Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH2:15]([CH:17]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:18]O)[CH3:16]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([O:14][CH2:18][CH:17]([CH2:15][CH3:16])[CH2:20][CH2:21][CH2:22][CH3:23])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCC(CC)CO
Reactant: CCCCCCCCCCCC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCCCCCCCCCCC(=O)OCC(CC)CCCC

Procedure:
2-ethylhexyl laurate was prepared by esterification reaction between lauric acid and 2-ethylhexanol in the presence of p-toluenesulfonic acid as a catalyst, and subsequent steps for recovery of unreacted 2-ethylhexanol, neutralization, washing with hot water, and dehydration.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][C:5]([NH:14][C:15](=[O:19])[O:16][CH2:17][CH3:18])=[C:4]([F:20])[CH:3]=1.O[CH:22]([C:28](C)=C)[C:23](OCC)=O.C(OCC)(=[O:35])C=CC.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]([N:14]2[C:18](=[O:35])[C:17](=[C:22]([CH3:28])[CH3:23])[O:16][C:15]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: CCOC(=O)Nc1cc(OC2CCCC2)c(Cl)cc1F
Reactant: C=C(C)C(O)C(=O)OCC
Reactant: CC=CC(=O)OCC
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)=C1OC(=O)N(c2cc(OC3CCCC3)c(Cl)cc2F)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55.6 %

Procedure:
Ethyl N-(4-chloro-5-cyclopentyloxy-2-flourophenyl)carbamate (3.01 g, 10 mmol), ethyl 2-hydroxy-3-methyl-3-butenoate (2.02 g, 14 mmol) and stannous acetate (23.7 mg, 0.1 mmol) were introduced into a flask (25 cc) equipped with an air condenser tube (20 cm), and the reaction was conducted at 200° C. for 2.5 hours under such a reduced pressure that the ethyl butenoate was refluxed below the middle of the air condenser tube. After the reaction solution was cooled to room temperature, toluene (20 mL) was added, and the reaction solution was washed with water (20 mL), then 1N hydrochloric acid (20 mL), 1N sodium hydroxide (20 mL) and 1N hydrochloric acid (20 mL). The organic layer was dried over magnesium sulfate. After the drying agent was filtered off, the filtrate was concentrated under reduced pressure. Acidic methanol (3.5 mL) was added to the resulting oily crude product to form a homogeneous solution. Then, 6N hydrochloric acid (0.4 mL) was further added, and the solution was left to stand at room temperature. The precipitated crystals were collected by filtration, washed with a 20:1 mixed solvent consisting of methanol and 6N hydrochloric acid and dried to obtain 3-(4-chloro-5-cyclopentyloxy-2-fluorophenyl)-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.97 g, yield 55.6%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18](Cl)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:29]2[CH:38]=[CH:37][C:36]3[C:35]([CH3:40])([CH3:39])[CH2:34][CH2:33][C:32]([CH3:42])([CH3:41])[C:31]=3[CH:30]=2)O1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([C:38]3[CH:29]=[CH:30][C:31]4[C:32]([CH3:42])([CH3:41])[CH2:33][CH2:34][C:35]([CH3:40])([CH3:39])[C:36]=4[CH:37]=3)[CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc(Cl)n2)CC1
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(-c3ccc4c(c3)C(C)(C)CCC4(C)C)n2)CC1

Procedure:
The preparation is carried out analogously to FS 103 starting from 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (preparation analogous to US 2005/176722) and 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.Cl.[N:15]([O-])=O.[Na+]>>[NH2:9][C:8]1[C:7]2[C:2](=[CH:3][C:4]([O:12][CH3:13])=[C:5]([O:10][CH3:11])[CH:6]=2)[NH:1][N:15]=1
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: COc1cc2[nH]nc(N)c2cc1OC
Yield: 147.5 %

