Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH:10]2[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[Cl:24][CH2:25][C:26](Cl)=[O:27]>CCOC(C)=O>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:26](=[O:27])[CH2:25][Cl:24])[CH:10]2[CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)CCl
Reactant: Clc1ccc2c(c1)C(C1CCCCC1)NCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CCl)N1CCc2ccc(Cl)cc2C1C1CCCCC1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
7-chloro-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (899 mg) was added to saturated aqueous sodium bicarbonate (15 mL), to which EtOAc (10 mL) was then further added. A solution of chloroacetyl chloride (390 mg) in EtOAc (5 mL) was added dropwise to the reaction liquid over 5 minutes. The reaction liquid was stirred for 1 hour, extracted with EtOAc, and dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 7-chloro-2-(chloroacetyl)-1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline (888 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1([OH:25])[CH2:24][CH2:23][CH2:22][CH2:21]1)[C:10]([O:12]CC1C=CC=CC=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([O:5][C:6]([NH:8][CH:9]([C:20]1([OH:25])[CH2:21][CH2:22][CH2:23][CH2:24]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NC(C(=O)OCc1ccccc1)C1(O)CCCC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(C(=O)O)C1(O)CCCC1
Yield: 82.9 %

Procedure:
A solution of N-(t-butoxycarbonyl)-α-(1-hydroxycyclopentyl)glycine, benzyl ester (1.81 g, 4.98 mmoles) in 30 ml of absolute ethanol at 25° C. was treated with 0.4 g of 10% palladium on charcoal and hydrogen at one atmosphere for 2.5 hours. The catalyst was filtered and the solvent evaporated. Benzene was added and evaporated. Crystallization from isopropyl ether (first crop) and hexane (second crop) gave a total of 1.07 g of product, melting point 132°-134° C.
Reaction SMILES: [C:1]([NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1)=O)(=S)[CH3:2].C([O-])(=O)C.[Na+].Cl.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][NH2:34])=[CH:29][C:28]=1[CH3:35]>O1CCOCC1.C(O)(=O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([CH:7]3[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12]3)=[N:4][C:1]([CH3:2])=[N:34]2)=[CH:29][C:28]=1[CH3:35]
Reactant: CC(=S)NC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(NN)ccc1Cl
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Cc1nc(C2CCN(C(=O)OC(C)(C)C)CC2)n(-c2ccc(Cl)c(C)c2)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
The product from step A (3.09 g, 10.79 mmol), sodium acetate (0.879, 10.7 mmol) and (4-chloro-3-methylphenyl)hydrazine hydrochloride (2.24 g, 11.6 mmol) were mixed in dioxane (25 mL) and acetic acid (25 mL). The reaction mixture was warmed at 90° C. with stirring for 16 h, cooled to rt and the volatiles were removed. Purification of the residue on SiO2 (5 to 60% ethyl acetate, hexanes) afforded the title compound, which was used without further purification. HPLC/MS: 335.0, 337.0 (M-55), Rt=3.40 (LC4).
Reaction SMILES: [CH2:1]([CH:8]([C:14](OCC)=O)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].IC[CH2:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25]>>[F:28][C:23]([F:29])([C:24]([F:27])([F:26])[F:25])[CH2:22][CH2:21][CH2:14][CH:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: C=CCCCCCC(C(=O)OCC)C(=O)OCC
Reactant: FC(F)(F)C(F)(F)CCCI
Product: C=CCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)OCC

Procedure:
Starting with the diethyl 2-(6-heptenyl)malonate prepared in Example 9 and the 1-iodo-4,4,5,5,5-pentafluoro-pentane prepared in Example 1, the same procedure as shown in Example 5 was repeated to give ethyl 2-(4,4,5,5,5-pentafluoropentyl)-8-nonenoate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1Cl.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.CC[O-].[Na+]>C(O)C.C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: Cc1ccc(Cl)c(C)c1
Reactant: c1c[nH]cn1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(-n2ccnc2)c(C)c1
Temperature: 110 °C
Yield: 48 %

