Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]2[S:10][CH:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1.C1O[C:23]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)([CH2:24][CH2:25][CH2:26]Cl)[O:22]C1>CN(C=O)C.CO>[ClH:3].[Cl:3][C:4]1[C:9]2[S:10][CH:11]=[C:12]([N:13]([CH2:26][CH2:25][CH2:24][C:23](=[O:22])[C:28]3[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=3)[C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1cccc2c(Nc3ccncc3)csc12
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cl
Product: O=C(CCCN(c1ccncc1)c1csc2c(Cl)cccc12)c1ccc(F)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
To a mixture of sodium hydride (645 mg, 16.13 mmole) in DMF (10 mL) was added dropwise a solution of 7-chloro-3-(4-pyridinyl)aminobenzo[b]thiophene (3.5 g, 13.44 mmole) in DMF (35 mL) and then 4'-fluoro-4-chlorobutyrophenone ethylene ketal (3.95 g, 16.13 mmole) was added. This mixture was heated with stirring at 70° C. for three hours, poured into ice and extracted with ethyl acetate. The organics were washed twice with water, dried (MgSO4), and then concentrated. The residue was flash chromatographed (silica gel; EtOAc, then 5% MeOH/EtOAc) to obtain a dark oil, which was dissolved in methanol and treated with "Norite" to obtain 2.88 g of a white froth after concentration. Concentrated HCl (30 mL) was added and the mixture was heated on a steam bath for 45 minutes. The reaction mixture was cooled, made basic with 10% sodium hydroxide and extracted with diethyl ether. The organics were washed with water and brine, dried (MgSO4), and concentrated to obtain a froth. The froth was dissolved in methanol and ethereal hydrogen chloride, concentrated, and the frothy oil was triturated with diethyl ether. The organics were decanted and the resulting solid was recrystallized from methanol and diethyl ether to obtain 2.09 g of a white solid, mp 229° C. (dec.), after drying under high vacuum, P2O5, and refluxing xylenes.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]=2[CH3:19])[O:3]1.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:21][CH2:19][C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[B:4]1[O:3][C:2]([CH3:20])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]1
Reactant: Cc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Temperature: 75 °C
Reaction time: 14 h
Yield: 101.8 %

Procedure:
A mixture of 47.3 g (176 mmol) of 4,4,5,5-tetramethyl-2-(2-methyl-1-naphthyl)-1,3,2-dioxaborolane, 33.0 g (185 mmol) of NBS (N-Bromosuccinimide) and 0.17 g of benzoyl peroxide in 340 ml of CCl4 was stirred at 75° C. for 14 h. Thereafter the reaction mixture was cooled to room temperature, filtered through glass frit (G3), and the filtrate was evaporated to dryness. This procedure gave 62.2 g (99%) of beige solid. Anal. calc. for C17H20BBrO2: C, 58.83; H, 5.81. Found: C, 59.00; H, 5.95. 1H NMR (CDCl3): 8.30 (m, 1H, 8-H), 7.84 (d, J=8.3 Hz, 1H, 4-H), 7.79 (m, 1H, 5-H), 7.43-7.52 (m, 3H, 3,6,7-H), 4.96 (s, 2H, CH2Br), 1.51 (s, 12H, CMe2CMe2).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)[CH:2]1O[CH2:3]1.[NH2:13][CH2:14][CH2:15][NH:16][C:17]1[N:18]([CH3:27])[C:19](=[O:26])[N:20]([CH3:25])[C:21](=[O:24])[C:22]=1[CH3:23].CN(C)C=O.[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([OH:38])=[O:37]>C(O)C.C(OCC)(=O)C>[C:33]([OH:40])(=[O:39])/[CH:34]=[CH:35]/[C:36]([O:38][CH:2]([CH2:3][NH:13][CH2:14][CH2:15][NH:16][C:17]1[N:18]([CH3:27])[C:19](=[O:26])[N:20]([CH3:25])[C:21](=[O:24])[C:22]=1[CH3:23])[CH2:1][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:37]
Reactant: Fc1ccc(OCC2CO2)cc1
Reactant: Cc1c(NCCN)n(C)c(=O)n(C)c1=O
Reactant: O=C(O)/C=C/C(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(NCCNCC(COc2ccc(F)cc2)OC(=O)/C=C/C(=O)O)n(C)c(=O)n(C)c1=O
Reaction time: 48 h