Procedure:
To a solution of 6-aminoveratronitrile (39 g, 0.2 mole) and conc. hydrochloric acid (329 ml) was added a solution of sodium nitrite (17 g, 0.25 mole in minimum amt. of water). The temperature was held below 0° during the addition. Keeping the temperature between 0° to 20° the resulting solution was added dropwise to stannous chloride (33.3 g, 1.76 mole) and conc. hydrochloric acid (153 ml). The precipitate was filtered and air dried overnight. The filter cake was placed in water (1100 ml), refluxed for 20-30 min and then filtered. The filtrate was cooled and then treated with sodium hydroxide (10% - 290 ml) to precipitate a tan solid. This solid was air dried at 60° to yield 57 g of 3-amino-5,6-dimethoxyindazole.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([CH3:15])[CH:14]=1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]2)C=C.CN(C)[C:19]1[CH:24]=CC=C[CH:20]=1>CCCCCC>[CH2:24]([C:6]1[C:5]([OH:4])=[CH:14][C:13]([CH3:15])=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10](=[O:16])[NH:11]2)[CH:19]=[CH2:20]
Reactant: C=CCOc1cc(C)c2[nH]c(=O)ccc2c1
Reactant: CN(C)c1ccccc1
Solvent: CCCCCC
Product: C=CCc1c(O)cc(C)c2[nH]c(=O)ccc12
Temperature: 200 °C
Reaction time: 11 h
Yield: 92.6 %

Procedure:
To 6-allyloxy-8-methylcarbostyril (10.11 (47.0 mmol)), N,N-dimethylaniline (25 ml) was added, and the mixture was stirred in a bath of 200° C. for 11 hours. Subsequently, the mixture was cooled. n-Hexane was added to the cooled mixture. The precipitated crystals were collected by filtration, and were washed with chloroform. The washed material was subjected to a recrystallizing procedure (chloroform--methanol--n-hexane) to obtain 9.36 g of 5-allyl-6-hydroxy-8-methylcarbostyril as colorless needles (92.6%).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([O:13][C:14]([N:16]([C:36]1[C:41]([O:42][CH3:43])=[N:40][C:39]([CH3:44])=[CH:38][N:37]=1)[S:17]([C:20]1[C:21]([C:26]2[CH:31]=[CH:30][C:29]([Si](C)(C)C)=[CH:28][CH:27]=2)=[N:22][CH:23]=[CH:24][CH:25]=1)(=[O:19])=[O:18])=[O:15])[CH:10]([CH3:12])[CH3:11]>C(#N)C>[I:1][C:29]1[CH:30]=[CH:31][C:26]([C:21]2[C:20]([S:17]([N:16]([C:14]([O:13][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:15])[C:36]3[C:41]([O:42][CH3:43])=[N:40][C:39]([CH3:44])=[CH:38][N:37]=3)(=[O:19])=[O:18])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:27][CH:28]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc([Si](C)(C)C)cc1
Solvent: CC#N
Product: COc1nc(C)cnc1N(C(=O)OCC(C)C)S(=O)(=O)c1cccnc1-c1ccc(I)cc1
Temperature: 65 °C
Reaction time: 24 h

Procedure:
N-Iodosuccinimide (0.84 g) was added to a solution of N-(isobutoxycarbonyl)-N-(3-methoxy-5-methylpyrazin-2-yl)-2-(4-trimethylsilylphenyl)pyridine-3-sulphonamide (1.58 g) in acetonitrile (15 ml) and the reaction mixture was stirred and heated at 65° C. for 17 hours. A further portion of N-iodosuccinimide (50 mg) was added and heating continued for 24 hours, then more N-iodosuccinimide (100 mg) was added and heating continued a further 24 hours. The mixture was cooled and volatile material was removed by evaporation. The residue was purified by chromatography on a silica gel Mega Bond Elut column, eluting with 0-25% ethyl acetate/hexane, followed by trituration with hexane (2×25 ml) to give 2-(4-iodophenyl)-N-isobutoxycarbonyl-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide as a solid, m.p. 156°-158° C.; 1H NMR (CDCl3): 0.7 (d, 6 H), 1.7 (m, 1 H), 2.5 (s, 3 H), 3.8 (d, 2 H), 4.0 (s, 3 H), 7.4 (d, 2 H), 7.5 (dd, 1 H), 7.7 (d, 2 H), 7.9 (s, 1 H), 8.8 (dd, 1 H), 8.9 (dd, 1 H); mass spectrum (+ve ESP): 583 (M+H)+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[CH:7][N:6]=1)[NH2:4].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([Cl:26])=O)=[CH:19][CH:18]=1>O1CCOCC1>[ClH:26].[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]2[O:1][N:2]=[C:3]([C:5]3[C:14]([OH:15])=[C:13]4[C:8]([CH:9]=[CH:10][CH:11]=[N:12]4)=[CH:7][N:6]=3)[N:4]=2)=[CH:19][CH:18]=1
Reactant: NC(=NO)c1ncc2cccnc2c1O
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: C1COCCO1
Product: Cl
Product: Oc1c(-c2noc(Cc3ccc(F)cc3)n2)ncc2cccnc12
Temperature: 160 °C
Yield: 14.9 %

