Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=O)[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][CH:6]=1.[Li].CC[O:18]CC>>[CH:6]1[O:7][C:8]([CH:13]([OH:18])[CH3:12])=[C:9]2[CH:10]=[CH:11][CH:3]=[CH:4][C:5]=12
Reactant: COC(=O)Cc1coc2ccccc12
Reactant: CCOCC
Agent: [Li]
Product: CC(O)c1occ2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of benzofuran-3-yl-acetic acid methyl ester (4.0 g, 21 mmol) in 25 ml of ether was added dropwise at RT to a suspension of lithium alanate (1.61 g, 59.5 mmol) in 35 ml of ether, and stirring was then carried out for 30 minutes. Excess alanate was then hydrolysed with ethanol, the mixture was suction-filtered over Kieselguhr, and the solvent was removed in vacuo. The product was obtained in the form of a yellowish oil in a yield of 3.0 g (89%).
Reaction SMILES: [N+:1]([CH:3](S(C1C=CC(C)=CC=1)(=O)=O)[CH2:4][CH2:5][CH2:6][CH3:7])#[C-:2].[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].CC(C)([O-])C.[K+]>O1CCCC1.O>[CH2:4]([C:3]1[NH:1][CH:2]=[C:19]([C:18]([O:22][CH2:23][CH3:24])=[O:21])[CH:20]=1)[CH2:5][CH2:6][CH3:7]
Reactant: [C-]#[N+]C(CCCC)S(=O)(=O)c1ccc(C)cc1
Reactant: C=CC(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1cc(C(=O)OCC)c[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution (120 mL) of 1-[(1-isocyanopentyl)sulfonyl]-4-methylbenzene (10.8 g) and ethyl acrylate (4.78 mL) in tetrahydrofuran was added dropwise to a solution (80 mL) of potassium tert-butoxide (5.79 g) in tetrahydrofuran while stirring at room temperature over 1 hr. The mixture was further stirred at the same temperature for 30 min, and the reaction product was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→8:2) to give the title compound as a yellow oil (yield 6.56 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[NH2:41][C:42]1([CH3:55])[CH2:47][CH2:46][N:45]([C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])[CH2:44][CH2:43]1>ClCCl>[C:51]([O:50][C:48]([N:45]1[CH2:46][CH2:47][C:42]([NH:41][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:30])([CH3:55])[CH2:43][CH2:44]1)=[O:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CC1(N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2(C)CCN(C(=O)OC(C)(C)C)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 2 h

Procedure:
To a stirred solution of racemic-(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (48.2 mg, 0.103 mmol) in dichloromethane (8 ml) were added N,N-DIISOPROPYLETHYLAMINE (72.7 mg, 98.3 μl, 563 μmol, Eq: 6) and N,N,N′,N′-tetramethyl-O-(7-aza-benzotriazol-1-yl)uranium hexafluorophosphate (HATU) (64.2 mg, 0.169 mmol) followed by tert-butyl 4-amino-4-methylpiperidine-1-carboxylate (20.1 mg, 0.0938 mmol, Astatech). The reaction mixture was stirred from 2:00 PM for 2 hrs. The reaction mixture was diluted with CH2Cl2 (80 mL), washed with sat Na2CO3 (15 mL), water (2×15 mL) and evaporated. The crude material was purified by flash chromatography (silica gel, 4 g, 5% to 70% EtOAc in hexanes) to give rac-4-{[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-4-methyl-piperidine-1-carboxylic acid tert-butyl ester as a white solid. MS (ES+) m/z Calcd: [(M+H)+]: 663. found: 663.
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[C:14]2[CH:13]=[CH:12][C:11](=[O:15])[NH:10][C:9]=2[CH:8]=[CH:7][C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]1=2>O.CO>[OH:3][C:4]1[C:14]2[C:9]([NH:10][C:11](=[O:15])[CH2:12][CH:13]=2)=[CH:8][CH:7]=[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=12
Reactant: O=c1ccc2c(=O)c3ccccc3ccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1CC=C2C(=CC=c3ccccc3=C2O)N1

Procedure:
A solution of 0.30 gram (8 millimoles) of sodium borohydride in 5 milliliters of water is added to a solution of 0.70 gram (3 millimoles) of 5-oxo-benzo[4,5]cyclohepta[1,2-b]pyrid-2(1H)one (prepared as described in Example I) in 50 milliliters of methanol and the resulting mixture heated for about twenty minutes at reflux temperature to obtain the desired 5-hydroxy-benzo[4,5]cyclohepta[1,2-b]pyrid-2(1H)one in the reaction mixture. The product is recovered by evaporating the solvent, and washing and drying the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[K+]>C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[CH:5]2
Reactant: BrCc1ccccc1
Reactant: Clc1ccc2[nH]ccc2c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Product: Clc1ccc2c(ccn2Cc2ccccc2)c1
Yield: 60 %

