Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][N:20]([CH3:36])[C@@H:21]1[CH2:25][CH2:24][N:23]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH2:22]1>C(O)C.N1CCCCC1>[CH3:19][N:20]([CH3:36])[C@@H:21]1[CH2:25][CH2:24][N:23]([C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])=[O:27])[CH2:22]1
Reactant: Cc1cc(C(=O)N2CC[C@@H](N(C)C)C2)c(C=O)[nH]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)N2CC[C@@H](N(C)C)C2)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.8 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 3-[(3R)-3-Dimethylamino-pyrrolidine-1-carbonyl]-5-methyl-1H-pyrrole-2-carbaldehyde (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[3-((R)-3-dimethylamino-pyrrolidine-1-carbonyl)-5-methyl-1H-pyrrol-2-ylmethylene]-4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (95 mg, 81%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11](=[S:12](=[O:14])=[O:13])[C:10]([O:15][CH3:16])=[C:9]([CH3:17])[CH:8]=[C:4]1[C:5](O)=[O:6].S(Cl)([Cl:20])=O>CN(C)C=O>[CH3:1][O:2][CH:3]1[C:11](=[S:12](=[O:14])=[O:13])[C:10]([O:15][CH3:16])=[C:9]([CH3:17])[CH:8]=[C:4]1[C:5]([Cl:20])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COC1=C(C)C=C(C(=O)O)C(OC)C1=S(=O)=O
Solvent: CN(C)C=O
Product: COC1=C(C)C=C(C(=O)Cl)C(OC)C1=S(=O)=O
Reaction time: 0.33 h

Procedure:
161 g of 2,4-dimethoxy-5-methyl sulphonyl-benzoic acid is reacted. 590 g of thionyl chloride, 5 drops of dimethylformamide and about half of the organic acid are placed in a 2 liter flask filtered with a reflux condenser. The resultant suspension is heated in a water bath at 55° for about 5 minutes. The second half of the organic acid is added and heating is continued for 20 minutes at 60°-65° then for 45 minutes at 70°-75°. The medium becomes fluid and turns yellow. The acid dissolves gradually, while the acid chloride begins to crystallise. When the reaction is over the excess thionyl chloride is distilled to constant weight, finishing up under vacuum.
Reaction SMILES: FC1C=CC(CN2CCC3C(=C(O)C(=O)N(C(C)C)C=3C(N(C)C)=[O:18])C2=O)=CC=1.N[C:31]1[C:32](=[O:60])[N:33]([CH2:56][CH:57]([CH3:59])[CH3:58])[C:34]([C:51]([N:53]([CH3:55])[CH3:54])=[O:52])=[C:35]2[C:40]=1[C:39](=[O:41])[N:38]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[C:45](Cl)[CH:44]=1)[CH2:37][CH2:36]2>>[F:49][C:46]1[CH:47]=[CH:48][C:43]([CH2:42][N:38]2[CH2:37][CH2:36][C:35]3[C:40](=[C:31]([OH:18])[C:32](=[O:60])[N:33]([CH2:56][CH:57]([CH3:59])[CH3:58])[C:34]=3[C:51]([N:53]([CH3:54])[CH3:55])=[O:52])[C:39]2=[O:41])=[CH:44][CH:45]=1
Reactant: CC(C)Cn1c(C(=O)N(C)C)c2c(c(N)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Reactant: CC(C)n1c(C(=O)N(C)C)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)cc1)CC2
Product: CC(C)Cn1c(C(=O)N(C)C)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)cc1)CC2

