Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH:29]2[C@:24](C)([CH2:25]CC(=O)[CH2:28]2)[C@@H:23]2[C@H:7]([C@H:8]3[C@:20]([CH3:32])([CH2:21][CH2:22]2)[C@@H:11]([C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]3)[CH2:6]1)(=[O:3])[CH3:2].[C:33]([O:36][C:37]([CH3:39])=[CH2:38])(=[O:35])[CH3:34].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:33]([O:36][C:37]1[CH2:39][C@@:24]2([CH3:25])[CH:29]([C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][C@@H:7]3[C@@H:23]2[CH2:22][CH2:21][C@@:20]2([CH3:32])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:19])[CH2:13][CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:28][CH:38]=1)(=[O:35])[CH3:34]
Reactant: C=C(C)OC(C)=O
Reactant: CC(=O)O[C@@H]1C[C@H]2[C@@H]3CC[C@H]([C@H](C)CCCC(C)C)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)CC12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)OC1=CCC2[C@H](OC(C)=O)C[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]3[C@@]2(C)C1
Yield: 95 %

Procedure:
A solution of 6β-acetoxycholestan-3-one (1) (1215 mg, 2.74 mmol) of isopropenyl acetate (15 ml) was refluxed in the presence of ρ-toluenesulfonic acid (20 mg) under argon for 3 hr. Most of the solvent was removed and the concentrated mixture was extracted with ethyl acetate. The extract was washed with saturated NaHCO3, and brine, and dried over MgSO4. The residue obtained upon evaporation of the solvent was purified by column chromatography on silica gel (40 g). Elution with benzene gave the enol-acetate (2) (1265 mg, 95%), glass; δ0.71(3H, s, 18-H3), 0.88(6H, d, J=6 Hz, 26- and 27-H3), 0.91(3H, d, J=6 Hz, 21-H3), 1.02(3H, s, 19-H3) 1.08 and 1.11 (6H, Sx2, 2- and 6-acetyl), 5.03(1H, m, 6α-H), and 5.23(1H, dd, J=5 and 2 Hz).
Reaction SMILES: [OH:1][C:2]1([C:9]([OH:11])=[O:10])[CH2:7][CH:6]2[CH2:8][CH:3]1[CH:4]=[CH:5]2.[H][H]>C(OCC)(=O)C.[C].[Pd]>[OH:1][C:2]1([C:9]([OH:11])=[O:10])[CH2:7][CH:6]2[CH2:8][CH:3]1[CH2:4][CH2:5]2
Reactant: [H][H]
Reactant: O=C(O)C1(O)CC2C=CC1C2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(O)C1(O)CC2CCC1C2
Yield: 143.1 %

Procedure:
In 100 ml of ethyl acetate, 10.0 g of the 2-hydroxy-5-norbornene-2-carboxylic acid of Formula (4a) obtained in Step b. was dissolved. To the resulting solution, 0.5 g of 10% palladium carbon was further added as a catalyst for catalytic hydrogenation. This solution was stirred for 2 hours in an atmosphere of hydrogen gas to carry out catalytic hydrogenation. After the reaction was completed, the catalyst was separated by filtration and the ethyl acetate was evaporated from the filtrate under reduced pressure to obtain 14.5 g of crude 2-hydroxynorbornane-2-carboxylic acid of Formula (5a).
Reaction SMILES: F[C:2](F)(F)C(O)=O.[OH:8][C:9]1[C:20]2=[C:21]3[CH:16]([CH2:17][C:18]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:19]=42)[CH2:15][N:14]([CH3:30])[CH2:13][C:12]3=[CH:11][C:10]=1[O:31][CH3:32].C1(C)C=CC=CC=1.[OH-].C1([N+](C)(C)C)C=CC=CC=1.[ClH:51]>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:2][O:8][C:9]1[C:20]2=[C:21]3[CH:16]([CH2:17][C:18]4[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[CH:22][C:19]=42)[CH2:15][N:14]([CH3:30])[CH2:13][C:12]3=[CH:11][C:10]=1[O:31][CH3:32].[ClH:51]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c(cc1OC)-c1c(O)c(OC)cc3c1C(C2)CN(C)C3
Agent: C[N+](C)(C)c1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1OC)-c1c(OC)c(OC)cc3c1C(C2)CN(C)C3

