Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[C:10]([C:11]2[NH:15][CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4].C1OCCOCCOCCOCCOC1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([S:50](Cl)(=[O:52])=[O:51])[CH:47]=[CH:48][CH:49]=1>O1CCCC1.O>[C:3]([C:5]1[C:10]([C:11]2[N:15]([S:50]([C:46]3[CH:47]=[CH:48][CH:49]=[C:44]([O:43][CH3:42])[CH:45]=3)(=[O:52])=[O:51])[CH:14]=[C:13]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[C:12]=2[F:26])=[CH:9][CH:8]=[CH:7][N:6]=1)#[N:4]
Reactant: CN(Cc1c[nH]c(-c2cccnc2C#N)c1F)C(=O)OC(C)(C)C
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2C#N)c1
Reaction time: 0.25 h
Yield: 95.4 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution (5 mL) of tert-butyl {[5-(2-cyanopyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (330 mg) in tetrahydrofuran, 15-crown-5 (330 mg) and 3-methoxybenzenesulfonyl chloride (310 mg) under ice-cooling and the mixture was stirred for 15 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 477 mg, 95%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:27]1(C)C=CC=C[CH:28]=1>C(O)C>[CH2:27]([O:14][C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:28]
Reactant: O=C(N[C@@H](CC1CCCCC1)C(=O)O)OCc1ccccc1
Reactant: Cc1ccccc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H](CC1CCCCC1)NC(=O)OCc1ccccc1
Reaction time: 18 h

Procedure:
243 g of 2(S)-benzyloxycarbonylamino-3-cyclohexylpropionic acid (manufacture: Helvetica Chimica Acta 57. 2131(1974)) are placed in 600 ml of toluene and 900 ml of ethanol. The reaction mixture is cooled to 0° and 88.3 g of thionyl chloride are added dropwise within 30 minutes. The cooling is removed and the mixture is stirred for 18 hours. The reaction mixture is filtered and the filtrate is concentrated. The residue is separated by means of flash chromatography (2 kg of silica gel 60, 40-63 μm, eluant F). The product-containing fractions are combined, concentrated by evaporation and dried under a high vacuum. The title compound is obtained in the form of a slightly yellowish oil. Rf (F)=0.2; Rf (B)=0.52.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20](O)=[O:21])=[CH:17][CH:18]=3)[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2].Cl.[CH3:27][NH:28][CH3:29].C(N(CC)CC)C.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:28]([CH3:29])[CH3:27])=[O:21])=[CH:17][CH:18]=3)[C:13]([C:23]#[N:24])=[CH:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(C(=O)O)ccc32)cc1
Reactant: CNC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(-n2cc(C#N)c3cc(C(=O)N(C)C)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
To a solution of 4-(5-carboxy-3-cyanoindol-1yl)benzoic acid ethyl ester (0.084 g), dimethylamine hydrochloride (0.061 g), triethylamine (0.13 g) and 4-dimethylaminopyridine (0.006 g) in dichloromethane (2.5 mL) was added N-ethyl-N′-3-dimethylaminopropylcarbodiimide (0.058 g) at room temperature, and this mixture was stirred at room temperature overnight. This reaction mixture was poured into 1 mol/L hydrochloric acid, and this mixture was extracted with ethyl acetate. This organic layer was washed with a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane=1/2) to give the title compound (0.020 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[Cl:9][S:10](O)(=[O:12])=[O:11]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:10]([Cl:9])(=[O:12])=[O:11]
Reactant: Cc1ccc(Br)cc1
Reactant: O=S(=O)(O)Cl
Product: Cc1ccc(Br)c(S(=O)(=O)Cl)c1
Temperature: 0 °C

Procedure:
40 g of 4-bromotoluene are slowly introduced into 250 ml of chlorosulfonic acid at −10° C. with stirring. The mixture is stirred at this temperature for 30 minutes, allowed to warm to 0° C. and poured onto excess ice. The product is filtered off with suction and washed with a little water. It is dried over P4O10 in vacuo and 63 g of a colorless solid are obtained, which is directly reacted further.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[P:17]([O:24]CC)([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])=[CH:4][C:3]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(F)c(Oc2ccccc2)c1)OCC
Temperature: 90 °C
Yield: 94.9 %

