Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5](=O)[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:3].[NH2:17][NH2:18].O>C(O)C>[CH2:6]([C:5]1[CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:2]([CH3:3])([CH3:1])[NH:18][N:17]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCC(=O)C(=C(C)C)c1ccccc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CCCCC1=NNC(C)(C)C1c1ccccc1
Yield: 98.6 %

Procedure:
To a magnetically stirred solution of 2-methyl-3-phenyloct-2-en-4-one (Intermediate III-1) (1.96 gram, 9.07 mmol) in absolute ethanol (15 ml) was added hydrazine.hydrate (0.88 ml, 18.14 mmol) and the resulting solution was heated at reflux temperature for 4 hours under a nitrogen atmosphere. The resulting solution was allowed to attain room temperature, concentrated and taken up in a mixture of MTBE and water. The organic layer was collected, dried over MgSO4, filtered and concentrated to give crude 3-(n-butyl)-5,5-dimethyl-4-phenyl-4,5-dihydropyrazole (Intermediate IV-1) (2.06 gram) as an oil. 1H-NMR (400 MHz, CDCl3) δ 0.80-0.89 (m, 6H), 1.23-1.37 (m, 5H), 1.42-1.54 (m, 2H), 2.06-2.35 (m, 2H), 3.52 (s, 1H), 4.90 (br s, 1H), 7.07 (br d, J˜8 Hz, 2H), 7.19-7.38 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]([NH2:20])=O)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[O:9]2)=[CH:4][CH:3]=1.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1N.C1(C)C=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:9])[C:12]3[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10](=[O:17])[N:21]3[CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]4[N:20]=[C:18]23)=[CH:4][CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: NC(=O)C1(c2ccc(F)cc2)OC(=O)c2ccccc21
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(O)(c2ccc(F)cc2)C2=NC3CCCCC3N12
Yield: 41.8 %

Procedure:
A mixture of 1-(4-fluorophenyl)-3-oxo-1,3-dihydro-2-benzofuran-1-carboxamide (5 g) (Step 1 of Example 2), trans 1,2-diaminocyclohexane (8.3 g), and toluene (75 mL) was heated at reflux for 66 h in a flask equipped with a water separator. The mixture was evaporated to dryness and the residual gum was extracted with hexane. The residue was chromatographed over silica gel and eluted with 10% methanol in methylene. Crystallization from ethyl acetate afforded the title compound (2.7 g) as a white solid m.p. 203-205° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[O:13][CH3:14])[CH3:2].CCO>[Pd].CCOC(C)=O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[O:13][CH3:14])[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOc1ccc(N)cc1OC
Yield: 103.3 %

Procedure:
A suspension of 2-ethoxy-5-nitroanisole from Step 1 (5.50 g, 27.9 mmol) and 10% Pd/C (1.0 g) in 1:1 EtOH:EtOAc (50 ml) was shaken under an atmosphere of H2 (35-40 psi) for 30 min. The reaction mixture was filtered through Celite and concentrated under vacuum to afford 4-ethoxy-3-methoxyaniline (4.82 g, 100%) as a brown solid: mp 54-56° C. 1H NMR (DMSO-d6) δ 6.61 (d, 1H), 6.25 (d, 1H), 6.03 (dd, 1H), 4.65 (s, 2H), 3.82 (q, 2H), 3.66 (s, 3H), 1.22 (t, 3H); 13C NMR (DMSO-d6) δ 143.6, 138.8, 116.6, 105.1, 99.9, 65.0, 55.1, 15.1; MS (ESI+) for m/z 168 [M+H]+.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([NH:11][C:12]([C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:21][C:20]=2[O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:16][N:15]=1)=[O:13])[CH3:10]>C(#N)C.[N+]([O-])([O-])=O.[Ce].[NH4+]>[CH2:9]([NH:11][C:12]([C:14]1[C:18]([I:1])=[C:17]([C:19]2[CH:24]=[C:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:22]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:21][C:20]=2[O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:16][N:15]=1)=[O:13])[CH3:10]
Reactant: O=C1CCC(=O)N1I
Reactant: CCNC(=O)c1cc(-c2cc(C(C)(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CC#N
Product: CCNC(=O)c1noc(-c2cc(C(C)(C)C)c(OCc3ccccc3)cc2OCc2ccccc2)c1I
Reaction time: 18 h
Yield: 62.2 %

