Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1)[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:41]=[CH:42][C:43]=1[F:44])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38](=[O:40])[CH3:39])[N:36]=2)[N:33]=1>CN(C)C(=O)C.O1CCCC1>[C:38]([NH:37][C:35]1[N:36]=[C:31]2[CH:30]=[CH:29][C:28]([O:27][C:26]3[CH:41]=[CH:42][C:43]([F:44])=[C:24]([NH:23][C:8]([C:6]4[N:5]([CH3:11])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=4)=[O:10])[CH:25]=3)=[N:33][N:32]2[CH:34]=1)(=[O:40])[CH3:39]
Reactant: CCc1cc(C(=O)O)n(C)n1
Reactant: CC(=O)Nc1cn2nc(Oc3ccc(F)c(N)c3)ccc2n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(C)=O)cn4n3)ccc2F)n(C)n1
Yield: 50.1 %

Procedure:
Using 3-ethyl-1-methyl-1H-pyrazole-5-carboxylic acid (215 mg, 1.39 mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (122 μL, 1.39 mmol), N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]acetamide (300 mg, 1.00 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 238, the title compound (219 mg, 50%) was obtained as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]2/[C:6](=[N:10]/[NH:11][C:12]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[O:13])/[CH:7]([CH3:9])[O:8][C:4]=2[CH:3]=1.FC(F)(F)C1C=CC(N=C=O)=CC=1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]2/[C:6](=[N:10]\[NH:11][C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=3)=[O:13])/[CH:7]([CH3:9])[O:8][C:4]=2[CH:3]=1
Reactant: CC1Oc2cc(Cl)ccc2/C1=N/NC(=O)Nc1ccc(C(F)(F)F)cc1
Agent: O=C=Nc1ccc(C(F)(F)F)cc1
Product: CC1Oc2cc(Cl)ccc2/C1=N\NC(=O)Nc1ccc(C(F)(F)F)cc1
Yield: 160 %

Procedure:
Treating the anti hydrazone (0.5 g) obtained in Step C with p-trifluoromethylphenylisocyanate (0.4 ml) in the same manner as in Step C resulted in the isolation of the desired product as a solid (0.8 g). m.p.=205°-207° C. NMR: (10.4 (br, NH), 9.4 (br, 1H), 8.2-7.0 (m, 7H), 5.8 (m, 1H), 1.47 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=2)=[CH:4][N:3]=1.[Se](=O)=[O:23]>O1CCOCC1>[CH:1]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=2)=[CH:4][N:3]=1)=[O:23]
Reactant: O=[Se]=O
Reactant: Cc1ncc(Oc2ccc(C(N)=O)cn2)c2ccccc12
Solvent: C1COCCO1
Product: NC(=O)c1ccc(Oc2cnc(C=O)c3ccccc23)nc1
Temperature: 80 °C

