Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@H:6]2[CH2:7][CH:8]([OH:10])[CH2:9][C@H:3]1[CH2:4][CH2:5]2.Cl.[CH3:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([CH3:22])[CH:21]=1)[C:16]([Cl:18])=[O:17].Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][C:20]1[CH:19]=[C:15]([C:16]([O:10][CH:8]2[CH2:9][C@H:3]3[N:2]([CH3:1])[C@H:6]([CH2:5][CH2:4]3)[CH2:7]2)=[O:17])[CH:14]=[C:13]([CH3:12])[CH:21]=1.[ClH:18]
Reactant: CN1[C@@H]2CC[C@H]1CC(O)C2
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(C)cc(C(=O)OC2C[C@H]3CC[C@@H](C2)N3C)c1
Yield: 58.8 %

Procedure:
A stirred mixture of tropine hydrochloride (5.27 g) and 3,5-dimethylbenzoyl chloride (5 g) is heated at 130°-140° C. for 30 minutes during which time the mixture liquifies, evolves hydrogen chloride gas and resolidifies. A solution of the cooled solid in water is basified with a solution of potassium carbonate and the base extracted with ethyl acetate. The ethyl acetate solution is washed several times with water, dried over mangnesium sulphate, and evaporated to yield the free base which is converted to the hydrochloride by the addition of ethereal hydrogen chloride. Recrystallization of the precipitated solid from ethanol yields tropyl 3,5-dimethylbenzoate hydrochloride (5.4 g) m.p. 260° C.
Reaction SMILES: [C:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3].OCC[N:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17]O)[CH2:12][CH2:11]1.C(=O)([O-])[O-].[K+].[K+].COC(=O)O.O[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36](CCO)[CH2:35][CH2:34]1>>[CH3:17][CH:16]([N:13]1[CH2:12][CH2:11][NH:10][CH2:15][CH2:14]1)[CH2:3][O:2][C:1](=[O:6])[O:4][CH2:5][CH:32]([CH3:31])[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1
Reactant: COC(=O)OC
Reactant: OCCN1CCN(CCO)CC1
Agent: COC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(COC(=O)OCC(C)N1CCNCC1)N1CCNCC1

Procedure:
A total of 180.0 grams (2.0 mole) of dimethyl carbonate, 17.4 grams (0.1 mole) of 1,4-bis(2-hydroxyethyl)piperazine and 1.0 gram (0.007 mole) of potassium carbonate were combined in a 250 milliliter round bottom flask equipped with a straight distillation head and a magnetic stirrer. The flask contents were heated to reflux under a nitrogen atmosphere. Initial reaction temperatures at reflux were 80° C. at the head and 88° C. on the kettle. A methanol/dimethyl carbonate azeotrope was removed overhead over a period of 7.5 hours. After this time, the flask contents were cooled and the kettle contents were analyzed by capillary gas chromatography (FlD) using a DB-1701 column. The 1,4-bis(2-hydroxyethyl)piperazine was totally converted to a mixture of methyl bis(2-piperazinoethyl)carbonate and bis(methyl 2-piperazinoethyl)carbonate. The kettle contents were heated for an additional period of 2.5 hours after which the reaction was stopped. The kettle contents were concentrated in vacuo at 20 mm Hg and a temperature of 60° C. using a rotary evaporator. A total of 26.6 grams of material which was about 88 percent pure in bis(methyl 2-piperazinoethyl)-carbonate was obtained. The major by-products were 1,4-bis(2-hydroxyethyl)piperazine methyl carbonate (ca. 1.5 percent) and bis[1,4-(2-hydroxyethyl)-piperazine]carbonate (ca. 9.9 percent).
Reaction SMILES: ClC(N(C)C)=C(C)C.[F:9][CH:10]([F:27])[CH2:11][O:12][C:13]1[N:21]=[C:20]([NH:22][CH3:23])[C:19]([N+:24]([O-:26])=[O:25])=[CH:18][C:14]=1[C:15]([OH:17])=O.N1C=CC=CC=1.[Br:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1>C(Cl)Cl.C1COCC1>[Br:34][C:35]1[CH:41]=[CH:40][C:38]([NH:39][C:15](=[O:17])[C:14]2[CH:18]=[C:19]([N+:24]([O-:26])=[O:25])[C:20]([NH:22][CH3:23])=[N:21][C:13]=2[O:12][CH2:11][CH:10]([F:9])[F:27])=[CH:37][CH:36]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CNc1nc(OCC(F)F)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CNc1nc(OCC(F)F)c(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(1-Chloro-2-methyl-propenyl)-dimethylamine (1.54 mL, 5.63 mmol) is added to 2-(2,2-difluoro-ethoxy)-6-methylamino-5-nitro-nicotinic acid (880 mg, 5.12 mmol) in DCM (15 mL) and THF (15 mL) and stirred at rt for 15 min. Pyridine (607 μL, 7.67 mmol) followed by 4-bromoaniline are added to the reaction mixture and it is stirred for 1 h at rt. The mixture is concentrated, diluted with water and filtered. The filtercake is washed with water and dried to give the sub-title compound.
Reaction SMILES: C(#N)C.[Br:4][C:5]1[C:6]([NH:31]C(=O)C2C=CC=CC=2)=[N:7][C:8]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)=[N:9][C:10]=1[O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:19]#[N:20])=[CH:14][C:13]=1[CH3:21].O.[OH-].[Li+]>CC(O)C>[CH3:18][C:17]1[CH:16]=[C:15]([C:19]#[N:20])[CH:14]=[C:13]([CH3:21])[C:12]=1[O:11][C:10]1[N:9]=[C:8]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[N:7]=[C:6]([NH2:31])[C:5]=1[Br:4]
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(NC(=O)c2ccccc2)c1Br
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: CC(C)O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(N)c1Br
Temperature: 59 °C
Reaction time: 0.5 h