Procedure:
3.85 g (30 mmol) 5-chloroindole was treated with 6.84 g (40 mmol) benzylbromide, 1.97 g (30 mmol) potassium hydroxide (85% powdered in mortar) and 0.25 g (1 mmol) 18-crown-6 as described in Synthesis 1979 p. 618, giving 4.35 g (60%) 5-chloro-1-benzyl-1H-indole, yellow oil, MS (Ei 70 eV) m/Z M+241.
Reaction SMILES: [CH:1]([O:14][C:15]([CH2:17][O:18]/[N:19]=[C:20](/[C:52]1[N:53]=[C:54]([NH:57][C:58]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[S:55][CH:56]=1)\[C:21]([NH:23][CH:24]1[C:50](=[O:51])[N:26]2[C:27]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:28]([CH2:32]Cl)[CH2:29][S:30](=[O:31])[C@H:25]12)=[O:22])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:77].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+].C(OCC)(=O)C>CC(C)=O>[CH:1]([O:14][C:15]([CH2:17][O:18]/[N:19]=[C:20](/[C:52]1[N:53]=[C:54]([NH:57][C:58]([C:71]2[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=2)([C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)[S:55][CH:56]=1)\[C:21]([NH:23][CH:24]1[C:50](=[O:51])[N:26]2[C:27]([C:34]([O:36][CH:37]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])=[C:28]([CH2:32][I:77])[CH2:29][S:30](=[O:31])[C@H:25]12)=[O:22])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Reactant: [I-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound obtained in (A) was dissoved in 380 ml of acetone, and 7.4 g (49 mmol) of sodium iodide was added thereto. The mixture was stirred at room temperature for 30 minutes. To the reaction solution, 300 ml of a 10% sodium thiosulfate aqueous solution and 1150 ml of ethyl acetate were added for extraction. Then, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flush column chromatography (ethyl acetate/n-hexane =1/1) to obtain 22.4 g of a powder of the above-identified compound (yield from the previous step: 86.7%).
Reaction SMILES: [Cl:1]C1C=C2C(C=CN2)=CC=1.C(O[C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([C:24]([NH2:26])=[O:25])[CH:19]=[C:18]2[N:27]=[C:28]=[O:29])C=C>>[Cl:1][C:23]1[CH:22]=[C:21]2[C:17]([C:18]([N:27]=[C:28]=[O:29])=[CH:19][N:20]2[C:24]([NH2:26])=[O:25])=[CH:16][CH:15]=1
Reactant: C=CCOc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Reactant: Clc1ccc2cc[nH]c2c1
Product: NC(=O)n1cc(N=C=O)c2ccc(Cl)cc21

Procedure:
was prepared from 6-chloroindole using the protocol described for steps B-E in scheme A4 for the preparation of 5-allyloxy-3-isocyanato-indole-1-carboxylic acid amide.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]([C:7]([C@H:9]2[CH2:11][C@H:10]2[C:12](O)=[O:13])=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[NH2:21][NH2:22]>C(O)C>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:9]2[CH:10]([C:12](=[O:13])[NH:21][N:22]=1)[CH2:11]2
Reactant: NN
Reactant: O=C(c1ccccc1-c1ccccc1)[C@H]1C[C@H]1C(=O)O
Solvent: CCO
Product: O=C1NN=C(c2ccccc2-c2ccccc2)C2CC12
Yield: 95.7 %

Procedure:
7.0 g (26.3 millimoles) of cis-2-(p-biphenylcarbonyl)-cyclopropanecarboxylic acid, 1.45 g (29.0 millimoles) of hydrazine and 100 ml of ethanol are refluxed for 8 hours. After filtering off the product at 0° C. and drying it under reduced pressure at 50° C., 6.6 g (96% of theory) of 2-(p-biphenylyl)-3,4-diazabicyclo[4.1.0]hept-2-en-5-one are obtained as colorless crystals, of melting point 220°-221° C. after recrystallization from ethanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([O:13]CC)=O)[N:10]=2)[CH:7]=1.[CH:16]([Mg]Cl)([CH3:18])[CH3:17].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH:16]([CH3:18])[CH3:17])=[O:13])[N:10]=2)[CH:7]=1
Reactant: CCOC(=O)c1cn2cc(Br)ccc2n1
Reactant: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)c1cn2cc(Br)ccc2n1
Temperature: -78 °C