Procedure:
The title compound was prepared in a manner similar to that described for 6-(4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isopropyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (Example 69), using 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-N,N-dimethyl-2-isobutyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxamide (Example 14). (ES MS M+1=416)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.C(N(CC)CC)C.[F:33][C:34]([F:41])([F:40])[CH2:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[F:33][C:34]([F:41])([F:40])[CH2:35][S:36]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:6]([C:8]2[C:9]3[CH:18]=[CH:17][NH:16][C:10]=3[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1)(=[O:38])=[O:37]
Reactant: Cn1cc(-c2cc(N)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Reactant: O=S(=O)(Cl)CC(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(-c2cc(NS(=O)(=O)CC(F)(F)F)ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
To a solution of Example 3 (0.05 g, 0.151 mmol) and triethylamine (0.053 mL, 0.377 mmol) in dichloromethane (1.0 mL) was added dropwise 2,2,2-trifluoroethanesulfonyl chloride (0.036 g, 0.196 mmol). The reaction mixture was stirred for 1 hour at room temperature and then purified by flash chromatography (silica gel, 0-5% methanol in dichloromethane) to afford 0.050 g (68%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 3.49 (s, 3H) 4.55 (q, J=9.91 Hz, 2H) 6.28 (t, J=2.38 Hz, 1H) 6.86 (d, J=7.54 Hz, 2H) 6.95-7.07 (m, 2H) 7.20-7.31 (m, 5H) 7.40 (d, J=2.78 Hz, 1H) 10.43 (s, 1H) 12.02 (s, 1H). MS (APCI+) m/z 478 [M+H]+.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[CH2:21]([O:28][CH2:29][C@@H:30]([CH2:32][OH:33])[OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C1C=CN=CC=1)C.CO>N1C=CC=CC=1>[CH2:21]([O:28][CH2:29][C@H:30]([CH2:32][O:33][C:1]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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)[OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OC[C@@H](O)COCc1ccccc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN(CC)c1ccncc1
Solvent: CO
Solvent: c1ccncc1
Product: O[C@H](COCc1ccccc1)COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Trityl chloride (56 g) was added portionswise to a solution of 1-O-benzyl-(R)-glycerol (36.4 g, 0.2 mol) and 4-diethylaminopyridine (1 g) in pyridine (300 mL) under stirring and cooling with ice. After 20 h stirring methanol (50 mL) was added, the mixture was stirred for 30 min and concentrated in vacuo to half of the original volume. Ethyl acetate (500 mL) was added and the mixture extracted with water (3×250 mL). The organic layer was briefly dried with MgSO4, filtered and evaporated in vacuo. The residue 4 was codistilled with toluene (200 ml portions) to remove the residual pyridine and used for further synthesis.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[CH:4][C:3]=1[Cl:9].C(OO)(=[O:12])C>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N+:5]([O-:12])=[CH:4][C:3]=1[Cl:9]
Reactant: CC(=O)OO
Reactant: Nc1c(Cl)cncc1Cl
Solvent: ClC(Cl)Cl
Product: Nc1c(Cl)c[n+]([O-])cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-amino-3,5-dichloro pyridine (5.0 gm, 0.0306 moles) in chloroform (100 mL) was added 20% peracetic acid solution (200 ml, 0.597 moles) (20% peracetic acid was prepared as per Vogel's Practical Organic Chemistry, Vol. V, page no. 458). Reaction mixture was then stirred at room temperature for 48 hrs, cooled to 5-10° C. and quenched with sodium sulphite till iodide test disappeared. Chloroform as well as acetic acid was removed under reduced pressure. The residue obtained was purified on silica gel column using 5% methanol in chloroform as an eluent to give product as light yellow solid.
Reaction SMILES: [K].[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].Br[C:12]1[CH:13]=[C:14]([O:18][CH3:19])[CH:15]=[CH:16][CH:17]=1>CN1C(=O)CCC1.O.[Cu]Cl>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7]
Reactant: OCc1cccc(O)c1
Reactant: COc1cccc(Br)c1
Agent: Cl[Cu]
Agent: [K]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cccc(Oc2cccc(CO)c2)c1
Temperature: 170 °C
Yield: 52.1 %