Procedure:
30 mmol of 2,4-dimethylchlorobenzene (4.2 g), 40 mmol of imidazole (2.7 g), 35 mmol of NaOEt solution in ethanol (10% by weight) and 230 mg of trans-di-μ-chlorobis[2-[bis(1,1-dimethylethyl)phosphino]-2-methylpropyl-C,P]dipalladium(II) (1.0 mol %) are suspended in 50 ml of THF and heated at 110° C. in a pressure tube for 9 hours. After removal of the salts by filtration, the solvent is removed under reduced pressure. This gives crude 1-(2,4-dimethylphenyl)imidazole as a brown liquid which can be purified by distillation (boiling point: 122° C./12 torr); yield: 48%.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[OH-].[K+].Cl[CH2:15][CH:16]([OH:20])[CH2:17][CH2:18][Cl:19]>O.C(O)(C)C>[Cl:19][CH2:18][CH2:17][CH:16]([OH:20])[CH2:15][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1
Reactant: OC(CCl)CCCl
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: OC(CCCl)COc1cccc(C(F)(F)F)c1
Temperature: 65 °C

Procedure:
To a mixture of 0.5 mole (75 g.) of m-trifluoromethylphenol, 1 mole (56 g.) of potassium hydroxide, 100 ml. of water and 400 ml. of isopropanol was added 0.6 mole (84 g.) of 1,4-dichloro-2-butanol with stirring at temperature below 55° C. The resulting reaction mixture was heated at 65° C. for 20 hr., mixed with 2 liters of water, and extracted with 400 ml. of isopropyl ether. The ether extract was washed with 0.5N sodium hydroxide and then with water, dried over sodium sulfate and distilled under reduced pressure. The distillate which was collected at 120°-124° C./0.01 mm. solidified at room temperature and melted at 50°-52° C.
Reaction SMILES: [H-].[Na+].C([O:7][C:8](=[O:20])[NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[N+:18]=[N-:19])(C)(C)C.[CH2:21](Br)[C:22]#[CH:23]>CCCCCC.CN(C=O)C>[N:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]([CH2:23][C:22]#[CH:21])[C:8](=[O:20])[OH:7])=[N+:18]=[N-:19]
Reactant: CC(C)(C)OC(=O)NCc1ccccc1N=[N+]=[N-]
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C#CCN(Cc1ccccc1N=[N+]=[N-])C(=O)O
Reaction time: 0.5 h

Procedure:
Sodium hydride (5.0 mg, 0.120 mmol, 60% suspension in mineral oil) was washed with hexane (2 mL) in a flame dried round bottomed flask under nitrogen atmosphere. To the resulting free floating powder, was added a solution of (2-azido-benzyl)-carbamic acid tert-butyl ester (20 mg, 0.08 mmol) in dry DMF (1 mL) at 0° C. The reaction mixture was stirred at this temperature for 30 min. Propargyl bromide (0.021 mL, 0.24 mmol) was added and the reaction mixture was stirred at r.t. for 2 h. After the completion of reaction as confirmed by TLC, crude product was extracted with ethylacetate (10 mL). The organic layer was washed with water (2×5 mL). Organic layer was dried over Na2SO4 and concentrated in vacuo to afford the crude compound which was purified by column chromatography (silica gel; 1:9 EtOAc:Pet.Ether) to afford (2-azido-benzyl)-prop-2-ynyl-carbamic acid ten-butyl ester (20 mg, 87%) as a viscous oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:26]=2[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28])[C:21]([Cl:38])=[CH:20][N:19]=1>>[Cl:38][C:21]1[C:22]([NH:24][C:25]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:26]=2[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-prop-2-ynyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (126 mg, 60%). LCMS (m/e) 523 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.33 (bs, 1H), 8.08 (s, 1H), 7.42-7.37 (m, 1H), 7.36-7.28 (m, 2H), 7.14 (s, 1H), 7.09 (d, 1H, J=7.9 Hz), 6.90 (d, 1H, J=8.1 Hz), 6.82 (s, 1H), 6.31-6.24 (m, 1H), 4.15-4.10 (m, 2H), 3.55 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.90-2.83 (m, 2H), 2.81-2.73 (m, 4H), 2.73-2.65 (m, 4H), 2.23-2.20 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12](Cl)=[CH:11][C:10]=1[C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)COC1C=CC([C:37]#[N:38])=CC=1Br)(C)(C)C.C[Si](C#C)(C)C>>[C:1]([O:5][C:6](=[O:22])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:37]#[N:38])=[CH:11][C:10]=1[C:16]#[C:17][Si:18]([CH3:21])([CH3:20])[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)COc1ccc(C#N)cc1Br
Agent: C#C[Si](C)(C)C
Product: CC(C)(C)OC(=O)COc1ccc(C#N)cc1C#C[Si](C)(C)C
Yield: 87 %