Procedure:
A mixture of 4-fluoro-3-phenoxybenzyl bromide (28.1 g, 100 mmol) and triethyl phosphite (18.27 g, 110 mmol) is heated at 90° C. for 30 minutes while allowing some low boiling materials to distill off. The resultant mixture is heated at 140° C. for 3.5 hours and distilled at 120° C./2 mmHg to give the title product as a syrup (32.1 g, 95% yield) which is identified by NMR spectral analyses.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[OH:20])[C:10](=[O:21])[C:9]=2[C:8](Br)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C([O-])(=O)C.[K+].[Cl-]>CO>[CH:1]([NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[OH:20])[C:10](=[O:21])[C:9]=2[C:8]([NH:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: NC1CCCCC1
Reactant: CC(C)Nc1ccc(Br)c2c1C(=O)c1c(O)cccc1C2=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Product: CC(C)Nc1ccc(NC2CCCCC2)c2c1C(=O)c1c(O)cccc1C2=O

Procedure:
18 g of 1-isopropylamino-4-bromo-8-hydroxy-anthraquinone, 36 ml of cyclohexylamine, 6.5 of potassium acetate and catalytic amounts of copperI chloride are stirred at 80°-90° until only a little starting material is still detectable. The mixture is now diluted with 36 ml of methanol and the reaction product which has separated out is filtered off at 60°, washed with boiling hot methanol, finally stirring with dilute hydrochloric acid, filtered off, washed until neutral and dried.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[NH2:9][C:10]1[CH:11]=[C:12]([C:16]2[C:20]([Br:21])=[CH:19][N:18]([CH3:22])[N:17]=2)[CH:13]=[CH:14][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:21][C:20]1[C:16]([C:12]2[CH:11]=[C:10]([NH:9][C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[O:7])[CH:15]=[CH:14][CH:13]=2)=[N:17][N:18]([CH3:22])[CH:19]=1
Reactant: Cn1cc(Br)c(-c2cccc(N)c2)n1
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(Br)c(-c2cccc(NC(=O)c3cccs3)c2)n1
Reaction time: 16 h
Yield: 73.6 %

Procedure:
To thiophene-2-carbonyl chloride (11 μL, 0.09 mmol) in CH2Cl2 (1 mL) was added dropwise a solution of 3-(3-aminophenyl)-4-bromo-1-methylpyrazole (25 mg, 0.09 mmol) and triethylamine (14 μL, 0.09 mmol) in CH2Cl2 (0.5 mL). The reaction mixture was stirred for 16 h and concentrated. Chromatography on flash silica (50% EtOAc/hexane) gave the title compound as a colourless solid (24 mg, 68%), m.p. 127.8-128.6° C. (EtOAc/hexane).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][NH2:12]>>[NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH3:11])=[O:6]
Reactant: Nc1ncccc1C(=O)O
Reactant: CN
Product: CNC(=O)c1cccnc1N

Procedure:
The intended compound was obtained according to the method of Example 1-(1) but using 2-aminonicotinic acid and methylamine.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][CH:17]=O>O>[O:7]=[C:3]1[C:2]2[CH:16]=[CH:17][O:8][C:1]=2[CH2:6][CH2:5][CH2:4]1
Reactant: O=CCCl
Reactant: O=C1CCCC(=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C1CCCc2occc21
Temperature: 25 °C
Reaction time: 45 h
Yield: 68 %