Procedure:
To a solution of the potassium salt of 3-hydroxybenzyl alcohol (8.1 g, 50 mmol) in N-methyl pyrolidinone (20 ml) were added 3-bromoanisole (11.22 g, 60 mmol), copper (I) chloride (0.1 g, 1 mmol) and p-hydroxyquinoline (0.1 g, 1 mmol) and the reaction was heated to 170° C. for fifty hours. The reaction was cooled to room temperature, diluted with water (150 ml) and extracted with ether (5×50 ml). The combined extracts were dried (MgSO4) and evaporated. The residue was purified by flash chromatography (eluting with 10% ethyl acetate/60°-80° petrol) to afford 3-(3-methoxyphenoxy)benzyl alcohol as a pale oil 6.0 g (52%); δH (CDCl3) 3.80 (3H, s, OCH3), 4.64 (2H, s, CH2OH), 6.54-6.70 (3H, m, ArH), 6.88-7.10 (3H, m, ArH), 7.18-7.36 (2H, m, ArH).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]2[CH2:26][CH2:25][CH2:24][CH2:23][C:6]=2[C:7]=1[C:8]([NH:10][C@H:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[CH3:12])=[O:9].CN1CCN(C)C1=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1>O>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([CH2:42][N:2]([CH3:1])[C:3]2[S:4][C:5]3[CH2:26][CH2:25][CH2:24][CH2:23][C:6]=3[C:7]=2[C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:44][CH:45]=1
Reactant: CNc1sc2c(c1C(=O)N[C@@H](C)c1ccc(C(=O)OC)cc1)CCCC2
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2c(N(C)Cc3ccc(Cl)cc3)sc3c2CCCC3)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To methyl 4-[(1S)-1-({[2-(methylamino)-4,5,6,7-tetrahydro-1-benzothien-3-yl]carbonyl}amino)ethyl]benzoate (0.41 g) was added 1,3-dimethyl-2-imidazolidinone (4.0 mL), and potassium carbonate (0.30 g) and 1-(bromomethyl)-4-chlorobenzene (0.34 g) were added thereto under ice-cooling, followed by stirring at 50° C. overnight. The reaction mixture was cooled to room temperature, and then water (50 mL) was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate: 15/1-4/1) to obtain methyl 4-{(1S)-1-[({2-[(4-chlorobenzyl)(methyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]ethyl}benzoate (0.15 g).
Reaction SMILES: [C:1](#[N:3])[CH3:2].[H-].[Na+].[Br:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10](OC)=[O:11].Cl>C1COCC1.O>[Br:6][C:7]1[CH:8]=[C:9]([C:10](=[O:11])[CH2:2][C:1]#[N:3])[CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)c1cccc(Br)c1
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCC(=O)c1cccc(Br)c1
Temperature: 75 °C
Yield: 92.1 %

Procedure:
Acetonitrile (21.86 mL, 419 mmol) was added to a stirred suspension of 60% NaH (7.25 g, 181 mmol) in THF (150 mL). Then, methyl 3-bromobenzoate (30 g, 140 mmol) was added and the mixture was heated at 75° C. for 4 h. After cooling to room temperature, water followed by 1N HCl (200 mL) was added and the mixture was extracted with ethyl acetate (500 mL), washed with sat .NaHCO3 solution (200 mL), dried (Na2SO4), filtered and concentrated to afford 3-(3-bromophenyl)-3-oxopropanenitrile (29 g, 129 mmol, 93% yield) as light yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.09 (t, J=1.7 Hz, 1H), 7.90-7.86 (m, 1H), 7.83 (ddd, J=8.0, 2.0, 1.1 Hz, 1H), 7.45 (t, J=7.9 Hz, 1H), 4.08 (s, 2H).
Reaction SMILES: [C]=O.[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:26]3[C:34]4[C:29](=[CH:30][C:31](Br)=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1.[CH:37]([O-])=[O:38].[Na+]>CN(C)C=O.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>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]([C:26]3[C:34]4[C:29](=[CH:30][C:31]([CH:37]=[O:38])=[CH:32][CH:33]=4)[N:28]([CH3:36])[CH:27]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: O=C[O-]
Reactant: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(Br)ccc23)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [C]=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)NC(=O)C(c2ccc3c(c2)OCO3)c2cn(C)c3cc(C=O)ccc23)cc1
Yield: 82.6 %

Procedure:
Carbon monoxide was bubbled through a stirred solution of 3-{1-(1,3-benzodioxol-5-yl)-2-[(4-methylphenyl)sulfonamido]-2-oxoethyl}-6-bromo-1-methyl-1H-indole (from Example 55, 400 mg, 0.79 mmol), sodium formate (107 mg, 1.57 mmol) and dichlorobis(triphenylphosphine)-palladium (II) (11 mg, 0.016 mmol) in dimethylformamide (6 ml) at 110° C. for 4 h. The reaction mixture was cooled and extracted from 1N hydrochloric acid with ethyl acetate (2×50 ml). The organic layers were dried (MgSO4) and concentrated. Flash column chromatography (elution with 95% dichloromethane/5% methanol) gave the product (320 mg) as a fawn solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]([CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2.[CH:40]1([S:43](Cl)(=[O:45])=[O:44])[CH2:42][CH2:41]1>>[CH:27]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([Cl:26])=[CH:8][CH:7]=2)[C:12]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[C:4]1[CH2:3][CH2:2][NH:1][S:43]([CH:40]1[CH2:42][CH2:41]1)(=[O:45])=[O:44])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COC(=O)c1ccc(OCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)C3CC3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 75 %

