Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1SC(C)=C([C:8]2[C:12]([F:14])([F:13])[C:11]([F:16])([F:15])[C:10]([F:18])([F:17])[C:9]=2C2C=C(Br)SC=2C)C=1.C[Si](C)(C)C1SC(C2SC(OB(O)O)=CC=2)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[F:13][C:12]1([F:14])[CH:8]=[CH:9][C:10]([F:18])([F:17])[C:11]1([F:15])[F:16]
Reactant: Cc1sc(Br)cc1C1=C(c2cc(Br)sc2C)C(F)(F)C(F)(F)C1(F)F
Agent: [Pd]
Agent: C[Si](C)(C)c1ccc(-c2ccc(OB(O)O)s2)s1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: FC1(F)C=CC(F)(F)C1(F)F
Reaction time: 0.08 h
Yield: 35 %

Procedure:
1,2-bis(5-bromo-2-methyl-3-thienyl)hexafluorocyclopentene (1.0 g, 0.002 mol) was dissolved in dimethoxyethane (50 ml), and palladium tetra(triphenylphosphine) (120 mg) was added to the mixture which was stirred for 5 minutes under argon atmosphere. With 5-(5-trimethylsilyl-2-thienyl)-2-thienyl boric acid (1.4 g, 0.006 mol) and an aqueous solution of potassium carbonate (0.1 mol dm-3, 10 ml) were added, the reaction mixture was refluxed for two hours. It was then concentrated under reduced pressures, extracted with diethylether and rinsed with water. With the diethylether removed under reduced pressures, the product was purified by alumina column chromatogram to give 1,2-bis[2-methyl-5{5-trimethylsilyl-2-thienyl)-2-thienyl}-3-thienyl]hexafluorocyclopentene (550 mg, 0.0007 mol).
Reaction SMILES: [C:1]1([CH:6]=[C:7]2[C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:18]([O:20][CH3:21])=[O:19])=[CH:13][CH:14]=3)[O:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH:2]=1.Cl.[NH:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([CH3:33])[CH:26]=1)[NH2:24].C(OCC)(=O)C.CCCCCC>C(O)C>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:23]2[CH:6]([C:1]3[CH2:5][CH2:4][CH2:3][CH:2]=3)[CH:7]3[CH2:8][O:9][C:10]4[CH:11]=[C:12]([C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][C:15]=4[C:16]3=[N:24]2)=[CH:26][C:27]=1[CH3:33])#[N:30]
Reactant: Cc1cc(NN)ccc1C#N
Reactant: COC(=O)c1ccc2c(c1)OCC(=CC1=CCCC1)C2=O
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)OCC1C2=NN(c2ccc(C#N)c(C)c2)C1C1=CCCC1
Temperature: 80 °C
Yield: 33 %

