Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:6]=2[CH:17]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B(O)O)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:29]4[N:25]([C:22]5[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=5)[N:26]=[CH:27][CH:28]=4)[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)=[CH:11][CH:12]=1
Reactant: Clc1ccc(-n2cnc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccnn1-c1ccc(F)cc1
Product: Fc1ccc(-n2nccc2-c2ccc3ncn(-c4ccc(Cl)cc4)c3c2)cc1

Procedure:
The title compound, off-white solid (44 mg, 35%), MS (ISP) m/z=389.4 [(M+H)+], mp 173° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-(4-chloro-phenyl)-1H-benzo[d]imidazole (intermediate H) (100 mg, 325 μmol) and 1-(4-fluoro-phenyl)-1H-pyrazol-5-ylboronic acid (intermediate A) (80.3 mg, 390 μmol).
Reaction SMILES: N1C=CN=C1.C(O[C:10]1[CH:33]=[CH:32][C:13]([C:14]2[CH2:15][O:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[C:19](OC(=O)C)[C:18]=3OC(=O)C)=[CH:12][CH:11]=1)(=O)C>C(O)C>[O:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[C:14]([C:13]2[CH:32]=[CH:33][CH:10]=[CH:11][CH:12]=2)[CH2:15]1
Reactant: CC(=O)Oc1ccc(C2=Cc3ccc(OC(C)=O)c(OC(C)=O)c3OC2)cc1
Agent: c1c[nH]cn1
Solvent: CCO
Product: C1=C(c2ccccc2)COc2ccccc21
Reaction time: 8 h

Procedure:
Imidazole (0.6 g) was added to a suspension of 4′,7,8-triacetoxyisoflav-3-ene (0.16 g, 0.4 mmol) in absolute ethanol (5.0 ml) and the mixture was refluxed for 45 min under argon. The solution was concentrated under reduced pressure and the product was precipitated by addition of distilled water (10 ml). The mixture was left overnight in the fridge and filtered to yield isoflav-3-ene. The crude product was recrystallised from methanol/benzene to yield Isoflav-3-ene-4′,7-8-triol (0.08 g, 75%). 1H NMR (CDCl3+d6-DMSO): δ 4.97 (s, 2H, H2), 6.30 (d, 1H, J 8.2 Hz, H6), 6.36 (d, 1H, J 8.3 Hz, H5), 6.55 (bs, 1H, H4), 6.72 (d, 1H, J 8.7 Hz, ArH), 7.17 (d, 2H, J 8.7 Hz, ArH).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:18])[CH3:17]>>[C:16]([NH:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:18])[CH3:17]
Reactant: Cc1ccccc1N
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccccc1C
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 67384.6 %

Procedure:
Ortho toluidine (0.75 mol, 80 grams) was taken in a 1 L round bottom flask equipped with a liquid addition funnel and a guard tube. Triethylamine (1.13 mmol, 113.77 grams) was added to it in one lot. Above mixture was cooled to 0-5° C. and acetyl chloride (1.13 mmol, 88.7 grams) was added drop wise by maintaining the temperature below 10° C. After addition of acetyl chloride, cooling was removed and the reaction mass was stirred at 25-28° C. for a period of 3 hours. After completion of the reaction, the reaction mixture was poured onto 500 grams of ice-water and extracted with dichloromethane (2×300 mL). The combined dichloromethane extracts were then washed with water, brine and dried over anhydrous magnesium sulfate. The volatiles were removed under the reduced pressure to obtain 113.6 grams of solid product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:7]#[N:8])[CH3:2].C(N)(=[S:17])C>Cl.CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[C:7]([NH2:8])=[S:17])[CH3:2]
Reactant: CC(N)=S
Reactant: CCOc1ccc(C#N)cc1OCC
Agent: Cl
Solvent: CN(C)C=O
Product: CCOc1ccc(C(N)=S)cc1OCC
Reaction time: 5 h
Yield: 63.5 %

Procedure:
A solution of 29 g of 3,4-diethoxybenzonitrile and 23 g of thioacetamide in 120 ml of 10% hydrochloric acid-DMF was stirred at 90° C. for 3 hours and then 130° C. for 5 hours. After evaporation of the solvent, the residue was washed with diethyl ether (2×100 ml) and water (2×100 ml). The resulting crystals were collected by filtration and dried to obtain 21.7 g of 3,4-diethoxythiobenzamide.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:11]([CH3:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1Cl
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])c(NC(=O)OC(C)(C)C)cc1N1CCCC1