Procedure:
To a mixture of 1.12 g (10 mmoles) of 1,3-cyclohexanedione and 8 ml of water was added 1.38 g (10 mmoles) of potassium carbonate, and then 2 ml of 40% aqueous solution of chloroacetaldehyde was added thereto. The resulting mixture was stirred at a room temperature for 45 hours. The reaction mixture was maintained at a pH of from 7.75 to 9.50 throughout the reaction. After completing the reaction, the obtained reaction mixture was treated and analyzed in the same manner as in Example 1. It was proved from the results of the analysis that 4-oxo-4,5,6,7-tetrahydrobenzofuran was produced in a 68% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2([C:26](O)=[O:27])[CH2:25][CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][C:5]1[S:9][C:8]([NH:10][C:26]([C:23]2([C:20]3[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=3)[CH2:25][CH2:24]2)=[O:27])=[N:7][CH:6]=1
Reactant: Nc1ncc(Cc2ccccc2Cl)s1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C(=O)Nc3ncc(Cc4ccccc4Cl)s3)CC2)cc1
Reaction time: 16 h
Yield: 54.4 %

Procedure:
5-(2-Chloro-benzyl)-thiazol-2-ylamine (0.250 g, 1.11 mmol) and 1-(4-methoxy-phenyl)-cyclopropanecarboxylic acid (0.213 g, 1.11 mmol) were dissolved in acetonitrile (20 mL) containing triethylamine (0.28 mL, 2.0 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 0.494 g, 1.3 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 5-40% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (0.2408 g, 0.6036 mmol, 54.4%). ESI-MS m/z calc. 398.1. found 399.0 (M+1)+. Retention time of 3.77 minutes. 1H NMR (400 MHz, CD3CN) d 1.21 (q, J=3.6 Hz, 2H), 1.59 (q, J=3.6 Hz, 2H), 3.78 (s, 3H), 4.19 (s, 2H), 6.88-6.96 (m, 2H), 7.07 (s, 1H), 7.23-7.46 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.Cl[C:11]1C(C)=NC(C)=NC=1>C1COCC1.CN1C(=O)CCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[Cl:1][C:2]1[N:7]=[C:6]([CH3:11])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Cc1ncc(Cl)c(C)n1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1nc(Cl)ncc1Cl
Temperature: 25 °C

Procedure:
2,4,5-trichloropyrimidine (1.83 g, 10 mmol) was dissolved in THF:NMP (10:1, 100 mL) at room temperature and iron(III) acetylacetonate (0.71 g, 2.0 mmol) was added under N2. MgBrMe (3M, 12 mmol) was added drop-wise via syringe. The mixture was cooled to RT, progress was verified by LC-MS: typical results show product vs starting material vs 5-chloro-2,4-dimethylpyrimidine side product ˜2:2:1 ratio. The reaction was quenched with ice cold, saturated ammonium chloride (, 100 mL), extracted with ethyl acetate (100 mL), washed with brine (100 mL, ×2), dried over MgSO4, filtered and concentrated i. vac. The crude mixture was purified by silica gel chromatography (5% ethylacetate/hexane) to yield the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[O:16])=[CH:12][CH:13]=2)[C:8]([S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[N:7]1.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH2:15][OH:16])=[CH:12][CH:13]=2)[C:8]([S:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)(=[O:19])=[O:18])=[N:7]1
Reactant: O=Cc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2cccc(Cl)c2)c2ccc(CO)cc12
Yield: 100 %

Procedure:
1-(3-Chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazole-5-carbaldehyde (0.18 g, 0.4 mmol) was dissolved in THF and treated under nitrogen with the excess of sodium borohydride (0.2 mmol). After 1 hr the reaction mixture was diluted with water and the product extracted with methylene chloride to afford after evaporation of the solvent the title compound as a colorless solid (0.18 g, 0.4 mmoles).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[S:13][N:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37](Cl)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1>C1COCC1>[Cl:26][C:27]1[C:36]2[C:31](=[CH:32][C:33]([S:37]([N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=3)[C:9]3[S:13][N:12]=[CH:11][N:10]=3)(=[O:39])=[O:38])=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1
Reactant: O=S(=O)(Cl)c1ccc2c(Cl)nccc2c1
Reactant: COc1ccc(CNc2ncns2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
Temperature: -70 °C
Reaction time: 0.75 h
Yield: 25.8 %

