Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3][CH2:2]1.[H-].[Na+].[C:11]([C:13]1[CH:14]=[C:15]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1F)#[N:12].Cl>O1CCCC1.O>[C:11]([C:13]1[CH:14]=[C:15]([S:20]([NH2:23])(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1[O:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)#[N:12]
Reactant: OCC1CCOCC1
Reactant: N#Cc1cc(S(N)(=O)=O)ccc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(S(N)(=O)=O)ccc1OCC1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To (tetrahydro-2H-pyran-4-yl)methanol (0.206 g) in tetrahydrofuran (5 mL) was added sodium hydride (0.284 g) and the reaction stirred at room temperature for 20 minutes. The reaction was cooled to 0° C. and 3-cyano-4-fluorobenzenesulfonamide (0.355 g) in tetrahydrofuran (2 mL) was added dropwise and the reaction was allowed to warm to room temperature. After 3 hours, the reaction was poured into water, made acidic (pH=1) with 1N HCl and extracted with dichloromethane (2×75 mL). The organics were combined, washed with brine (50 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound.
Reaction SMILES: [CH:1](O)=[O:2].[NH2:4][C:5]1[C:6](=[O:21])[NH:7][CH:8]=[C:9]([CH3:20])[C:10]=1[S:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1>C(OCC)=O>[CH:1]([NH:4][C:5]1[C:6](=[O:21])[NH:7][CH:8]=[C:9]([CH3:20])[C:10]=1[S:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)=[O:2]
Reactant: O=CO
Reactant: Cc1cc(C)cc(Sc2c(C)c[nH]c(=O)c2N)c1
Solvent: CCOC=O
Product: Cc1cc(C)cc(Sc2c(C)c[nH]c(=O)c2NC=O)c1
Yield: 58 %

Procedure:
Formic acid (2 ml) was added to a solution of amine 8a (0.10 g, 0.4 mmole) in ethyl formate (previously distilled over calcium hydride) (8 ml). The mixture was heated under reflux for 12 hours. After evaporation of the volatile substances, the residue was washed twice with ethanol and once with ethyl acetate. It was purified by column chromatography using a mixture of dichloromethane and ethanol (95:5) as eluant and, at the end, ethyl acetate, to give compound 11a (0.06 g, 58%) in the form of a white powder: melting point 221-222° C.; NMR-1H (DMSO-d6) δ 11.96 (1H, s, NH-1), 8.28 (1H, s, NH-3) 7.23 (1H, s, H-6), 6.88 (1H, d, H-4'), 6.78 (2H, s, H-2' and 6'), 2.23 (6H, s, CH3 -3' and 5'), 1.85 (3H, s, CH3 -5). Anal. C15H16N2O2S (C, H, N, S).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.S(Cl)([Cl:12])=O>>[I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][Cl:12]
Reactant: OCc1ccccc1I
Reactant: O=S(Cl)Cl
Product: ClCc1ccccc1I

Procedure:
o-Iodobenzyl chloride was prepared from o-iodobenzyl alcohol using thionyl chloride according to the procedure described by Brooks et al, Org. Syn. Coll. Vol. 3, p. 698 (1955). The crude product was distilled at reduced pressure to yield a clear, colorless liquid having a bp of 143°/4 mm Hg.
Reaction SMILES: ClC1C=C(/C=C/C(N2CCC(=O)NCC2)=O)C=CC=1Cl.[F:21][C:22]([F:35])([F:34])[C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=1)/[CH:26]=[CH:27]/[C:28]([OH:30])=O.Cl.Cl.[N:38]1([CH2:44][CH2:45][CH2:46][N:47]2[C:53](=[O:54])[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:44][CH2:45][CH2:46][N:47]2[C:53](=[O:54])[CH2:52][CH2:51][N:50]([C:28](=[O:30])/[CH:27]=[CH:26]/[C:25]3[CH:31]=[CH:32][CH:33]=[C:23]([C:22]([F:21])([F:35])[F:34])[CH:24]=3)[CH2:49][CH2:48]2)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: O=C1CCNCCN1CCCN1CCCCC1
Reactant: O=C(O)/C=C/c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCN1
Product: O=C(/C=C/c1cccc(C(F)(F)F)c1)N1CCC(=O)N(CCCN2CCCCC2)CC1