Procedure:
The title compound was prepared from (5-chloro-4-methyl-2-nitro-phenyl)-carbamic acid tert-butyl ester (Example B8) (3.01 g, 10.5 mmol) and pyrrolidine (4.33 ml, 52.3 mmol) in DMSO (30 mL) at 55° C. according to the general procedure C. Obtained as a yellow solid (3.27 g, 97%).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH3:12][C:13]1[N:14]=[C:15]([C:24]([NH2:26])=O)[S:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:24]([C:15]1[S:16][C:17]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[C:13]([CH3:12])[N:14]=1)#[N:26]
Reactant: Cc1nc(C(N)=O)sc1-c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1nc(C#N)sc1-c1ccncc1
Temperature: 90 °C
Reaction time: 21 h
Yield: 53.3 %

Procedure:
p-Toluenesulfonyl chloride (860 mg) was added to a stirred suspension of 4-methyl-5-(4-pyridinyl)-thiazole-2-carboxamide (450 mg) in dry pyridine (5 ml) under ice-cooling, and the mixture was stirred at 90° C. for 21 hours. The mixture was evaporated to dryness, and the residue was dissolved 2N hydrochloric acid aqueous solution (10-15 ml), washed twice with chloroform, and made alkaline by addition of 2N sodium hydroxide aqueous solution. The resulting precipitates were extracted with chloroform, washed with water, dried over magnesium sulfate, and evaporated to dryness. The residue was washed with petroleum ether, and was recrystallized from iso-propanol (twice) to give 2-cyano-4-methyl-5-(4-pyridinyl)-thiazole (220 mg, yield 53%) as pale yellow needles.
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:27][CH3:28])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:16]2[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][CH:17]=2)(C)[C:12](O)=O)=[CH:7][CH:6]=1)[CH3:3].[OH-].[Na+]>>[CH2:25]([N:22]([CH2:23][CH3:24])[C:19]1[CH:20]=[CH:21][C:16]([C:11]([C:8]2[CH:7]=[CH:6][C:5]([N:4]([CH2:27][CH3:28])[CH2:2][CH3:3])=[CH:10][CH:9]=2)=[CH2:12])=[CH:17][CH:18]=1)[CH3:26]
Reactant: CCN(CC)c1ccc(C(C)(C(=O)O)c2ccc(N(CC)CC)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C=C(c1ccc(N(CC)CC)cc1)c1ccc(N(CC)CC)cc1
Reaction time: 2 h
Yield: 74.3 %

Procedure:
Into 200 ml of IN--HCl solution was dissolved 10 g of 2,2-bis(4-diethylaminophenyl)propionic acid. Thereto was gradually added 5.7 g of ferric chloride at room temperature and the mixture was reacted with stirring for 2 hours. The reaction mixture was adjusted to alkaline with addition of aqueous solution of sodium hydroxide and then extracted with 50 ml of toluene. The toluene layer was concentrated at a reduced pressure to obtain crystals. The crystal was recrystallized from ethanol to give 6.5 g (yield 74.3%) of 1,1-bis(4-diethylaminophenyl)ethylene, having a melting point of 100°~102° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[O:14][N:13]=[C:12]([CH:15]2[CH2:17][CH2:16]2)[N:11]=1)(C)(C)C.[ClH:19]>ClCCl>[ClH:19].[CH:15]1([C:12]2[N:11]=[C:10]([CH2:9][CH2:8][NH2:7])[O:14][N:13]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NCCc1nc(C2CC2)no1
Agent: Cl
Solvent: ClCCl
Product: NCCc1nc(C2CC2)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4.00 g (15.79 mmol) tert-butyl[2-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-ethyl]-carbamate are placed in 40 ml dichloromethane, 80 ml 1 molar ethereal hydrochloric acid are added. The reaction mixture is stirred for 3 hours at reflux temperature and 72 hours at ambient temperature, then evaporated down. The residue is dissolved in acetone, mixed with diethyl ether and suction filtered.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][C:19]2[N:27]=[CH:26][CH:25]=[CH:24]C=2C(O)=O)=[CH:16][CH:15]=1.CN(C=O)C>C(Cl)Cl>[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]1[CH:29]=[CH:28][C:17]([O:18][C:19]2[N:27]=[CH:26][CH:25]=[CH:24][C:1]=2[C:2]([Cl:4])=[O:3])=[CH:16][CH:15]=1
Reactant: O=C(O)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccnc1Oc1ccc(Nc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 2M solution of oxaloyl chloride (3.86 mL, 7.71 mmol) was added slowly to a suspension of 2-(4-(pyridin-2-ylamino)phenoxy)nicotinic acid (1580 mg, 5.14 mmol) in CH2Cl2 (20 mL). DMF (0.040 mL, 0.514 mmol) was added drop wise and the mixture was stirred at RT for 2 h. The mixture was concentrated under reduced pressure to deliver a yellow solid. The solid was suspended in CH2Cl2 (5 ml) and filtered to deliver 2-(4-(pyridin-2-ylamino)phenoxy)nicotinoyl chloride as a yellow solid that was taken on without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:15][O:14][C:13]2[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[C:19]([CH3:20])[C:12]=2[O:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:24][C:25]1[C:30](O)=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35].C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)Cl>O.C(OCC)(=O)C>[F:24][C:25]1[C:30]([O:22][C:21]([C:18]2[CH:17]=[CH:16][C:13]3[O:14][CH2:15][CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[O:11][C:12]=3[C:19]=2[CH3:20])=[O:23])=[C:29]([F:32])[C:28]([F:33])=[C:27]([F:34])[C:26]=1[F:35]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: Cc1c(C(=O)O)ccc2c1OC(CO[Si](C)(C)C(C)(C)C)CO2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc2c1OC(CO[Si](C)(C)C(C)(C)C)CO2
Reaction time: 0.17 h
Yield: 83.6 %

