Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Cl:11][C:12]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:13]=1[CH2:14][SH:15].[Na]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:14]([S:15][CH:14](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[C:13]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:12]=1[Cl:11])[C:13]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:12]=1[Cl:11]
Reactant: Cc1ccc(CS)c(Cl)c1
Reactant: C#Cc1ccc(Cl)cc1Cl
Agent: [Na]
Product: Cc1ccc(C(/C=C\c2ccc(Cl)cc2Cl)SC(/C=C\c2ccc(Cl)cc2Cl)c2ccc(C)cc2Cl)c(Cl)c1

Procedure:
A solution of 2,4-dichlorophenylacetylene (0.02 mol), 2-chloro-4-methylbenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-dichlorostyryl-2-chloro-4-methylbenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:34])([CH3:33])[C:28]([O:30]CC)=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:35]=2)=[N:7][C:6]([CH3:36])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+]>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([C:22]5[CH:23]=[N:24][N:25]([C:27]([CH3:34])([CH3:33])[C:28]([OH:30])=[O:29])[CH:26]=5)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:35]=2)=[N:7][C:6]([CH3:36])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(C)(C)n1cc(-c2ccc3c(c2)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)cn1
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2cn3c(n2)-c2ccc(-c4cnn(C(C)(C)C(=O)O)c4)cc2OCC3)n(C(C)C)n1

Procedure:
Ethyl 2-(4-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)-1H-pyrazol-1-yl)-2-methylpropanoate 23 was treated with aqueous lithium hydroxide to give II.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:10]3[S:14][C:13]([NH:15][C:16]([NH:18][CH2:19][CH3:20])=[O:17])=[N:12][C:11]=3[CH:21]=2)[S:4][N:3]=1.C(N(CC)CC)C.Cl.[CH2:36]([C:38]1([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)C>CN(C=O)C>[CH2:19]([NH:18][C:16]([NH:15][C:13]1[S:14][C:10]2[C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:8][C:7]([C:5]3[S:4][N:3]=[C:2]([N:41]4[CH2:42][CH2:43][C:38]([CH3:36])([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:39][CH2:40]4)[N:6]=3)=[CH:21][C:11]=2[N:12]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)C1(CC)CCNCC1
Reactant: CCNC(=O)Nc1nc2cc(-c3nc(Cl)ns3)cc(-c3ccccn3)c2s1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2cc(-c3nc(N4CCC(C)(C(=O)OCC)CC4)ns3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a solution of 1-[5-(3-chloro-1,2,4-thiadiazol-5-yl)-7-(pyridin-2-yl)-1,3-benzothiazol-2-yl]-3-ethylurea (100 mg, 0.24 mmol) and Triethylamine (73 mg, 0.72 mmol) in DMF (10 mL) was added ethyl 4-ethylpiperidine-4-carboxylate hydrochloride (100 mg, 0.48 mmol) and the mixture stirred at rt for 1 h giving a suspension. LCMS showed only SM so the reaction was heated at 90° C. for 3 days after which time LCMS showed a major product peak. The reaction mixture was concentrated in vacuo to give an orange gum, which was purified by flash column chromatography (Biotage SP4, 12 g 2-10% MeOH/DCM)) to give the desired product as a cream solid (100 mg, 52%) MS: 552.11 [M+H]+.
Reaction SMILES: CO.C[O-].[Na+].[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N:14]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH:32]=O)[CH:8]=1.Cl>C(=O)(OC)OC.O>[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]2[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH2:15][CH2:16][CH2:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:32][C:9]=2[CH:8]=1
Reactant: COC(=O)CCCCN(Cc1ccc(OC)cc1)c1cc(C)c(Br)cc1C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: COC(=O)OC
Solvent: CO
Product: COC(=O)C1=Cc2cc(Br)c(C)cc2N(Cc2ccc(OC)cc2)CCC1
Temperature: 50 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
A methanol solution of sodium methoxide (28%, 1.9 g) was added to a solution of methyl 5-((4-bromo-2-formyl-5-methylphenyl)(4-methoxybenzyl)amino)pentanoate (3.4 g) in dimethyl carbonate (50 ml), after which the mixture was stirred under nitrogen atmosphere at 50° C. for 3 hours. After cooling down to 0° C., water was added and the mixture was neutralized with 1N hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:1) to give methyl 8-bromo-1-(4-methoxybenzyl)-9-methyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (2.42 g) as a brown oily material.
Reaction SMILES: ClC1C=CC(C2C=CN3[C:14](=[O:17])NN=C3C=2C2C=CN=CC=2)=CC=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]3[C:37](=[O:51])[N:38]([CH2:40][C:41]4[CH:46]=[CH:45][C:44](S(C)(=O)=O)=[CH:43][CH:42]=4)[N:39]=[C:33]3[C:32]=2[C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][N:34]3[C:37](=[O:51])[N:38]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:17][CH3:14])=[CH:43][CH:42]=4)[N:39]=[C:33]3[C:32]=2[C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)c1ccc(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)cc1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Product: COc1ccc(Cn2nc3c(-c4ccncc4)c(-c4ccc(Cl)cc4)ccn3c2=O)cc1