Procedure:
In analogy to the procedure described in intermediate 1A, (E)-3-(trifluoromethyl)cinnamic acid and 4-(3-piperidin-1-yl-propyl)-[1,4]diazepan-5-one-dihydrochloride (intermediate 4B, suspended in CH2Cl2 with 4 equivalent of Et3N) gave after purification on catridges, Si-Amine, 70 mL, 20 g (EtOAc) the title compound as a light yellow viscous oil. MS: 438.4 (MH+).
Reaction SMILES: [CH3:1][O-:2].[Na+].F[C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([Cl:12])[CH:6]=1>CO>[Br:11][C:9]1[CH:10]=[C:5]([O:2][CH3:1])[CH:6]=[C:7]([Cl:12])[CH:8]=1
Reactant: C[O-]
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)cc(Br)c1
Temperature: 25 °C
Yield: 28.6 %

Procedure:
Sodium methoxide (4.5M solution in methanol, 2.20 ml, 10.0 mmol) was added dropwise to a stirred solution of 1-fluoro-3-chloro-5-bromobenzene (1.00 g, 4.77 mmol) in methanol (28 ml) at room temperature under a nitrogen atmosphere. The mixture was heated under reflux for 3 days and then cooled to room temperature. The mixture was evaporated under reduced pressure and the resulting yellow oil was dissolved in dichloromethane (30 ml). The dichloromethane solution was washed with water (2×20 ml) dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with cyclohexane to provide the title compound as a colourless oil (302 mg).
Reaction SMILES: [CH2:1]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([C:25]([OH:27])=[O:26])[CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[OH-].[Na+:29]>C(O)C.O>[CH2:1]([C:16]1[NH:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[C:20]([C:25]([O-:27])=[O:26])[CH:19]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Na+:29]
Reactant: CCCCCCCCCCCCCCCc1cc2ccc(C(=O)O)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCCCCCCc1cc2ccc(C(=O)[O-])cc2[nH]1
Yield: 93.2 %

Procedure:
A solution of 2-(n-pentadecyl)indole-6-carboxylic acid (15.0 g) in hot ethanol (100 ml) was treated with a solution of sodium hydroxide (2.0 g) in water (50 ml), and a white precipitate was obtained. The precipitate was recrystallised from aqueous ethanol (1:1) (300 ml) to give sodium 2-(n-pentadecyl)-indole-6-carboxylate (14.8 g), in the form of white crystals, m.p. greater than 340° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=5)[NH:23][N:22]=4)[N:19]=3)[N:14]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:13]=2)=[O:11])[CH3:8])[CH:2]=1.[H-].[Na+].Br[CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[C:29]5[C:24](=[CH:25][C:26]([Cl:30])=[CH:27][CH:28]=5)[N:23]([CH2:42][CH2:43][N:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)[N:22]=4)[N:19]=3)[N:14]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[CH:13]=2)=[O:11])[CH3:8])[CH:2]=1
Reactant: BrCCN1CCOCC1
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CCN4CCOCC4)c4cc(Cl)ccc34)nc12)c1cccnc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
2-(6-Chloro-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-3-yl-ethyl)-amide (100 mg, 0.18 mmol) was combined with DMF (2 mL) at 0° C. to give a yellow solution. Sodium hydride (60% in mineral oil, 22 mg, 0.55 mmol) was added and the reaction was stirred at 0° C. for 10 min. 4-(2-Bromoethyl)morpholine hydrocholoride (63 mg, 0.27 mmol) was added and the reaction was stirred at 0° C. for 30 min then warmed to room temperature and stirred for 2 h. The reaction mixture was quenched with 5 mL of brine and 10 mL of water and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water and brine then dried with MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0-10% methanol in dichloromethane) to afford 40 mg (33%) of 2-[6-chloro-1-(2-morpholin-4-yl-ethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-pyridin-3-yl-ethyl)-amide as a foaming solid. MS: (M+H)+=662.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[C:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[C:22]([O:21][C:19]([N:26]1[CH2:31][CH2:30][N:29]([C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)[CH2:28][CH2:27]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=S(=O)(Oc1cccc2cnccc12)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3cnccc23)CC1

Procedure:
The product from step (a) above (209 mg, 0.75 mmol) and 1-BOC-piperazine (210 mg, 1.1 mmol, Aldrich) was reacted under the conditions of Example 132b to give the title compound as yellow amorphous solid, which was used for the next step. MS (ESI, pos. ion) m/z: 314 (M+1)
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:14])[CH2:11][CH2:12][Cl:13])=[CH:6][CH:5]=1>O1CCCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([OH:14])[CH2:11][CH2:12][Cl:13])=[CH:8][CH:9]=1
Reactant: O=C(CCCl)c1ccc(Br)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(CCCl)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of sodium borohydride (3.8 g, 100 mmol) in tetrahydrofuran (100 mL) was added a solution of 1-(4-bromo-phenyl)-3-chloro-propan-1-one (25 g, 100 mmol) dropwise at 0° C. under nitrogen atmosphere. The mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was concentrated to about 50 mL under reduced pressure and diluted with water. Extractive workup was performed with ethyl acetate and the extracts were dried over anhydrous sodium sulfate. After concentration, the residue was purified by flash column chromatography on silica gel (hexane/ethyl acetate=3/1 as an eluant) to yield 1-(4-bromo-phenyl)-3-chloro-propan-1-ol (25 g, 100 mmol, 100%) as yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[N:12][C:11]=2[C:24]([O:26]CC)=[O:25])=[CH:6][CH:5]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[N:12][C:11]=2[C:24]([OH:26])=[O:25])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(OCC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)O)cc1
Yield: 120.1 %