Procedure:
2.2 g. (±)-5,6,6a,7-Tetrahydro-1-hydroxy-2,9,10-trimethoxy-5-methyl-4H-dibenz(de,g)isoquinoline trifluoro acetate (see Example 3) are dissolved in 10 ml. of a mixture of toluene and dimethylformamide (9:1 v/v) and methylated with phenyltrimethylammonium hydroxide in a manner analogous to that described in Example 7. When the reaction is finished, the reaction mixture is evaporated in a vacuum and the residue is partitioned between water and methylene chloride. The organic phase is worked up in the usual manner and the crude product obtained is converted, either directly or after previous chromatography on silica gel with chloroform as eluent, into the hydrochloride by treatment with ethanolic hydrochloric acid. Crystallisation from ethanol/diethyl ether gives (±)-5,6,6a,7-tetrahydro-1,2,9,10-tetramethoxy-5-methyl-4H-dibenz(de,g)isoquinoline in the form of a yellow hydrochloride; m.p. 212°-225° C.
Reaction SMILES: [N:1]1[C:9]2[CH2:8][CH2:7][N:6](C(OCC)=O)[CH2:5][C:4]=2[S:3][C:2]=1[C:15]([O:17]CC)=[O:16].[ClH:20]>[OH-].[K+]>[ClH:20].[N:1]1[C:9]2[CH2:8][CH2:7][NH:6][CH2:5][C:4]=2[S:3][C:2]=1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)c1nc2c(s1)CN(C(=O)OCC)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: O=C(O)c1nc2c(s1)CNCC2
Temperature: 0 °C
Yield: 60 %