Procedure:
To a round bottom flask equipped with magnetic stirring and a nitrogen inlet was added 3-(tert-butyldimethylsilyloxymethyl)-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid (0.72 g, 2.13 mmol) and ethyl acetate (11 mL). To this was added pentafluorophenol (0.82 g, 2.23 mmol) followed by 1 M dicyclohexylcarbodiimide in methylene chloride (2.34 mL, 2.34 mmol). This mixture was stirred at room temperature for four hours. A few milliliters of water were added and stirring continued for 10 min. The reaction was filtered, diluted with ethyl acetate, washed once with 1 N HCl, once with saturated aqueous sodium bicarbonate solution, once with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to give an oil. This oil was flash chromatographed on silica gel eluting with hexanes to give a clear colorless oil, 3-(tert-butyldimethylsilyloxymethyl)-5-methyl-2,3-dihydrobenzo[1,4]dioxine-6-carboxylic acid pentafluorophenyl ester, (0.90 g, 1.78 mmol) in 84% yield. 1H-NMR (300 MHz, CDCl3) δ (ppm): 0.10 (s, 6H), 0.90 (s, 9H), 2.50 (s, 3H), 3.90 (m, 2H), 4.14 (m, 1H), 4.24 (m, 1H), 4.40 (m, 1H), 6.83, (d, 1H), 7.86, (d, 1H); TLC Rf=0.88 (1:1 ethyl acetate/hexane).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])=[CH:23][C:22]=2[C:32]([CH2:35][CH3:36])([CH3:34])[CH3:33])=[O:14])[CH:3]=1.[OH:37][C:38]1[CH:43]=[CH:42][C:41]([S:44](Cl)(=[O:46])=[O:45])=[CH:40][C:39]=1[N+:48]([O-])=O>>[NH2:48][C:39]1[CH:40]=[C:41]([S:44]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH2:30][CH3:31])([CH3:28])[CH3:29])=[CH:23][C:22]=3[C:32]([CH2:35][CH3:36])([CH3:34])[CH3:33])=[O:14])[CH:3]=2)(=[O:46])=[O:45])[CH:42]=[CH:43][C:38]=1[OH:37]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1O
Reactant: CCC(C)(C)c1ccc(OCCCCNC(=O)c2cc(N)c3ccccc3c2O)c(C(C)(C)CC)c1
Product: CCC(C)(C)c1ccc(OCCCCNC(=O)c2cc(NS(=O)(=O)c3ccc(O)c(N)c3)c3ccccc3c2O)c(C(C)(C)CC)c1

Procedure:
This compound was prepared in two steps by conventional procedures of the type well known in the art. 4-Amino-1-hydroxy-N-[4-(2,4-di-tert-pentylphenoxy)butyl]-2-naphthamide (U.S. Pat. No. 3,954,476, column 25) was converted to the sulfonamide by reaction with 4-hydroxy-3-nitrobenzenesulfonyl chloride. Secondly, the nitro group was reduced to the amino compound by catalytic hydrogenation.
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[NH2:39][C@H:40]([C:45]([OH:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44]>C1COCC1>[C:1]([S:4][CH2:5][CH2:6][C:7]([N:9]1[C@H:13]([C:14]([NH:39][C@H:40]([C:45]([OH:47])=[O:46])[CH2:41][CH2:42][S:43][CH3:44])=[O:16])[CH2:12][S:11][C@@H:10]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)O
Reactant: CSCC[C@H](N)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CSCC[C@H](NC(=O)[C@@H]1CS[C@H](c2ccccc2O)N1C(=O)CCSC(C)=O)C(=O)O
Yield: 22 %