Procedure:
Ethyl 5-(4-ethoxyphenyl)-2-(4-nitrophenyl)imidazole-4-carboxylate (27.6 g) was dissolved in ethanol. 1 M Sodium hydroxide solution was added and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-ethoxyphenyl)-2-(4-nitrophenyl) imidazole-4-carboxylic acid (30.7 g), melting point 148-152° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([CH2:7][C:8]2[CH:16]=[CH:15][C:11]3[S:12][CH:13]=[CH:14][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].C([Li])CCC.CCCCCC.[P:30](Cl)([O:35][CH2:36][CH3:37])([O:32][CH2:33][CH3:34])=[O:31]>C1COCC1>[CH2:33]([O:32][P:30]([C:13]1[S:12][C:11]2[CH:15]=[CH:16][C:8]([CH2:7][C:6]3[CH:17]=[CH:18][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=3)=[CH:9][C:10]=2[CH:14]=1)(=[O:31])[O:35][CH2:36][CH3:37])[CH3:34]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCc1ccc(Cc2ccc3sccc3c2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1cc2cc(Cc3ccc(CC)cc3)ccc2s1
Reaction time: 1 h

Procedure:
To a solution of 5-(4-ethylbenzyl)benzo[b]thiophene (1.50 g) in THF (11.8 mL) was added 2.44 M n-butyllithium/n-hexane solution (2.9 mL) at −78° C., and the reaction mixture was stirred for 1 hr at same temperature. Diethyl chlorophosphate (0.9 mL) was added to the reaction mixture at −78° C., and the reaction mixture was stirred for 0.5 hr at −78° C. The reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=1/2) to give the title compound (1.79 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[S:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=3)=[CH:11][C:10]([C:20]([O:22]CC)=O)=[N:9]2)=[CH:4][CH:3]=1.C[O-].[Na+].O.C([NH2:31])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[S:14][C:15]([S:18][CH3:19])=[CH:16][CH:17]=3)=[CH:11][C:10]([C:20]([NH2:31])=[O:22])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NC=O
Reactant: CCOC(=O)c1cc(-c2ccc(SC)s2)n(-c2ccc(F)cc2)n1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: CSc1ccc(-c2cc(C(N)=O)nn2-c2ccc(F)cc2)s1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of ethyl 1-(4-fluorophenyl)-5-[5-(methylthio)-2-thienyl]pyrazole-3-carboxylate (2.1 g) and sodium methoxide (895 mg) in formamide (10 ml) was stirred at 100° C. for 1 hour. Water was added to the reaction mixture, and the precipitates were collected, washed with water, and dried invacuo to give crystals of 1-(4-fluorophenyl)-5-[5-(methylthio)-2-thienyl]pyrazole-3-carboxamide (1.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[C:11]1[N:12]=[C:13]([C:17]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[CH2:19][CH2:18]2)[S:14][C:15]=1[CH3:16].[H-].[Na+].Br[CH2:30][C:31]#[N:32]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([CH3:10])=[CH:4][C:3]=1[C:11]1[N:12]=[C:13]([C:17]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH2:30][C:31]#[N:32])[CH2:19][CH2:18]2)[S:14][C:15]=1[CH3:16]
Reactant: COc1cc(Cl)c(-c2nc(C3(c4ccccc4O)CC3)sc2C)cc1C
Reactant: N#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cl)c(-c2nc(C3(c4ccccc4OCC#N)CC3)sc2C)cc1C
Reaction time: 0.5 h