Procedure:
Diethyl 6,7-dihydrothiazolo[5,4-c]pyridine-2,5(4H)-dicarboxylate (1.76 mmol) in 3.5 N KOH solution (3 ml) was refluxed for 3 h (monitored by TLC). The reaction mixture was cooled to 0° C. and acidified with conc. HCl. The solid was collected by filtration and dried to yield the desired product. Yield: 60%.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].C([O-])([O-])=O.[K+].[K+].[Cl:25][C:26]1[C:31](Cl)=[N:30][CH:29]=[CH:28][N:27]=1.CC(OC)(C)C.C(Cl)Cl>CN(C=O)C>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:31]2[C:26]([Cl:25])=[N:27][CH:28]=[CH:29][N:30]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: Clc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(Oc2nccnc2Cl)cc1)c1nc2ccccc2[nH]1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a solution of compound (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (100 g, 0.42 mol) in anhydrous DMF (1.1 L) was added K2CO3 (145 g, 1.05 mol, 2.5 eq.) and 2,3-dichloropyrazine (75.08 g, 0.50 mol, 1.2 eq.). The reaction was stirred at 90° C. for 18 h. LCMS analysis of the reaction mixture showed that the reaction was complete. The reaction mixture was cooled to ambient temperature and ice-water (3 L) was added, stirred for 30 minutes. The resulting solid was filtered and washed with water (3 L) followed by MTBE (2×500 mL) and dried under vacuum. The solid was treated with 50% MTBE/DCM at 50° C. for 1 h and filtered hot, washed with 50% MTBE/DCM and dried under vacuum overnight to obtain product. Mother liquor was refluxed with 50% MTBE/DCM for 2 h and filtered hot and washed with 50% MTBE/DCM to get another batch of product. MS (ESI, pos. ion) m/z: 351.0 (M+1). IC50 (uM) +.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:27][C:28]([OH:30])=O)=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:20])=[CH:15][CH:14]=2)[S:11][CH:12]=1.Cl.[N:32]1([C:37]([NH2:39])=[NH:38])[CH:36]=[CH:35][CH:34]=[N:33]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:27][C:28](=[O:30])[NH:39][C:37](=[NH:38])[N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([NH:21][CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:20])=[CH:15][CH:14]=2)[S:11][CH:12]=1
Reactant: N=C(N)n1cccn1
Reactant: CCC(CC)NC(=O)c1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)O)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(CC)NC(=O)c1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)n2cccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
[4-(2-Chlorophenyl)-2-(4-{[(1-ethylpropyl)amino]carbonyl}phenyl)thien-3-yl]acetic acid (0.125 g, 0.282 mmol) was dissolved in CH2Cl2 (2 mL) and carbonyldiimidizole (0.229 g, 1.41 mmol) was added. The solution was stirred under argon at room temperature for 30 min. 1-H-Pyrazole-1-carboxamidine hydrochloride (0.413 g, 2.82 mmol) and diisopropyl ethylamine (0.737 mL, 4.23 mmol) were added to the solution and stirred overnight. The solvent was removed and the mixture was absorbed onto silica gel and purified by flash chromatography (20:1 CHCl3:MeOH) to yield 4-(4-(2-chloro-phenyl)-3-{[(imino-pyrazol-1-yl-methyl)-carbamoyl]-methyl}-thiophen-2-yl)-N-(1-ethyl-propyl)-benzamide (0.087 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=[C:7]2[C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C.[C:30]([CH2:34][C:35](Cl)=[O:36])([CH3:33])([CH3:32])[CH3:31].O>C(Cl)Cl>[CH3:31][C:30]([CH3:33])([CH3:32])[CH2:34][C:35]([O:20][C:17]1[CH:16]=[CH:15][C:14]([C:7]2[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=[CH:4][CH:5]=3)[N:9]([CH2:11][CH2:12][CH3:13])[N:8]=2)=[CH:19][CH:18]=1)=[O:36]
Reactant: CCCn1nc(-c2ccc(O)cc2)c2cccc(Cl)c21
Reactant: CC(C)(C)CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCn1nc(-c2ccc(OC(=O)CC(C)(C)C)cc2)c2cccc(Cl)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of 4-(7-chloro-1-propyl-1H-indazol-3-yl)phenol (0.100 g, 0.35 mmol) and N,N-diisopropylethyl amine (0.5 g, 0.38 mmol) in CH2Cl2 (5 mL) was added dropwise tert-butylacetyl chloride (0.051 g, 0.38 mmol). The solution was allowed to stir overnight at room temperature. Water was added and the solution was extracted with CH2Cl2. The organic layer was washed with brine and dried (MgSO4). The product was purified by flash chromatography (5/1 hexane/ethyl acetate) to yield a white solid (0.098 g, 72%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:6]([CH3:18])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]=1[CH3:10].[N+:20]([O-])([OH:22])=[O:21]>OS(O)(=O)=O>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[C:6]([CH3:18])=[N:7][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:20]([O-:22])=[O:21])=[CH:14][CH:13]=2)[C:9]=1[CH3:10]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Cc1c(C)nn(Cc2ccccc2)c1C
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2)c1C
Temperature: -7 °C

Procedure:
Under cooling, (1-benzyl-3,5-dimethyl-1H-pyrazol-4-yl)-acetic acid methyl ester (intermediate 1.1.1, 3.10 g, 12.0 mmol) was dissolved in conc. H2SO4 (7 mL). The mixture was cooled to −7° C. and HNO3 (65%, 0.77 mL) was added dropwise under stirring, keeping the temperature below 0° C. The reaction mixture was allowed to come to room temperature and stirred for 20 min at room temperature. The reaction mixture was poured into ice water, extracted with dichloromethane and the organic layer was concentrated under reduced pressure. The resulting product is a mixture of regioisomers, with the 4-nitro isomer as the main product.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([C:17]([O:23][C:24]4[CH:25]=[C:26]5[C:30](=[CH:31][CH:32]=4)[NH:29][CH:28]=[C:27]5[CH3:33])=[N:18][CH:19]=[N:20]3)=[CH:15][C:14]=2[O:34][CH3:35])[CH2:7][CH2:6]1)=[O:4].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1.[I-].[K+]>CN(C=O)C>[CH3:35][O:34][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:13]=1[O:12][CH2:11][CH:8]1[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[CH2:6][CH2:7]1)[N:20]=[CH:19][N:18]=[C:17]2[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH3:33]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(C(=O)CCl)CC1
Reactant: C1CCNC1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCC1CCN(C(=O)CN2CCCC2)CC1
Temperature: 80 °C