Procedure:
To a suspension of N′,8-dihydroxy[1,6]naphthyridine-7-carboximidamide (50 mg, 0.244 mmol) in dioxane (3 mL) was-added 4-fluorophenylacetyl chloride (40 μL, 0.293 mmol). The reaction vessel was sealed and heated at 160° C. in a microwave chamber for 10 minutes. The solids were collected on a filter, then triturated with methano/ether to provide 7-[5-(4-fluorobenzyl)-1,2,4-oxadiazol-3-yl][1,6]naphthyridin-8-ol hydrochloride (13 mg, 15%) as an orange solid. 1H NMR (CD3OD) δ 9.43 (d, J=4 Hz, 1H), 9.34 (s, 1H), 9.05 (d, J=8.0 Hz, 1H), 8.14 (dd, J=8.4, 4.8 Hz, 1H), 7.48 (dd, J=8.4, 5.2 Hz, 2H), 7.12 (t, J=8.8 Hz, 2H), 4.92 (s, 2 H); MS m/z 323 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12](Cl)=[O:13].[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([CH:34]3[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]3)[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([O:32][CH3:33])[CH:26]=3)[C:17]=12>ClCCl.N1C=CC=CC=1>[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([CH:34]3[CH2:35][CH2:36][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH2:39]3)[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][C:12](=[O:13])[C:3]4[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=4[F:1])=[C:27]([O:32][CH3:33])[CH:26]=3)[C:17]=12
Reactant: COc1cc(-c2nn(C3CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.9 %

Procedure:
2-Fluoro-4-(trifluoromethyl)-1-benzenecarbonyl chloride (3.05 mL, 20.2 mmol) in dichloromethane (25 mL) was added to a solution of tert-butyl 4-[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (8.77 g, 20.0 mmol) in pyridine (50 mL) at 0° C. After 5 minutes, the ice water bath was removed and the reaction mixture stirred at room temperature for 1 hours. 2-Fluoro-4-(trifluoromethyl)-1-benzenecarbonyl chloride (0.5 mL, 3.31 mmol) was added and the reaction mixture was stirred for addition 30 minutes. The solvent was evaporated and the residue was dissolved in dichloromethane. The organic layer was washed with water, brine then dried over MgSO4. The solvent was evaporated and the residue was purified by flash column chromatography using ethyl acetate/dichloromethane (80:20 to 100:0) as mobile phase to give tert-Butyl 4-[4-amino-3-(4-[2-fluoro-4-(trifluoromethyl)benzoyl]amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-piperidinecarboxylate (11.2 g, 89%). 1H NMR (CDCl3-d) δ 1.48 (s, 9H), 2.04 (m, 2H), 2.30 (m, 2H), 2.98 (m, 2H), 4.05 (s, 3H), 4.32 (m, 2H), 4.95 (m, 1H), 5.89 (bs, 2H), 7.33 (m, 2H), 7.51 (d, J=11.62 Hz, 1H), 7.61 (d, J=8.21 Hz, 1H), 8.36 (m, 2H), 8.72 (d, J=8.18 Hz, 1H), 9.32 (d, J=14.39 Hz, 1H).
Reaction SMILES: [C:1]1([N:7]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:19][CH:18]=2)[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I:38][CH2:39][CH2:40][CH3:41]>>[I-:38].[C:1]1([N:7]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:21][CH:22]=2)[C:8]([C:10]2[CH:11]=[N+:12]([CH2:39][CH2:40][CH3:41])[CH:13]=[CH:14][CH:15]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCI
Reactant: CCCCCCCCCCCCCCOc1ccc(CN(C(=O)c2cccnc2)c2ccccc2)cc1
Product: CCCCCCCCCCCCCCOc1ccc(CN(C(=O)c2ccc[n+](CCC)c2)c2ccccc2)cc1
Product: [I-]
Temperature: 100 °C
Yield: 99.9 %