Procedure:
3.36 g. 4-Fluorophenyl glycidyl ether and 8.5 g. 4-(2-aminoethylamino)-1,3,5-trimethylpyrimidine-2,6-(1H,3H)-dione are dissolved in 10 ml. dimethylformamide and left to stand for 2 days at ambient temperature. The reaction mixture is then poured into 100 ml. water, extracted with methylene chloride, dried and evaporated. The viscous oil obtained is separated by column chromatography using silica gel and, as elution agent, methylene chloride-ammonia-saturated methanol (20:1 v/v). The product obtained by evaporation of the pure fractions is dissolved in 20 ml. ethyl acetate, whereafter 1.8 g. fumaric acid, dissolved in ethanol, is added thereto. After filtering off with suction, the crystalline product obtained is recrystallized from ethanol, with the addition of 0.9 g. fumaric acid and with the use of active charcoal. There are obtained 5.2 g. (52% of theory) of the desired product in the form of colorless crystals; m.p. 163°-167° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([CH3:22])[CH:13]=2)[N:3]=1.[Cl:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26][N:25]=1>>[Cl:23][C:24]1[CH:29]=[C:28]([C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[C:14]([CH3:22])[CH:13]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH:27]=[CH:26][N:25]=1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Reactant: OB(O)c1ccnc(Cl)c1
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidine (example A.38) (0.68 g, 2.0 mmol) and commercially available 2-chloro-pyridine-4-boronic acid (0.35 g, 2.2 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.33 g, 39%). MS (ISP) 418.3 [(M+H)+]; mp 105.5° C.
Reaction SMILES: [OH2:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:13])[CH2:12][NH:11][CH2:10]2)=[C:5]([F:14])[CH:4]=1.[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O.C(=O)(O)[O-].[Na+]>[C:23]([N:11]1[CH2:10][C:9]([C:6]2[CH:7]=[CH:8][C:3]([NH:2][C:23]([O:22][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:1])=[CH:4][C:5]=2[F:14])([CH3:13])[CH2:12]1)([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: O
Reactant: CC1(c2ccc(N)cc2F)CNC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(c2ccc(NC(=O)OCc3ccccc3)cc2F)CN(C(=O)OCc2ccccc2)C1
Temperature: 0 °C
Reaction time: 65 h

Procedure:
A 500 mL round bottom flask equipped with a magnetic spinbar and addition funnel was charged with 85 mL water, 38.4 g sodium bicarbonate (0.46 mol) and a solution of 9.82 g 3-(4-amino-2-fluorophenyl)-3-methylazetidine (0.051 mol theory) in 165 mL acetone. The resulting orange suspension was cooled to 0° C. and treated with 43 mL benzylchloroformate (0.30 mol) with gas evolution and the reaction turning a light yellow color. The cooling bath was removed and the reaction mixture was stirred at room temperature for 65 hours. TLC indicates incomplete consumption of the starting aminoaniline and an additional 12.8 g sodium bicarbonate (0.15 mol) and 14 mL benzylchloroformate (0.10 mol) was added with additional gas evolution. After two hours, the reaction mixture was diluted with 350 mL saturated sodium bicarbonate and extracted three times with ethyl acetate (300 mL). The combined organics were washed once with water (200 mL), once with brine (200 mL), dried over MgSO4, filtered, and concentrated to give 29.86 g of a light yellow oil. This crude material was purified by LC on 850 g (230-400) silica gel eluting with 25% ethyl acetate/hexanes to afford 11.67 g (51%) of the title compound as a light yellow solid. Rf 0.18 (25% ethyl acetate/hexanes); IR (neat) 1735, 1707, 1693, 1600, 1534, 1455, 1424, 1414, 1221, 1081 cm−1; 1H NMR (300 MHz, CDCl3) δ7.35 (m, 11H, aromatic), 6.96 (m, 3H, aromatic & NH), 5.19 (s, 2H, Ph—CH2), 5.09 (s, 2H, Ph—CH2), 4.30 (d, 2H, J=8.2 Hz, N—CH2as), 4.00 (d, 2H, J=8.4 Hz, N—CH2bs), 1.59 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3) 160.4 (d, JCF=245 Hz), 156.6, 153.0, 138.1 (d, JCF=11 Hz), 136.5, 135.7, 128.6, 128.4, 128.2, 127.9, 127.8, 127.5, 127.0, 126.9, 113.9, 106.6 (d, JCF=27 Hz), 67.1, 66.6, 60.8, 60.2, 36.1, 28.2; Anal. Calcd for C26H25N2O4F1: C, 69.63; H, 5.62; N, 6.25. Found: C, 69.37; H, 5.69; N, 5.87
Reaction SMILES: [CH3:1][N+:2]([O-:4])=[O:3].[CH3:5][O:6][C:7](=[O:28])[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](C=O)[C:13]=1[B:20]1[O:25][CH2:24]C(C)(C)C[O:21]1.[OH-].[Na+].Cl.[CH3:32]C#N>O>[CH2:5]([O:6][C:7](=[O:28])[CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]2[B:20]([OH:21])[O:25][CH:24]([CH2:1][N+:2]([O-:4])=[O:3])[C:14]=2[CH:15]=[CH:16][CH:17]=1)[CH3:32]
Reactant: COC(=O)CCCOc1cccc(C=O)c1B1OCC(C)(C)CO1
Reactant: CC#N
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)CCCOc1cccc2c1B(O)OC2C[N+](=O)[O-]
Temperature: 25 °C