Procedure:
The title compound was prepared by coupling 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one with the requisite benzyl halide in a manner analogous to that in which 7-(4-chlorophenyl)-2-(4-(methylsufonyl)benzyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one was prepared. HPLC/MS: retention time=2.213 min, [M+H]+=444.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11].[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17](C1C=CC(OC)=C2C=1C=CN2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]
Reactant: Clc1n[nH]c2ccc(Br)cc12
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]nc(Cl)c2c1

Procedure:
3-(3-Chloro-1H-indazol-5-yl)-3-phenyl-acrylic acid ethyl ester CCXV was prepared from 5-bromo-3-chloro-1H-indazole using the procedure described for preparation of 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (Example 13).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.CC(C)=O.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:22][C:21]3[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH3:17])[CH:20]=3)[CH:8]=2)[N:3]=1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Reactant: COc1cccc(CBr)c1
Solvent: O
Solvent: CC(C)=O
Product: COc1cccc(COc2ccc3nc(Cl)ccc3c2)c1
Yield: 44.5 %

Procedure:
To a stirred solution of 2-chloro-6-hydroxy-quinoline (0.6 g, 3.0 mmol) in aceton (15 ml) potassium carbonate (0.55 g, 4.0 mmol) and 3-methoxybenzylbromide (0.8 g, 4.0 mmol) were added at ambient temperature. Then the reaction mixture was heated to reflux for 3 h. Upon cooling to ambient temperature water was added and the whole mixture extracted twice with ethyl acetate. The combined organic phases were dried on sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography on silica gel (heptane, ethyl acetate 1:0=>1:4) yielded 2-chloro-6-(3-methoxy-benzyloxy)-quinoline as a white solid (0.4 g, 40%), MS 300.8 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH3:13][N:14]([CH3:33])[CH2:15][CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][N:27]([CH3:32])[C:28](=[O:31])[CH:29]=[CH2:30])=[CH:18]1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:33][N:14]([CH3:13])[CH2:15][CH2:16][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH2:26][N:27]([CH3:32])[C:28](=[O:31])/[CH:29]=[CH:30]/[C:2]2[CH:11]=[N:10][C:9]3[NH:8][C:7](=[O:12])[CH2:6][CH2:5][C:4]=3[CH:3]=2)=[CH:18]1
Reactant: C=CC(=O)N(C)Cc1cn(CCN(C)C)c2ccccc12
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: CN(C)CCn1cc(CN(C)C(=O)/C=C/c2cnc3c(c2)CCC(=O)N3)c2ccccc21
Yield: 17.2 %