Procedure:
A mixture of 0.80 g of product from Example 146 and 13.58 g of iodopropane is heated, in a sealed tube, at 100° C. for 10 hours. The reaction is concentrated in vacuo to give 1.07 g of the desired product as orange crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([F:19])[C:13]=2[Cl:20])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[C:24]([O:31][C:32]([F:35])([F:34])[F:33])[CH:23]=1.[CH3:36][PH:37](=[O:39])[CH3:38]>>[Cl:20][C:13]1[C:14]([F:19])=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[CH:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:25]2[CH:26]=[CH:27][C:22]([P:37]([CH3:38])([CH3:36])=[O:39])=[CH:23][C:24]=2[O:31][C:32]([F:35])([F:34])[F:33])[CH:3]=1)[CH3:11]
Reactant: C[PH](C)=O
Reactant: OB(O)c1ccc(Br)cc1OC(F)(F)F
Reactant: CC(Oc1cc(Br)cnc1N)c1c(Cl)ccc(F)c1Cl
Product: CC(Oc1cc(-c2ccc(P(C)(C)=O)cc2OC(F)(F)F)cnc1N)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared from 5-bromo-3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine, 4-bromo-2-trifluoromethoxyphenyl boronic acid, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3; ESMS: m/z 537 (M+H)+.
Reaction SMILES: [NH:1]=[C:2]([C:9]1[C:10](=[O:23])[N:11]([CH3:22])[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13][C:14]=1[OH:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1.[C:38](Cl)(Cl)=[O:39]>C1C=CC=CC=1>[CH3:22][N:11]1[C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:13][C:14]2[O:15][C:38](=[O:39])[N:1]=[C:2]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:9]=2[C:10]1=[O:23]
Reactant: Cn1c(-c2ccccc2)cc(O)c(C(=N)c2ccccc2)c1=O
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cn1c(-c2ccccc2)cc2oc(=O)nc(-c3ccccc3)c2c1=O
Reaction time: 18 h

Procedure:
A mixture of 10 g. (0.0348 mole) of 3-(α-iminobenzyl)-4-hydroxy-6-phenyl-1-methyl-2(1H)-pyridone and 7.3 g. (0.0724 mole) triethylamine in 200 ml. toluene is treated portionwise with 30 ml. (27.8 g., 0.0348 mole) of a 12.5% solution of phosgene in benzene. The resulting mixture becomes warm and the solids are separated out. The mixture is then stirred at room temperture for 18 hours and then poured onto water and filtered. The solids are washed with toluene. The toluene and water filtrate is separated and the toluene dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting solid is recrystallized with hot toluene to give 6-methyl-4,7-diphenyl-2H-pyrido[3,4-e]-1,3-oxazine-2,5-dione, m.p. 178°-179° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[S:22][C:21]([C:23]([OH:25])=O)=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:19]=3[CH:32]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[O:37]1[CH2:38][CH2:39][CH:34]([NH:33][C:23]([C:21]2[S:22][C:18]3[CH:17]=[CH:16][C:15]([NH:14][S:11]([C:8]4[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])=[CH:6][CH:7]=4)(=[O:12])=[O:13])=[CH:32][C:19]=3[C:20]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])[CH2:35][CH2:36]1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3sc(C(=O)O)c(-c4ccccc4)c3c2)cc1
Reactant: NC1CCOCC1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc3sc(C(=O)NC4CCOCC4)c(-c4ccccc4)c3c2)cc1
Yield: 50 %