Procedure:
To 6-(1-methylisoquinolin-4-yloxy)nicotinamide (Preparation 19) (135 mg, 0.48 mmol) in dioxane (6 mL) under argon was added selenium dioxide (54 mg, 0.48 mmol). The mixture was heated to 80° C. for 3 h after which time selenium dioxide (54 mg, 0.48 mmol) was added. After a further 0.5 h at 80° C. the mixture was cooled, filtered through Celite and washed with EtOAc (50 mL). The organic phase was washed with NaHCO3 (30 mL), water (30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed in vacuo to give the title compound: RT=2.93 min; m/z (ES+)=294.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].I[CH2:33][CH2:34][CH3:35]>C(C(C)=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH2:20][N:21]1[CH:25]=[N:24][CH:23]=[N:22]1)([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:10]([O:12][CH2:33][CH2:34][CH3:35])=[O:11]
Reactant: CCCI
Reactant: COc1ccccc1C(Cc1ccccc1)(Cn1cncn1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOC(=O)C(Cc1ccccc1)(Cn1cncn1)c1ccccc1OC
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A mixture of 2-(2-methoxyphenyl)-3-phenyl-2-[(1,2,4-triazol-1-yl)methyl]propanoic acid (6.0 g, 0.0178 mole) and potassium carbonate (3.6 g, 0.0213 mole) in methyl ethyl ketone (50 mL) was stirred and heated to reflux for 1 hour. Iodopropane (3.6 g, 0.0213 mole) was added and the mixture continued heating at reflux for an additional 4 hours and then allowed to cool to room temperature. The solvent was removed by distillation and 100 mL of water and 100 mL of ethyl acetate added. The organic phase was then separated, dried and concentrated on a rotary evaporator to afford 5.5 g of solid product (melting point 129°-130° C.; yield 82%), Example 100 of Table 1.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=O)[CH2:14][OH:15])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:17](#[N:21])[CH2:18][C:19]#[N:20].C(NCC)C.O>CN(C=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[C:18]([C:19]#[N:20])=[C:17]([NH2:21])[O:15][CH:14]=3)=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: N#CCC#N
Reactant: CC(=O)N1CCc2cc(C(=O)CO)ccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(=O)N1CCc2cc(-c3coc(N)c3C#N)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a suspension of 1-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-2-hydroxyethanone (0.53 g, 2.41 mmol) and malononitrile (176 mg, 2.66 mmol, 1.1 equiv) in DMF (4 mL) chilled in an ice bath was added diethylamine (380 uL, 3.63 mmol, 1.5 equiv) over a 3 minute period. The resulting mixture was stirred in the ice bath for another 20 minutes, and then the ice bath was removed. The brownish suspension was stirred at ambient temp for 2 hours. LCMS showed product formed in 75%. To the suspension was added 20 mL of water. The warm suspension was filtered. The cake was washed with water, and dried under house vacuum overnight to give 4-(1-acetyl-2,3-dihydro-1H-indol-5-yl)-2-amino-3-furancarbonitrile (360 mg) as beige solids. LC-MS (ES) m/z=268 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[Cl:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[Cl:26][C:27]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: OB(O)c1cccc(F)c1Cl
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cccc(F)c1Cl

Procedure:
The title compound was prepared in analogy to example 58, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-chloro-3-fluoro-benzeneboronic acid (CAS RN 871329-52-1) and using preparative HPLC for the chromatographic purification. Off-white sticky solid (36%). MS (ESI): m/z=477.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:22])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:21]=1>O1CCOCC1.C(O)C.[Ni]>[OH:1][C:2]1[C:3]([OH:22])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: O=c1c(-c2ccc([N+](=O)[O-])cc2)coc2cc(O)c(O)cc12
Agent: [Ni]
Solvent: CCO
Solvent: C1COCCO1
Product: Nc1ccc(-c2coc3cc(O)c(O)cc3c2=O)cc1
Reaction time: 18 h

Procedure:
6,7-Dihydroxy-3-(4-nitrophenyl)-4H-1-benzopyran-4-one [cp. J. Inst. Chem. (Calcutta) 43, 234 (1971)] (1 g) is dissolved in 250 ml of a mixture of dioxan and ethanol 1:1. Raney nickel (0.45 g) is added and the mixture is hydrogenated for 18 h at room temperature, then filtered. The solution is evaporated under vacuum to about one third of its original volume until a precipitate occurs which is filtered and crystallized in dioxan to give 6,7-dihydroxy-3-(4-aminophenyl)-4H-1-benzopyran-4-one, m.p. 305°-306°.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:10](=O)[C:11](=[O:15])[C:12]=2[O:13]C)[CH2:5][CH2:4]1)[CH3:2].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C>C(O)C>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:12](=[O:13])[C:11](=[O:15])[C:10]=2[N:21]2[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCN1CCN(c2c(OC)c(=O)c2=O)CC1
Solvent: CCO
Product: CCN1CCN(c2c(N3CCN(C)CC3)c(=O)c2=O)CC1

