Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:31]4[CH:32]=[CH:33][C:34]5[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=5)[CH:30]=4)[C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc5ccccc5c4)c3O2)cc1
Yield: 35.9 %

Procedure:
Treatment of (±)-(7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.32 mmol) with 2-naphthaleneboronic acid (0.86 g, 4.97 mmol), tetrakis(triphenylphosphine)palladium(0) (0.38 g, 0.33 mmol), and potassium phosphate (1.41 g, 6.64 mmol) generally according to the procedure described for Intermediate 50 provided 0.513 g (36%) of (±)-[7-(2-naphthyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.42 (silica, ethyl acetate:hexanes 1:3); Anal. calcd. for C26H22O4S: C, 72.54; H, 5.15. Found: C, 72.04; H, 5.04.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1.[C:19](C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.CI>C(Cl)Cl.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[CH3:19][O:1][CH2:2][C@@H:3]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:9])[C@H:5]([C:15]([O:17][CH3:18])=[O:16])[CH2:4]1
Reactant: COC(=O)[C@@H]1C[C@H](CO)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CI
Product: COC[C@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To a solution of (2S,4S)-1-tert-butyl 2-methyl 4-(hydroxymethyl)pyrrolidine-1,2-dicarboxylate (2.57 g, 9.9 mmol) in CH2Cl2 (50 mL) was added AgOTf (4.07 g, 15.8 mmol) and 2,6-di-tert-butylpyridine (4.4 mL, 19.8 mmol). The reaction mixture was cooled to 0° C. (external temperature, ice bath) and MeI (0.98 mL, 15.8 mmol) was slowly added. The resulting slurry was stirred at 0° C. for 1.5 h and at room temperature for 1.5 h. The slurry was diluted with CH2Cl2 and filtered through celite. The filtrate was concentrated to dryness, dissolved in Et2O, and washed with HCl (1N) and brine. The aqueous layers were backextracted with Et2O and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by silica gel chromatography (10% to 75% to 100% EtOAc/Hexanes) to provide (2S,4S)-1-tert-butyl 2-methyl 4-(methoxymethyl)pyrrolidine-1,2-dicarboxylate (2.11 g, 78%). 1H-NMR: 400 MHz, (CDCl3) δ: (mixture of rotamers, major reported) 4.20 (t, 1H), 3.71 (s, 3H), 3.67 (m, 1H), 3.34 (m, 2H), 3.30 (s, 3H), 3.16 (t, 1H), 2.43 (m, 2H), 1.74 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[C:24]([NH2:25])=[N:23][C:22]([NH2:26])=[C:21]([Cl:27])[N:20]=2)=[O:18])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][I:29]>CC(C)=O>[I-:29].[CH2:1]([CH:8]1[CH2:9][CH2:10][N+:11]([CH2:14][CH2:15][NH:16][C:17]([C:19]2[C:24]([NH2:25])=[N:23][C:22]([NH2:26])=[C:21]([Cl:27])[N:20]=2)=[O:18])([CH3:28])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(N)c(C(=O)NCCN2CCC(Cc3ccccc3)CC2)nc1Cl
Reactant: CI
Solvent: CC(C)=O
Product: C[N+]1(CCNC(=O)c2nc(Cl)c(N)nc2N)CCC(Cc2ccccc2)CC1
Product: [I-]
Temperature: 25 °C

Procedure:
A solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid [2-(4-benzyl-piperidin-1-yl)-ethyl]-amide (39 mg, 0.10 mmol) and methyl iodide (0.031 mL, 0.50 mmol) in acetone (2 mL) is heated at reflux for 3 h. After cooling to RT the solvent is removed in vacuo to afford the title compound as yellow solid. M+ 403. 1H NMR (400 MHz, DMSO-d6) δ 8.30 (1H, t), 7.62 (2H, br), 7.39-7.36 (2H, m), 7.29-7.23 (3H, m), 7.16 (2H, br), 3.73-3.47 (6H, m), 3.35-3.28 (2H, m), 3.14 (3H, s), 2.67 (2H, d), 1.92-1.81 (1H, m), 1.74-1.68 (4H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=O)[C:6]1[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:5]2=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:22])[C:6]1[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:5]2=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccc(Cl)cc2c2c1[nH]c1ccccc12
Product: Clc1ccc2nc(Cl)c3[nH]c4ccccc4c3c2c1

