Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH2:31])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH:32]([CH3:34])[CH3:33])[C:15]=2[N:16]=[CH:17][N:18]=1>N1C=CC=CC=1>[NH2:12][C:13]1[C:14]2[C:21]([C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])(=[O:10])=[O:9])[CH:25]=3)=[O:23])=[CH:20][N:19]([CH:32]([CH3:34])[CH3:33])[C:15]=2[N:16]=[CH:17][N:18]=1
Reactant: Cc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(N)n1
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: c1ccncc1
Product: Cc1cc(C(=O)c2cn(C(C)C)c3ncnc(N)c23)cc(NS(=O)(=O)c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.7 %

Procedure:
2-Fluoro-benzenesulfonyl chloride (68.9 mg, 035 mmol) was added to a solution of (4-Amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-(2-amino-6-methyl-pyridin-4-yl)-methanone (100 mg, 0.32 mmol) in pyridine (2 mL). The mixture was stirred for 2 h at room temperature. The reaction mixture was quenched with H2O (2 mL) and concentrated in vacuo. The resulting residue was triturated with MeOH, filtered, and dried. Purification by flash column chromatography [ethyl acetate/hexanes 3:7—(20% NH4OH/MeOH)/ethyl acetate/hexanes 5:65:30] afforded the title compound as a yellow oil (94 mg, 62%). MS: 469.3 (MH+); HPLC Rf: 4.46 min. (HPLC method 4).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#N.[H-].C([Al+]CC(C)C)C(C)C.CC[O:26]CC.Cl>ClCCl.CCCCCC>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:26]
Reactant: CCOCC
Reactant: N#Cc1cc(C(F)(F)F)ccc1Br
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: O=Cc1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-5-(trifluoromethyl)benzonitrile (10.0 g, 40 mmol) in dichloromethane (100 mL) was dropwise added a 1.0 M solution of diisobutylaluminum hydride in hexane (48 mL). The resulting solution was stirred under nitrogen at ambient temperature for 1 h and was then diluted by addition of ether (100 mL). After cooling in an ice bath, a 3 N solution of HCl was carefully added, and the mixture was vigorously stirred at ambient temperature for 15 min. The organic layer was washed with brine, dried (MgSO4) and evaporated. The resulting oil was purified by flash chromatography (5% EtOAc/hexane) affording 5 g of 2-bromo-5-trifluoromethylbenzaldehyde. 1H NMR (CDCl3) δ 10.39 (s, 1H), 8.18 (d, J=2 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.70 (dd, J=8.5 Hz, 2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([CH3:27])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([CH3:27])[S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Cc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: Cc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-dichlorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])C.[NH2:18][C:19]1[NH:23][N:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.CN(C)C=O>O>[CH2:15]([N:12]1[C:9]2[N:10]=[CH:11][C:6]3[C:4](=[O:5])[N:23]4[N:22]=[CH:21][CH:20]=[C:19]4[NH:18][C:7]=3[C:8]=2[CH:14]=[N:13]1)[CH3:16]
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Reactant: Nc1ccn[nH]1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1ncc2c3[nH]c4ccnn4c(=O)c3cnc21

Procedure:
126 g. of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.5 mol.), 41.5 g. of 5-amino-pyrazole (0.5 mol.) and 50.6 g. of triethylamine (0.5 mol.) are heated at reflux temperature with stirring in 250 ml. of dimethylformamide for 16 hours. After cooling, about 300 ml. of water are added and the white precipitated product, 3-ethyl-3,11-dihydro-6H-pyrazolo[1,5-a]pyrazolo-[4',3':5,6]pyrido[4,3-d]pyrimidin-6-one is filtered off, yield 57.7 g (45.4%); m.p. >300° (DMF).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[N:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:13][CH2:14][CH2:15][CH2:16]Br.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[Br:13][CH2:14][CH2:15][CH2:16][N:9]1[C:8](=[O:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=[N:10]1
Reactant: BrCCCBr
Reactant: O=c1[nH]ncn1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1n(-c2ccccc2)cnn1CCCBr
Temperature: 25 °C
Reaction time: 4 h