Procedure:
To a stirred, refluxing solution of 2.2 grams of 3-(4-ethyl-1-piperazinyl)-4-methoxy-3-cyclobutene-1,2-dione dissolved in 30 ml. of absolute ethanol under an atmosphere of dry nitrogen, is added a solution of 1.0 gram of 1-methylpiperazine in 30 ml. of absolute ethanol. The resulting mixture is refluxed for 4 hours and then stripped of solvent under reduced pressure until the volume is approximately 15 ml. The concentrate is treated with decolorizing charcoal and filtered through a bed of diatomaceous earth. Crystallization is induced in the filtrate and the resulting crystalline precipitate is filtered, washed with absolute ethanol, and dried in a steam cabinet. The resulting product, 3-(4-ethyl-1-piperazinyl)-4-(4-methyl-1-piperazinyl)-3-cyclobutene-1,2-dione, is obtained as white crystals melting at about 166.5°-169° C. This product is represented by the following structural formula. ##STR9##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]2[C:13](=[O:19])[NH:12][C:11](=[O:20])[CH2:10]3)[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[CH3:23][C:24]([CH3:28])=[CH:25][CH2:26]Br.O>CN(C)C=O>[CH3:23][C:24]([CH3:28])=[CH:25][CH2:26][N:12]1[C:11](=[O:20])[CH2:10][C@@:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C@H:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[C:13]1=[O:19]
Reactant: CC(C)=CCBr
Reactant: COc1cccc([C@@]23CCCC[C@H]2C(=O)NC(=O)C3)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc([C@@]23CCCC[C@@H]2C(=O)N(CC=C(C)C)C(=O)C3)c1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
A solution of 4 g (14.7 mmoles) of 4a-(m-methoxyphenyl)-1,3-diketo-trans-decahydroisoquinoline in 50 ml of anhydrous dimethylformamide was added dropwise to 700 mg of a 55% suspension of sodium hydride in mineral oil in 50 ml of dimethylformamide at 70°. The reaction mixture was heated for 1 hour after the addition was complete and then cooled to 25°. 3,3-Dimethylallyl bromide (2.37 g, 15.8 mmoles) in 10 ml of dimethylformamide was added dropwise and the solution stirred overnight at 25°. After heating at 80° for 1 hour it was poured into water and extracted with ether to yield 4.74 g of N-(3,3-dimethylallyl)-4a-(m-methoxyphenyl)-1,3-diketo-cis-decahydroisoquinoline (oil), which was evaporatively distilled, bp 225° (0.005 mm).
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:30])/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=CC=1)([O-])=O.[CH3:31][C:32]([CH3:43])([NH2:42])[CH2:33][CH2:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>O1CCCC1>[F:29][C:25]1[CH:24]=[C:23]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:42][C:32]([CH3:43])([CH3:31])[CH2:33][CH2:34][CH2:35][C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)=[O:30])[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(/C=C/C=C(c1cccc(F)c1)c1cccc(F)c1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(N)CCCc1cccnc1
Solvent: C1CCOC1
Product: CC(C)(CCCc1cccnc1)NC(=O)/C=C/C=C(c1cccc(F)c1)c1cccc(F)c1

Procedure:
As in Example 134, a solution of (E)-5,5-bis(3-fluorophenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.63 g) and alpha,alpha-dimethyl-3-pyridinebutanamine (0.9 mL) in tetrahydrofuran (20 mL) was stirred for 29 hours at reflux and was then worked up in the usual manner. The crude amide was crystallized from ethyl acetate-hexane to furnish 1.6 g of (E)-5,5-bis(3-fluorophenyl)-N-[l,1-dimethyl-4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 135°-136° C.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[CH:9]=[N:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:12]([CH2:13][CH3:14])[C:3]=12.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH2:13]([C:12]1[C:3]2[C:4](=[C:5]([N:10]3[CH2:11][CH2:12][CH2:3][CH2:4][CH2:9]3)[N:6]=[N:7][C:2]=2[N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:9]=[N:10][C:11]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:14]
Reactant: CCc1c(-c2ccccc2)ncc2c(Cl)nnc(Cl)c12
Reactant: C1CCNCC1
Product: CCc1c(-c2ccccc2)ncc2c(N3CCCCC3)nnc(N3CCCCC3)c12