Procedure:
269 mg of 6-bromo-2-ethoxycarbonyl-imidazo[1,2-a]pyridine obtained in Example 117 was dissolved in 10 ml of tetrahydrofuran, cooled down to −78° C., and 0.5 ml of 2M isopropylmagnesium chloride was dropped thereto. After heating to −40° C., water was added and the products were extracted with ethyl acetate. Organic layer was dried with anhydrous magnesium sulfate, and the solvents were distilled outunder reduced pressure. The obtained residues were purified by silicagel column chromatography (hexane:ethyl acetate=50:50) to obtain 58.5 mg of the above compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]([CH2:11][C:12]2[CH:13]=[C:14]([C:18]3[CH:22]=[C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:20][C:19]=3[S:27]([NH:30]C(C)(C)C)(=[O:29])=[O:28])[CH:15]=[CH:16][CH:17]=2)[CH:8]=[CH:9][N:10]=1.B(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:46]([O:48][CH2:49][CH2:50][CH2:51][CH3:52])=[O:47]>C(Cl)Cl.O>[CH2:49]([O:48][C:46]([NH:30][S:27]([C:19]1[S:20][C:21]([CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:22][C:18]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:13]=1)(=[O:29])=[O:28])=[O:47])[CH2:50][CH2:51][CH3:52]
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3cccs3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: CCCCOC(=O)Cl
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2-c2cccs2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 3-[3-(2-thiophen-2-yl-imidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (42 mg, 0.082 mmol; see step (a)) in CH2Cl2 (1 mL) was added BCl3 (0.3 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in CH2Cl2 (5 mL) was added Na2CO3 (39.0 mg, 0.377 mmol), water (2 mL) and butyl chloroformate (15.6 μL, 0.0123 mmol), and the reaction mixture was stirred for 9 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by LCMS (20-100% CH3CN in water) to give the title compound as a white solid in 55% yield, over two steps, (25 mg, 0.045 mmol).
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.Br[CH2:10][C:11]1[C:12]([Cl:22])=[C:13]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:14]([O:16][CH3:17])=[O:15].O>C(#N)C>[Cl:22][C:12]1[C:11]([CH:10]=[O:5])=[C:20]([Cl:21])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1ccc(Cl)c(CBr)c1Cl
Reactant: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(Cl)c(C=O)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
At reflux, 696.2 g (2.97 mol) of aqueous 50% strength N-methylmorpholine N-oxide solution were added to a solution of 312.0 g (0.99 mol) of methyl 3-bromomethyl-2,4-dichlorobenzoate in 2 l of acetonitrile. After stirring for 48 hours at room temperature, the reaction solution was stirred into 6 l of water. The precipitate was filtered off with suction, washed with water and dried under reduced pressure. 141.3 g of methyl 2,4-dichloro-3-formylbenzoate were obtained.
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18](O)=[O:19])[CH2:14][CH2:13]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][N:28](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:29].[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.CNC.C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]1([CH:7]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([N:28]([CH3:29])[CH3:27])=[O:19])[CH2:14][CH2:13]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 58.9 %

Procedure:
1-[1-(Diphenylmethyl)azetidin-3-yl]piperidine-4-carboxylic acid (0.35 g, 0.9 mmol) was dissolved in DMF (8 mL) and to the solution were added TBTU (0.39 g, 1.2 mmol), DIPEA (0.21 mL, 1.2 mmol) and a solution of dimethylamine (3.0 mL, 2M in THF, 6 mmol). The mixture was stirred at RT for 14 h. An aqueous solution of NaHCO3 was added and the mixture was extracted three times with methylene chloride. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed by evaporation and the product was purified by reversed phase chromatography (C8) using acetonitrile and aqueous ammonium acetate solution (0.1 M) as eluent. There was obtained 0.20 g (59%) of 1-[1-(diphenylmethyl)azetidin-3-yl]-N,N-dimethylpiperidine-4-carboxamide. 1H NMR (500 MHz, CDCl3): δ 1.6-2.0 (cm, 6H), 2.4-2.5 (m, 1H), 2.8 (m, 2H), 2.9-3.0 (m, 5H), 3.1 (s, 3H), 3.4 (t, 2H), 4.4 (s, 1H), 7.2 (t, 2H), 7.3 (t, 4H), 7.4 (d, 4H); LCMS: m/z 378 (M+1)+.
Reaction SMILES: [H-].[Na+].[CH2:3]=[C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[CH:12][CH:13]=3)[C:8]=2[CH2:7][CH2:6][N:5]1[C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20].CN(C=[O:28])C>>[CH:21]1([C:19]([N:5]2[CH2:6][C:7]3[C:8](=[O:28])[C:9]4[CH:10]=[C:11]([O:17][CH3:18])[CH:12]=[CH:13][C:14]=4[NH:15][C:16]=3[C:4]2=[CH2:3])=[O:20])[CH2:22][CH2:23]1
Reactant: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C(=O)C1CC1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C=C1c2[nH]c3ccc(OC)cc3c(=O)c2CN1C(=O)C1CC1
Reaction time: 48 h
Yield: 38 %