Procedure:
A mixture of 7-{[1-(chloroacetyl)piperidin-4-yl]methoxy}-6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]quinazoline (0.118 g), pyrrolidine (0.059 ml), potassium iodide (0.01 g) and DMF (3 ml) was stirred and heated to 80° C. for 40 minutes. The mixture was cooled to ambient temperature, the solvent was removed by evaporation under vacuum and the residue was purified by column chromatography on silica using increasingly polar solvent mixtures, starting with dichloromethane and ending dichloromethane/methanol saturated with ammonia (3.5M) (94/6). Evaporation of the solvents gave a foam which was triturated under ether/pentane (70/30) to give a solid which was collected by filtration and dried under vacuum to give 6-methoxy-4-[(3-methyl-1H-indol-5-yl)oxy]-7-{[1-(pyrrolidin-1-ylacetyl)piperidin-4-yl]methoxy}quinazoline (0.096 g).
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].CS(O[CH2:19][CH:20]=[CH:21][C:22]([F:25])([F:24])[F:23])(=O)=O>>[CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([CH2:19][CH:20]=[CH:21][C:22]([F:25])([F:24])[F:23])[C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: CS(=O)(=O)OCC=CC(F)(F)F
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Product: COC(=O)c1c(C=O)c(C)c(C)n1CC=CC(F)(F)F

Procedure:
The title compound (trans) was prepared as a pale yellow oil in 60.0% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 4,4,4-trifluoro-2-butenyl methanesulfonate (trans).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C@@H:4]([CH2:5][C:6](=O)[CH3:7])[C@H:3]1[C:9]([OH:11])=[O:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OC(=O)C)(=O)C.C1C=CC=CC=1.CCOCC>[CH3:7][C:6]1[O:10][C:9](=[O:11])[C@@H:3]2[C@H:4]([CH:5]=1)[C:2]2([CH3:12])[CH3:1]
Reactant: CC(=O)C[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC1=C[C@H]2[C@@H](C(=O)O1)C2(C)C
Yield: 92.8 %

Procedure:
A solution of 20 g (0.17 mol) of (1R,cis)-2,2-dimethyl-3-(2-oxopropyl)cyclopropane-1-carboxylic acid and 3 g (0.016 mol) of p-toluenesulfonic acid monohydrate in 93 ml of acetic anhydride and 150 ml of benzene was stirred for 30 minutes at 10°-20° C. The slightly darkened mixture was diluted with ether and washed with ice cold saturated sodium bicarbonate solution until the washings were basic. The organic phase was dried over anhydrous magnesium sulfate and decolorized with charcoal. The solvent was evaporated in vacuo to give 24 g (93%) of the product as a tan solid. Recrystallization from pentane gave a white solid (III) mp 44°-45.5° C., [α]D25 -85.6° (c, 2.0; CHCl3).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]([C:23]([N:25]([CH2:35][CH2:36][O:37][CH3:38])[C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-])=O)=[CH:28][CH:27]=3)=[O:24])[CH2:11]2)=[CH:6][CH:5]=1)[CH3:2].[Sn]>>[NH2:32][C:29]1[CH:28]=[CH:27][C:26]([N:25]([CH2:35][CH2:36][O:37][CH3:38])[C:23]([CH:12]2[CH2:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=3)[CH2:15][CH2:14][N:13]2[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:24])=[CH:31][CH:30]=1
Reactant: CCOc1ccc(N2CCN(Cc3ccccc3)C(C(=O)N(CCOC)c3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: [Sn]
Product: CCOc1ccc(N2CCN(Cc3ccccc3)C(C(=O)N(CCOC)c3ccc(N)cc3)C2)cc1