Procedure:
A suspension of 60 g. of 2-chloro-7H-indolo[2,3-c]quinolin-6(5H)-one in 950 ml. of phosphorous oxychloride was heated under nitrogen on a steam bath for 2 hours. The deep yellow granular complex that formed was collected and washed thoroughly with anhydrous ether (85.5 g.). After drying, this complex was suspended in 500 ml. of water to which 300 ml. of concentrated aqueous ammonium hydroxide solution was added, in portions, with stirring. The resulting pale yellow solid was collected and washed with water. After recrystallization from 2 l. of acetonitrile, 37.5 g. (68 percent) of colorless needles of 2,6-dichloro-7H-indolo[2,3-c]quinoline was obtained, which had a melting point of 262°-264°. sample, melting point 265°-266°.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19]C#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.Cl[CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([N:10]([C@H:22]2[CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][CH2:27]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:38][CH2:39][N:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)=[CH:17][N:18]=2)=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)[C@H]2CC[C@H](C)CC2)CC1
Reactant: ClCCN1CCCCC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCCCC3)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)piperidine
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:40].[C:41](Cl)(=O)[O:42]C1C=CC([N+]([O-])=O)=CC=1.[NH2:54][C@@H:55]([CH2:58][CH3:59])[CH2:56][OH:57].C(N(CC)CC)C>ClCCl>[Si:33]([O:32][C:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:41]([NH:54][C@@H:55]([CH2:58][CH3:59])[CH2:56][OH:57])=[O:42])=[C:3]([F:40])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[CH:22][CH:21]=1)([C:24]([F:25])([F:26])[F:27])[C:28]([F:31])([F:29])[F:30])([C:36]([CH3:37])([CH3:39])[CH3:38])([CH3:34])[CH3:35]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)OC(c1ccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CC[C@H](N)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@@H](CO)NC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A solution of (4-amino-3-fluorophenyl)(4-(4-(2-(tert-butyldimethylsilyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl)benzyl)piperazin-1-yl)methanone (0.421 mmol, 250 mg) and 4-nitrophenyl carbonochloridate (0.421 mmol, 85 mg) in dichloromethane (1 ml) was stirred at room temperature for 30 minutes. (S)-2-Aminobutan-1-ol (0.839 mmol, 0.079 mL, 74.8 mg) was added, followed by triethylamine (1.263 mmol, 0.176 mL, 128 mg) and the reaction stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (3 ml) and washed with saturated aqueous sodium hydrogen carbonate solution (5 ml). The organic phase was concentrated and the resulting residue was purified by column chromatography (2-5% methanol in dichloromethane) to afford the title compound (215 mg). MS (ESI) m/z 709.2 [M+H]+
Reaction SMILES: [N+]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])([O-])=O.NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.C(N(CC)CC)C.[F:63]C1C=CC(C(Cl)=O)=CC=1>ClCCl>[F:63][C:32]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][CH:9]([C:11]2[N:16]=[N:15][C:14]([NH:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=3)=[N:13][CH:12]=2)[CH3:10])=[O:7])=[CH:4][CH:33]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc(F)cc3)nn2)cc(OC)c1OC

Procedure:
In a similar manner as described for Intermediate 10, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (0.30 g, 1.0 mmol), triethylamine (0.28 mL, 2.0 mmol) and 4-fluorobenzoyl chloride (0.16 g, 1.0 mmol) in dichloromethane (10 mL) gave 4-fluoro-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (0.32 g) as a white solid. MS m/z 428 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][NH:13][CH3:14].C1COCC1>O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([N:13]([CH3:14])[CH3:12])=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1I
Reactant: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1c(F)cccc1I
Reaction time: 16 h