Procedure:
After dissolving 4-phenyl-2,4-dihydro[1,2,4]triazol-3-one (CAS 1008-30-6) (1.00 g) and 1,3-dibromopropane (1.89 ml) in N,N-dimethylformamide (15 ml), sodium hydride (60% in oil) (273 mg) was added and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography. The obtained solid was washed with n-heptane to obtain the title compound (840 mg).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:18][C:19]([CH:25]1[CH2:27][CH2:26]1)([CH3:24])[CH2:20][C:21]([NH2:23])=[O:22]>>[NH2:23][C:21](=[O:22])[CH2:20][C:19]([NH:18][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][CH:15]([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH:25]1[CH2:27][CH2:26]1)[CH3:24]
Reactant: O=C(O)c1cc(OCC(F)F)c(C2CC2)cn1
Reactant: CC(N)(CC(N)=O)C1CC1
Product: CC(CC(N)=O)(NC(=O)c1cc(OCC(F)F)c(C2CC2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(2,2-difluoroethoxy)pyridine-2-carboxylic acid (example 145d) and 3-amino-3-cyclopropyl-butanamide (example 270c) as starting materials and isolated (55 mg, 52%) as a racemate; MS (ESI, m/z): 368.3 (M+H+).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[OH-].[Na+].[NH2:12][C:13]1[C:14]([OH:47])=[C:15]([N:23]=[N:24][C:25]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[N:26][NH:27][C:28]2[CH:33]=[C:32]([S:34]([OH:37])(=[O:36])=[O:35])[CH:31]=[CH:30][C:29]=2[C:38]([OH:40])=[O:39])[CH:16]=[C:17]([S:19]([OH:22])(=[O:21])=[O:20])[CH:18]=1>O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:12][C:13]2[C:14]([OH:47])=[C:15]([N:23]=[N:24][C:25]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)=[N:26][NH:27][C:28]3[CH:33]=[C:32]([S:34]([OH:37])(=[O:35])=[O:36])[CH:31]=[CH:30][C:29]=3[C:38]([OH:40])=[O:39])[CH:16]=[C:17]([S:19]([OH:22])(=[O:21])=[O:20])[CH:18]=2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1cc(S(=O)(=O)O)cc(N=NC(=NNc2cc(S(=O)(=O)O)ccc2C(=O)O)c2ccccc2)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(S(=O)(=O)O)cc1NN=C(N=Nc1cc(S(=O)(=O)O)cc(Nc2nc(Cl)nc(Cl)n2)c1O)c1ccccc1
Temperature: 1.5 °C

Procedure:
9.22 parts of cyanuric chloride are suspended in 150 parts of ice-water. The pH is brought to 5 with 1 N sodium hydroxide solution and the temperature is kept at 0 to 2° C. A neutral solution of 29.80 parts of the copper complex of 5-amino-3-[3-phenyl-5-(2-carboxy-5-sulfophenyl)-1-formazano]-4-hydroxybenzenesulfonic acid in 250 parts of water is added to this suspension at 0 to 3° C. During the addition the pH is kept at 5 with a 2 N sodium hydroxide solution. After the addition, the mixture is stirred at 0 to 3° C. and pH 5 for about a further 2 hours. A solution of 5-[4,6-dichloro-1,3,5-triazin-2-ylamino]-3-[3-phenyl-5-(2-carboxy-5-sulfophenyl)-1-formazano]-4-hydroxybenzenesulfonic acid is obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([CH2:8][N:9]2[C:15](=[O:16])[C@@H:14]([NH:17][C:18]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH:30]=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[NH:28][C:27]4=[O:37])[CH2:22][CH2:21]3)=[O:19])[CH2:13][NH:12][C@H:11]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:10]2)[CH2:7][CH2:6]1.C(N(CC)CC)C>ClCCl>[C:1]([N:12]1[CH2:13][C@@H:14]([NH:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH:28][C:27]3=[O:37])[CH2:24][CH2:25]2)=[O:19])[C:15](=[O:16])[N:9]([CH2:8][CH:5]2[CH2:6][CH2:7]2)[CH2:10][C@@H:11]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:3])[CH3:2]
Reactant: O=C(N[C@H]1CN[C@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C[C@@H](NC(=O)N2CCC(n3cc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N(CC2CC2)C[C@@H]1c1ccccc1
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Acetyl chloride (2.1 □L, 0.03 mmol) was added to a solution of N-[(3R,6S)-1-(cyclopropylmethyl)-7-oxo-3-phenyl-1,4-diazepan-6-yl]-4-(2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxamide (16.9 mg, 0.03 mmol) and triethylamine (9 □L, 0.06 mmol) in dichloromethane (0.5 mL). After 30 min, the mixture was concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→5% methanol/dichloromethane) gave the title compound (17 mg). MS 571.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.Br[C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[N:21][CH:22]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CN(C=O)C.O.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([C:17]3[CH:22]=[N:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: Cc1ccc(Br)cn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2ccc(C)nc2)CCN(C)C1
Yield: 3 %