Procedure:
To the methyl 4-{2-[2-(2-aminoethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]ethoxy}benzoate (Step 5, Example 1)was added cyclopropanesulfonyl chloride according to the procedure in Example 1 Step 7 to generate the product in 75% yield.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)(C)C.[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34]>ClCCl>[CH2:40]([Sn:35]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:36][CH2:37][CH2:38][CH3:39])[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC(C)[Mg]Br
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Under an argon atmosphere, a solution of 4-iodo-1-trityl-1H-imidazole (1.00 g, 2.29 mmol) in dichloromethane (10 mL) was treated with isopropylmagnesium bromide (2.75 mL of 1 M, 2.75 mmol, in tetrahydrofuran) and stirred at ambient temperature for 1 hour. After this time, the reaction was treated with tributyltin chloride (0.81 mL, 2.98 mmol) and the resulting mixture stirred overnight at ambient temperature. The reaction mixture was then diluted with dichloromethane (50 mL) and successively washed with saturated ammonium chloride (50 mL), water (50 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 1.37 g of crude 4-tributylstannyl-1-trityl-1H-imidazole.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.FC(F)(F)S(O[CH2:23][CH2:24][C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])(=O)=O.Cl>C(COC)OC>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:23][CH2:24][C:25]([F:36])([F:37])[C:26]([F:34])([F:35])[C:27]([F:32])([F:33])[C:28]([F:31])([F:30])[F:29])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: O=S(=O)(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Oc1ccc(-c2ccc(OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
In a Schlenk tube whose content had been replaced with Ar, 9.0 g of 60% sodium hydride and 400 ml of dry dimethoxyethane were placed. While this solution was being cooled with ice water, 29.8 g of 4,4'-dihydroxybiphenyl was added. Thereafter, the reaction solution was allowed to warm up to room temperature, and was stirred for two hours. Thereafter, the reaction solution was cooled to -60° C. After 86 g of 2-(perfluorobutyl)ethyl trifluoromethane sulfonate was added dropwise to the reaction solution, the reaction solution was allowed to warm up to room temperature, and was stirred overnight. Subsequently, the reaction solution was poured into dilute hydrochloric acid, and an organic layer was extracted with benzene. After the benzene layer was washed with water and dried over sodium sulfate anhydrous, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: benzene), and recrystallized from toluene to give 18.8 g of 4-hydroxy-4'-[2-(perfluorobutyl)ethyloxy]biphenyl (Y: 27.1%). The purity of the compound thus obtained was 98.4% by GC.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH:12]([CH3:14])[CH3:13])[N:6]=1)=O.[Li+].[BH4-].O>C1COCC1>[CH:12]([S:11][C:7]1[N:6]=[C:5]([CH2:3][OH:2])[CH:10]=[CH:9][CH:8]=1)([CH3:14])[CH3:13]
Reactant: COC(=O)c1cccc(SC(C)C)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Sc1cccc(CO)n1
Temperature: 40 °C
Reaction time: 1 h
Yield: 71.6 %

Procedure:
6-Isopropylsulfanyl-pyridine-2-carboxylic acid methyl ester (0.13 g, 0.61 mmol) obtained in Step A was dissolved in anhydrous THF (3 mL). 2.0M LiBH4 solution (0.5 mL, 1 mmol) was added thereto, and the mixture was stirred at 40° C. for 1 hour. After the termination of the reaction, the reactant was cooled to room temperature, added with water, and extracted with EtOAc. The organic layer was separated, dried with MgSO4, and concentrated under reduced pressure to obtain the title compound (0.08 g, 70%).
Reaction SMILES: [Cl: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([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[NH:12][CH2:13][CH3:14].Br[CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:26][CH:25]=1>CCCCCC.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:23][C:24]1[CH:36]=[CH:35][C:27]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])=[CH:26][CH:25]=1)[C:6](=[O:11])[C:5]2([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])[NH:12][CH2:13][CH3:14]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Reactant: CCNC1(c2ccccc2Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCNC1(c2ccccc2Cl)C(=O)N(Cc2ccc(C(=O)OC(C)(C)C)cc2)c2ccc(Cl)cc21
Yield: 47.5 %