Procedure:
Following the general method as outlined in Intermediate 2, starting from tert-butyl(2-bromo-4-cyanophenoxy)acetate (Intermediate 44) and (trimethylsilyl)acetylene (Aldrich), the title compound was obtained as a dark brown sticky solid in 87% yield.
Reaction SMILES: CC(C)(C(=O)[N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][N:9]([C:14]1[C:15]3[CH:22]=[CH:21][NH:20][C:16]=3[N:17]=[CH:18][N:19]=1)[CH2:10]2)C#N.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=CC=1C(O)=O>CN(C=O)C>[CH2:12]1[C:11]2([CH2:10][N:9]([C:14]3[C:15]4[CH:22]=[CH:21][NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:8][CH2:7][NH:6]2)[CH2:13]1
Reactant: CC(C)(C#N)C(=O)N1C2CCC1CN(c1ncnc3[nH]ccc13)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)c1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Reaction time: 16 h

Procedure:
(intermediate 2) (0.05 mmol) was dissolved in dry DMF (0.3 mL). Triethylamine (0.18 mmol) and HATU (0.09 mmol) was added followed by 2-pyridincarboxylic acid (0.07 mmol). The reaction mixture was left at rt for 16 hours. The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].O[C:10](=[C:13]1C(=O)OC(C)(C)[O:15][C:14]1=O)[CH2:11][CH3:12].CCOCC>CCCCCC>[CH2:11]([C:10]1[NH:1][C:2]([CH3:8])=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:14](=[O:15])[CH:13]=1)[CH3:12]
Reactant: CCC(O)=C1C(=O)OC(C)(C)OC1=O
Reactant: COC(=O)/C=C(/C)N
Solvent: CCOCC
Solvent: CCCCCC
Product: CCc1cc(=O)c(C(=O)OC)c(C)[nH]1
Temperature: 120 °C
Reaction time: 18 h
Yield: 11.8 %

Procedure:
A mixture of methyl 3-aminocrotonate (5 g) and 5-(1-hydroxypropylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10 g) (obtained as described in J. Org. Chem., 1978, 43, 2087) was heated at 120° C. for 1 hour. The residue was cooled to ambient temperature and treated with a mixture of ether and hexane (1:6 v/v; 35 ml) and allowed to stand for 18 hours. The solvent was removed by decanting and the insoluble residue purified by flash chromatography, eluting with methanol/dichloromethane (1:9 v/v) to give methyl 1,4-dihydro-6-ethyl-2-methyl-4-oxopyridine-3-carboxylate (1 g), as a yellow solid, m.p. 176°-180° C.; NMR (CDCl3): 1.2(t,3H); 2.45(s,3H), 2.45(q,2H), 3.8(s,3H), 6.3(s,1H); mass spectrum (chemical ionisation, ammonia): 196(M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][CH2:7][N:8]1[C:13]([C:14](=[O:23])[C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)=[C:12]([CH2:24][CH3:25])[C:11](=[O:26])[NH:10][C:9]1=[O:27])=[O:4].O.[C:29]1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:2][C:3]([CH:5]=[CH:6][CH2:7][N:8]1[C:13]([C:14](=[O:23])[C:15]2[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=2)=[C:12]([CH2:24][CH3:25])[C:11](=[O:26])[NH:10][C:9]1=[O:27])=[O:4])[CH3:29]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC=CC(=O)OC)c(=O)[nH]c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C=CCn1c(C(=O)c2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Reaction time: 48 h
Yield: 148.4 %

Procedure:
To a solution of 100 mg (0.27 mmol) of the compound obtained from Example 8 in 10 ml of anhydrous ethanol was added 20 mg of p-toluenesulfonic acid monohydrate. The reaction mixture was refluxed with stirring for about 48 hours, neutralized with sodium bicarbonate, and evaporated under reduced pressure to give a light brown residue, which was purified by flash chromatography using a mixture of ethyl acetate and hexane (1:2) as an eluent to afford 60 mg (yield 58%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH2:13]([N:15](CC)CC)C.CN>CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:15][CH3:13])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: CCN(CC)CC
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: CN
Solvent: CO
Product: CNc1nc(Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.7 %