Procedure:
In a manner similar to Preparation 20, react 4-(4-ethoxyphenyl)-N-(2-methoxyethyl)-N-(4-nitrophenyl)-1-(phenylmethyl)-2-piperazinecarboxamide with tin II chloride to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]1.[C:17](O)(=[O:19])[CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:10][C:11](=[O:16])[C:12](=[C:17]([OH:19])[CH3:18])[C:13](=[O:15])[CH2:14]1
Reactant: CC(=O)O
Reactant: O=C1CC(=O)CC(c2cc(Cl)ccc2Cl)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(O)=C1C(=O)CC(c2cc(Cl)ccc2Cl)CC1=O
Temperature: 25 °C
Reaction time: 36 h
Yield: 80.2 %

Procedure:
To a solution of 5-(2,5-dichlorophenyl)cyclohexane-1,3-dione (1.5 g), 4-dimethylaminopyridine (1.1 g) and acetic acid (0.63 g) in dimethylformamide (60 ml) was added dicyclohexylcarbodiimide (1.3 g), and the mixture was stirred at room temperature for 36 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was extracted with 1N sodium hydroxide solution, and the aqueous layer was filtered. Insoluble materials were filtered off, and the filtrate was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated to give 5-(2,5-dichlorophenyl)-2-(1-hydroxyethylidene)cyclohexane-1,3-dione (1.4 g), which was dissolved in ethanol (30 ml). To the solution was added hydrazine hydrate (0.26 g), and the mixture was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate-hexane) to give 6-(2,5-dichlorophenyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (1.2 g) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:23])[NH:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[N:8]([CH3:10])[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[N:24]1[CH:29]=[CH:28][C:27]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.C(O)C(N)(CO)CO>ClCCl.CN(C=O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([N:34]3[CH2:35][CH2:36][N:31]([CH2:30][C:27]4[CH:26]=[CH:25][N:24]=[CH:29][CH:28]=4)[CH2:32][CH2:33]3)=[O:19])=[CH:21][CH:22]=2)=[O:23])[N:8]([CH3:10])[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(C(=O)O)cc1
Reactant: c1cc(CN2CCNCC2)ccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccncc3)CC2)cc1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
To a solution of 4-[3-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-ureido]benzoic acid (0.08 g, 0.26 mmol) in a mixture of dichloromethane (4 mL) and DMF (0.20 mL) is added 1-(4-pyridinylmethyl)piperazine (0.046 g, 0.26 mmol), PS-DCC (0.41 g, 0.52 mmol) and HOBT (0.035 g, 0.26 mmol). The mixture is stirred overnight at 45° C. in a closed tube (orbital stirring). Then PS-Trisamine is added (0.52 mmol) and the mixture is stirred for 4 hr at room temperature, filtrated, and washed three times with dichloromethane. The solvents are evaporated under reduced pressure and the residue is purified by biotage column chromatography (eluent: ethyl acetate/methanol 10:1) to give 0.020 g (0.04 mmol), 16% as white solid. ES+(m/z)=476 [M+H].
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1.CC(N(C)C)=O>CO>[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[C:3]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)(=[O:15])=[O:14])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:25][CH:24]=1
Reactant: O=S(=O)(Nc1nc2ccccc2nc1Cl)c1ccccc1
Reactant: Nc1ccc(F)cc1
Solvent: CO
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Nc1nc2ccccc2nc1Nc1ccc(F)cc1)c1ccccc1
Temperature: 120 °C
Yield: 61.8 %