Procedure:
A solution of 2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.2 g, 1 mmol), 5-bromo-2-methyl-pyridine (0.348 g, 2 mmol), K3PO4 (0.424 g, 2 mmol), CuI (19 mg, 0.1 mmol) and L-Proline (23 mg, 0.2 mmol) in dry DMF (3 mL) was stirred at 150° C. for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(6-methyl-pyridin-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as semisolid (8.6 mg). 1H NMR (HCl salt, CD3OD) δ (ppm): 8.6 (s, 1H), 8.05 (d, 1H), 7.7 (d, 1H), 7.19 (s, 1H), 7.19-7.05 (dd, 2H), 4.8 (m, 1H), 4.4 (m, 1H), 3.90-3.8 (m, 1H), 3.6-3.50 (m, 1H), 3.25-3.20 (m, 1H), 3.2 (s, 3H), 3.05-3.0 (m, 1H), 2.75 (s, 3H), 2.45 (s, 3H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[N:19]4)(=O)=O)=CC=1.[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][NH:40][CH2:41][CH:42]=1>CS(C)=O.C(OCC)(=O)C>[F:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][CH:32]=[C:31]2[C:37]1[CH2:38][CH2:39][N:40]([CH2:12][CH:13]2[O:26][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[CH:21][CH:20]=[N:19]4)[CH2:41][CH:42]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nccnc4c3O2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Fc1ccc2[nH]cc(C3=CCN(CC4COc5ccc6nccnc6c5O4)CC3)c2c1
Temperature: 80 °C

Procedure:
To a solution of (2R)-2,3-dihydro[1,4]dioxino[2,3-f]quinoxalin-2-ylmethyl 4-methylbenzenesulfonate (0.462 g, 1.241 mmole) in methyl sulfoxide (25 mL) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (1.073 g, 4.962 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (250 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.382 g (74%) of the (S)-enantiomer of the title compound as a tan solid. Rf=0.37 (silica, methanol:ethyl acetate 1:9); mp>200° C. dec.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([O:24][Si](C)(C)C)C#N)=[CH:17][CH:16]=1)[CH3:14].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=[O:33]>CCCCCC.COCCOC>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21](=[O:24])[CH:32]([C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[F:29])[OH:33])=[CH:17][CH:16]=1)[CH3:14]
Reactant: CCc1ccc(C(C#N)O[Si](C)(C)C)cc1
Reactant: O=Cc1ccccc1F
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCc1ccc(C(=O)C(O)c2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add 217 ml (0.54 mol) of a 2.5 M n-butyllithium solution in hexane dropwise at −78° C. to a solution of 77 ml (56 g, 0.55 mol) N,N-diisopropylamine in 960 ml 1,2-dimethoxyethane in such a way that the temperature does not exceed −60° C. After stirring for 15 min at this temperature, add a solution of 116 g (0.50 mol) (4-ethylphenyl)[(trimethylsilyl)oxy]acetonitrile [D. S. Dhanoa, J. Med. Chem. 1993, 36 (23), 3738-3742] in 373 ml 1,2-dimethoxyethane dropwise in the space of 30 min. Next, after stirring for 30 min at this temperature, add a solution of 64 g (0.50 mol) 2-fluorobenzaldehyde in 373 ml 1,2-dimethoxyethane dropwise in the space of 20 min. Leave the reaction mixture to warm to room temperature in 4 h. After adding 1900 ml satd. aqueous ammonium chloride solution, extract with ethyl acetate. Wash the organic phase with satd. ammonium chloride solution, dry over sodium sulphate and filter. Concentrate the filtrate by vacuum evaporation. Add 1900 ml dioxan, 1350 ml methanol and 1560 ml 1 M hydrochloric acid to the residue and stir for 16 h at room temperature. After adding 4000 ml satd. aqueous sodium chloride solution, extract with 2000 ml ethyl acetate. Wash the organic phase with 1000 ml water and 1000 ml satd. sodium chloride solution, dry over sodium sulphate and filter. Concentrate the filtrate by vacuum evaporation. Purify the residue by flash chromatography on silica gel (solvent: cyclohexane/ethyl acetate 5:1). Mix the product fraction thus obtained in 80 ml diisopropyl ether and 240 ml petroleum ether, filter, wash with petroleum ether and dry under vacuum. 50 g (85% purity, 33% of theor.) of the title compound is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH3:46])[C:33](B2OC(C)(C)C(C)(C)O2)=[C:34]([NH2:36])[CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]([C:10]1[S:11][C:12]([S:25][CH3:26])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:33]3[C:32]([CH3:46])=[CH:31][C:30]([O:29][CH3:28])=[CH:35][C:34]=3[NH2:36])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(Br)c1
Reactant: COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)c(N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc(C)c(-c2cccc(S(=O)(=O)c3cc(C(=N)NC(=O)OC(C)(C)C)sc3SC)c2)c(N)c1
Temperature: 80 °C
Yield: 40 %