Procedure:
3.0 g. of 1,4-dichloro-8-ethyl-7-phenylpyrido[3,4-d]-pyridazine was heated together with 15 g. of piperidine at 120° C for 1.5 hours, after which time the excess piperidine was distilled off. To the residue was added 60 ml. of water and the resultant crystals were recovered by filtration and were chromatographed on a column packed with silica gel, followed by elution with a mixed solvent of acetone-benzene (1:8). The combined eluate is concentrated and the residue was dissolved in 100 ml. of ethanol. Following the addition of 5 ml. of water, the solution was concentrated to dryness. The concentrate was diluted with 100 ml. of water and stirred, whereupon 2.5 g. of 8-ethyl-7-phenyl-1,4-dipiperidinopyrido-[3,4-d]pyridazine was obtained. Melting point: 64°-65° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]2[O:7][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][O:10][C:5]=2[CH:4]=1)[CH3:2].C([O:22]O)(C)(C)C>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:3]1[CH:17]=[CH:16][C:6]2[O:7][CH:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][O:10][C:5]=2[CH:4]=1)(=[O:22])[CH3:2]
Reactant: CC(C)(C)OO
Reactant: CCOC(=O)C1COc2cc(CC)ccc2O1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)C1COc2cc(C(C)=O)ccc2O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Add 2 g (8.5 mmol) of ethyl 6-ethyl-2,3-dihydro-1,4-benzodioxin-2-carboxylate dissolved in 5 cm3 of anhydrous methylene chloride to a mixture at 0° C. of 0.042 g (0.42 mmol) of chromium trioxide and 5.35 g (59.3 mmol) of 70% tert-butyl hydroperoxide in 30 cm3 of methylene chloride. Stir for 2 hours at 0° C. and then for 72 hours at room temperature. The crude product obtained by concentrating to dryness is purified by chromatography on a silica column (eluant: methylene chloride). Ethyl 6-acetyl-2,3-dihydro-1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 62%.
Reaction SMILES: [C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:35])C(=O)C1>CN(C=O)C.O>[C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[C:9]([Br:35])=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc2c(cc1Br)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reaction time: 0.75 h
Yield: 90.7 %

Procedure:
A solution of 506 mg of 19d in 4 ml of DMF was treated with 210 mg of NBS. The reaction was stirred for 45 min, then diluted with water, and stirred for an additional 15 min. The white precipitate was filtered and dried, to provide 543 mg of dibromide 25a.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([SH:11])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:20])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CO>[NH2:1][C:2]1[N:10]=[C:9]([S:11][CH3:21])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:20])[N:6]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1
Reactant: Nc1nc(S)nc2c1nc(O)n2Cc1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CI
Product: CSc1nc(N)c2nc(O)n(Cc3ccc(F)cc3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
6-amino-9-(4-fluorobenzyl)-8-hydroxy-2-mercaptopurine (200 mg, 0.687 mmol) was suspended in methanol (20 ml). To the suspension were added potassium carbonate (190 mg, 1.37 mmol) and methyl iodide (975 mg, 6.87 mmol) in order. The mixture was stirred at room temperature for 30 minutes. The reaction mixture were evaporated in vacuo to dryness and extracted with chloroform. The organic layer was dried on sodium sulfate. After removal of the solvent in vacuo, the residue was purified by silica gel chromatography (3% methanol/chloroform) to give the subject compound (63 mg, yield 30%).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:16]O>C(O)(=O)C>[O:16]=[C:11]1[C:12]2[C:13](=[O:15])[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[S:6][C:7]=2[CH:8]=[CH:9][CH2:10]1
Reactant: OO
Reactant: O=c1c2ccccc2sc2ccccc12
Solvent: CC(=O)O
Product: O=C1CC=Cc2sc3ccccc3c(=O)c21
Reaction time: 0.5 h