Procedure:
2-{1-[4-(2-Chloro-4-methoxy-5-methyl-phenyl)-5-methyl-thiazol-2-yl]-cyclopropyl}-phenol (Example 126) (15 mg, 0.04 mmol) was dissolved in tetrahydrofuran (THF) (1 ml), treated with 1.1 mg NaH (0.044 mmol) at room temperature and stirred for 30 min. Bromoacetonitrile (5.5 mg, 0.044 mmol) was then added to the reaction vessel. The reaction mixtures was stirred overnight. The reaction mixture was quenched with 0.5 ml water and the THF removed in vacuo The residue was partitioned between ethyl acetate and water and the organic solution was separated and concentrated in vacuo then dissolved in methanol/dimethylsulfoxide (DMSO) 1:1 and purified via reversed phase HPLC chromatography (vide supra). Yield 11.5 mg (68%). [MH]+ 425.0, 427.0.
Reaction SMILES: [C:1]([CH2:3][CH:4]([N:8]1[CH:12]=[C:11]([C:13]2[N:18]3[CH:19]=[CH:20][N:21]=[C:17]3[CH:16]=[C:15]([C:22]([O:24]C)=[O:23])[N:14]=2)[CH:10]=[N:9]1)[CH:5]1[CH2:7][CH2:6]1)#[N:2].CO.[Li+].[OH-]>>[C:1]([CH2:3][CH:4]([N:8]1[CH:12]=[C:11]([C:13]2[N:18]3[CH:19]=[CH:20][N:21]=[C:17]3[CH:16]=[C:15]([C:22]([OH:24])=[O:23])[N:14]=2)[CH:10]=[N:9]1)[CH:5]1[CH2:6][CH2:7]1)#[N:2]
Reactant: COC(=O)c1cc2nccn2c(-c2cnn(C(CC#N)C3CC3)c2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: N#CCC(C1CC1)n1cc(-c2nc(C(=O)O)cc3nccn23)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 20 mL flask, methyl 5-(1-(2-cyano-1-cyclopropylethyl)-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine-7-carboxylate (0.127 g, 0.378 mmol) was dissolved in MeOH (1.89 mL, 0.378 mmol) and treated with LiOH (0.755 mL, 0.755 mmol). The reaction mixture was stirred at ambient temperature for 1 hour, then concentrated down to dryness and used directly in the next step. MS (apci) m/z=323.1 (M+H).
Reaction SMILES: C([Mg]Br)C.C[CH2:6][O:7]CC.[C:10]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=1[OH:26])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:12])[CH3:11].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1COCC1>[C:10]([C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH:6]=[O:7])[C:20]=1[OH:26])([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH3:12])[CH3:11]
Reactant: Cc1ccc(O)c(C(C)(C)c2ccccc2)c1
Reactant: CCOCC
Agent: CC[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C=O)c(O)c(C(C)(C)c2ccccc2)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
Ethylmagnesium bromide 21.0 ml (an ether solution, 3.0N, 63.1 mmol) and THF 40 ml were charged in a 500 ml reactor purged with nitrogen, 20 ml of a THF solution containing 2-cumyl-4-methylphenol 13.61 g (60.1 mmol) was added dropwise to the reactor at 0° C. in 1 hour and after that, the temperature was gradually raised to a room temperature and the resultant mixture was stirred for 30 minutes at a room temperature, in which toluene 220 ml was added, and then heated to 100° C. and about 50 ml of the mixed solvents of ether and THF were evaporated off to obtain a slightly opaque slurry. After the slurry was cooled to 24° C., p-formaldehyde 4.37 g (145.5 mmol) and triethylamine 12.0 ml (86.0 mmol) were added and the resultant mixture was stirred at 90° C. for 1 hour. After being cooled to a room temperature, the mixture was quenched with 42 ml of 18% hydrochloric acid and an organic layer was concentrated and the obtained liquid was purified by silica gel column chromatography to obtain 3-cumyl-5-methylsalicylaldehyde 14.13 g (yield 92%).
Reaction SMILES: [CH:1]1([N:6]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:7](=[O:26])[C:8]2[CH:13]=[CH:12][C:11]([CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)O)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.S(=O)(=O)(O)O.[Pd].C(OCC)(=O)C.CCCCCC>[CH:27]1([N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:7](=[O:26])[C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=3)=[CH:12][CH:13]=2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COc1ccc(C(O)c2ccc(C(=O)N(C3CCCC3)C3CCCC3)cc2)cc1OC
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(Cc2ccc(C(=O)N(C3CCCC3)C3CCCC3)cc2)cc1OC