Procedure:
To a cooled (−10° C.) solution of 2,4-dichloro-5-trifluoromethylpyrimidine (20 g, 0.089 mol) in methanol (100 mL) was added triethylamine (12.5 mL, 0.089 mol) and a 2 M solution of methylamine in methanol (45 mL). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated and re-dissolved in ethyl acetate. The solution was washed with sat. NaHCO3, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (5-25% EtOAc in heptane) to give 2-chloro-N-methyl-5-(trifluoromethyl)pyrimidin-4-amine (8.6 g, 45%). 1H-NMR (DMSO): δ 8.37 (s, 1H), 7.90 (s, 1H), 2.90 (s, 3H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:35])=[CH:28]\[CH2:29]OS(C)(=O)=O)[C:21]=1[CH3:36])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.[K].O>CN(C)C=O>[Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:35])=[CH:28]\[CH2:29][N:41]2[C:37](=[O:47])[C:38]3=[CH:46][CH:45]=[CH:44][CH:43]=[C:39]3[C:40]2=[O:42])[C:21]=1[CH3:36])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C/C(=C/COS(C)(=O)=O)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: C/C(=C/CN1C(=O)c2ccccc2C1=O)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To a solution of 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-3-methanesulfonyloxy-1-methyl-1-propenyl)benzene (132 mg) in N,N-dimethylformamide was added potassium phthalimide (55 mg) at ambient temperature under nitrogen atmosphere, and the mixture was stirred at the same temperature overnight. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (n-hexane:ethyl acetate =4:1, V/V) to give 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((z)-1-methyl-3-phthalimido-1-propenyl)benzene (99 mg) as colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:12][O:11][CH:10]2[CH:5]([C@:6]3([CH2:25][CH2:24][C@H:23]4[C@@H:13]([CH2:14][CH2:15][CH:16]5[C@:21]4([CH3:22])[CH2:20][CH2:19][C@H:18]([OH:26])[CH2:17]5)[C@@H:8]3[CH2:9]2)[CH3:7])[O:4]1.[CH2:27]([O:29][CH:30]([O:33][CH2:34][CH3:35])[CH2:31]Br)[CH3:28].O>O1CCCC1>[CH2:27]([O:29][CH:30]([O:33][CH2:34][CH3:35])[CH2:31][O:26][C@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[CH:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[CH2:24][CH2:25][C@@:6]2([CH3:7])[C@H:8]3[CH2:9][CH:10]3[O:11][CH2:12][CH2:3][O:4][CH:5]32)[CH2:17]1)[CH3:28]
Reactant: CCOC(CBr)OCC
Reactant: C[C@]12CC[C@H](O)CC1CC[C@@H]1[C@@H]2CC[C@]2(C)C3OCCOC3C[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(CO[C@H]1CC[C@@]2(C)C(CC[C@@H]3[C@@H]2CC[C@]2(C)C4OCCOC4C[C@@H]32)C1)OCC
Reaction time: 2 h

Procedure:
To a suspension of 5.5 g of NaH (60% dispersion in mineral oil) in 400 ml of dry tetrahydrofuran 8.5 g of 17-ethylenedioxy-androstan-3β-ol were added at room temperature under nitrogen atmosphere. The mixture was kept at 40° C. for 2 hrs, then 26 ml of bromoacetaldehyde diethylacetal were added and the suspension was kept at the same temperature for 4 hrs; 50 ml of water were added cautiously, and the tetrahydrofuran was distilled under reduced pressure. The residue was extracted with methylene chloride, the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography (SiO2) using n-hexane/ethyl acetate 80/20 as eluant to give 7.5 g of 3β-(2,2-diethoxyethoxy)-17-ethylenedioxy-androstane as a thick oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][C:11]2=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH3:20][N:21]1[CH2:25][CH2:24][CH2:23][C:22]1=O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[C:22]3[CH2:23][CH2:24][CH2:25][N:21]3[CH3:20])[C:11]2=[O:19])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(N2C(=O)Cc3ccccc32)cc1F
Reactant: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc(N2C(=O)C(=C3CCCN3C)c3ccccc32)cc1F