Procedure:
N-iodosuccinimide (9.0 g, 40 mmol) was added to a suspension of 5-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-isoxazole-3-carboxylic acid ethylamide (9.9 g, 20.4 mmol) in acetonitrile (60 ml). Ammonium cerium nitrate (0.25 g, 0.46 mmol) was added and the suspension stirred for ˜18 hrs. The resulting suspension was concentrated and the residue taken up in dichloromethane (125 ml). The resulting solution was washed aqueous sodium metabisulphite solution (2×100 ml, 5%), water (100 ml) and saturated aqueous sodium chloride solution (100 ml). The solution was dried over anhydrous sodium sulphate and concentrated to a pale red gum. Trituration with ethanol (25 ml) gave an off-white solid, solids were removed by filtration and washed with ethanol. Dried in vacuo (40° C.), to give 5-(2,4-Bis-benzyloxy-5-tert-butyl-phenyl)-4-iodo-isoxazole-3-carboxylic acid ethylamide as an off-white powder (7.75 g, 62%).
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]\[C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]1(/[CH:7]=[CH:8]\[C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)/C=C\c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C\c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
1.1 g of methyl (Z)-3-phenylacrylate are dissolved in a mixture of 30 ml of tetrahydrofuran and 10 ml of water, and 340 mg of lithium hydroxide are added. The mixture is stirred at 60° C. After four hours, the reaction mixture is acidified by adding one molar hydrochloric acid solution and extracted five times with 50 ml of ethyl acetate each time. The combined organic phases are dried over MgSO4 and then the solvent is removed in vacuo. 900 mg of (Z)-3-phenylacrylic acid are obtained as an oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[CH:28]1([C:31](O)=[O:32])[CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31]([CH:28]5[CH2:30][CH2:29]5)=[O:32])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)C1CC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)C1CC1

Procedure:
The title compound, white solid (31 mg, 49%), MS (ISP) m/z=399.3 [(M+H)+], mp 193° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (70.4 mg, 0.16 mmol) cyclopropane-carboxylic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1O)([O-:3])=[O:2].[C:11](=[O:14])([O-])[O-].[K+].[K+].Br[CH:18]([Cl:21])[CH2:19]C>C(#N)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:14][CH2:11][CH2:19][CH2:18][Cl:21])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C([O-])[O-]
Reactant: CCC(Cl)Br
Reactant: O=[N+]([O-])c1ccccc1O
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(OCCCCl)cc1
Temperature: 25 °C

Procedure:
Nitrophenol (10 g, 72 mmol) was dissolved in acetonitrile (100 mL) and potassium carbonate (24.9 g, 180 mmol) added followed by bromochloropropane (113.2 g, 720 mmol). The mixture was heated and stirred under reflux overnight. The reaction was cooled to room temperature, the solid was then filtered off and the solvent evaporated under reduced pressure, taking care to remove all excess alkylating agent, to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11](Cl)[NH:10][C:9]=2[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:16][C:17]1[C:18]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=NC=C[CH:22]=1.[CH:29]([N:32](CC)C(C)C)(C)[CH3:30]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:12]=[C:11]([N:26]3[CH2:25][CH2:24][N:23]([C:18]4[CH:30]=[CH:29][N:32]=[CH:22][C:17]=4[Cl:16])[CH2:28][CH2:27]3)[NH:10][C:9]=2[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: Clc1cccnc1N1CCNCC1
Reactant: CC(C)(C)c1ccc2nc(Cl)[nH]c2c1
Agent: Cl
Product: CC(C)(C)c1ccc2nc(N3CCN(c4ccncc4Cl)CC3)[nH]c2c1