Procedure:
NaH (1.2 eq; 60% suspension in oil) is added to a solution of 1-methylene-2-cyclopropylcarbonyl-6-methoxy-1,2,3,4-tetrahydro-β-carboline (500 mg; 1.7 mmol) in DMF (5 ml). The mixture is stirred under an oxygen atmosphere for 48 hours, further NaH (1.1 eq) is then added and stirring is continued overnight. The DMF is then distilled off under reduced pressure. The crude product is taken up in water and then filtered off. Saturated NH4Cl solution is added to the aqueous phase. The mixture is stirred for 30 minutes. The precipitate is filtered off and then washed successively with water, an MeOH/CH2Cl2 mixture (10/90), acetone and then ethyl acetate. After drying, 2-cyclopropylcarbonyl-7-methoxy-3-methylene-9-oxo-1,3,4,9-tetrahydropyrrolo[3,4-b]quinoline is obtained (yield=38%).
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](O)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.N>CN(C)C=O.O>[Br:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH2:24])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Reaction time: 0.5 h
Yield: 676.3 %

Procedure:
19.8 g (56.9 mmol) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylic acid were suspended in 100 ml of N,N-dimethylformamide, treated at room temperature with 10.1 g (62.6 mmol) of 1,1'-carbonyldiimidazole and stirred at 70° for 30 minutes. 50 ml of 25% ammonia were added dropwise at 25°-30°. The reaction mixture was diluted with 50 ml of water and cooled to 0°, and the crystallizate was filtered off under suction and dried. There were obtained 133.6 g (69%) of (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamide of m.p. 314°-317°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[CH:13]1[C:18]([NH:19][NH2:20])=[CH:17][CH:16]=[C:15]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:14]=1.Cl>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:20][NH:19][C:18]1[CH:17]=[CH:16][C:15]([S:21]([NH2:24])(=[O:22])=[O:23])=[CH:14][CH:13]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc2c(c1)C(=O)C(=O)N2
Agent: Cl
Product: Cc1ccc2c(c1)C(=NNc1ccc(S(N)(=O)=O)cc1)C(=O)N2
Yield: 86 %

Procedure:
The title compound was prepared from 5-methyl-1H-indole-2,3-dione (Gassman, et al., Journal of Organic Chemistry 1977, 42, 1344-8) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 86% yield: 1H NMR (DMSO-d6): δ 2.3 (s, 3H), 6.76 (d, J=7.9 Hz, 1H), 7.11 (d, J=7.9 Hz, 1H), 7.20 (s, 2H), 7.57 (d, J=8.8 Hz, 2H), 7.77 (d, J=8.8 Hz, 2H), 8.02 (s, 1H), 10.51 (s, 1H), 10.62 (s, 1H); APCI−MS m/z 329 (M−1)−. Anal. Calcd for C15H14N4O3S: C, 54.54, H, 4.27; N, 16.96; S, 9.71. Found C, 54.54, H, 4.32; N, 16.87; S. 9.62.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([CH2:29][C:30]2[C:31](=[O:38])[N:32]=[C:33](SC)[NH:34][CH:35]=2)=[CH:25][N:24]=1>C(O)C>[CH3:21][O:22][C:23]1[N:24]=[CH:25][C:26]([CH2:29][C:30]2[C:31](=[O:38])[N:32]=[C:33]([NH:18][CH2:17][CH2:16][C:13]3[CH:14]=[CH:15][C:10]([O:9][C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=4)=[CH:11][CH:12]=3)[NH:34][CH:35]=2)=[CH:27][N:28]=1
Reactant: COc1ncc(Cc2c[nH]c(SC)nc2=O)cn1
Reactant: NCCc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Solvent: CCO
Product: COc1ncc(Cc2c[nH]c(NCCc3ccc(Oc4ccc(C(F)(F)F)cn4)cc3)nc2=O)cn1
Temperature: 125 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
2-[4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl]ethylamine (0.246 mmol, 1.3 eq) and 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-methylsulfanyl-1H-pyrimidin-4-one (0.189 mmol, 1 eq) were dissolved in dry ethanol (300 μL) and stirred at 125° C. for 16 hours. Solvent was evaporated and crude product was purified by Waters Mass Direct Autopurification system giving 5-(2-methoxy-pyrimidin-5-ylmethyl)-2-{2-[4-(5-trifluoromethyl-pyridin-2-yloxy)phenyl]-ethylamino}-1H-pyrimidin-4-one (0.090 mmol; yield: 36%, HPLC-MS/UV: [M+H]+=499.34; rt: 10.40 min; purity: 94%). 1H NMR (300 MHz; CDCl3) δ/ppm 2.93 (t, J=7.05, 2H), 3.51 (s, 2H), 3.58-3.74 (m, 2H), 3.95 (s, 1H), 5.31 (br.s., 1H), 6.98-7.13 (m, 3H), 7.22-7.32 (m, 2H), 7.61-7.67 (m, 1H), 7.89 (dd, J=8.50, J=2.64, 1H), 8.38 (m, 1H)
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CN1C(=O)CCC1.O>[N+:8]([C:4]1[CH:3]=[C:2]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: C1CNCCN1
Reactant: O=[N+]([O-])c1cccc(F)c1
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Temperature: 70 °C
Yield: 70.5 %

