Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[O:9]=C(CCC(O)=O)C(O)=O.O=C1O[C@H]([C@H](CO)O)C(O)=C1O>>[OH:9][C@@H:6]1[CH2:7][CH2:8][NH:1][C@@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)CCC(=O)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Product: O=C(O)[C@H]1NCC[C@H]1O
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
The enzyme preparation to be determined is added to 100 mM TES buffer (pH 7.0) containing 5 mM L-proline, 5 mM 2-ketoglutaric acid, 1 mM ferrous sulfate and 5 mM L-ascorbic acid to make 100 μl in total, and the mixture was allowed to stand at 35° C. for 10 minutes. The reaction mixture is heated at 100° C. for 2 minutes so as to stop the reaction, and the amount of cis-3-hydroxy-L-proline produced in the reaction mixture is determined by high performance liquid chromatography (hereinafter referred to as HPLC).
Reaction SMILES: [N:1]([CH2:4][C:5](Cl)=[O:6])=[N+:2]=[N-:3].C(N(CC)CC)C.[N:15]12[C:21](=[O:22])[CH2:20][CH:19]1[CH2:18][C:17](=[O:23])[CH:16]2[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>C(Cl)Cl>[N:1]([CH2:4][C:5]([O:23][C:17]1[CH2:18][CH:19]2[N:15]([C:21](=[O:22])[CH2:20]2)[C:16]=1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:6])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCC(=O)Cl
Reactant: O=C1CC2CC(=O)N2C1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCC(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)CC2C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Azidoacetyl chloride (21 μl) is added by syringe in an ice-cold, stirring solution of triethylamine (42 μl) and benzyl 1-azabicyclo[3.2.0]heptane-3,7-dione-2-carboxylate (52 mg) in anhydrous methylene chloride (2 ml). After stirring 30 mins in the cold, the reaction mixture is diluted with methylene chloride (5 ml), washed with H2O (2 ml), pH 3 phosphate buffer (2 ml), and 5% NaHCO3 (2 ml), dried with MgSO4, filtered, and evaporated in vacuo. Chromatography of the residue on a silica gel GF plate gives benzyl 3-(α-azidoacetoxy)-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[F:21][C:22]([F:39])([F:38])[C:23]1[CH:24]=[C:25]([NH:29][NH:30]C(OC(C)(C)C)=O)[CH:26]=[CH:27][CH:28]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:39])[F:38])[CH:24]=2)[N:30]=1
Reactant: CC(C)(C)OC(=O)NNc1cccc(C(F)(F)F)c1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3cccc(C(F)(F)F)c3)c(=O)[nH]2)c1)C(F)(F)F
Yield: 55.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl 2-[3-(trifluoromethyl)phenyl]hydrazinecarboxylate (0.428 g, 1.55 mmol), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.400 g of the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+].CN1CCCN(C)C1=O>C1COCC1>[CH2:16]([O:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[C:7]([O:14][CH3:15])[CH:6]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2cc(O)cnc2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COc1cc2cc(OCc3ccccc3)cnc2cc1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-hydroxy-6,7-dimethoxyquinoline (150 mg; 0.73 mmol) in 3 mL THF is added benzyl bromide (0.13 mL; 188 mg; 1.10 mmol) and NaH (59 mg; 1.46 mmol). This is stirred at room temperature for 1 hour and 25 mg of NaH added followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (DMPU) (255 mg; 2.07 mmol) and stirred at room temperature for 31/2 hours. The reaction mixture is partitioned between EtOAc and distilled H2O and extracted 2× with EtOAc. The latter is washed with brine, dried (MgSO4), filtered, evaporated to dryness and chromatographed with 1% MeOH/CHCl3 to obtain 3-benzyloxy-6,7-dimethoxyquinoline m.p. 146.5°-148.5° C.).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([P:30](=[O:37])([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[C:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].N1C2C(=CC=CC=2)C=CC=1.[H][H]>C(O)C.[Pd]>[CH2:32]([O:31][P:30]([C:9]([P:4](=[O:8])([O:3][CH2:1][CH3:2])[O:5][CH2:6][CH3:7])=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])(=[O:37])[O:34][CH2:35][CH3:36])[CH3:33]
Reactant: CCCCCCCCCCCC#Cc1ccccc1C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: c1ccc2ncccc2c1
Product: CCCCCCCCCCC/C=C\c1ccccc1C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reaction time: 3 h
Yield: 30.5 %