Procedure:
A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (0.61 g, 2.70 mmole), N-[1-(2-dimethylaminoethyl)-1H-indol-3-ylmethyl]-N-methyl-acrylamide (1.00 g, 3.50 mmole), Pd(OAc)2 (0.08 g, 0.35 mmole), tri-ortho-tolylphosphine (0.21 g, 0.70 mmole), and diisopropylethylamine (0.91 mL, 5.25 mmole) in propionitrile (70 mL) was deoxygenated, then was and heated to reflux under a N2 overnight. The dark mixture was filtered through a pad of celite®, and the filter pad was rinsed with acetonitrile (250 mL). The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography on silica gel (10% MeOH/CHCl3 containing 5% NH4OH in the MeOH). The title compound (0.20 g. 13%) was obtained as a light yellow solid after drying in vacuo: MS (ES) m/e432 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[O:21][CH2:22][O:23][CH3:24])=[CH:10][C:9]=1[NH2:25])([CH3:4])([CH3:3])[CH3:2].[N:27]1([C:32]2[CH:33]=[C:34]([C:38]3[O:43]C(C)(C)[O:41][C:40](=O)[CH:39]=3)[CH:35]=[CH:36][CH:37]=2)[CH:31]=[CH:30][N:29]=[CH:28]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[O:21][CH2:22][O:23][CH3:24])=[CH:10][C:9]=1[NH:25][C:40](=[O:41])[CH2:39][C:38]([C:34]1[CH:35]=[CH:36][CH:37]=[C:32]([N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[CH:33]=1)=[O:43])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCOc1cc(F)ccc1-c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Reactant: CC1(C)OC(=O)C=C(c2cccc(-n3ccnc3)c2)O1
Product: COCOc1cc(F)ccc1-c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnc3)c2)c1

Procedure:
Prepared from (3-amino-4′-fluoro-2′-methoxymethoxy-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G42) (181 mg, 0.5 mmol)and 6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10) (135 mg, 0.5 mmol) according to the general procedure K. Obtained as a yellow amorphous substance (221 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Na+:12].[OH-].[Na+]>C(O)(C)C>[Na+:12].[CH2:4]([O:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][CH:3]=1)[CH:3]=[C:2]=[CH:7][CH3:6]
Reactant: O=S(=O)([O-])c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC=C=CCOc1ccc(S(=O)(=O)[O-])cc1
Temperature: 67.5 °C
Yield: 119.8 %

Procedure:
To a suspension of sodium 4-hydroxybenzenesulfonate (1.3 g, 5.6 mmol) in iso-propanol (20 ml) was added product from Example 8 (700 mg, 6.8 mmol) followed by 1N sodium hydroxide (6.1 ml, 6.1 mmol) and the resulting mixture was heated at 65-70° C. for 15 hours. The reaction mixture was concentrated in vacuo, the solid collected and washed with diethy ether to give 880 mg (53%) of the product as a solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8])([CH3:3])[CH3:2].O=S(Cl)[Cl:15]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([Cl:15])=[O:8])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)c1cccc(C(=O)O)c1
Product: CC(C)c1cccc(C(=O)Cl)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A mixture of 3-isopropyl-benzoic acid (5.00 g, 30.4 mmol) in SOCl2 (50 ml) was stirred at 100° C. for 2 h. The reaction mixture was concentrated to give 3-isopropyl-benzoyl chloride (5.00 g, 91%).
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].C(N(CC)C(C)C)(C)C.FC(F)(F)C(O[C:24]1[C:29]([F:30])=[C:28]([F:31])[C:27]([F:32])=[C:26]([F:33])[C:25]=1[F:34])=O>C(Cl)Cl>[O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([O:8][C:24]1[C:25]([F:34])=[C:26]([F:33])[C:27]([F:32])=[C:28]([F:31])[C:29]=1[F:30])=[O:7]
Reactant: CC(=O)CCCC(=O)O
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)CCCC(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 1 h
Yield: 79.3 %