Procedure:
The benzoimidazole from step (b) above (0.209 g, 1 mmol), 1-(3-chloropyridin-2-yl)piperazine hydrochloride (0.304 g, 1.3 mmol, Example 3b) and N,N-diisopropylethylamine (0.45 mL, 2.6 mmol, Aldrich) were reacted under the conditions of Example 1d to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 371 (M+1).
Reaction SMILES: N1CC[CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:35]=[CH:34][C:15]4[N:16]([C:19]5[CH:20]=[C:21]([NH:25][C:26]([NH:28][CH2:29][C:30]([F:33])([F:32])[F:31])=[O:27])[CH:22]=[CH:23][CH:24]=5)[CH:17]=[N:18][C:14]=4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3]C1.[CH2:36]([O:38]C(N1C=C(B2OC(C)(C)C(C)(C)O2)C=N1)C)[CH3:37]>>[CH2:36]([O:38][CH:4]([N:7]1[CH:11]=[C:10]([C:12]2[CH:35]=[CH:34][C:15]3[N:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26]([NH:28][CH2:29][C:30]([F:32])([F:31])[F:33])=[O:27])[CH:22]=[CH:23][CH:24]=4)[CH:17]=[N:18][C:14]=3[CH:13]=2)[CH:9]=[N:8]1)[CH3:3])[CH3:37]
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-n2cnc3cc(-c4cnn(C5CCNCC5)c4)ccc32)c1
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CCOC(C)n1cc(-c2ccc3c(c2)ncn3-c2cccc(NC(=O)NCC(F)(F)F)c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 21 (step 3) starting from N-{3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-benzimidazol-1-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea (prepared from the procedure for Example 21, step 4) and 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Adesis, Cat. No. 9-243), LCMS (M+H)+: m/z=473.1.
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([SH:13])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:20]([C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].O>CN(C)C=O>[C:1]([N:5]1[C:10](=[O:11])[C:9]([Cl:12])=[C:8]([S:13][CH2:28][C:27]2[CH:30]=[CH:31][C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:25][CH:26]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CCl)cc1
Reactant: CC(C)(C)n1ncc(S)c(Cl)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CSc2cnn(C(C)(C)C)c(=O)c2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
In 15 ml of N,N-dimethylformamide was dissolved 2.0 g (0.0092 mol) of 2-t-butyl-4-chloro-5-mercapto-3(2H)-pyridazinone. The resulting solution was added with 1.3 g (0.0123 mol) of anhydrous sodium carbonate and 1.6 g (0.0088 mol) of 4-t-butylbenzyl chloride, and then heated under stirring at 80°~110° C. for two hours. The resulting mixture was cooled to room temperature, and then added with 100 ml of water and stirred. The solid thus precipitated was filtered off, washed with water, dried, and recrystallized from ethanol to obtain 2.9 g of 2 -t-butyl-5-(p-t-butylbenzylthio)-4-chloro-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][C:2]1[C:12](=[O:13])[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:4](=[O:5])[CH:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23]C(O)=O)=[CH:19][CH:18]=1)([OH:16])=[O:15]>>[CH3:1][C:2]1[C:12](=[O:13])[CH:11]2[CH:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)[C:4](=[O:5])[C:3]=1[CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:14]([OH:16])=[O:15])=[CH:18][CH:19]=1
Reactant: CC1=CC(=O)c2ccccc2C1=O
Reactant: O=C(O)Cc1ccc(C(=O)O)cc1
Product: CC1=C(Cc2ccc(C(=O)O)cc2)C(=O)C2C=CC=CC2C1=O
Yield: 12 %

