])=[CH:26][C:20]=1[C:21]([N:23]=[C:24]=[O:25])=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:18][C:19]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])=[CH:26][C:20]=1[C:21]1[NH:23][C:24](=[O:25])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:17])[CH:4]=2)[N:9]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(Cl)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(Cl)c(F)c3)c(=O)[nH]2)c1)C(F)(F)F
Yield: 37104.1 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-(4-chloro-3-fluorophenyl)hydrazinecarboxylate (Intermediate-71, 0.828 g, 0.003 mmol), 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 1.3 g, 0.043 mmol), DCM (20 mL), trifluoro acetic acid (5.0 mL) to afford 0.500 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 4.45 (d, 2H), 7.48 (d, J=15.0 Hz, 1H), 7.68-7.83 (m, 3H), 7.85 (d, 1H), 7.99 (d, J=17.1 Hz, 1H), 10.08 (d, J=12.0 Hz, 1H), 12.73 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=3)=[CH:11][C:10]([C:21]([OH:23])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(N2C(C3C=C(F)C=C(Cl)C=3)=CC(C([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=O)=N2)C=CC=1F>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:14]=[C:15]([F:20])[CH:16]=[C:17]([F:19])[CH:18]=3)=[CH:11][C:10]([C:21]([N:47]3[CH2:51][C:50](=[O:52])[NH:49][CH2:48]3)=[O:23])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Reactant: O=C(O)c1cc(-c2cc(F)cc(F)c2)n(-c2cccc(Cl)c2)n1
Product: O=C1CN(C(=O)c2cc(-c3cc(F)cc(F)c3)n(-c3cccc(Cl)c3)n2)CN1

Procedure:
The preparation of the title compound takes place starting from the compound of Example 73A in analogy to the synthesis of the compound of Example 1. 28 mg (73% of theory) of the title compound are obtained.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][C:12]1[S:16][C:15]([C:17]#[N:18])=[CH:14][CH:13]=1.O>O1CCCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[O:11][C:12]1[S:16][C:15]([CH2:17][NH2:18])=[CH:14][CH:13]=1
Reactant: N#Cc1ccc(Oc2cccc(Br)c2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(Oc2cccc(Br)c2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Next, to a solution of lithium aluminum hydride (204 mg, 5.39 mmol) in tetrahydrofuran (10 mL) was added a solution of the resulting 5-(3-bromophenoxy)-thiophene-2carbonitrile (1.01 g, 3.59 mmol) in tetrahydrofuran (10 mL), and the solution was stirred at room temperature for 2 hours. Then, lithium aluminum hydride (68 mg, 1.80 mmol) was added, and the solution was further stirred at room temperature for 1 hour. Water was added to the reaction solution, which was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain a mixture of the title compound and debrominated compound (740 mg) as a pale brown oil. As this mixture cannot be purified, it was used in the next reaction without purification.