Procedure:
To a suspension of methyl 3-(cyclopentenylmethylene)-4-oxochroman-7-carboxylate; Preparation 34 (260 mg, 0.92 mmol) in ethanol (7 mL) was added 4-hydrazinyl-2-methylbenzonitrile hydrochloride; Preparation 2 (218 mg, 1.2 mmol). The slurry was heated to 80° C. for eighteen hours. The solution was returned to ambient temperature and the resulting solid was collected by vacuum filtration and washed with cold ethanol. Chromatography (normal phase, ethyl acetate/hexane) provided largely the cis isomer of methyl 2-(4-cyano-3-methylphenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylate (yellow solid, 125 mg, 33% yield). LC/MS on 4.6×50 mm C-18 column, tR=6.98 minutes (10 to 90% acetonitrile/water over 8 minutes at 2 mL/minute with detection 254 nm, at 50° C.); ES-MS m/z 414 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.63-1.83 (m, 2H), 2.05-2.11 (m, 2H), 2.14-2.20 (m, 2H), 2.39 (s, 3H), 3.83 (s, 3H), 3.88 (dd, J=13.02, 10.34 Hz, 1H), 3.98-4.03 (m, 1H), 4.67 (dd, J=10.20, 5.64 Hz, 1H), 5.45 (d, J=11.01 Hz, 1H), 5.60 (br. s., 1H), 6.86 (br. s., 1H), 7.11 (br. s., 1H), 7.44 (d, J=1.34 Hz, 1H), 7.53 (d, J=8.59 Hz, 1H), 7.58 (dd, J=8.06, 1.61 Hz, 1H), 7.93 (d, J=8.06 Hz, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][C:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]([O:21][CH3:22])[C:15]=2[O:14][CH:13]=1)C>C1COCC1>[CH3:22][O:21][C:20]1[C:15]2[O:14][CH:13]=[C:12]([CH2:11][CH2:10][OH:9])[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)Cc1coc2c(OC)cccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc2c(CCO)coc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of LiAlH4 (200 mg, excess) in THF at 0° C., ethyl(7-methoxy-1-benzofuran-3-yl)acetate (1.17 g, 5 mmol) in THF (20 mL) was added slowly. After the addition, the reaction mixture was stirred at room temperature for 1 hr and quenched with saturated NH4Cl solution. The product was extracted with chloroform and washed well with water. It was dried over anhydrous MgSO4; filtered and concentrated. The product, 2-(7-methoxy-1-benzofuran-3-yl)ethanol obtained as a white oil, was pure enough and taken to the next step without purification. Yield: 800 mg (83%); 193 (M+H).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([N:10]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:20])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.IC.[C:23](=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH3:23][N:1]1[C:5]2=[N:6][C:7]([N:10]3[C:18](=[O:19])[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[C:11]3=[O:20])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: O=C1c2ccccc2C(=O)N1c1ccc2cc[nH]c2n1
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CC#N
Product: Cn1ccc2ccc(N3C(=O)c4ccccc4C3=O)nc21
Reaction time: 16 h
Yield: 116.7 %

Procedure:
2-(1H-Pyrrolo[2,3-b]pyridin-6-yl)-isoindole-1,3-dione (179 mg, 0.68 mmol) was suspended in acetonitrile (3.4 mL). Iodomethane (53 μL, 0.843 mmol) and cesium carbonate (443 mg, 1.36 mmol) were then added. After 16 h, water was added and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried (sodium sulfate), filtered and concentrated in vacuo to give 2-(1-methyl-1H-pyrrolo[2,3-b]pyridin-6-yl)-isoindole-1,3-dione (0.22 g, 117%) as a light brown solid, which was used directly in the next step without further purification. LCMS (EI/CI) m/z: 278 [M+H].
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:14]=[C:13]([CH3:33])[N:12]=1>O1CCCC1>[CH3:33][C:13]1[N:12]=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:14]=1
Reactant: Cc1cc(NCCCCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c(Cl)n1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NCCCCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c(Oc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
Phenol (9.45 g, 100 mmol) was added over a period of 10 minutes to a chilled (0° C.) suspension of sodium hydride (4.24 g of 60%, 106 mmol) in anhydrous tetrahydrofuran (100 mL). The reaction mixture was allowed to stir at 0° C. for 30 minutes. A solution of tert-butyl 4-[(2-chloro-6-methyl-3-nitropyridin-4-yl)amino]butylcarbamate (33.92 g, 94.5 mmol) in anhydrous tetrahydrofuran (250 mL) was added over a period of 50 minutes while maintaining the reaction mixture at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred overnight before being concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL), washed with 1N sodium hydroxide (300 mL), dried over magnesium sulfate and then concentrated to dryness. The crude product was purified by column chromatography (400 g silica gel eluting with 7:3 hexanes:ethyl acetate to provide 25.4 g of tert-butyl 4-[(6-methyl-3-nitro-2-phenoxypyridin-4-yl)amino]butylcarbamate.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[N:12]([CH3:14])[CH3:13])([O-:8])=[O:7].CN(C)[CH:20]=[O:21]>>[N+:6]([C:9]1[CH:10]=[C:11]([N:12]([CH3:13])[CH3:14])[CH:15]=[CH:16][C:17]=1[CH:20]=[O:21])([O-:8])=[O:7]
Reactant: CN(C)C=O
Reactant: CN(C)c1cccc([N+](=O)[O-])c1
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1ccc(C=O)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 66 %