Procedure:
The suspension of mixed anhydride in THF is prepared by using 5.3 g of (2R,4R)-3-(S-acetyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid, 1.5 g of N-methylmorpholine and 2.0 g of isobutyl chlorocarbonate. To the suspension the aqueous solution of 4.5 g of L-methionine and 3.0 g of N-methylmorpholine is added, and treated in the same manner as Example 1 to give 1.6 g (66%) of the titled compound.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([CH:14]([OH:54])[C:15](=[O:53])[N:16]([C@H:26]([CH3:52])[C@@H:27]([C:43]1[CH:48]=[CH:47][C:46]2[O:49][CH2:50][O:51][C:45]=2[CH:44]=1)[CH2:28][C:29]1[O:30][C:31]([C:34](=[O:42])[NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:33]=1)[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:5][C:6]([C:8](=[C:14]([OH:54])[C:15](=[O:53])[N:16]([C@H:26]([CH3:52])[C@@H:27]([C:43]1[CH:48]=[CH:47][C:46]2[O:49][CH2:50][O:51][C:45]=2[CH:44]=1)[CH2:28][C:29]1[O:30][C:31]([C:34](=[O:42])[NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:33]=1)[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)CC(C(=O)OC(C)(C)C)C(O)C(=O)N(C/C=C/c1ccccc1)[C@H](C)[C@H](Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CC#N
Product: COC(=O)CC(C(=O)OC(C)(C)C)=C(O)C(=O)N(C/C=C/c1ccccc1)[C@H](C)[C@H](Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2
Yield: 74.4 %

Procedure:
384 mg of methyl (3RS,4RS)-3-(tert-butoxycarbonyl)-4-hydroxy-4-[N-[(1R,2R)-1-methyl-2-(3, 4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl]-N-{(E)-3-phenyl-2-propenyl}carbamoyl]butanoate was dissolved in 15 ml of acetonitrile and stirred together with 219 mg of tetrapropylammonium perruthenate at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was preliminarily purified by silica gel short column chromatography [chloroform→methanol] and the purified again by silica gel column chromatography [hexane/ethyl acetate=2/1→3/2] to give 285 mg (yield: 74%) of the title compound as a colorless oily substance.
Reaction SMILES: [C:1]1([CH:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3C(=O)C4=CC=CC=C4C3=O)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH:7]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:11][CH2:10]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 68.2 %

Procedure:
3.70 g of potassium phthalimide was dissolved in 20 ml of N,N-dimethylformamide; 5.4 ml of 1,5-dichloropentane was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1). The desired fraction was collected to yield 4.68 g of N-(5-bromopentyl)phthalimide as an oily substance. 4.68 g of N-(5-bromopentyl)phthalimide and 4.25 g of 4-(diphenylmethoxy)piperidine were dissolved in 30 ml of N,N-dimethylformamide; 2.42 g of potassium carbonate was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate-triethylamine (50:50:1). The desired fraction was collected to yield 6.67 g of N-[5-[4-(diphenylmethoxy)piperidino]pentyl]phthalimide as an oily substance. 6.6 g of N-[5-[4-(diphenylmethoxy)piperidino]pentyl]phthalimide was dissolved in 30 ml of ethanol; 0.694 ml of hydrazine monohydrate was added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure; ethyl acetate was added to the residue; the crystal precipitated was collected, dissolved in 15 ml of a 1 N aqueous solution of sodium hydroxide and 20 ml of water and extracted with ethyl acetate; the extract was washed with saline and dried with sodium sulfate. The dry product was concentrated under reduced pressure; the crystal obtained was collected to yield 3.29 g of the title compound.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[N:10]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:11]2[C:16]([C:17]=1[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2>C1(C)C=CC=CC=1.CO>[Br:8][C:9]1[N:10]([CH2:28][CH2:29][C:30]([O:32][CH3:1])=[O:31])[C:11]2[C:16]([C:17]=1[CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1)=[CH:15][CH:14]=[C:13]([C:24]([O:26][CH3:27])=[O:25])[CH:12]=2
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CCC(=O)O)c2c1
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)CCn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
1.6 eq of (Trimethylsilyl)diazomethane (2 M solution in hexanes) was added dropwise to a solution of 3-[2-bromo-3-cyclohexyl-6-(methoxycarbonyl)-1H-indol-1-yl]propanoic acid in a mixture toluene:MeOH (7:3; 0.2 M) and the solution allowed to stir at RT for 1 h. Excess (Trimethylsilyl)diazomethane was quenched with acetic acid and then the solution was concentrated in vacuo. The crude was purified by flash chromatography (Biotage cartridge Si4OS, 1:9 EtOAc/PE) to afford the title compound in 63% yield (over two steps). MS (ES+) m/z 422 (M+H)+, m/z 424 (M+H)+
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:25])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:26][C@@H:27]1[O:31][C:30](=[O:32])[NH:29][CH2:28]1>>[CH:1]1([C:4]2[CH:5]=[C:6]([CH3:25])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([N:29]5[CH2:28][C@H:27]([CH3:26])[O:31][C:30]5=[O:32])=[CH:20][CH:19]=4)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: C[C@H]1CNC(=O)O1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(I)cc2)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C[C@H](C)OC3=O)cc2)CC1
Yield: 81.9 %