Procedure:
2-Fluoro-6-iodobenzoylchloride 1.0 mL, 6.9 mmol was added dropwise to a solution of dimethylamine in THF (2.0 M 7.0 mL, 10 mmol). The reaction mixture was stirred for 16 h and then transferred into water. The resulting suspension was collected by filtration and dried to afford the title compound as a pale yellow solid. The product was used in the next reaction step without further purification. mp 86-89° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([OH:3])=[O:2].Cl[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1>>[Cl:20][C:19]1[C:14]([C:7]2[CH:8]=[CH:9][C:4]([C:1]([OH:3])=[O:2])=[CH:5][CH:6]=2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: Clc1cccnc1Cl
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: O=C(O)c1ccc(-c2ncccc2Cl)cc1

Procedure:
The title compound may be prepared from 4-carboxybenzeneboronic acid and 2,3-dichloropyridine using the procedure outlined in Description 29 (D29), for the synthesis of 4-(6-methyl-2-pyridyl)-benzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:14]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][NH:12][CH:11]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[F:27])[C:5]2=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].C1(C)C=CC=CC=1.[C:41](Cl)([Cl:43])=[O:42]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:14]([CH2:15][C:16]([CH3:18])([CH3:19])[CH3:17])[CH2:13][N:12]([C:41]([Cl:43])=[O:42])[CH:11]3[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[F:27])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: O=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)Cl)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-1H-spiro[indole-3,3′-pyrrolidin]-2-one prepared in Example 6 (0.12 g, 0.28 mmol) in dichloromethane (3 mL) was added saturated aqueous NaHCO3 solution (3 mL). The temperature of the mixture was lowered to 0° C., and a toluene solution (Aldrich, 20%) of phosgene (0.27 mL, 0.51 mmol) was added dropwise via a syringe. The reaction mixture was stirred at room temperature for 30 min, then diluted dichloromethane. The organic layer was separated, the aqueous layer was extracted with dichlormethane twice. The combined organic layers were washed with water, brine, dried over MgSO4, and concentrated to give crude rac-(2′S,3′S,4′S)-6-chloro-2′-(3-chloro-2-fluoro-phenyl)-4′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-1′-carbonyl chloride as a light yellow oil, which was used in the next step without further purification (0.14 g, 100%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:51]=[CH:50][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]OS(C5C=CC(C)=CC=5)(=O)=O)=[CH:28][CH:27]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:52]([O-:55])(=[S:54])[CH3:53].[K+].O>O1CCCC1.C(O)C>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:26]4[CH:27]=[CH:28][C:29]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:55][C:52](=[S:54])[CH3:53])=[CH:50][CH:51]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:14][CH:13]=4)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCCCCCOc2ccc(-n3c4ccc(-c5ccccc5)cc4c4cc(-c5ccccc5)ccc43)cc2)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(=S)OCCCCCCCCOc1ccc(-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)ccc32)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
The obtained toluene-4-sulfonic acid 8-[4-(3,6-diphenylcarbazol-9-yl)phenoxy]octyl ester (1.90 g, 2.7 mmol) was dissolved in a solvent mixture of tetrahydrofuran (THF) (40 mL) and ethanol (20 mL). Under nitrogen flow, potassium thioacetate (0.55 g, 4.8 mmol) was added to the resultant solution, and the mixture was refluxed for 7 hours and left to cool to room temperature. Next, the mixture was poured to water, followed by extraction with ethyl acetate. In addition, the mixture was washed with water and dried and the solvent was evaporated, to thereby obtain a crude product. The crude product was purified through silica gel column chromatography using toluene an eluent, to thereby obtain 1.32 g of thioacetic acid 8-[4-(3,6-diphenylcarbazol-9-yl)phenoxy]octyl ester as pale orange oily matter.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23]N[CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2].[CH2:25]=O.[BH3-][C:28]#[N:29].[Na+]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][N:29]([CH2:28][CH3:25])[CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CCOc1ccccc1-c1cc(NC(=O)C2CCNCC2)ncn1
Reactant: C=O
Agent: [Na+]
Product: CCOc1ccccc1-c1cc(NC(=O)C2CCN(CC)CC2)ncn1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a stirred mixture of piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #1A) (0.28 g, 0.86 mmol) and 33% formalin solution (0.045 ml) in 10 ml of AcN:MeOH:H2O (2:1:1) at 0° C. was added NaCNBH3 (0.13 g, 2.1 mmol). The reaction mixture was stirred at room temperature for 30 minand extracted with ethyl acetate (3×20 ml). The organic layers were separated, combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (C-18, AcN:H2O with 0.05% TFA) to afford 1-ethyl-piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #2A) (0.195 g, 66%) as a white solid.
Reaction SMILES: [CH2:1]([CH:5]1[CH2:11][C:10](=[O:12])[O:9][C:7](=[O:8])[CH2:6]1)[CH:2]([CH3:4])[CH3:3].[CH:13]1([SH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([S:19][C:10]([CH2:11][C@H:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[CH2:6][C:7]([OH:9])=[O:8])=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(C)CC1CC(=O)OC(=O)C1
Reactant: SC1CCCCC1
Product: CC(C)C[C@H](CC(=O)O)CC(=O)SC1CCCCC1