Procedure:
720 parts of phosphorus oxychloride is added at 25°C to a solution of 498 parts of m-nitrodimethylaniline in 1800 parts by volume of dimethylformamide. The mixture is then heated within 1 hour to 75° to 80°C and stirred at this temperature for six hours. After the solution has cooled it is poured into 6000 parts of ice-water. The precipitate is suction filtered, washed and recrystallized from acetone. 385 parts (66% of theory) of 2-nitro-4-dimethylaminobenzaldehyde having a melting point of 115° to 116°C is obtained. ##SPC14##
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[C:13]([OH:15])=O)([O-:3])=[O:2].Cl.CN.C1C=CC2N(O)N=[N:25][C:23]=2C=1.CCN(C(C)C)C(C)C.Cl.CN(C)CCCN=C=NCC>CN1CCCC1=O.C(OCC)(=O)C>[CH3:23][NH:25][C:13]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1)=[O:15]
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of compound 54 (100 mg, 0.483 mmol), methylamine hydrochloride (52.2 mg, 0.773 mmol), HOBt (130 mg, 0.966 mmol) and DIEA (0.34 mL, 1.95 mmol) in N-methylpyrrolidinone was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (148 mg, 0.773 mmol). The reaction was stirred at room temperature for 2 hrs and diluted with 10 mL of ethyl acetate. The mixture was washed with water and a yellow solid precipitated. The precipitate was collected by filtration to give compound 55 (67 mg).
Reaction SMILES: Cl.N[C@H]1CCCC[C@H]1CNCCO.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH:23][C:24]([C:26]1[C:27](=[O:56])[C:28]([O:48]CC2C=CC=CC=2)=[C:29]2[C:45](=[O:46])[N:33]3[CH:34]4[CH:39]([CH2:40][N:41]([CH2:42][CH2:43][OH:44])[CH:32]3[CH2:31][N:30]2[CH:47]=1)[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:25]>>[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH2:22][NH:23][C:24]([C:26]1[C:27](=[O:56])[C:28]([OH:48])=[C:29]2[C:45](=[O:46])[N:33]3[CH:34]4[CH:39]([CH2:40][N:41]([CH2:42][CH2:43][OH:44])[CH:32]3[CH2:31][N:30]2[CH:47]=1)[CH2:38][CH2:37][CH2:36][CH2:35]4)=[O:25]
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C3CCCCC3CN(CCO)C1C2
Agent: Cl
Agent: N[C@H]1CCCC[C@H]1CNCCO
Product: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1C3CCCCC3CN(CCO)C1C2