Procedure:
As starting materials for the coupling reaction menadione and 4-carboxyphenylacetic acid were used. Synthesis is realized according to the general procedure described in general procedure of example 1. After chromatography on silica gel (petroleum ether:CH2Cl2=1:3, UV), 102 mg (0.33 mmol, 12% yield) of P_TM50 were isolated as yellow solid.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:33])[NH:29][CH:30]([CH3:32])[CH3:31])[CH:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:42])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28](=[O:33])[NH:29][CH:30]([CH3:31])[CH3:32])[CH:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CC(C)NC(=O)c1cccc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)NC(=O)c1cccc(-c2cnc3[nH]cc(C(=O)N[C@H](C)C(=O)N4CC(C#N)C4)c3n2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
To a solution of 2-(3-isopropylcarbamoyl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (52 mg, 0.088 mmol) in CH2Cl2 (4 mL) was added TFA (1.5 mL). The reaction mixture was stirred at room temp for 3 h then concentrated. The residue was redissolved in CH2Cl2 (4 mL) and ethylenediamine (0.5 mL) was added. The reaction mixture was stirred at room temp for 0.5 h then concentrated. The residue was purified by silica gel chromatography (50% to 100% EtOAc/hexanes to 5% MeOH) then triturated with Et2O to isolate 30 mg (70%) of 2-(3-isopropylcarbamoyl-phenyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white powder. MS: (M+H)+=460.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([NH2:21])[CH2:10][CH:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:22][CH3:23])=[O:4].C(O)(=O)C.[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([C@H:9]([NH:21][CH2:33][C:32]3[CH:35]=[C:36]([C:38]([F:40])([F:41])[F:39])[CH:37]=[C:30]([C:29]([F:28])([F:42])[F:43])[CH:31]=3)[CH2:10][C@H:11]([CH3:20])[N:12]2[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=1[O:22][CH3:23])=[O:4]
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2C(N)CC1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)N1c2cc(C(=O)OC)c(OC)cc2[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 4-amino-6-methoxy-2-methyl-3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-ethyl ester 7-methyl ester (208 mg, 0.64 mmol) in anhydrous 1,2-dichloroethane (5 mL) was added acetic acid (0.041 mL, 0.71 mmol), followed by 3,5-bis(trifluoromethyl)benzaldehyde (172 mg, 0.71 mmol) and sodium triacetoxyborohydride (0.205 g, 0.97 mmol). The reaction was stirred at room temperature for 2 h. The reaction mixture was partitioned between dichloromethane (45 ml) and water (100 ml) and the aqueous phase was adjusted to pH 9. The aqueous phase was extracted with dichloromethane (3×10 mL). The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 20% acetone/hexanes as eluent afforded the title product (337 mg, 95%). MS m/z 567 (M+ +NH4); 1H NMR (CDCl3) δ 1.40 (d, 3H), 7.14 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][OH:12])[C:5]=2[N:6]=1.CCN(CC)CC.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1COCC1.O>[CH3:20][S:21]([O:12][CH2:11][CH:7]1[C:5]2[N:6]=[C:2]([NH2:1])[S:3][C:4]=2[CH2:10][CH2:9][CH2:8]1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1nc2c(s1)CCCC2CO
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCC1CCCc2sc(N)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-4-yl)methanol (3.3 mmol) and Et3N (1.4 mL, 10 mmol) in THF (10 mL) was added MsCl (0.3 mL, 3.6 mmol) dropwise at room temperature. The resulting mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water (200 mL), filtered, and dried to give the crude product, which was used directly in the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7]O)[CH:3]=[N:2]1.[NH2:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[SH:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C(Cl)Cl>[NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][S:17][C:11]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:10]=2[NH2:9])[CH:3]=[N:2]1
Reactant: OCCc1cn[nH]c1
Reactant: Nc1cc(Cl)ccc1S
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Nc1cc(Cl)ccc1SCCc1cn[nH]c1