Procedure:
By the procedure of Example B5, except to use ethyl acetate as eluant, 1-(3-fluoro-4-methoxyphenyl)-2(1H,3H)-indolone (2.0 g, 7.8 mmoles) and 1-methyl-2-pyrrolidone (1.5 ml, 15.6 mmole) were converted to title product, 0.32 g, m.p. 68°-71°.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
Procedure D may also be used to couple 4-chloro-3-(pyridin-2-yl)aniline and 2-chloro-4-(methylsulfonyl)benzoyl chloride to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide which is collected by suction filtration and the HCl salt is washed with Et2O (or alternatively with MTBE). This material is freebased using EtOAc/aq NaHCO3 and the organics are dried and concentrated to the solid freebase. This material is then crystallized from acetone:EtOAc (80:20, approx 10 mL/g) which is then finally recrystallized from hot slurry of iPrOAc. 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide HCl salt may also be dissolved in distilled water followed by freebasing with 0.5 N NaOH solution (pH to 11) and filtering and vacuum drying the precipitate.
Reaction SMILES: [OH:1][C@H:2]1[CH:6]=[CH:5][C@@H:4]([O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[CH2:3]1>CCOC(C)=O.CCCCCC>[O:7]([C@H:4]1[CH:5]=[CH:6][C@H:2]([OH:1])[CH2:3]1)[Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C=C[C@H](O)C1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)O[C@H]1C=C[C@H](O)C1
Yield: 81 %

Procedure:
Compound 14 was subjected to general procedure J. Yield=81%. TLC: Rf=0.50 (10% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3): δ0.05 (s, 6H), 0.90 (s, 9H), 2.20 (m, 1H), 2.30 (m, 1H), 5.10 (s, 1H), 6.05 (m, 2H), 6.10 (m, 1H), 8.20 (d, 2H), 8.20 (d, 2H). Subsequent subjection of the product to general procedure E gave compound 22. Yield=85%. TLC: Rf=0.33 (25% EtOAc/Hexane). 1H NMR (400 MHz, CDCl3): δ0.05 (s, 6H), 0.90 (s, 9H), 2.05 (m, 2H), 5.00 (m, 1H), 5.05 (m, 1H), 5.95 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[CH:13]2.[OH:19][C@@H:20]([CH3:38])[CH2:21][N:22]1[C:26]([CH3:27])=[C:25]([C:28](O)=[O:29])[C:24](=[O:31])[N:23]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.CN(C=O)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:28]([C:25]2[C:24](=[O:31])[N:23]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[N:22]([CH2:21][C@@H:20]([OH:19])[CH3:38])[C:26]=2[CH3:27])=[O:29])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][N:12]=[CH:13]2
Reactant: Nc1ccc(-c2cccc3cnccc23)c(F)c1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C[C@H](C)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(-c3cccc4cnccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C[C@H](C)O
Reaction time: 120 h
Yield: 33435.8 %

Procedure:
3-fluoro-4-(isoquinolin-5-yl)benzenamine (309.9 mg, 1301 μmol) and (S)-1-(2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (359 mg, 1301 μmol) were suspended in DCM (6.5 ml) and DMF (0.65 ml) and hatu (579 mg, 1523 μmol) was added. The reaction was stirred under nitrogen for 5 days, and then filtered. The solid was washed with DCM, and the filtrate was concentrated and purified on silica gel (50:1->40:1->30:1->10:1 DCM/MeOH. The fractions with product were collected, concentrated, treated with MeOH and filtered. The solid was washed with MeOH, collected, and dried under high vacuum to afford the desired N-(3-fluoro-4-(isoquinolin-5-yl)phenyl)-1-((S)-2-hydroxypropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (216.0 mg, 435.0 mmol, 33% yield). MS (ESI pos. ion) m/z: 497 (MH+). Calc'd exact mass for C29H25FN4O3: 496. 1H NMR (400 MHz, CDCl3) δ 10.93 (s, 1H), 9.30 (s, 1H), 8.49 (d, J=6.0 Hz, 1H), 8.01 (dd, J=7.0 Hz, 3.0 Hz, 1H), 7.87 (dd, J=12.0 Hz, 2.0 Hz, 1H), 7.71-7.64 (m, 2H), 7.59-7.52 (m, 3H), 7.48 (d, J=8.0 Hz, 1H), 7.42-7.34 (m, 3H), 7.31 (d, J=8.0 Hz, 1H), 4.00-3.83 (m, 2H), 3.72 (dd, J=15.0 Hz, 3.0 Hz, 1H), 2.89 (s, 3H), 1.29-1.24 (m, 1H), 1.11 (d, J=6.0 Hz, 3H).