Procedure:
MeNO2 (1.3 mL, 25 mmol) was added dropwise to a stirred solution of crude 4-[2-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-3-formyl-phenoxy]-butyric acid methyl ester (9.4 g), NaOH (1.0 g, 25 mmol) and H2O (35 mL) in MeCN (90 mL) at rt. The mixture was stirred at rt O/N and then acidified (pH 2) using 4 M HCl. The THF was removed in vacuo and the aqueous layer was extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by flash chromatography (10% to 30% EtOAc in hexane) to give the title compound as a yellow oil: yield 2.52 g (45% over 2 steps).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7](O)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[SH:19][C:20]1C=C[C:23]([B:26]([OH:28])[OH:27])=[CH:22][CH:21]=1>CC(O)=O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]([C:21]2[CH:22]=[C:23]([B:26]([OH:28])[OH:27])[S:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(S)cc1
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Solvent: CC(=O)O
Product: COc1ccc(C(c2ccc(OC)cc2)c2csc(B(O)O)c2)cc1
Temperature: 60 °C

Procedure:
4,4′-Dimethoxybenzhydrol (2.7 g, 11 mmol) and 4-mercaptophenylboronic acid (1.54 g, 10 mmol) were dissolved in AcOH (20 mL) and heated at 60° C. for 1 h. Solvent was evaporated and the residue was dried under high vacuum. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14](I)[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:37][OH:38].CN(C)[CH:41]=[O:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:29])[C:10]2[CH:15]=[C:14]([C:37]([O:42][CH3:41])=[O:38])[CH:13]=[CH:12][C:11]=2[NH:17][C:18]([CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[O:19])=[N:6][CH:7]=1
Reactant: CC(C)N1CCC(C(=O)Nc2ccc(I)cc2C(=O)Nc2ccc(Cl)cn2)CC1
Reactant: CN(C)C=O
Reactant: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)C2CCN(C(C)C)CC2)c(C(=O)Nc2ccc(Cl)cn2)c1
Temperature: 60 °C
Yield: 38 %

Procedure:
To a stirring solution of N-(5-chloropyridin-2-yl)-5-iodo-2-[(1-isopropylpiperidin-4-ylcarbonyl)amino]benzamide (0.49 g, 0.92 mmol) in N,N-dimethylformamide (10 mL) was added triethylamine (0.4 mL, 2.8 mmol), followed by PdCl2 (PPh3)2, and then methanol 15 mL). The mixture was placed under a carbon monoxide atmosphere, heated to 60° C. for 18 h, and concentrated in vacuo. The crude product was purified by chromatography over silica gel, eluting with a step gradient of 10-20% 2 M solution of ammonia/methanol in dichloromethane. The chromatography product was recrystallized from methanol to give 0.16 g (38%) of a white solid.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[C:12]1([C:18]2[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:21]([CH3:29])[O:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CI.[NH4+].[Cl-]>C1COCC1>[C:12]1([C:18]2[C:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[C:21]([CH2:29][CH3:1])[O:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [Li]CCCC
Reactant: Cc1onc(-c2ccccc2)c1-c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1onc(-c2ccccc2)c1-c1ccccc1
Temperature: -78 °C
Yield: 75 %