Procedure:
A schematic of the catalytic enantioselective thiolysis of 3-isobutylglutaric anhydride using cyclohexane thiol to afford (R)-3-cyclohexylsulfanylcarbonylmethyl-5-methyl-hexanoic acid is provided in FIG. 1. Thiolysis of 3-isobutylglutaric anhydride in methyltertbutylether (MTBE), at room temperature (rt) in the presence of catalytic quantities of C1 affords 3-cyclohexylsulfanylcarbonylmethyl-5-methyl-hexanoic acid in quantitative yield with the (R) enantiomer obtained in 93% ee.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.C([O-])([O-])=O.[Ca+2].[I:18]I>CO.C(Cl)Cl>[NH2:1][C:2]1[C:11]([I:18])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[CH:3]=1.[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([Cl:12])[C:3]=1[I:18]
Reactant: COC(=O)c1ccc(N)cc1Cl
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(I)c(N)cc1Cl
Product: COC(=O)c1ccc(N)c(I)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of compound 70m (1.18 g, 6.38 mmol) and CaCO3 (12.8 mmol, 1.28 g) in MeOH (13 mL) was added a solution of iodine monchloride (6.70 mmol, 1.09 g) in CH2Cl2 (6 mL) dropwise at room temperature. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction mixture was concentrated and then partitioned between EtOAc and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 20-25% EtOAc/hexanes) to provide methyl 4-amino-2-chloro-5-iodo-benzoate 70n as major the product and methyl 4-amino-2-chloro-3-iodo-benzoate 70o as the minor product.
Reaction SMILES: [C:1]1([C:11]2[CH:12]=[C:13](Br)[CH:14]=[C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Mg].Br[CH2:30][CH2:31]Br.I[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43](I)=[CH:42][CH:41]=2)=[CH:36][CH:35]=1>C1COCC1>[C:1]1([C:11]2[CH:12]=[C:13]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4[CH:45]=[C:44]([C:4]5[C:5]6[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=6)[CH:1]=[CH:2][CH:3]=5)[C:43]([C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)=[C:42]([C:20]5[C:30]6[C:31](=[CH:19][CH:18]=[CH:17][CH:26]=6)[CH:23]=[CH:22][CH:21]=5)[CH:41]=4)=[CH:36][CH:35]=3)[CH:14]=[C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: BrCCBr
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: Brc1cc(-c2cccc3ccccc23)cc(-c2cccc3ccccc23)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: c1ccc(-c2c(-c3cccc4ccccc34)cc(-c3ccc(-c4cc(-c5cccc6ccccc56)cc(-c5cccc6ccccc56)c4)cc3)cc2-c2cccc3ccccc23)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A solution of 3,5-di-α-naphthyl bromobenzene (10.0 g, 0.0244 mol) in anhydrous THF (70 mL ) was added dropwise to magnesium turnings (0.59 g, 0.0244 mol) in 10 mL THF. The solution was heated at 60° C. during the addition and the reaction was initiated using 1,2-dibromoethane. After the addition was complete, the brown solution was heated at reflux for 2 hrs. and then cooled to room temperature. In a separate flask, 4,4′-diiodobiphenyl (3.3 g 0.008 mol) and 0.3 g of dichlorobis(triphenyl phosphine) palladium(II) were placed under nitrogen and 30 mL of anhydrous THF was added. The Grignard reagent prepared about THF solution was then added using needle-transfer and an orange solution resulted. Heat was applied and the solution turned to almost black. The mixture was then heated at reflux for 45 min. and cooled to room temperature during which time a solid precipitated out of solution. A 2.0 M solution of HCl was added to the mixture and after stirring for 30 minutes, the water layer was removed. The solid precipitate was collected by filtration and washed with water and diethyl ether to yield a white solid (5.3 g, 81%)
Reaction SMILES: O=C[C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12](O)(=O)[CH2:13]C(O)=O.N1CCCCC1>C(O)(=O)C>[CH:12]([C:11]1[CH:10]=[C:8]([OH:9])[C:5]([O:6][CH3:7])=[CH:4][CH:3]=1)=[CH2:13]
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(C=O)ccc1O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: C=Cc1ccc(OC)c(O)c1
Yield: 51 %