Procedure:
According to Step 1, after reaction of 5-(4-tert-Butylbenzenesulfonylamino)-3-phenyl-1-benzothiophene-2-carboxylic acid (155 mg, 0.33 mmol) with 4-aminotetrahydropyrane (22 mg, 0.35 mmol), the desired compound is obtained at 50% yield (92 mg).
Reaction SMILES: C[O:2][C:3](=[O:10])[CH2:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7].C[O-].[Na+].CO.[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([Cl:27])[C:22]=1[C:23](Cl)=[N:24]O>C1COCC1.O>[Cl:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([Cl:27])[C:22]=1[C:23]1[C:4]([C:3]([OH:2])=[O:10])=[C:5]([CH:6]([CH3:8])[CH3:7])[O:9][N:24]=1
Reactant: ON=C(Cl)c1c(Cl)cncc1Cl
Reactant: COC(=O)CC(=O)C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1onc(-c2c(Cl)cncc2Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
N-chlorosuccinimide (1.36 g, 10.2 mmol) was added to a stirred solution of 3,5-dichloro-4-pyridinecarbaldehyde oxime (1.94 g, 10.2 mmol) in dimethylformamide (8 mL) and the solution was heated in a 65° C. oil bath for 1.5 hours. The solution was poured into water and extracted with ether. The organic layer was dried with MgSO4, filtered and concentrated to yield a crude carboximidoyl chloride. A solution of methylisobutyrylacetate (1.7 mL, 12.3 mmol) in THF (2.5 mL) was stirred at 0° C. as 0.5 N solution of sodium methoxide in methanol (24.6 mL, 12.3 mmol) was added. The solution was allowed to stir for ten minutes before the addition of the crude 3,5-dichloro-N-hydroxy-4-pyridinecarboximidoyl chloride in THF (8.1 mL). The solution was allowed to stir at room temperature overnight. The solution was then concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was dried with MgSO4, filtered and concentrated. The residue was purified by chromatography (silica gel, hexane to 1:9 ethyl acetate:hexanes). Fractions containing the intermediate were combined and concentrated. The residue was azetroped with methanol then was diluted with THF (11 mL) and methanol (5.5 mL). A 1 N solution of sodium hydroxide (3.3 mL) was added and the solution of heated to 100° C. for 500 seconds in a microwave reactor. The solution was neutralized with 1 N HCl and concentrated to yield a white solid. The residue was slurried in water and filtered to yield 3-(3,5-dichloro-4-pyridinyl)-5-(1-methylethyl)-4-isoxazolecarboxylic acid (0.57 g, 18%). 1H NMR (400 MHz, DMSO-d6): δ 13.39 (s, 1H), 8.81 (s, 2H), 3.82 (septet, J=7 Hz, 1H), 1.34 (d, J=7 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[C:7](/[CH:8]=[CH:9]\[Sn](CCCC)(CCCC)CCCC)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:23][C:24]1[C:29](I)=[CH:28][CH:27]=[CH:26][N:25]=1>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:23][C:24]1[C:29](/[CH:9]=[CH:8]\[C:7]2[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: Fc1ncccc1I
Reactant: CCCC[Sn](/C=C\c1cccnc1F)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: Fc1ncccc1/C=C\c1cccnc1F

Procedure:
A mixture of Z-2-fluoro-3-(2-tributylstannylethenyl)pyridine (1.39 g), 2-fluoro-3-iodopyridine (0.75 g) and bis(triphenylphosphine)palladium dichloride (0.010 g) in toluene (20 mL) was refluxed under argon for 4 hours. Most of the solvent was evaporated and the residue was treated overnight with aqueous potassium fluoride. The organic phase was dried and evaporated to give Z-1,2-di-(2-fluoropyridinyl)ethylene as a solid which was recrystallized from hexane/ethyl acetate (0.47 g) mp 93°-95° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[CH:17][N:18]3[CH2:27][CH:26]=[CH2:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ccc23)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCn1ccc2c(N3CCN(C(=O)OC(C)(C)C)CC3)cccc21
Reaction time: 48 h