Procedure:
The compound prepared in Example 10 (0.40 g, 0.84 mmol) in ethyl alcohol (20 mL) containing concentrated sulfuric acid (2 drops) was hydrogenated at 60 psi and room temperature using 5% Pd/C as catalyst. The catalyst was filtered and the filtrate concentrated in vacuo to give the crude product as an oil. Chromatography of the crude product on silica gel using mixtures of ethyl acetate and hexane as eluents gave the title compound as a crystalline solid, m. pt. 138-142° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[CH2:25][O:26][C:27]4[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:28]=4[CH:29]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:35])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(OCC)(=O)C.CO>[ClH:34].[Cl:34][C:32]1[CH:31]=[CH:30][C:28]2[CH:29]=[C:24]([S:21]([N:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)[C:16](=[O:35])[CH2:17]3)(=[O:22])=[O:23])[CH2:25][O:26][C:27]=2[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)C3=Cc4ccc(Cl)cc4OC3)CC2=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CN(S(=O)(=O)C2=Cc3ccc(Cl)cc3OC2)CCN1CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 198.4 %

Procedure:
To 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-(7-chloro-2H-benzopyran-3-sulfonyl)-2-piperazinone (1.856 g) were added 4N hydrochloric acid in ethyl acetate (40 ml) and methanol (25 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give colorless crystals of 4-(7-chloro-2H-benzopyran-3-sulfonyl)-1-(piperidin-4-ylmethyl)-2-piperazinone hydrochloride (1.618 g).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:18][O:19]C1CCCCO1)[C:6]#[C:7][C:8]1[S:12][C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].OS(O)(=O)=O>CO>[C:1]([O:4][CH:5]([CH2:18][OH:19])[C:6]#[C:7][C:8]1[S:12][C:11]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C#Cc1ccc(-c2cccs2)s1)COC1CCCCO1
Agent: O=S(=O)(O)O
Solvent: CO
Product: CC(=O)OC(C#Cc1ccc(-c2cccs2)s1)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
5-(3-Acetoxy-4-tetrahydropyranyloxy-1-butynyl)-2,2'-bithiophene (2.8 g) was dissolved in methanol (40 ml). H2SO4 solution (3 ml, 2N) was added slowly in ice bath and stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate. The extract was thus washed with 10 ml of NaHCO3 three time, 50 ml of water twice and dried over anhydrous magnesium sulfate. After removal of solvent residual solid was purified by silica gel column chromatography, eluted with ethyl acetate/n-hexane (1/3). Light brown product (1.83 g, 84%) was obtained.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH:26][CH3:27])[CH:21]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(Cl)Cl>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:20]3[CH:21]=[C:22]([NH:26][CH3:27])[N:23]=[CH:24][N:25]=3)=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2ccc(N)c([N+](=O)[O-])c2)CC1
Reactant: CNc1cc(Cl)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCN1CCN(c2ccc(Nc3cc(NC)ncn3)c([N+](=O)[O-])c2)CC1
Temperature: 100 °C
Yield: 29 %

Procedure:
A degassed mixture of 4-(4-ethylpiperazin-1-yl)-2-nitroaniline (2.1 g, 8.4 mmol), 6-chloro-N-methylpyrimidin-4-amine (Procedure 2A, step e; 1.2 g, 8.4 mmol), Pd2(dba)3 (1.54 g, 1.68 mmol), xantphos (1.94 g, 3.36 mmol) and Cs2CO3 (5.48 g, 16.8 mmol) in toluene (45 mL) was heated at 100° C. for 1 hour. The reaction was concentrated, and the residue was purified by flash chromatography on silica eluting with MeOH:DCM=1:40-1:20 to obtain the title compound (870 mg, yield: 29%). MS (ESI): 358 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([N+:24]([O-])=O)[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1C=CC=C[CH:3]=1.[N+](C1C(C2C=CC=CC=2)=C(OCCC)C=C(C=1)C(O)=O)([O-])=O>>[NH2:24][C:16]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([O:8][CH2:1][CH2:2][CH3:3])[CH:10]=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: CCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Product: CCCOc1cc(C(=O)O)cc(N)c1-c1ccccc1

Procedure:
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenylbenzoic acid with 5-nitro-4-phenyl-3-n-propoxybenzoic acid, and following the procedure described, 5-amino-4-phenyl-3-n-propoxybenzoic acid is obtained with a melting point of 101°-102° C.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[OH:17]>C1(C)C=CC=CC=1>[CH:1]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[OH:17])=[O:6])([CH3:3])[CH3:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: CC(C)N=C=O
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of isopropyl isocyanate (221 mg, 2.6 mmol) in toluene, 2-amino-5-nitrophenol (400 mg, 2.6 mmol) was added. The reaction mixture was stirred at 80° C. for 24 hours, then cooled to room temperature. The product was purified by precipitation from toluene and filtering (570 mg, 92%). m.p: 159.8-161.4° C.; EI-MS m/z 240 (M+H)+.