Procedure:
A mixture of vanillin (2.50 g, 0.0164 mol), malonic acid (3.41 g, 0.0328 mol), piperidine (3–5 ml) and acetic acid (10–20 mL) were taken in a 100 ml Erlenmeyer flask fitted with a loose funnel at the top. The flask was shaken well and placed inside the microwave oven and irradiated for 1–7 minutes in parts. The cooled mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with dil HCl., saturated sodium chloride and then organic layer dried over sodium sulphate. The solvent was evaporated under reduced pressure to obtain liquid which was purified on silica gel column chromatography using mixture of hexane and ethyl acetate (9:1 to 6:4), provided sweet and pleasant smelling liquid in 51% yield; 1H NMR (CDCl3) δ 6.96 (3H, m, 3,5,6-Ar), 6.70 (1H, dd, J=7.8 Hz, CH═CH2), 5.93 (1H, s, OH), 5.66 (1H, d, J=17.6, cis-CH═CH2), 5.19 (1H, d, J=10.9 Hz, trans-CH═CH2), 3.90 (3H, s, OMe); 13C NMR (CDCl3) δ 147.1 (C-1), 146.07 (C-2), 137.1 (CH═CH2), 130.7 (C-4), 120.4 (C-6), 114.9 (C-5), 111.8 (CH═CH2), 108.5 (C-3), 56.2 (OCH3).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:18])[CH:8]=2)[N:3]=1.O.[NH2:20][NH2:21]>>[Br:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:20][NH2:21])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: Clc1cc(-c2ccccc2)c2cc(Br)ccc2n1
Solvent: O
Product: NNc1cc(-c2ccccc2)c2cc(Br)ccc2n1

Procedure:
In the manner given in Example 1, 2-chloro-6-bromo-4-phenylquinoline is reacted with hydrazine hydrate at reflux to give 6-bromo-4-phenyl-2-hydrazinoquinoline.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[N:6]=[C:7]([CH3:11])[S:8][C:9]=1[CH3:10].O.[NH2:14][NH2:15]>C(O)CCC>[CH3:11][C:7]1[S:8][C:9]([CH3:10])=[C:5]([CH2:4][C:3]([NH:14][NH2:15])=[O:2])[N:6]=1
Reactant: COC(=O)Cc1nc(C)sc1C
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: Cc1nc(CC(=O)NN)c(C)s1
Yield: 68 %

Procedure:
As described for example 112a, (2,5-dimethyl-thiazol-4-yl)-acetic acid methyl ester in butanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture was then heated under reflux for 20 h. Evaporation of all volatiles and crystallization from n-butanol and toluene afforded the title compound as a white solid (yield: 68%). 1H-NMR (300 MHz, DMSO): δ=2.31 (s, 3H), 2.51 (s, 3H), 3.37 (s, 2H), 4.20 (s, 2H), 9.10 (s, 1H).