Procedure:
A solution of 1-t-butoxycarbonyl-4-(1H-indol-4-yl)piperazine (prepared as described above) in tetrahydrofuran (50 mL) was added dropwise to a suspension of sodium hydride (0.7 g of a 60% mineral oil suspension) in tetrahydrofuran (150 mL) at room temperature. After stirring for further 30 min a solution of allyl bromide (3.5 mL) in tetrahydrofuran (50 mL) was added dropwise. After stirring for 48 h the mixture was poured onto ice-water followed by standard work-up with ethyl acetate giving an oil, which was purified by flash chromatography (eluent: heptane/ethyl acetate 85:15) giving 1-t-butoxycarbonyl-4-(1-allyl-1H-indol-4-yl)piperazine as an oil (3.2 g). The oil was dissolved in methanol (15 mL) and a saturated solution of HCl in diethyl ether (100 mL) was added. After stirring for 16 h at room temperature, the resulting colorless crystals consisting of the hydrochloride of the title compound (2.5 g) was collected by filtration and dried in vacuo.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH2:5][CH2:6][N:7]([CH3:14])[CH2:8][CH2:9][CH2:10][NH:11][CH:12]=[O:13])=[O:2].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][Cl:22])=[CH:19][C:18]=1[N+:25]([O-:27])=[O:26]>C(#N)C>[Cl-:22].[CH3:14][N+:7]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[C:18]([N+:25]([O-:27])=[O:26])[CH:19]=1)([CH2:6][CH2:5][CH2:4][NH:3][CH:1]=[O:2])[CH2:8][CH2:9][CH2:10][NH:11][CH:12]=[O:13]
Reactant: CN(CCCNC=O)CCCNC=O
Reactant: COc1ccc(CCl)cc1[N+](=O)[O-]
Solvent: CC#N
Product: COc1ccc(C[N+](C)(CCCNC=O)CCCNC=O)cc1[N+](=O)[O-]
Product: [Cl-]
Reaction time: 2 h

Procedure:
A mixture of 54.0 parts of N,N-bis(3-formamidopropyl)methylamine, 50.4 parts of 4-methoxy-3-nitrobenzyl chloride, and 78 parts of acetonitrile was stirred at reflux for seven and a half hours. An additional 78 parts of acetonitrile was added to the reaction mixture causing an oil to separate. Heating at reflux was continued for an additional two hours and the 140 parts of acetonitrile was distilled away and 200 parts of water was added. The remaining acetonitrile was removed by distillation and the cooled reaction mixture was filtered with the aid of diatomaceous earth to obtain an aqueous solution of N-methyl-N-(3-nitro-4-methoxybenzyl)-N,N-bis(3-formamidopropyl)ammonium chloride. The solution was used directly for reduction of the nitro group.
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[NH:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19](O)=O)=[N:12]1.N>>[NH:11]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[C:18]([C:19]3[O:1][N:2]=[C:3]([C:4]4[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=4)[N:10]=3)[CH:22]=[CH:23][CH:24]=2)=[N:12]1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cccc(-c2cc[nH]n2)c1
Agent: N
Product: c1cncc(-c2noc(-c3cccc(-c4cc[nH]n4)c3)n2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 3-(1H-pyrazol-3-yl)benzoic acid (Maybridge). 1H NMR (300 MHz, DMSO-d6) δ 6.91 (d, J=2.4 Hz, 1 H), 7.62-7.69 (m, 1 H), 7.72 (t, J=7.8 Hz, 1 H), 7.79-7.92 (m, 1 H), 7.82-7.88 (m, 1H), 8.10-8.20 (m, 3 H), 8.49 (dt, J=8.2, 1.9, 1.7 Hz, 1 H), 8.64 (s, 1 H), 8.83 (dd, J=4.7, 1.7 Hz, 1 H), 9.29 (dd, J=2.2, 0.8 Hz, 1 H) ppm; MS (DCI/NH3) m/z 290 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][CH:6]=[C:5]([N+:10]([O-])=O)[C:3]=1[NH2:4].C(O)C.[OH-].[Na+]>O.[Zn]>[CH3:1][C:2]1[C:3]([NH2:4])=[C:5]([NH2:10])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc([N+](=O)[O-])c(N)c1C
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)c(N)c1C
Reaction time: 0.5 h

Procedure:
To a 125 mL round bottom flask 2.20 g of 2,3-dimethyl-6-nitro-aniline (13.2 mmol) was added. Then 15 mL of ethanol was added to the flask followed by the addition of 4 mL of 20 wt % NaOH in water. Then 2.0 g of zinc dust was added to the flask. The flask was fitted with a condenser and was left to reflux with stirring. After about 0.5 hours the mixture became very pale-brown. After refluxing for 18 hours the mixture was filtered hot to give a pale filtrate which quickly became dark red. C8H12N2, fw=136.19. Yield 1.78 g, 98.7%. Mp: 60° C. (melt). 1H NMR (300 MHz, CDCl3): δ 6.54(s, 2H), 3.46 (br s, 2H), 3.21 (br s, 2H), 2.22 (s, 3H), 2.11 (s, 3H). Rf=0.68 (ethyl acetate/silica).