Procedure:
5-Oxohexanoic acid (2.6 g; 20 mmol) was dissolved in CH2Cl2 (50 mL). N,N-Diisopropylethylamine (10.4 mL, 60 mmol) was added followed by pentafluorophenyl trifluoroacetate (3.61 mL; 21 mmol). The reaction mixture was kept at room temperature for 1 hour and evaporated. The residue was resuspended in EtOAc:Hexanes (1:1) and loaded on a silica gel column (5×20 cm) equilibrated and developed with the same mixture. Fractions containing the product (14) (Rf ˜0.7) were pooled and concentrated to give 4.7 g (79%) of yellowish oil after drying in vacuum. 1H NMR (CDCl3) δ 2.05 (m, 2H), 2.18 (s, 3H), 2.61 (t, 2H), 2.74 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])[NH:8]2)=[CH:4][C:3]=1[C:29]([O:31]CC)=[O:30].B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:16])([F:15])[F:17])[NH:8]2)=[CH:4][C:3]=1[C:29]([OH:31])=[O:30]
Reactant: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(NC(c1cccc(C(F)(F)F)c1)C(F)(F)F)c1cc2cc(C(=O)O)c(Cl)cc2[nH]1
Temperature: -10 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
Ethyl 6-chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate (2.90 g, 5.0 mmol, 85% pure) was dissolved in 5 ml of dichloromethane and a solution of boron tribromide in dichloromethane (27.5 ml, 27.5 mmol) was added dropwise at −10° C. The reaction mixture was stirred at −10° C. for 1 h and then at room temperature for 2 h. Water was added and the precipitated solid was filtered off with suction and dried. 1.85 g (79% of theory) of 6-chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylic acid were obtained.
Reaction SMILES: [OH-].[Na+].[S:3]1[CH2:7][C:6](=[O:8])[NH:5][C:4]1=[O:9].[F:10][C:11]([F:25])([F:24])[C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[CH2:15]Br.C(O)C>O>[F:10][C:11]([F:24])([F:25])[C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=1)[CH2:15][N:5]1[C:6](=[O:8])[CH2:7][S:3][C:4]1=[O:9]
Reactant: O=C1CSC(=O)N1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CSC(=O)N1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
5N Aqueous sodium hydroxide (0.5 mL) was added to a mixture of 2,4-thiazolidinedione (198.7 mg, 1.69 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (0.50 g, 1.63 mmol) and ethanol (5 mL), and the mixture was refluxed for 4 hours. After the reaction mixture was cooled to room temperature, it was poured into water and extracted with ethyl acetate. After the ethyl acetate layer was washed with brine and dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=3:1→2:1) to give the title compound (405.6 mg, 72.5%) as a white crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.Cl.[NH2:18][C:19]1[C:28]([NH2:29])=[C:27]2[C:22]([CH:23]=[C:24]([C:31]([OH:33])=[O:32])[CH:25]=[C:26]2[OH:30])=[CH:21][CH:20]=1.S(=O)(O)[O-].[Na+]>CCO.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([C:14]3[NH:18][C:19]4[CH:20]=[CH:21][C:22]5[C:27](=[C:26]([OH:30])[CH:25]=[C:24]([C:31]([OH:33])=[O:32])[CH:23]=5)[C:28]=4[N:29]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Nc1ccc2cc(C(=O)O)cc(O)c2c1N
Reactant: Cc1ccc(-c2ccc(C=O)o2)cc1C
Agent: Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2ccc(-c3nc4c(ccc5cc(C(=O)O)cc(O)c54)[nH]3)o2)cc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 17.6 %

Procedure:
To an agitated solution of 5-(3,4-dimethylphenyl)-furan-2-carbaldehyde (0.030 g, 0.15 mmol) in EtOH (0.80 mL) was added 7,8-diamino-1-hydroxy-3-naphthoic acid dihydrochloride (0.029 g, 0.10 mmol) and sodium bisulfite (30 mg) in water (0.20 mL). The solution was heated to 60° C. and agitated overnight. The solution was cooled to room temperature, the tan precipitate was isolated by filtration and washed with water and ethyl acetate to provide the title compound (0.007 g, 15%) MS(ES) m/z 399 [M−H].
Reaction SMILES: [OH:1][NH:2][C:3]([CH:5]1[CH:11]([CH2:12][O:13]C(=O)C)[CH2:10][CH:9]=[CH:8][CH2:7][N:6]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:4].OCC1CCCCN(S(C2C=CC(OC)=CC=2)(=O)=O)C1C(O)=O>>[OH:1][NH:2][C:3]([CH:5]1[CH:11]([CH2:12][OH:13])[CH2:10][CH:9]=[CH:8][CH2:7][N:6]1[S:17]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)(=[O:19])=[O:18])=[O:4]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(COC(C)=O)C2C(=O)NO)cc1
Agent: COc1ccc(S(=O)(=O)N2CCCCC(CO)C2C(=O)O)cc1
Product: COc1ccc(S(=O)(=O)N2CC=CCC(CO)C2C(=O)NO)cc1