Procedure:
A suspension of 3-fluoronitrobenzene (23 ml; 0.21 mol) and piperazine (55.5 g; 0.64 mol) in anhydrous NMP (30 ml) was heated to 70° C. for five days. The cooled mixture was diluted with water (250 ml) and extracted with dichloromethane. The combined extracts were dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column-chromatography on silica gel eluting subsequently with mixtures of ethyl acetate and methanol (4:1 v/v) and (1:1 v/v) to leave the desired product as oily crystals (30.7 g; 71%).
Reaction SMILES: [H-].[Na+].[C:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:19][CH:20]=2)=[C:8]([CH2:26][CH2:27][C:28]([F:31])([F:30])[F:29])[C:7]=1[OH:32])(=[O:5])[CH3:4].[CH3:33]I.Cl>CN(C)C=O>[C:3]([C:6]1[CH:25]=[CH:24][C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:19][CH:20]=2)=[C:8]([CH2:26][CH2:27][C:28]([F:29])([F:31])[F:30])[C:7]=1[O:32][CH3:33])(=[O:5])[CH3:4]
Reactant: CI
Reactant: CC(=O)c1ccc(OCCCOc2cccc([N+](=O)[O-])c2)c(CCC(F)(F)F)c1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(C(C)=O)ccc(OCCCOc2cccc([N+](=O)[O-])c2)c1CCC(F)(F)F

Procedure:
5,530 mg of sodium hydride are added to a solution of 7.46 g of 3-{3-[4-acetyl-3-hydroxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-nitrobenzene in 75 ml of dimethylformamide and the reaction mixture is warmed to 40°. 5.7 g of methyl iodide are added dropwise in the course of 15 minutes. Thereafter, the reaction mixture is kept at 40° C. for a further hour. After cooling, it is poured onto dilute hydrochloric acid and extracted with methylene chloride and the extract is evaporated. Recrystallisation from ether/hexane gives 3-{3-[4-acetyl-3-methoxy-2-(3,3,3-trifluoropropyl)-phenoxy]-propoxy}-nitrobenzene.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1>CCOCC>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][O:20]1
Reactant: OCCCCCCCl
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: ClCCCCCCOC1CCCCO1
Temperature: 2.5 °C
Reaction time: 0.5 h

Procedure:
6-Chlorohexanol (6.85 g, 10 mmol) and p-toluenesulphonic acid (500 mg), were dissolved in dry ether (75 ml) and cooled to 0-5° C. in an ice bath. Dihydropyran (4.3 g, 10 mmol) in dry ether (25 ml) was added dropwise with constant stirring over a 30 minute period. After complete addition, the cooling bath was removed and stirring continued for 16 hours. The solution was extracted with water (50 ml×2), dried (MgSO4), filtered and the solvent evaporated under reduced pressure to leave a pale yellow oil. This oil was shown by 13C NMR spectroscopy to be sufficiently pure to be used without purification in the subsequent reactions. Yield 10.1 g (91%).