Procedure:
In a manner similar to that described in example Z-35, from 16a (45 mg, 0.0957 mmol) and racemic-2-({[(1S,2S)-2-aminocyclohexyl]methyl}amino)ethanol hydrochloride (102 mg, 0.418 mmol) was prepared racemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-(2-hydroxyethyl)-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (7 mg, 12%) as a white solid after silica gel chromatography (1-12% methanol/dichloromethane gradient elution). This material was deprotected in a second step similar to the procedure described in example Z-37. Thus, from racemic-(4aS,6aS,14aS)—N-[(2,4-difluorophenyl)methyl]-6-(2-hydroxyethyl)-11,13-dioxo-12-[(phenylmethyl)oxy]-1,2,3,4,4a,5,6,6a,7,11,13,14a-dodecahydropyrido[1′,2′:4,5]pyrazino[1,2-a]quinazoline-10-carboxamide (7 mg, 0.0118 mmol) the title compound was prepared after purification by HPLC (3 mg, 50%). 1H NMR (CDCl3) 12.57 (br s, 1H), 10.45 (m, 1H), 8.29 (s, 1H), 7.34 (m, 1H), 6.78 (m, 2H), 4.80 (m, 1H), 4.71 (s, 1H), 4.62 (m, 2H), 4.44 (m, 1H), 4.33 (m, 1H), 3.75 (m, 1H), 3.62-3.20 (m, 3H), 3.13 (m, 1H), 2.74-2.71 (m, 2H), 2.24 (m, 1H), 1.90-137 (m, 12H), 1.27-1.23 (m, 3H) 1.12 (m, 1H); ES+ MS: 503 (M+1).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.CC(C)([O-])C.[K+].O>CN(C)C=O>[CH2:1]([O:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=1[N:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(-n2cccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Benzylbromide (2.9 ml) was added to the mixture of methyl 4-hydroxy-3-(pyrrol-1-yl)benzoate (5.0 g) and potassium t-butoxide (2.7 g) in N,N-dimethylformamide (40 ml) under ice-cooling and the mixture was stirred for 5 hours at ambient temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The extract layer was washed with brine and dried over magnesium sulfate. The solvent was removed by concentration. The residue was crystallized from the mixture of toluene and diisopropyl ether and collected by filtration to give methyl 4-benzyloxy3-(pyrrol-1-yl)benzoate (4.2 g).
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH:8]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][S:18][CH2:19][CH2:20][NH:21][C:22]([NH:26][CH3:27])=[N:23][C:24]#[N:25])[N:16]=1)[C:9]([NH2:11])=[NH:10]>N1C=CC=CC=1.O>[C:5]([N:10]=[C:9]([NH2:11])[NH:8][C:12]1[S:13][CH:14]=[C:15]([CH2:17][S:18][CH2:19][CH2:20][NH:21][C:22]([NH:26][CH3:27])=[N:23][C:24]#[N:25])[N:16]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=NC#N)NCCSCc1csc(NC(=N)N)n1
Solvent: c1ccncc1
Solvent: O
Product: CNC(=NC#N)NCCSCc1csc(NC(N)=NC(C)=O)n1
Reaction time: 2 h

Procedure:
Acetic anhydride (0.39 g.) was added to a stirred suspension of 2-guanidino-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole (1.10 g.) in pyridine (6 ml.) at room temperature. After stirring for two hours, the mixture was diluted with water (50 ml.), extracted with methylene chloride (3×30 ml.) and the combined extracts washed with water (100 ml.) and dried over magnesium sulphate. The solution was filtered and evaporated to dryness to leave a gum which was purified by column chromatography (silica column, eluted with ethyl acetate/ethanol/ammonia (s.g. 0.880) 6:1:1 v/v/v) to give 2-(2-acetylguanidino)-4-[2-(2-cyano-3-methylguanidino)ethylthiomethyl]thiazole as an amorphous solid. The n.m.r. spectrum in d6 dimethyl sulphoxide using tetramethylsilane as internal standard had the following resonances (δ): 2.1 (3H, singlet); 2.7 (5H, multiplet); 3.3 (multiplet, obscured by H2O); 3.7 (2H, singlet); 6.8 (1H, singlet); 7.0 (2H, broad multiplet); 9.0 (2H, very broad) and 10.7 (1H, broad).
Reaction SMILES: [Li][C:2](C)(C)[CH3:3].CCCCC.[C:11]1([S:17]([N:20]2[C:24]3=[N:25][CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)[CH:28]=[C:23]3[CH:22]=[CH:21]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(I)C>C1COCC1>[C:11]1([S:17]([N:20]2[C:24]3=[N:25][CH:26]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)[CH:28]=[C:23]3[CH:22]=[C:21]2[CH2:2][CH3:3])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [Li]C(C)(C)C
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(-c3cccc(F)c3)cnc21
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CCI
Product: CCc1cc2cc(-c3cccc(F)c3)cnc2n1S(=O)(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 36 %