Procedure:
To a well stirred solution of 10.3 g of thioxanthen-9-one in 100 ml of glacial acetic acid at 80° C. 5 ml of hydrogen peroxide (35%) was added dropwise. The solution was stirred for 30 minutes, and then concentrated under reduced pressure and additional dichloromethane was added. The organic phase was washed with a solution of sodium hydroxide and then with water. After drying (Na2SO4) the solvent was removed under vacuum and 11 g of an oil were obtained. The oil was purified with a flash chromatography (SiO2) eluting with CH2Cl2 and CH2Cl2/Ethyl acetate 9:1; 8.44 g of a yellow solid were obtained in a yield of 72%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.NC1C([N+:17]([O-:19])=[O:18])=C(C)C=C(C)N=1.OS(O)(=O)=O.[N+]([O-])(O)=O.[NH4+].[OH-]>>[NH:1]([C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1)[N+:17]([O-:19])=[O:18]
Reactant: Cc1cc(C)c([N+](=O)[O-])c(N)n1
Reactant: Cc1cc(C)nc(N)c1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Product: Cc1cc(C)nc(N[N+](=O)[O-])c1
Temperature: 0 °C
Yield: 97.3 %

Procedure:
2-Amino-4,6-dimethyl-3-nitropyridine 2-Amino-4,6-dimethylpyridine (10.0 g, 81.8 mmol) was added portion-wise to 65 mL of H2SO4 (conc. d=1.84) which was stirred (mechanical) at 0° C. After complete addition, the mixture was warmed to room temperature until the mixture became homogeneous. The solution was then cooled to -10 C. and a pre-cooled (0° C.) mixture of concentrated HNO3 (11.5 mL, d=1.40) and H2SO4 (8.2 mL, d=1.84) was added at such a rate as not to raise the internal reaction temperatures above -9° C. Ten minutes after the addition was complete this cooled (-10°C.) mixture was poured onto 400 g of crushed ice. The resulting slurry was neutralized by the addition of conc NH4OH (to pH 5.5) while cooling (ice bath). The solid was isolated by filtration, and dried at room temperature to give 13.3 g of 2-nitramino-4,6-dimethylpyridine as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH2:11][CH2:12][O:13][C:14]1[C:18]([C:19]2[CH:27]=[CH:26][C:22]3[O:23][CH2:24][O:25][C:21]=3[CH:20]=2)=[C:17]([N:28](S(C2C=CC(C(C)(C)C(OCC)=O)=CC=2)(=O)=O)[S:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[N:16]([CH3:63])[N:15]=1)(=O)C.[Cl-].[NH4+].Cl>CO.ClCCl>[O:23]1[C:22]2[CH:26]=[CH:27][C:19]([C:18]3[C:14]([O:13][CH2:12][CH2:11][OH:10])=[N:15][N:16]([CH3:63])[C:17]=3[NH:28][S:29]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([CH3:45])([CH3:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:36][CH:37]=3)(=[O:31])=[O:30])=[CH:20][C:21]=2[O:25][CH2:24]1
Reactant: CCOC(=O)C(C)(C)c1ccc(S(=O)(=O)N(c2c(-c3ccc4c(c3)OCO4)c(OCCOC(C)=O)nn2C)S(=O)(=O)c2ccc(C(C)(C)C(=O)OCC)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)c1ccc(S(=O)(=O)Nc2c(-c3ccc4c(c3)OCO4)c(OCCO)nn2C)cc1
Reaction time: 8 h