Procedure:
Following the General Procedure J, the title intermediate was prepared from 2-(1H-pyrazol-4-yl) ethanol (472 mg, 4.218 mmol), 2-amino-4-chlorobenzenethiol (1.01 g, 6.327 mmol), PPh3 (2.21 g, 8.436 mmol) and di-tert-butylazodicarboxylate (1.9 g, 8.436 mmol) in CH2Cl2 (20 ml).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[CH:20]=O.C(O)(=O)C.[O:26]=[C:27]1[CH2:32][NH:31][CH2:30][CH2:29][NH:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:5]2[CH2:20][N:31]1[CH2:30][CH2:29][NH:28][C:27](=[O:26])[CH2:32]1
Reactant: O=C1CNCCN1
Reactant: O=Cc1c(-c2ccccc2)[nH]c2c([N+](=O)[O-])cc(Cl)cc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C1CN(Cc2c(-c3ccccc3)[nH]c3c([N+](=O)[O-])cc(Cl)cc23)CCN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.1 %

Procedure:
5-Chloro-3-formyl-7-nitro-2-phenyl-1H-indole (0.5 g, 1.66 mmol) prepared in Step A was dissolved in dichloroethane (20 mL). Acetic acid (0.10 g, 1.66 mmol), 2-oxopiperazine (0.3 g, 3.32 mmol) and sodium triacetoxyborohydride (0.71 g, 3.32 mmol) were added in drops thereto, and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the reaction mixture was diluted with water, extracted with dichloromethane, washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (0.55 g, Yield 86%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:13][CH2:12]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:36][O:37][C:38]1[CH:39]=[C:40]([C:48]2[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=2)[CH2:51][Cl:52])[CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45]>>[ClH:52].[ClH:52].[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[CH:23]=[CH:22][N:21]=[C:20]([C:24]5[CH:29]=[C:28]([O:30][CH3:31])[C:27]([O:32][CH3:33])=[C:26]([O:34][CH3:35])[CH:25]=5)[CH:19]=4)[CH2:15][CH2:16]3)[CH2:51][C:50]3[CH:53]=[CH:54][CH:55]=[C:48]([C:40]4[CH:41]=[C:42]([O:46][CH3:47])[C:43]([O:44][CH3:45])=[C:38]([O:37][CH3:36])[CH:39]=4)[CH:49]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cc(-c2cc(CN3CCC(Nc4ccc5c(c4)CCC5)CC3)ccn2)cc(OC)c1OC
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cccc(CN(c3ccc4c(c3)CCC4)C3CCN(Cc4ccnc(-c5cc(OC)c(OC)c(OC)c5)c4)CC3)c2)cc(OC)c1OC
Product: Cl

Procedure:
4-(5-Indanylamino)-1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]piperidine (60 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (114 mg) were condensed in the same manner as described in Example 9. The title compound was obtained as yellow powder after converting a free base to a dihydrochloride.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH3:34][C:35]1[O:39][N:38]=[C:37]([CH:40]=O)[CH:36]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:40][C:37]5[CH:36]=[C:35]([CH3:34])[O:39][N:38]=5)[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: Cc1cc(C=O)no1
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(CN2CCC(n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5)ncnc43)CC2)no1

Procedure:
4-(4-Methanesulfonyl-phenoxy)-1-[1-(5-methyl-isoxazol-3-ylmethyl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidine was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with 5-methylisoxazole-3-carboxaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.92-1.95 (m, 2H), 2.17-2.33 (m, 4H), 2.40 (s, 2H), 2.95-2.97 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.57 (s, 2H), 4.74-4.80 (m, 1H), 6.24 (s, 1H), 7.62-7.64 (m, 2H), 8.04-8.07 (m, 2H), 8.37 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=469.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Reactant: [O-]B([O-])Oc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3ccc(F)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.0 g), 4-fluorophenyl borate (0.465 g) and potassium carbonate (0.84 g) in toluene/ethanol/water (30/3/3 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.17 g), and the mixture was refluxed for 20 hours, cooled, extracted with ethyl acetate, saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:1) and recrystallized from ethyl acetate/hexane=1:1 to give pale yellow crystals of methyl 7-(4-fluorophenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (656.3 mg).