Procedure:
To a solution of N-(4-methoxybenzyl)-1,2,4-thiadiazol-5-amine (1.40 g, 6.33 mmol) in THF (42.2 mL) at −70° C. under an argon atmosphere was added lithium bis(trimethylsilyl)amide, 1.0 M solution in tetrahydrofuran (6.96 mL, 6.96 mmol) dropwise. The reaction mixture was removed from cooling and stirred for 45 min. The mixture was again cooled to −70° C. (internal temperature) to give a yellow suspension. Then solid 1-chloroisoquinoline-6-sulfonyl chloride (1.82 g, 6.96 mmol) was added in one portion. After 15 min, the mixture was warmed to room temperature and concentrated. The residue was absorbed onto a plug of silica gel and purified by chromatography through a silica gel column (80 g), eluting with a gradient of 0% to 50% EtOAc in hexane, to provide 1-chloro-N-(4-methoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (0.73 g, 1.633 mmol) as an orange solid. MS (ESI): 447.0 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ ppm 3.65 (s, 3H), 5.24 (s, 2H), 6.77 (m, J=8.66 Hz, 2H), 7.28 (m, J=8.66 Hz, 2H), 8.10 (dd, J=5.9, 10.8 Hz, 1H), 8.15 (d, J=6.4 Hz, 1H), 8.42 (d, J=8.6 Hz, 1H), 8.45 (s, 1H), 8.50 (d, J=5.56 Hz, 1H), 8.77 (d, J=1.71 Hz, 1H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([F:23])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][OH:22])[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]([O:26][C:27](=[O:30])[CH2:28]Br)[CH3:25].[H-].[Na+].Cl>O1CCCC1>[CH2:24]([O:26][C:27](=[O:30])[CH2:28][O:22][CH2:21][C@@H:19]1[CH2:18][S:17][C:16]([C:13]2[NH:14][C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([F:23])=[CH:8][C:7]=3[NH:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:20]1)[CH3:25]
Reactant: OC[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COC[C@@H]1CSC(c2cc3cc(F)cc(NC4CCCC4)c3[nH]2)=N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.8 %

Procedure:
The compound (50 mg, 0.15 mmol) prepared in Example 5 was dissolved in tetrahydrofuran (5 ml). Bromoacetic acid ethyl ester (30 mg, 0.18 mmol) and sodium hydride (8 mg, 0.18 mmol) were added thereto, and the mixture was stirred for 3 h at room temperature. After completion of the reaction, 1N hydrochloric acid was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was distilled under reduced pressure, and purified by column chromatography to give the title compound (15 mg, Yield 24%) and the acid compound (40 mg, Yield 68%) of Example 171.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[O:11]([CH2:18][C:19](Cl)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>CCOCC.O>[O:20]=[C:19]([NH:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:18][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCCN
Reactant: O=C(Cl)COc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CCCNC(=O)COc1ccccc1
Yield: 53 %