Procedure:
1.7 M solution of t-BuLi in pentane (0.71 mL, 1.20 mmol) was added dropwise to a stirred and cooled (−78° C.) solution of 12 (352.0 mg, 1.00 mmol) in THF (2.0 mL). The mixture turned red-brown. After the addition, the mixture was stirred for 30 min at −78° C. Neat EtI (150 μL, 1.88 mol) was added in one portion, and the mixture was allowed to reach 0° C. over a period of 1 h 15 min. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution. The mixture was then extracted with AcOEt (3×3 mL). Combined organic solutions were washed with brine, dried (MgSO4), concentrated and purified by SGC with hexane:AcOEt as eluent in gradient to afford 13 (138.5 mg, 36%) as white solid. 1H NMR (400 MHz, CDCl3) δ 1.42 (t, J=7.3 Hz, 3H), 3.21 (qd, J=7.3, 1.2 Hz, 2H), 6.39 (t, J=1.2 Hz, 1H), 7.07 (dddd, J=8.4, 8.0, 2.5, 1.0 Hz, 1H), 7.25 (ddd, J=9.9, 2.5, 1.7 Hz, 1H), 7.34 (ddd, J=7.7, 1.7, 1.0 Hz, 1H), 7.42 (ddd, J=8.0, 7.7, 5.9 Hz, 1H), 7.46-7.51 (m, 2H), 7.54-7.60 (m, 1H), 7.86 (d, J=2.2 Hz, 1H), 8.15-8.19 (m, 2H), 8.57 (d, J=2.2 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[C:18]([CH3:33])=[N:19][C:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)=[CH:21][CH:22]=3)[CH:13]=2)[CH:8]=[CH:7]1)[CH3:2].C([BH3-])#N.[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16][C:17]3[C:18]([CH3:33])=[N:19][C:20]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=4)=[CH:21][CH:22]=3)[CH:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1ccc2ccc(OCc3ccc(-c4ccc(C(F)(F)F)cc4)nc3C)cc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)CN1CCc2ccc(OCc3ccc(-c4ccc(C(F)(F)F)cc4)nc3C)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 10° C. cold solution of {6-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester (17 mg, 0.036 μmol) in acetic acid (0.5 ml) was added sodium cyanoborohydride (14 mg, 0.22 μmol). The reaction mixture was naturally warmed to ambient temperature, stirred for 4 h and poured onto ice water/brine/AcOEt 1/1/2. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with sat. sodium bicarbonate solution/brine 1/1 and brine/ice water 1/1 and dried over sodium sulfate. The solvent was removed under reduced pressure to give 17 mg (0.036 μmol, quant.) of the title compound as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH3:19])[CH2:17][CH3:18].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:16]([CH3:19])[CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: CCC(C)Br
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C)Sc1ccc(Br)cc1
Reaction time: 0.25 h

Procedure:
1-Bromo-4-(1-methylpropylthio)benzene is prepared by the following procedure. To a solution of 4-bromobenzenethiol (4.73 g, 25.0 mmol) in 25 ml of DMF at 70° under N2 is added potassium carbonate (4.15 g, 30.0 mmol). The mixture is allowed to stir for 15 min., after which 3-bromobutane (4.8 ml, 44.0 mmol) is added dropwise. The mixture is stirred at 70° for ca. 5 hours. Water is added to the cooled solution and the aqueous phase is extracted with ether (3X). The combined organic layers are washed with water and with brine and dried and the solvent is removed in vacuo to give, following purification by distillation under vacuum, 1-bromo-4-[1-methylpropylthio)benzene.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:3]=1[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1.CN1CCOCC1.Cl[C:37]([O:39][CH3:40])=[O:38].O>COCCOC.CCCCCC.[Hg]>[NH2:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:3]=1[CH2:4][N:5]([CH2:6][C:7]1[CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=[C:9]([C:17]([F:18])([F:19])[F:20])[CH:8]=1)[C:37](=[O:38])[O:39][CH3:40]
Reactant: COC(=O)Cl
Reactant: Nc1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Hg]
Solvent: O
Solvent: CN1CCOCC1
Solvent: CCCCCC
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1N