Procedure:
Tetraethyl[2-[2-(1-tridecynyl)phenyl]ethenylidene]bisphosphonate (1.5 g, 2.7 mmol) prepared according to Example 9 was dissolved in ethanol (17 ml), and quinoline (0.043 ml) and 5% palladium on calcium carbonate poisoned with lead (13 mg) was added. A balloon filled with hydrogen was attached to the flask after purging with hydrogen. After stirring for 3 hours the hydrogen pressure was released, and the reaction mixture was filtered through Celite. The filtrate was stripped. 1H NMR showed that only small amount of starting material had been converted to product. The hydrogenation was repeated using twice the amount of catalyst and quinoline for 4.5 hours, then workup as before. 1H NMR showed that a considerable amount of starting material remained. Three additional hydrogenations totaling 47 hours were done before the conversion was greater than 90%. Chromatography on silica eluting with 5% ethanol in petroleum ether (90°-110° C. boiling range) gave the product, 0.459 g, 0.825 mmol, 30.5 % yield; 1H NMR (CDCl3) ∂ 0.88 (t, J=6.7 Hz, 3H), 1.03 to 1.45 (several m, 30H), 2.09 (m, 2H), 3.96 (m, 4H), 4.20 (m, 4H), 5.79 (dt, J=11.5, 7.4 Hz, 1H), 6.37 (d, J =11.4 Hz, 1H), 7.28 (m, 3H), 7.78 (d, J=7.3 Hz, 1H), 8.31 (dd, J=47.8, 28.4 Hz, 1H); CI mass spectrum m/z 557 (M+H)+.
Reaction SMILES: C(NC(=NC(C)C)O[C:7]([CH3:10])([CH3:9])[CH3:8])(C)C.[CH:15]1([C:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C(Cl)Cl>[CH:15]1([C:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30]([O:32][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:31])=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CC(C)N=C(NC(C)C)OC(C)(C)C
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Yield: 58 %

Procedure:
2 eq of tert-butyl N,N′-diisopropylimidocarbamate (prepared according to literature precedent: Synthesis 1979, 561) were added to a solution of 3-cyclohexyl-1H-indole-6-carboxylic acid (prepared as described in published International patent application WO2004087714) in CH2Cl2 (0.4 M) and the mixture heated at reflux under N2 for 16 h. A further 2.5 eq of tert-butyl N,N′-diisopropylimidocarbamate were then added portionwise over 3 h, with heating being resumed after each addition. The reaction mixture was then filtered whilst hot through a pad of CELITE and the filtrate concentrated in vacuo. The residue was purified by flash chromatography (5% EtOAc/PE) to afford the title compound (58%); MS (ES−) m/z 298 (M−H)−.
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[O:16][C:15]3[CH:17]=[CH:18][C:19]([C:21]([NH2:23])=[O:22])=[CH:20][C:14]=3[CH2:13][CH2:12][C:11]=2[CH:24]=1.[CH:26]1([CH:29]=O)[CH2:28][CH2:27]1.[BH3-]C#N.[Na+]>CO.CC(O)=O>[CH:26]1([CH2:29][N:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[O:16][C:15]4[CH:17]=[CH:18][C:19]([C:21]([NH2:23])=[O:22])=[CH:20][C:14]=4[CH2:13][CH2:12][C:11]=3[CH:24]=2)[CH2:4][CH2:3][CH:2]([CH3:25])[CH3:1])[CH2:28][CH2:27]1
Reactant: CC(C)CCNCc1ccc2c(c1)CCc1cc(C(N)=O)ccc1O2
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)CCN(Cc1ccc2c(c1)CCc1cc(C(N)=O)ccc1O2)CC1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.3 %