Procedure:
A solution of {[4-(3-bromo-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 27: step c) 1.50 g, 3.05 mmol) in toluene:EtOH (2:1, 45 mL) was treated with 5-methoxy-3-methyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (((Example 198: step d) 1.61 g, 6.11 mmol), aqueous Na2CO3 (2 M, 12.2 mL, 24.4 mmol) and Pd (PPh3)4 (0.706 g, 0.611 mmol). The mixture was heated to 80° C. 4 h. The reaction was cooled to room temperature, diluted with EtOAc, washed with brine (1×75 mL) and water (2×75 mL), dried over MgSO4 and concentrated in vacuo. Silica gel chromatography (25% then 35% then 50% EtOAc in hexanes) afforded the product {[4-(2′-amino-4′-methoxy-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.680 g, 40%) as a yellow-brown solid. 1H NMR (MeOD): δ 8.223 (s, 1H), 8.001 (d, 1H, J=7.2 Hz), 7.879 (t, 1H, J=1.6 Hz), 7.698 (t, 1H, J=8.0 Hz), 7.549 (d, 1H, J=8.0 Hz), 6.287 (dd, 2H, J=7.2 Hz, J=2.4 Hz), 3.770 (s, 3H), 2.669 (s, 3H), 1.900 (s, 3H), 1.510 (s, 9H). C25H29N3O5S3: 548.13 (M+1) found 547.70.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:13])(OCC)=O)C.[NH:29]1[CH:33]=[C:32]([CH:34]=O)[CH:31]=[N:30]1>C1COCC1.CCOC(C)=O>[NH:29]1[CH:33]=[C:32](/[CH:34]=[CH:11]/[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:13])[CH:31]=[N:30]1
Reactant: O=Cc1cn[nH]c1
Reactant: CCOP(=O)(CC(=O)Nc1ccccc1NC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1cn[nH]c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.2 %

Procedure:
A 60% suspension of NaH in paraffin oil (192 mg, 5 mmol) was added portionwise to a solution of tert-butyl (2-(2-(diethoxyphosphoryl)acetamido)phenyl)carbamate (1.93 g, 5 mmol) in anhydrous THF (25 mL) at 0° C. The reaction mixture was stirred for 30 min before being warmed up to room temperature. 1H-pyrazole-4-carbaldehyde (400 mg, 4.16 mmol) dissolved in anhydrous THF (5 mL) was then added and the reaction mixture was stirred for 72 h under a nitrogen atmosphere. After completion of the reaction as indicated by HPLC, the mixture was diluted with EtOAc (80 mL) and quenched with a saturated NH4Cl solution (10 mL). The organic layer was separated and washed with water (40 mL) and brine (20 mL). It was dried over anhydrous Na2SO4 and the solid was filtered. The filtrate was evaporated under vacuum. The isolated crude was purified by silica gel column chromatography using a gradient of 0-100% EtOAc in hexanes to provide 986 mg of (E)-tert-butyl (2-(3-(1H-pyrazol-4-yl)acrylamido)phenyl)carbamate as a white solid. 1HNMR (300 MHz, CD3OD): δ 7.93 (broad s, 2H), 7.64 (d, 1H, J=15.6 Hz), 7.56 (d, 1H, J=7.2 Hz), 7.45 d, 1H, J=7.8 Hz), 7.11-7.24 (m, 2H), 6.59 (d, 1H, J=15.6 Hz), 1.50 (s, 9H), MS: ES+(M+Na)+: 351
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([CH3:11])[CH:3]=1.[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.[NH4+].[Cl-]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:15][CH2:16][O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:9]#[N:10])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(F)ccc1CC#N
Reactant: BrCCOC1CCCCO1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1C(C#N)CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
(4-Fluoro-2-methylphenyl)acetonitrile (6.0 g, 40 mmol), dissolved in THF (25 mL), was added to a suspension of NaH (2.1 g, 60% in mineral oil, 52 mmol) in THF (25 mL) under a stream of nitrogen. The mixture was then heated to reflux, which initiated the reaction. The reaction proceeded without external heating for 1 h whereupon the visual generation of gas ceased. The mixture was cooled and then 2-(2-bromoethoxy)tetrahydro-2H-pyran (10.9 g, 52 mmol), dissolved in THF (25 mL), was added. The mixture was stirred at 0° C. for 30 min and then at room temperature overnight. The mixture was poured over an aqueous solution of NH4Cl, which was extracted twice with ether. The combined organic solutions were dried over Na2SO4 and then the solvent was evaporated. The product was purified by chromatography on silica gel using CH2Cl2 and there was obtained 8.1 g (72%) of 2-(4-fluoro-2-methylphenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile as an oil. 1H NMR (300 MHz, CDCl3): 1.4-2.2 (m, 8H), 2.4 (s, 3H), 3.4-3.6 (m, 2H), 3.8-4.0 (m, 2H), 4.2 (m, 1H), 4.6 (m, 1H), 6.8-7.0 (m, 2H), 7.4 (m, 1H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][C:4]2[C:8]([CH2:11][CH2:12][NH2:13])=[CH:9][NH:10][C:3]=2[CH:2]=1.Cl.[C:15](O)(=[O:24])/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C=O>[OH:7][C:6]1[CH:5]=[C:4]2[C:3](=[CH:2][CH:1]=1)[NH:10][CH:9]=[C:8]2[CH2:11][CH2:12][NH:13][C:15](=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCc1c[nH]c2ccc(O)cc12
Reactant: O=C(O)/C=C/c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1)NCCc1c[nH]c2ccc(O)cc12
Temperature: 0 °C
Reaction time: 16 h
Yield: 50.2 %