Procedure:
A CEM microwave reaction vessel was charged with N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (52 mg, 0.16 mmol), prepared using procedures similar to those described in the above step, 4-fluoroaniline (36 mg, 0.32 mmol), and 0.8 mL of dimethylacetamide. The vessel was sealed and the reaction mixture was heated under microwave radiation for 25 m at 120° C. in a CEM Discover microwave instrument. Methanol (1 mL) was added to the reaction mixture and after 20 minutes the product precipitated out of the solution. Filtration yielded N-(3-(4-fluorophenylamino)quinoxalin-2-yl)benzenesulfonamide (39 mg, 62%). 1H-NMR (400 MHz, do-DMSO): δ 12.30 (s, 1H), 9.11 (s, 1H), 8.16-8.10 (d, 2H), 8.02-7.90 (m, 3H), 7.68-7.58 (m, 3H), 7.55-7.51 (m, 1H), 7.41-7.32 (m, 2H), 7.25-7.16 (m, 2H); MS (EI) m/z C20H15FN4O2S: 395.0 (MH+).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[C:17]([C:36]2[CH:48]=[C:47]([F:49])[C:39]3[N:40]=[C:41]([CH3:46])[N:42]([CH:43]([CH3:45])[CH3:44])[C:38]=3[CH:37]=2)=[N:18][C:19]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:25][N:24]=2)=[N:20][CH:21]=1.[CH3:50][C:51]([CH3:53])=O.ClCCCl>C(O)(=O)C>[F:15][C:16]1[C:17]([C:36]2[CH:48]=[C:47]([F:49])[C:39]3[N:40]=[C:41]([CH3:46])[N:42]([CH:43]([CH3:45])[CH3:44])[C:38]=3[CH:37]=2)=[N:18][C:19]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][N:30]3[CH2:31][CH2:32][N:33]([CH:51]([CH3:53])[CH3:50])[CH2:34][CH2:35]3)=[CH:25][N:24]=2)=[N:20][CH:21]=1
Reactant: CC(C)=O
Reactant: Cc1nc2c(F)cc(-c3nc(Nc4ccc(CN5CCNCC5)cn4)ncc3F)cc2n1C(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1nc2c(F)cc(-c3nc(Nc4ccc(CN5CCN(C(C)C)CC5)cn4)ncc3F)cc2n1C(C)C
Temperature: 60 °C

Procedure:
Add sodium triacetoxyborohydride (299.9 mg) to a mixture of [5-fluoro-4-(7-fluoro-3-isopropyl-2-methyl-3H-benzoimidazol-5-yl)-pyrimidin-2-yl]-(5-piperazin-1-ylmethyl-pyridin-2-yl)-amine (130 mg), acetone (31.6 μL), 1,2-dichloroethane (9 mL) and acetic acid (16.3 μL). Heat at 60° C. for 1 h. Remove the solvent under vacuum. Purify by strong cation exchange cartridge (SCX) eluting with methanol and then methanol-NH3 2 M followed by silica gel column chromatography eluting with DCM/methanol-NH3 2 M (3%) to afford 115 mg of the title compound. MS (ES+): m/z=521 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[CH:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].S(=O)(=O)(O)O>C(O)(=O)C.O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[CH3:10][O:9][C:7]([CH2:6][C:5]1[O:1][N:2]=[C:3]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[C:4]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: COC(=O)CC=C(C(=NO)c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Cc1onc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Yield: 90 %

Procedure:
A 3.7 g quantity of methyl 5-hydroxyimino-4,5-bis(4-methoxyphenyl)-3-pentenoate was heated at 60° C. with stirring for 24 hours in 40 ml of acetic acid in the presence of 0.4 g of cobalt acetate tetrahydrate while passing air through the mixture. After addition of 3N sulfuric acid, the reaction mixture was subjected to extraction with ethyl acetate, and the organic layer was washed with a saturated solution of potassium carbonate and then with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The organic layer was concentrated at a reduced pressure, and the residue was subjected to silica gel column chromatography (eluants: ethyl acetate-n-hexane) for separation and purification, giving 3.3 g (yield 90%) of the above-identified compound as a while solid product.