Procedure:
To a solution of amine of example 1 (30 mg, 0.09 mmol) in MeOH-AcOH 5% (0.5 mL) add cyclopropanecarboxaldehyde (0.18 mmol). Stir the mixture at room temperature overnight. Add NaBH3CN and stir the mixture at room temperature for about two hours. Add more aldehyde (1.5 mmol) and stir overnight. Purify by SCX ion-exchange chromatography to obtain the title compound (22 mg). 1H-NMR (CD3OD, 300 MHz): 7.72-7.69 (m, 2H), 7.21-7.09 (m, 4H), 3.64 (s, 2H), 3.14 (bs, 4H), 2.61-2.56 (m, 2H), 2.37 (d, 2H, J=6.5 Hz), 1.60-1.37 (m, 4H), 0.87 (d, 6H, J=6.7 Hz), 0.55-0.49 (m, 2H), 0.13-0.08 (m, 2H). Electrospray MS M+1 ion=393.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH3:9])[CH:4]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O.C(OCC)C>[CH2:10]([N:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH2:4][CH:5]1[CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccnc(C)c1
Solvent: CCOCC
Solvent: CC(C)=O
Product: CC1CC(=O)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.5 %

Procedure:
6.97 g of 4-methoxy-2-methylpyridine was dissolved in 200 ml of acetone and 13.5 g of benzyl bromide was added thereto. Then the resulting mixture was heated under reflux for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature and diluted with diethyl ether. The precipitate was taken up by filtration and the solid matter was dissolved in 60 ml of water. Next, 5.35 g of sodium borohydride was added thereto in portions. After stirring for 15 minutes, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with water and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. To the obtained residue was added 5 N hydrochloric acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was made basic by adding potassium carbonate, extracted with ethyl acetate, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 6.84 g of the title compound as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=3[C:6]=2[CH:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.[Na+]>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][C:13]4[CH2:12][CH2:11][N:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9][C:8]=4[C:6]=3[CH:7]=2)(=[O:32])=[O:31])=[CH:28][CH:29]=1
Reactant: COc1ccc(S(=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(Br)cc3c2C1
Agent: [Na+]
Product: COc1ccc(S(=O)(=O)c2ccc3oc4c(c3c2)CN(C(=O)OC(C)(C)C)CC4)cc1
Yield: 41 %

Procedure:
The product of Example 29, step B and sodium 4-methoxybenzenesulfinate were coupled using the procedure of Example 29, step C. Purification by flash column chromatography (SiO2, 4:1 hexane/ethyl acetate) provided tert-butyl 8-(4-methoxyphenylsulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (221 mg, 41%) as a light-yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.05 (s, 1H), 7.90-7.86 (m, 2H), 7.79 (d, J=9.0 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H), 6.98-6.91 (m, 2H), 4.56 (s, 2H), 3.83 (m, 5H), 2.86 (m, 2H), 1.50 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][C:3]=1[Cl:11].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(O)C>[NH2:21][C:17]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([Cl:11])[CH:4]=2)[C:15](=[O:14])[CH:16]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1ccc(Br)c(Cl)c1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(Br)c(Cl)c2)[nH]1
Reaction time: 2 h