Procedure:
3-Hydroxymethyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid hydroxyamide was synthesized from Acetic acid 2-hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepin-3-ylmethyl ester in the same manner as the procedures used for the preparation of 3-Hydroxymethyl-1-(4-methoxybenzenesulfonyl)-azepane-2-carboxylic acid hydroxamide: MS (M-H)- =355.
Reaction SMILES: [Br:1]/[CH:2]=[CH:3]\[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:14][C:15]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[Br:1]/[CH:2]=[CH:3]\[CH2:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:15]=2[CH3:14])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(OC/C=C\Br)cc1
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Product: Cc1c(NCc2ccc(OC/C=C\Br)cc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 57A and 2-methyl-3-nitroaniline were processed as described in Example 6A to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=1[C:12]1[N:17]2[N:18]=[C:19]([CH2:24][CH3:25])[C:20]([N+:21]([O-])=O)=[C:16]2[CH:15]=[CH:14][CH:13]=1.C(O)(=O)C>C(O)C.O.[Zn]>[CH3:11][O:10][C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[C:12]1[N:17]2[N:18]=[C:19]([CH2:24][CH3:25])[C:20]([NH2:21])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: CCc1nn2c(-c3c(OC)cc(C)cc3OC)cccc2c1[N+](=O)[O-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1nn2c(-c3c(OC)cc(C)cc3OC)cccc2c1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
After dissolving 7-(2,6-dimethoxy-4-methylphenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (600 mg) in a mixture of ethanol (30 mL) and water (30 mL), acetic acid (3 mL) and zinc powder (600 mg) were added and the mixture was stirred at 60° C. for 2 hours. The ethanol of the obtained reaction mixture was distilled off under reduced pressure, and then saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the residue and extraction was performed with ethyl acetate. The obtained organic layers were combined, washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridine-3-amine (500 mg) as a crude product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH:42](/[S:50](Cl)(=[O:52])=[O:51])=[CH:43]\[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(#N)C>[CH:42](/[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51])=[CH:43]\[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=S(=O)(Cl)/C=C/c1ccccc1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)/C=C/c3ccccc3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 210.4 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0269 g, 0.0583 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0490 mL, 0.350 mmol) and trans-β-styrenesulfonyl chloride (0.0350 g, 0.175 mmol) to obtain 4-(trans-β-styrenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0770 g, yield 21%).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:99]=[C:100]([F:102])[CH:101]=1)[CH2:50][N:51]1[CH:55]=[CH:54][C:53]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:73][CH2:72]5)=[C:67]([NH:84][S:85]([CH3:88])(=[O:87])=[O:86])[CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:99]=[C:100]([F:102])[CH:101]=1)[CH2:50][N:51]1[CH:55]=[CH:54][C:53]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:72][CH2:73][N:74]([C:77]([O:79][C:80]([CH3:83])([CH3:82])[CH3:81])=[O:78])[CH2:75][CH2:76]5)=[C:67]([NH:84][S:85]([CH3:88])(=[O:87])=[O:86])[CH:66]=4)[CH:63]=3)[NH:58][CH:57]=2)=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccn(Cc4cc(F)cc(F)c4)n3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5ccn(Cc6cc(F)cc(F)c6)n5)c4c3)cc2NS(C)(=O)=O)CC1
Yield: 78.7 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(1-(3,5-difluorobenzyl)-1H-pyrazol-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonamido)phenyl)piperazine-1-carboxylate (55 mg, 0.067 mmol) was hydrolyzed by lithium hydroxide (9 mg, 0.201 mmol) in THF/methanol/water (2/2/1 ml) to yield 35 mg (79.0% yield) of the titled compound after preparative TLC (Silicagel-1000 micron) using 60% ethyl acetate in hexane as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[C:4]([N+:13]([O-])=O)[CH:3]=1.[H][H]>C(O)C>[NH2:13][C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][CH2:9][CH2:10][CH2:11][OH:12]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1NCCCO
Reactant: [H][H]
Solvent: CCO
Product: Nc1cc(Cl)ccc1NCCCO

Procedure:
A mixture of 34.6 parts of 3-[(4-chloro-2-nitrophenyl)amino]-1-propanol and 320 parts of ethanol is hydrogenated at normal pressure and at room temperature with 8 parts of Raneynickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 30 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol as an oily residue.