Procedure:
By reaction and treatment in the same manner as in Example 149 and using [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (447 mg) described in Preparation Example 97 and (S)-5-methyloxazolidin-2-one (121 mg) described in Preparation Example 42, the title compound (344 mg) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[CH:15]=[C:16]([OH:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[CH3:31]>>[CH3:31][C:22]1[CH:23]=[C:24]([C:25]([O:27][CH3:28])=[O:26])[CH:29]=[CH:30][C:21]=1[O:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:14][CH2:13][C:12]=2[CH:15]=1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Product: COC(=O)c1ccc(Oc2ccc3c(c2)CCN(C(=O)OC(C)(C)C)CC3)c(C)c1

Procedure:
The title compound was prepared from 7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylic acid tert-butyl ester (PCT Int. Appl. (2002), WO 02/40471) and methyl 4-bromo-3-methylbenzoate using the method outlined in Example 128 (211 mg, 29%); NMR (CDCl3) δ 1.49 (9H, s), 2.32 (3H, m), 2.86 (4H, m), 3.55 (4H, m), 3.89 (3H, s), 6.71-6.81 (3H, m), 7.08 (H, m), 7.80 (H, m), 7.94 (H, s)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[NH2:24][OH:25].C([O-])(O)=O.[Na+]>CN(C=O)C.O.C(Cl)Cl>[OH:25][N:24]=[C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:13][CH:12]=1)[NH2:15]
Reactant: Cc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2ccc(C(N)=NO)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.9 %

Procedure:
To a stirring solution of 4′-methyl-[1,1′-biphenyl]-4-carbonitrile (524 mg, 2.71 mmol) in DMF (10 mL) were added triethylamine (0.98 mL, 6.78 mmol) and hydroxylamine hydrochloride (471 mg, 6.78 mmol). After stirring at room temperature for 20 h, the reaction mixture was poured into NaHCO3 (50 mL), water (20 mL) and DCM (20 mL) then stirred for 20 min. The precipitate was isolated by filtration using water (2×10 mL) to wash the filter cake. The filter cake was then evaporated with toluene (2×5 mL) and dried under vacuum to afford 435 mg (70%) of N′-hydroxy-4′-methyl-[1,1′-biphenyl]-4-carboximidamide INT-40 as a white solid. LCMS-ESI (m/z) calculated for C14H14N2O: 226; found 227 [M+H]+, tR=1.34 min (Method 10).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][C@H:22]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]1.CCN(C(C)C)C(C)C>C(O)CCC>[OH:28][C@H:25]1[CH2:26][CH2:27][C@H:22]([NH:21][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:23][CH2:24]1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1cccnc1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=C(Nc1nc2cccc(N[C@H]3CC[C@H](O)CC3)n2n1)c1cccnc1
Reaction time: 0.67 h

Procedure:
A solution of N-(5-chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B4), 100 mg; 0.37 mmol; 1.0 eq.), trans-4-aminocyclohexanol hydrochloride (ABCR), 277 mg; 1.83 mmol; 5.0 eq.), DIEA (472 mg; 3.65 mmol; 10.0 eq.) in n-butanol (1.0 mL) was heated at 220° C. for 20 min under microwave irradiation. The reaction mixture was directly purified by reverse phase chromatography (Starting with water then up to 60% ACN in water in 40 min.). The title compound was isolated after lyophilisation as a white powder (31 mg, 24%). HPLC, Rt: 1.77 min. (purity 80.2%). LC/MS, M+(ESI): 353.1, M−(ESI): 351.1.