Procedure:
48.8 g of 4-bromo-3-chlorobenzylhydrazine are added dropwise under nitrogen to a solution of 33.2 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of toluenesulphonic acid in 150 ml of ethanol. After stirring for a further two hours, the mixture was left to stand and the compound identified above began to crystallise out after four hours. It was filtered off and twice recrystallised from ethanol. Melting point: 145°-146°, 23 g (37%).
Reaction SMILES: I[CH2:2][O:3][C:4](=[S:10])[O:5][CH:6]([CH2:8][CH3:9])[CH3:7].[CH2:11]([O:18][P:19]([O-:29])([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:4](=[S:10])([O:5][CH:6]([CH2:8][CH3:9])[CH3:7])[O:3][CH2:2][O:29][P:19]([O:18][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: O=P([O-])(OCc1ccccc1)OCc1ccccc1
Reactant: CCC(C)OC(=S)OCI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CCC(C)OC(=S)OCOP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Example 19B (7.3 g, 27 mmoles) and tetrabutylammonium dibenzylphosphate (13.8 g, 26.6 mmol) were mixed in 20 ml of tetrahydrofuran and stirred at room temperature for 24 hours. The mixture was diluted with 100 mL of tetrahydrofuran, filtered through celite and the solvent was evaporated. The residue was resuspended in 200 mL of 20% ethyl acetate in hexane and the precipitate was filtered and washed with an additional 100 mL of 20% ethyl acetate. The organic filtrates were combined and the solvent was evaporated. Final product was obtained by flash chromatography on silica using 20% ethyl acetate in hexane. Fractions containing product were combined and the solvent was removed to give 8.7 g (78%) of a colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm 0.91 (t, J=7.29 Hz, 3 H) 1.31-1.45 (m, 2 H) 1.55-1.65 (m, 2 H) 2.80-2.90 (m, 2 H) 5.07 (d, J=7.80 Hz, 4 H) 5.65 (d, J=13.90 Hz, 2 H) 7.34 (s, 10 H).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH3:21][C:22]1[N:23]=[C:24]([C:27]2[CH:28]=[C:29]([CH:32]=[CH:33][N:34]=2)[CH:30]=O)[S:25][CH:26]=1>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][N:34]=[C:27]([C:24]3[S:25][CH:26]=[C:22]([CH3:21])[N:23]=3)[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: Cc1csc(-c2cc(C=O)ccn2)n1
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccnc(-c2nc(C)cs2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with 2-(4-methylthiazol-2-yl)isonicotinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.86 min.; [M+H]+: 426.01 g/mol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.[OH-].[Na+]>C(O)C.O>[C:2]1([CH2:1][O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:17][CH:18]([OH:27])[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: OC(CCl)CCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: OC(CCc1cccnc1)COc1ccc(OCc2ccccc2)cc1
Yield: 61.6 %

Procedure:
Prepared according to the method described in Example 24b) from 4-(benzyloxy)phenol (1.00 g), (±)-α-(chloromethyl)-3-pyridinepropanol (0.50 g) and sodium hydroxide (0.23 g) in ethanol (20 ml) and water (5 ml) with heating at reflux for 45 minutes. After work up the residue was purified by column chromatography over silica eluting with dichloromethane:ethanol (19:1) and then using a fresh column of silica eluting with ethyl acetate to give the title compound as a solid (0.58 g). Recrystallisation from ethyl acetate:hexane gave colourless crystals.
Reaction SMILES: [CH2:1]([Sn:5](Cl)(Cl)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[F-:12].[F-:13].[NH4+].[NH4+]>>[CH2:1]([Sn:5]([F:13])([F:12])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](Cl)(Cl)CCCC
Reactant: [F-]
Agent: [NH4+]
Product: CCCC[Sn](F)(F)CCCC

Procedure:
Advantageously, dibutyl tin chloride and an ammonium difluoride are reacted to form a dibutyl tin difluoride precipitate. Dibutyl tin dichloride (DBTCl) is solubilized in an alcohol, preferably methanol, in a first reaction vessel. In a second such vessel, ammonium difluoride (NH4F, HF) is dissolved in a solvent which is preferably water. The contents of one reaction vessel are poured into the other and, on contact of the two solutions, a dibutyl tin difluoride precipitate is formed. The mixture is stirred to enhance the contact between the two solutions and to maximize the yield of precipitate. The resulting precipitate is recovered, drained, washed with water, washed with a solvent such as acetone to eliminate any remaining water and dried.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:12]=1)[C:7]([OH:9])=O)=[O:3].FC(F)(F)C(O)=O.N[C@@H:30]([CH2:44][C:45]1[CH:50]=[C:49](F)[CH:48]=[C:47](F)[CH:46]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1>>[CH2:44]([C@H:30]([NH:1][C:2](=[O:3])[C:4]1[CH:5]=[C:6]([CH2:7][OH:9])[CH:10]=[C:11]([C:13]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])=[O:14])[CH:12]=1)[C@H:31]([OH:43])[CH2:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCN(CCC)C(=O)c1cc(C(N)=O)cc(C(=O)O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCCN(CCC)C(=O)c1cc(CO)cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(OC)c2)c1