Procedure:
Serotonin hydrochloride (300 mg, 1.41 mmol) and trans-cinnamic acid (208 mg, 1.41 mmol) were dissolved in a mixed solvent of dichloromethane (6 ml) and N,N-dimethylformamide (6 ml), and the solution was maintained at 0° C. To this solution were added triethylamine (216 μl, 1.55 mmol), 1-hydroxybenzotriazole hydrate (HOBt H2O, 237 mg, 1.55 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI HCl, 297 mg, 1.55 mmol), and the mixture was gradually warmed to room temperature and stirred at room temperature for 16 hours. The solvent was removed under reduced pressure, water (10 ml) was added to the residue, and the mixture was extracted twice with ethyl acetate (10 ml). The ethyl acetate layer was washed twice with 5% aqueous citric acid solution (5 ml), once with saturated brine (5 ml), twice with 5% aqueous sodium hydrogen carbonate solution (5 ml), and once with saturated brine (5 ml), and dried over anhydrous magnesium sulfate. Magnesium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure, and purified by preparative thin-layer chromatography (PTLC, eluent: ethyl acetate) to give N-[2-(5-hydroxy-1H-indol-3-yl)ethyl]-3-phenyl-2-propenamide (217 mg, yield 50.0%) as a viscous oil.
Reaction SMILES: [C:1]1([CH:7]([CH2:10][CH2:11][O:12][Si](C)(C)C)[C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([OH:19])C>S(=O)(=O)(O)O.O>[C:1]1([CH:7]2[CH2:10][CH2:11][O:12][C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)OCCC(C#N)c1ccccc1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1OCCC1c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 62 %

Procedure:
A suspension of potassium tert-butoxide (12.3 g) in toluene (200 mL) was treated dropwise with a mixture of phenylacetonitrile (12.9 g) and (2-bromoethoxy)trimethyl-silane (23.8 g) at room temperature. Upon completion of the addition, the reaction mixture was refluxed for 5 h, then cooled to room temperature and quenched by pouring onto a mixture of ice and water. The formed organic phase was separated and the aqueous phase was extracted with benzene. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to give 2-phenyl-4-trimethylsilanyloxy-butyronitrile. The obtained butyronitrile derivative was redissolved in a mixture of ethanol (40 mL) and 70% aqueous sulfuric acid (40 mL), stirred at 50° C. for 3 h and, after cooling to room temperature, diluted with water (150 mL). The resulted organic phase was separated and the aqueous phase was extracted with benzene. The combined organic phases were washed with water, then with saturated aqueous solution of sodium bicarbonate, dried over magnesium sulfate, filtered, concentrated on a rotary evaporator and distilled in vacuum to give 11.0 g (62%) of the title compound.