Procedure:
In a 250-mL flask equipped with a septum inlet, magnetic stirring bar, and connecting tube leading to a mercury bubbler was placed 12 g (0.029 mol) of [2-amino-5-(trifluoromethyl)benzyl][3,5-bis(trifluoromethyl)benzyl]amine in 120 mL DME. To the reaction flask with stirring was added 6.4 mL (0.058 mol) N-methylmorpholine and the mixture was cooled in an ice bath under nitrogen. To this mixture was added dropwise over ten minutes, 2.7 mL (0.035 mol) of methyl chloroformate. Afterwards, the mixture was allowed to stir for 15 minutes and HPLC showed no starting material present. Water was added to the mixture and the contents were diluted with hexane and transferred to a separatory funnel. The layers were separated, then washed with brine, dried over magnesium sulfate, filtered and concentrated to give 13 g crude oil. The oil was chromatographed on a Biotage 40M cartridge with methylene chloride/hexane to give methyl [2-amino-5-(trifluoromethyl)benzyl][3,5-bis(trifluoromethyl)benzyl]carbamate as a yellow oil.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9](Cl)=[O:10].[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][NH2:26])=[CH:21][CH:20]=1>C(N(CC)CC)C>[F:16][C:17]([F:29])([F:30])[O:18][C:19]1[CH:28]=[CH:27][C:22]([O:23][CH2:24][CH2:25][NH:26][C:9](=[O:10])[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[Cl:6])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NCCOc1ccc(OC(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCOc1ccc(OC(F)(F)F)cc1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofuran (5 ml) solution of 2-chlorobenzoyl chloride (0.88 g) was added dropwise under ice-cooling and stirring to a tetrahydrofuran (20 ml) solution of 2-(4-trifluoromethoxyphenoxy)ethylamine (1.10 g) and triethylamine (0.51 g) and the mixture was further stirred at room temperature for one hour.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CS(O[CH2:37][CH2:38][CH2:39][CH:40]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[NH:42][C:41]1=[O:49])(=O)=O.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.C(OCC)(=O)C>[O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:37][CH2:38][CH2:39][CH:40]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[NH:42][C:41]3=[O:49])[CH2:8][CH2:7]2)[N:5]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23]
Reactant: CS(=O)(=O)OCCCC1C(=O)Nc2ccccc21
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCC4C(=O)Nc5ccccc54)CC3)C2=O)c1
Yield: 82.2 %

Procedure:
tert-Butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.25 g, 0.593 mmol), 3-(2-oxoindolin-3-yl)propyl methanesulfonate (0.16 g, 0.593 mmolmmol), sodium iodide (0.027 g, 0.178 mmol) and potassium carbonate (0.12 g, 0.890 mmol) in 2-butanone (8 mL) were stirred at 78° C. for 2 hours. The reaction was diluted with ethyl acetate, washed with water and brine, dried (MgSO4), and evaporated. The residue was purified by PTLC (5% methanol/dichloromethane) to give product as an oil (0.29 g, 82%); MS for C36H42N4O4 m/z 595 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1.Cl[C:11]1[N:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([N:3]2[CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=[C:2]2[CH3:1])=[N:16][CH:15]=1)#[N:18]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: Cc1nc(C(=O)O)c[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)O)cn1-c1ccc(C#N)cn1
Temperature: 100 °C

Procedure:
A mixture of 2-methyl-1H-imidazole-4-carboxylic acid (490 mg), 6-chloropyridine-3-carbonitrile (800 mg), and K2CO3 (1.1 g) in DMF (6 mL) is heated to 100° C. overnight. The crude product is purified by HPLC. LC (method 20): tR=0.73 min; Mass spectrum (APCI): m/z=229 [M+H]+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:7]=1)(=O)C.CO>O>[O:12]([C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[CH2:5][OH:4])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)OCc1cccc(Oc2ccccc2)c1
Solvent: CO
Solvent: O
Product: OCc1cccc(Oc2ccccc2)c1
Reaction time: 9 h
Yield: 90 %

Procedure:
2.42 g. (0.01 mole) of 3-phenoxybenzyl acetate, 10 cm3. of methanol, 10 cm3. of water and 0.2 g. of acid ion exchange resin (Nafion H) are refluxed with stirring for nine hours. After cooling the reaction mixture is filtered off and evaporated. The residue is dissolved in 30 cm3. of methylene chloride, washed with 10 cm3. of 1N sodium hydroxide solution and 10 cm3. of water then evaporated. 1.8 g. of 3-phenoxybenzyl alcohol are obtained. nD20 : 1.593, yield 90%.