Procedure:
This compound is prepared according to the procedure described in step A of EXAMPLE 96 from 1.19 g of 5-chloro-3-(2-chlorophenyl)-3-(ethylamino)-1,3-dihydroindol-2-one and 1.1 g of tert-butyl 4-bromomethylbenzoate. Chromatography on silica using a gradient of a hexane/AcOEt mixture (from 95/5; v/v to 90/10; v/v) as the eluent gives 0.9 g of the expected product, which is used as such.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1.C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1.O>[CH2:19]([O:18][C:16]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)[C@H]1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 6 h
Yield: 49.1 %

Procedure:
A solution of (S)-piperidine-3-carboxylic acid (XXXI) (10.0 g, 77.4 mmol) in a mixture of 80 ml of THF and 50 ml of water was cooled to 0° C. and sodium bicarbonate (13.0 g, 15.5 mmol) and benzyl chloroformate (15.8 g, 92.9 mmol) were added simultaneously. The reaction mixture was stirred at 0° C. for 6 hours and concentrated under reduced pressure. The aqueous layer was extracted with ethyl ether to remove excess of benzyl chloroformate, then it was acidified with 1 M HCl solution to pH 6 followed by extraction with ethyl acetate. The organic layer was separated, dried over sodium sulfate and concentrated to provide (S)-piperidine-1,3-dicarboxylic acid 1-benzyl ester (XXXII) (10.0 g, 49%).
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:14])=[CH:11]/[CH:12]=[O:13].O>C1COCC1>[CH3:16][CH:2]([CH2:3][CH2:4][CH2:5]/[C:6](/[CH3:15])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:14])=[CH:11]/[CH:12]=[O:13])[CH3:1]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/C=O
Solvent: O
Solvent: C1CCOC1
Product: C/C(=C\C=O)CC/C=C(\C)CCCC(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 0.53 g of 2 in 150 mL of dry THF in a round-bottom flask equipped with a water-cooled condenser was added a solid mixture of 31.04 g of NiCl2.6H2O and 4.27 g of Al powder (caution: exothermic). The reaction mixture was stirred at room temperature for 6 h. The solid mass was removed by filtration, and the solvent was dried over MgSO4 and removed by rotary evaporation, which afforded 0.50 g of racemic 3, predominantly the (E)-isomer. 1H NMR δ (ppm) 9.8 (t, CHO), 5.2 (t, CH3C(CH3)═CH and CH2C(CH3)═CH), 2.3 (m, CH2C(CH3)═CH), 2.2-2.4 (qd, CH2CHO), 2.0 (m, C═CHCH2CH2C(CH3)═CHCH2), 1.6-1.7 (all s, CH3C(CH3)═CHCH2CH2CCH3), 1.2-1.5 (m, CH2CH(CH3)CH2CO), 0.9 (d, CH2C(CH3)═CH).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)=[C:25]([CH:28]=1)[CH:26]=O.N1CCC[C@H]1C(O)=O>CO>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)=[C:25]([C:26]2[N:14]([C:15]([CH3:16])([CH3:18])[CH3:17])[C:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=4)=[CH:9][C:10]=3[N:19]=2)[CH:28]=1
Reactant: O=Cc1cc(Br)ccc1-n1cncn1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CO
Product: CC(C)(C)n1c(-c2cc(Br)ccc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 60 °C
Yield: 30.9 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (100 mg, 0.39 mmol) in MeOH (5 mL) are added 5-bromo-2-1,2,4-triazol-1-yl-benzaldehyde (refer to example 4 step 1) (147 mg, 0.58 mmol) and L-proline (4 mg, 0.04 mmol) at room temperature. The solution is heated to 60° C. for 24 hours and then cooled down and is concentrated under reduced pressure. The residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (59 mg, 31%) as a white foam. LCMS (ESMS): m/z 489.20 (M+)