Procedure:
Solid potassium carbonate (290 mg) was added at room temperature to a solution of impure ethyl 2-{4-[([3-[2-(acetyloxy)ethoxy]-4-(1,3-benzodioxol-5-yl)-1-methyl-1H-pyrazol-5-yl]{[4-(2-ethoxy-1,1-dimethyl-2-oxoethyl)phenyl]sulfonyl}amino)sulfonyl]phenyl}-2-methylpropanoate (Preparation 51) in a mixture of methanol (3 ml) and dichloromethane (3 ml). The reaction was left overnight, then an aqueous saturated solution of ammonium chloride (10 ml) was added. The aqueous phase was acidified by the addition of an aqueous solution of HCl (1N, few drops), the phases were separated and the aqueous phase was extracted with dichloromethane (2×10 ml). The organic fraction was dried over sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography (silica, 3.5 g) eluted with hexane:ethyl acetate (1:1) yielding the title compound as a colourless oil (240 mg).
Reaction SMILES: [CH3:1][N:2]1[C:19](=[O:20])[CH2:18][CH2:17][C:5]2([C:9]3[CH:10]=[C:11]([N+:14]([O-])=O)[CH:12]=[CH:13][C:8]=3[O:7][CH2:6]2)[CH2:4][CH2:3]1>C(O)(=O)C>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]2[O:7][CH2:6][C:5]3([CH2:17][CH2:18][C:19](=[O:20])[N:2]([CH3:1])[CH2:3][CH2:4]3)[C:9]=2[CH:10]=1
Reactant: CN1CCC2(CCC1=O)COc1ccc([N+](=O)[O-])cc12
Solvent: CC(=O)O
Product: CN1CCC2(CCC1=O)COc1ccc(N)cc12
Yield: 30.9 %

Procedure:
This material was prepared from 1,2,3,5,6,7-hexahydro-1-methyl-5'-nitro-7-oxospiro[4H-azepine-4,3'(2H)-benzofuran] (D27, 0.68 g, 2.5 mmol) following the procedure of DESCRIPTION 6, but using acetic acid as solvent. This gave the title compound (0.19 g, 31%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3B3OC(C)(C)C(C)(C)O3)[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C.[F:43][C:44]1[CH:49]=[C:48]([O:50][CH3:51])[C:47](I)=[CH:46][C:45]=1[C:53]1[CH:58]=[CH:57][C:56]([C:59]([O:61][CH3:62])=[O:60])=[CH:55][C:54]=1[CH3:63].C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>O.CCO.C1(C)C=CC=CC=1.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.CCCCCC>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=3[C:47]3[CH:46]=[C:45]([C:53]4[CH:58]=[CH:57][C:56]([C:59]([O:61][CH3:62])=[O:60])=[CH:55][C:54]=4[CH3:63])[C:44]([F:43])=[CH:49][C:48]=3[O:50][CH3:51])[C@H:14]2[CH3:39])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cc(I)c(OC)cc2F)c(C)c1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1
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: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: COC(=O)c1ccc(-c2cc(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c(OC)cc2F)c(C)c1

Procedure:
(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one-methane (1.30 g, 2.18 mmol) (INTERMEDIATE 9), the title compound from Step B (1.30 g, 3.25 mmol), tetrakis(triphenylphosphine)palladium (250 mg, 10% mol) and sodium carbonate (507 mg, 4.79 mmol) in 50 ml of water/EtOH/toluene (1:2:4) was heated to reflux for 4 h. TLC (CH2Cl2:hexane/1:1) showed that the reaction was complete. The solvents were removed. Water (20 ml) was added. The organic was extracted with methylene chloride (3×30 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after flash column using CH2Cl2:hexane/8:2 as the elute. 1H NMR (CDCl3, 500 MHz): δ a mixture of 1:1 atopoisomers 7.98 (d, J=4.5 Hz, 1H), 7.89 (s, 2H), 7.68 (m, 4H), 7.42 (t, J=6.0 Hz, 1H), 7.30 (d, J=7.5 Hz, 0.5H), 7.26 (d, J=7.5 Hz, 0.5H), 7.07 (t, J=8.0 Hz, 1H), 6.87 (d, J=5.5 Hz, 0.5H), 6.85 (d, J=6.0 Hz, 0.5H), 5.63 (d, J=8.0 Hz, 0.5H), 5.41 (d, J=8.0 Hz, 0.5H), 5.00 (d, J=15.5 Hz, 0.5H), 4.92 (d, J=16.0 Hz, 0.5H), 4.17 (d, J=15.5 Hz, 0.5H), 3.95 (d, J=16.0 Hz, 0.5H), 3.95 (s, 3H), 3.88 (s, 3H), 3.84(m, 1H), 2.32 (s, 1.5H), 2.28 (s, 1.5H), 0.64 (d, J=7.0 Hz, 1.5H), 0.62 (d, J=6.5 Hz, 1.5H). LC/MS M+744.2