Procedure:
n-Butyllithium in hexane (2.19M, 0.213 mL, 0.4675 mmol) is added to 3,4-diphenyl-5-methylisoxazole (P10, 0.100 g, 0.425 mmol) in THF (5 mL) kept stirring at −78° C. in a nitrogen atmosphere. The reaction mixture obtained is kept stirring for 1 hour at −78° C. before adding CH3I (4.25 mmol). The reaction mixture is brought to ambient temperature and then blocked by adding an aqueous solution of NH4Cl. The two phases are separated and the aqueous phase is extracted three times with ethyl acetate. The combined organic extracts are dried over Na2SO4 and the solvent is then evaporated in a vacuum. The residue is subjected to column chromatography (silica gel, petroleum ether:ethyl acetate=10/1) and 3,4-diphenyl-5-ethylisoxazole is obtained with a yield of 75%. M.p. 85-87° C. (hexane), white crystals. FT-IR (KBr): 3029, 3005, 2923, 2848, 1625, 1596, 1493, 1467, 1437, 1410, 1327, 1282, 1210, 1011, 905, 771, 702 cm−1. 1H NMR (200 MHz, CDCl3, δ): 1.29 (t, 3H), 2.78 (q, 2H); 7.12-7.43 (m, 10H). 13C NMR (75 MHz, CDCl3, δ): 12.5, 19.7, 115.2, 127.9, 128.7, 128.9, 129.4, 129.5, 130.2, 130.7, 161.3, 171.4. GC-MS (70 eV) m/z (rel.int.): 249 [M+, 100], 234 (6), 221 (18), 220 (99), 194 (9), 193 (61), 192 (46), 165 (17), 115 (7), 103 (8), 89 (53), 77 (15), 63 (10), 51 (10).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([CH2:22][O:23][CH2:24][C:25]([OH:27])=O)=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([CH:35]([NH:55][C:56]([CH:58]2[CH2:63][CH2:62][C:61]([F:65])([F:64])[CH2:60][CH2:59]2)=[O:57])[CH2:36][CH2:37][N:38]2[CH:43]3[CH2:44][CH2:45][CH:39]2[CH2:40][CH:41]([N:46]2[C:50]([CH3:51])=[N:49][N:48]=[C:47]2[CH:52]([CH3:54])[CH3:53])[CH2:42]3)=[CH:31][CH:30]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:21])[CH2:22][O:23][CH2:24][C:25](=[O:27])[NH:28][C:29]1[CH:30]=[CH:31][C:32]([CH:35]([NH:55][C:56]([CH:58]2[CH2:63][CH2:62][C:61]([F:64])([F:65])[CH2:60][CH2:59]2)=[O:57])[CH2:36][CH2:37][N:38]2[CH:43]3[CH2:44][CH2:45][CH:39]2[CH2:40][CH:41]([N:46]2[C:50]([CH3:51])=[N:49][N:48]=[C:47]2[CH:52]([CH3:54])[CH3:53])[CH2:42]3)=[CH:33][CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)COCC(=O)NCCCCCCCNC(=O)OCc1ccccc1
Reactant: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)c1ccc(N)cc1
Solvent: CN(C)C=O
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)c1ccc(NC(=O)COCC(=O)NCCCCCCCNC(=O)OCc2ccccc2)cc1
Yield: 72 %