Procedure:
To a stirred mixture of ethyl 4-aminobutanoate hydrochloride (3.4 g) and phenoxyacetyl chloride (2.76 ml) in 50 ml of Et2O and 50 ml of water was added one portion of NaHCO3 (4.2 g). After 2 hr the layers were separated and the organic phase was washed (1N HCl, brine), dried (MgSO4), and filtered. Evaporation of the solvent under vacuum gave 3.1 g (53%) of the title compound as an oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH2:51]([O:53][C:54]([C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[NH:62][CH:61]([C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([NH2:72])[CH:67]=1)[C:60]([CH3:74])([CH3:73])[CH2:59]2)=[O:55])[CH3:52]>ClCCl>[CH2:51]([O:53][C:54]([C:56]1[CH:57]=[C:58]2[C:63](=[CH:64][CH:65]=1)[NH:62][CH:61]([C:66]1[CH:71]=[CH:70][CH:69]=[C:68]([NH:72][C:8](=[O:10])[CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:67]=1)[C:60]([CH3:73])([CH3:74])[CH2:59]2)=[O:55])[CH3:52]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)Cc3ccccc3)c1)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a stirred solution of phenylacetic acid (850 mg, 6.2 mmol), 2-(1H-7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyl uronium hexafluorophosphate Methanaminium (HATU) (3.5 g, 9.3 mmol) and triethyl amine (2.6 mL, 18.6 mmol) in dichloromethane (20 mL) was added 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.0 g, 6.2 mmol) at room temperature and stirred at room temperature for overnight. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-(3-phenylacetylamino-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (2.7 g, quant.) as a light yellow solid which was used for next step without further purification: LC/MS m/e calcd for C28H30N2O3 (M+H)+: 443.56, observed: 443.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.C1C(=O)N([Br:17])C(=O)C1.[OH-].[Na+]>S(=O)(=O)(O)O.O>[Br:17][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: COc1ccnc(Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Cl)ncc1Br
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-4-methoxypyridine (10.0 g, 69.7 mmol) in 50 mL of sulfuric acid at 0° C. was added NBS. The reaction mixture was allowed to stir and warm up to room temperature for 2 hour and then heated at 60° C. for 5 hours. Then it was cooled to room temperature and neutralized with 1 N NaOH (pH ˜7), diluted with water (50 mL) and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layers were washed with water (2×50 mL), saturated NaHCO3, brine, dried over Mg2SO4 and concentrated to provide an oil, which was chromatographed. On elution with 0-25% EtOAc/hexanes the final product was obtained.
Reaction SMILES: [CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:46])[CH3:45])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([OH:29])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:51]([S:53][CH2:54][CH3:55])[CH3:52].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C.C(OCC)(=O)C>[CH2:1]([C@H:8]([NH:30][C:31](=[O:50])[C@H:32]([CH:47]([CH3:49])[CH3:48])[NH:33][C:34]([N:36]([CH2:38][C:39]1[N:40]=[C:41]([CH:44]([CH3:45])[CH3:46])[S:42][CH:43]=1)[CH3:37])=[O:35])[CH2:9][C@H:10]([O:29][CH:51]([S:53][CH2:54][CH3:55])[CH3:52])[C@@H:11]([NH:19][C:20]([O:22][CH2:23][C:24]1[S:28][CH:27]=[N:26][CH:25]=1)=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCSCC
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCSC(C)O[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1csc(C(C)C)n1)C(C)C)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Yield: 75 %

Procedure:
To a solution of the compound of Example 1 (0.50 g, 0.69 mmol) and ethyl sulfide (1.9 mL) in acetonitrile (5 mL) at 0° C. was added benzoyl peroxide (0.84 g) in three portions over 3 hours. The reaction was diluted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over MgSO4, filtered and evaporated. The residue was chromatographed on silica gel, eluting with a gradient of 50-100% ethyl acetate in chloroform to give the title compound (0.42 g, 75% yield).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH2:8][CH2:9][Cl:10].BrCCBr>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][CH2:9][Cl:10])[CH:6]=1.[I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1
Reactant: ClCCBr
Agent: Ic1cn[nH]c1
Solvent: BrCCBr
Solvent: Cc1ccccc1
Product: ClCCn1cc(I)cn1

Procedure:
When an equivalent amount of 4-iodopyrazole is substituted for 1-ethoxycarbonyl-2H-indazolin-3-one and 2-bromochloroethane is substituted for 1,2-dibromoethane in the procedure of Example 19 using toluene as solvent, 2-(4-iodo-1H-pyrazol-1-yl)ethyl chloride is isolated after column chromatography (4-iodopyrazole, Aldrich, 41%, C).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C([Li])CCC.CN([CH:17]=[O:18])C.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:17]=[O:18])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(F)cn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of 2-bromo-5-fluoropyridine (25 g) in toluene (142 mL) was added at −78° C. n-butyllithium (2.5M toluene solution, 68 mL), and the mixture was stirred at −78° C. for 1 hr. To this mixture was added at −78° C. DMF (16.5 mL), and the mixture was stirred at −78° C. for 2 hr, and saturated aqueous ammonium chloride solution (300 mL) was added. The mixture was extracted with ethyl acetate (300 mL), dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (20% ethyl acetate/hexane) to give 5-fluoropyridine-2-carbaldehyde (4.7 g, 26%) as a yellow oil.