Procedure:
Following the procedure of CHART P and EXAMPLE 739 and making non-critical variations but using 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoic acid (IX) and (2R,3S)-3-amino-1-[(3-methoxybenzyl)amino]4-phenyl-2-butanol (VIII), the title compound is obtained, HRMS (FAB)=615.3571.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[S:4][C:3]1([CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:22][CH2:21]1)[C:13]([O:15][CH3:16])=[O:14].[BH4-].[Na+].O>CO>[OH:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[S:4][C:3]1([CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:22][CH2:21]1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)C1(CCCN2CCN(c3ccccc3)CC2)Sc2ccccc2CCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C1(CCCN2CCN(c3ccccc3)CC2)Sc2ccccc2CCC1O
Yield: 74.7 %

Procedure:
To a solution of 0.2 g of methyl 3-oxo-2-[3-(4-phenyl-1-piperazinyl)propyl]-2,3,4,5-tetrahydro-1-benzothiepin-2-carboxylate obtained in Example 2 in 20 ml of methanol, 50 mg of sodium borohydride is added in small portions with stirring. After stirring for one hour, the reaction mixture is treated with water and extracted with ethyl acetate. The organic layer is washed with water, dried, and evaporated under reduced pressure. The residue is recrystallized from ethyl acetate-hexane, to give 0.15 g of methyl 3-hydroxy-2-[3-(4-phenyl-1-piperazinyl)propyl]-2,3,4,5-tetrahydro-1-benzothiepin-2-carboxylate as crystals, obtained in Example 7: m.p. 152°-154° C.
Reaction SMILES: I[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH2:11]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:14]#[CH:15])[CH3:12].C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH2:14]([Si:13]([C:11]#[C:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:2][CH:3]=[CH:4]2)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:15]
Reactant: In1ccc2ccccc21
Reactant: C#C[Si](CC)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[Si](C#Cc1ccc2[nH]ccc2c1)(CC)CC
Temperature: 60 °C

Procedure:
To a scintillation vial was added -iodo-1H-indole (1.1 eq.), triethyl(ethynyl)silane (1 eq.), triethylamine (5 eq.), and anhydrous DMF (0.2 M). Vacuumed and nitrogen flushed for three times. CuI (0.1 eq.) and bis(triphenylphosphine)dichloro-palladium(II) (0.1 eq) were added. The vial was sealed and heated at 60° C. overnight. Upon completion of the reaction as monitored by TLC, the content of the vial was loaded onto a silica gel column pretreated with hexanes. Column was washed with hexanes and diethylether until all eluents containing product were collected. Carefully distill off hexanes and ether using rotary evaporator with minim heating afforded product 5-((triethylsilyl)ethynyl)-1H-indole as colorless oil, which was carried directly on to the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]([Cl:20])=[C:7]([C:21]#[C:22][Si](C)(C)C)[N:6]=1)=[O:4].[OH:27]S(O)(=O)=O>CC(C)=O.O>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]([Cl:20])=[C:7]([C:21](=[O:27])[CH3:22])[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc(C#C[Si](C)(C)C)c(Cl)c(F)c1Nc1ccccc1F
Reactant: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1nc(C(C)=O)c(Cl)c(F)c1Nc1ccccc1F
Reaction time: 3 h

Procedure:
A mixture of 5-chloro-4-fluoro-3-(2-fluorophenylamino)-6-trimethylsilanylethynyl-pyridine-2-carboxylic acid methyl ester (1.00 equivalent), HgSO4 (1.00 equivalent), and conc. H2SO4 (2.00 equivalents) in acetone-water is refluxed with stirring for 3 hours. The reaction mixture is concentrated in vacuo, diluted with EtOAc, and washed with water and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vauco to give the crude material that is purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Br)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1.[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:20][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]([C:9]#[N:10])=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: CSc1nc(N)nc(Br)c1C#N
Reactant: OCc1ccccc1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1nc(N)nc(OCc2ccccc2)c1C#N

Procedure:
From 2-amino-4-bromo-6-methylsulfanyl-pyrimidine-5-carbonitrile, benzyl alcohol and DBU in DME. ES-MS m/e (%): 273 (M+H+, 100).