Procedure:
The title compound was prepared according to the general amide coupling procedure by reacting acid 22 with amine 6 in DMF overnight. The crude product was purified with chromatography using CH2Cl2/MeOH (13/1) as eluent to give 260 mg white foaming, in 72% yield. 1H NMR (400 MHz, CDCl3): δ8.96 (s, 1H), 7.57 (d, J=8.48 Hz, 2H), 7.35-7.27 (m, 5H), 7.24 (d, J=8.48 Hz, 2H), 6.75 (m, 1H), 6.70 (m, 1H), 5.12-5.08 (m, 3H), 4.91 (m, 1H), 4.29 (m, 1H), 4.14 (s, 2H), 4.09 (s, 2H), 3.40 (m, 1H), 3.37 (m, 1H), 3.30 (q, J=6.68 Hz, 2H), 3.15 (q, J=6.71 Hz, 2H), 2.99 (m, 1H), 2.48 (s, 3H), 2.43 (t, J=6.48 Hz, 2H), 2.30-2.04 (m, 6H), 2.01-1.71 (m, 8H), 1.70-1.46 (m, 9H), 1.376 (d, J=6.80 Hz, 3H), 1.373 (d, J=6.84 Hz, 3H), 1.35-1.31 (m, 6H); 13C NMR (100 MHz, CDCl3): δ 173.50, 168.64, 167.15, 159.17, 156.55, 150.59, 138.31, 136.66, 136.51, 128.54, 128.12, 128.00, 127.12, 120.51, 77.24, 71.66, 71.50, 66.60, 58.90, 58.30, 51.68, 47.77, 47.24, 42.83, 40.98, 39.14, 35.33, 34.59, 32.82 (J 13C-19F 25.7 Hz), 29.82, 29.36, 28.71, 26.75 (J 13C-19F 10 Hz), 26.48, 25.87, 21.65, 13.15. mp 65-67° C. IR v (Diamond, cm−1): 3273, 1656, 1529, 1515, 1251, 1106, 697. MS (ESI) m/z found 891.9 (M+H)+.
Reaction SMILES: C(C1N=NC([Cl:14])=CC=1)C1C=CC=CC=1.C(C1N=NC=CC=1)C1C=CC=CC=1.[CH3:28][C:29]1[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:30]=1[CH2:31][C:32]1[N:33]=[N:34][CH:35]=[CH:36][CH:37]=1.[CH3:43][C:44]1[CH:56]=[C:55]([CH3:57])[CH:54]=[C:53]([CH3:58])[C:45]=1[CH2:46][C:47]1[N:48]=[N:49][CH:50]=[CH:51][CH:52]=1>>[Cl:14][C:35]1[N:34]=[N:33][C:32]([CH2:31][C:30]2[C:38]([CH3:42])=[CH:39][CH:40]=[CH:41][C:29]=2[CH3:28])=[CH:37][CH:36]=1.[Cl:14][C:50]1[N:49]=[N:48][C:47]([CH2:46][C:45]2[C:53]([CH3:58])=[CH:54][C:55]([CH3:57])=[CH:56][C:44]=2[CH3:43])=[CH:52][CH:51]=1
Reactant: Cc1cccc(C)c1Cc1cccnn1
Reactant: Cc1cc(C)c(Cc2cccnn2)c(C)c1
Reactant: Clc1ccc(Cc2ccccc2)nn1
Agent: c1ccc(Cc2cccnn2)cc1
Product: Cc1cc(C)c(Cc2ccc(Cl)nn2)c(C)c1
Product: Cc1cccc(C)c1Cc1ccc(Cl)nn1

Procedure:
By proceeding in a similar manner but replacing the 3-chloro-6-(2-methylbenzyl)pyridazine by 6-benzyl-3-chloropyridazine (prepared as described in Netherlands Pat. No. 66-09504), 3-chloro-6-(2,6-dimethylbenzyl)pyridazine and 3-chloro-6-(2,4,6-trimethylbenzyl)pyridazine, there were prepared, respectively, 3-benzylpyridazine, m.p. 62°-64° C., 3-(2,6-dimethylbenzyl)pyridazine, m.p. 102°-103° C., and 3-(2,4,6-trimethylbenzyl)pyridazine, m.p. 110°-110.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([C:10]1([NH:13][C:14]([C@@H:16]2[CH2:20][C@@H:19]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH2:18][NH:17]2)=[O:15])[CH2:12][CH2:11]1)#[N:9].[C:30](O)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:8]([C:10]1([NH:13][C:14]([C@@H:16]2[CH2:20][C@@H:19]([S:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)(=[O:23])=[O:22])[CH2:18][N:17]2[C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:15])[CH2:12][CH2:11]1)#[N:9]
Reactant: O=C(O)c1ccccc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3)CN2)CC1
Solvent: O=C(O)C(F)(F)F
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3)CN2C(=O)c2ccccc2)CC1

Procedure:
L22. (2S,4R)-4-benzenesulfonyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide trifluoro-acetate from experiment K3 was coupled with benzoic acid in analogy to experiment A1 to give (2S,4R)-4-benzenesulfonyl-1-benzoyl-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide as a pale yellow solid. MS: 424.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Cl)=[CH:12][CH:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=2)[CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: Fc1ccc(CCl)cc1
Product: Oc1ccc(F)cc1Cc1ccc(F)cc1

Procedure:
Alkylation of 4-fluorophenol with 4-fluorobenzyl chloride according to the procedure described in J. Chem. Soc, 2431 (1958) gave 4-fluoro-2-(4'-fluorobenzyl)phenol. This material was converted to compound 77, mp 228-230° C., and compound 78, mp 134.5-139° C., by the procedure similar to that in Example 18 method B.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH3:10])=[O:8].[H-].[Na+].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.O.C(OCC)(=O)C>[CH2:13]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH3:10])=[O:8])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of methyl (2S)-5-pyrrolidone-2-carboxylate (80 g) in tetrahydrofuran (900 ml) was added sodium hydride (60% in oil, 23.5 g) by portions. After the addition, the reaction mixture was heated to 60° C., and benzyl bromide (69.8 ml) was added dropwise thereto. After 3 hours, the reaction mixture was cooled to room temperature and water (100 ml) was added dropwise thereto. The reaction mixture was poured into a mixture of ethyl acetate (2 l) and water (800 ml). The organic layer was separated, washed with brine, and dried over magnesium sulfate. Evaporation of the solvent gave an oil, which was chromatographed on silica gel (2 l) eluting with a mixture of hexane and ethyl acetate (1:1→1:2, V/V) to give methyl (2S)-1-benzyl-5-pyrrolidone-2-carboxylate (100.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH2:8][NH:9][C:10](=[O:12])[O-:11].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:7]([O:12][C:10]([NH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:15]=[CH:14][CH:13]=1)[O:4][C:3]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:2]=1[NH:1][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:11])([CH3:13])([CH3:8])[CH3:6]
Reactant: Nc1ccc(Cl)cc1Oc1cccc(CNC(=O)[O-])c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 131.8 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzylcarbamate (5.2 g, 15 mmols), ethyl bromoacetate (3.3 ml, 30 mmols), potassium carbonate (2.1 g, 15 mmols) and N,N-dimethylformamide (30 ml) was stirred at 60° C. for 12 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 2-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminoacetate (4.3 g, 66%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][CH:21]1[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:48][C:49]1[C:57](O)=[CH:56][CH:55]=[C:54]2[C:50]=1[CH:51]=[N:52][NH:53]2.Cl.O1CCOCC1>O1CCCC1.CO>[ClH:48].[NH:24]1[CH2:23][CH2:22][CH:21]([O:20][C:57]2[C:49]([Cl:48])=[C:50]3[C:54](=[CH:55][CH:56]=2)[NH:53][N:52]=[CH:51]3)[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Oc1ccc2[nH]ncc2c1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: Clc1c(OC2CCNCC2)ccc2[nH]ncc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 171.3 %

Procedure:
Under a nitrogen atmosphere, triphenylphosphine (280 mg, 1.07 mmol), tert-butyl 4-hydroxypiperidine-1-carboxylate (179 mg, 0.890 mmol) and diisopropyl azodicarboxylate (193 μl, 0.979 mmol) were added at 0° C. to a solution of the 4-chloro-1H-indazol-5-ol (150 mg, 0.890 mmol) obtained in Example 468 in tetrahydrofuran (6 ml). After 30 minutes, the mixture thus obtained was heated to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the resulting residue was diluted with chloroform and then washed with a 1M-aqueous sodium hydroxide solution. After the aqueous layer was re-extracted with chloroform, the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). The oil thus obtained was dissolved in methanol (3 ml) at room temperature and 4N-hydrochloric acid-dioxane (3 ml) was added thereto. After 1 hour, the mixture thus obtained was concentrated under reduced pressure and the resulting residue was washed with ethyl acetate by repulping to obtain 5-(piperidin-4-yloxy)-4-chloro-1H-indazole hydrochloride (219.7 mg, 86%).