Procedure:
1350 ml of acetonitrile was taken into a RB flask at 27±3° C. To this was added 900 ml of IPA. To the reaction mixture 150 g of N-[5-bromo-6-(4-cyano-2,6-dimethylphenoxy)-2-(4-cyano-phenylamino)pyrimidin-4-yl]benzamide and 35.2 g of lithium hydroxide monohydrate were added and heated to 59±3° C. The reaction mixture was maintained at the same temperature for 10 hrs. After completion of the reaction, the reaction mixture was cooled to 47±3° C. and filtered. The solid was washed with acetonitrile and suck dried. The wet cake was taken into another flask to which was added 1500 ml of water, stirred for 30 mins and filtered to obtain the solid. The solid was washed with water and dried under vacuum at 73±3° C. to isolate Etravirine.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:12]=2)[N:6]=[C:5]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=2)[C:4]=1[C:34]#[N:35].[CH:36](=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(N(CC)CC)C.C([BH3-])#N.[Na+]>CN(C=O)C.CO>[NH2:2][C:3]1[N:8]=[C:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]3[CH2:19][CH2:20][N:21]([CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:22][CH2:23]3)[N:12]=2)[N:6]=[C:5]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=2)[C:4]=1[C:34]#[N:35]
Reactant: CC(=O)Nc1ccc(-c2nc(SCc3cccc(CN4CCNCC4)n3)nc(N)c2C#N)cc1
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2nc(SCc3cccc(CN4CCN(Cc5ccccc5)CC4)n3)nc(N)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
The compound of Example 18 (146 mg), benzaldehyde (28 mg) and triethylamine (75 mg) were dissolved in a mixture of 1 mL of DMF and 2 mL of methanol, the resulting mixture was stirred at room temperature overnight. To the reaction mixture under ice temperature, 30 mg of sodium cyanoborohydride was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was evaporated to dryness under reduced pressure, thereto ice-water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (methylene chloride-methanol-triethylamine=600:20:1) to give 60 mg of N-(4-{6-amino-2-[6-(4-benzylpiperazin-1-ylmethyl)pyridin-2-ylmethylsulfanyl]-5-cyanopyrimidin-4-yl}phenyl)acetamide as a white powder.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[N:13]=[C:14]([Cl:21])[C:15]2[CH:20]=[CH:19][NH:18][C:16]=2[N:17]=1.[CH3:22][Si:23]([CH2:26][CH2:27][O:28][CH2:29]Cl)([CH3:25])[CH3:24]>C1COCC1>[Cl:11][C:12]1[N:13]=[C:14]([Cl:21])[C:15]2[CH:20]=[CH:19][N:18]([CH2:29][O:28][CH2:27][CH2:26][Si:23]([CH3:25])([CH3:24])[CH3:22])[C:16]=2[N:17]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: C[Si](C)(C)CCOCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)nc(Cl)nc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
In a 1000 mL flask, LiHMDS (140 mL, 140 mmol) was diluted in dry THF (100 mL) and cooled to −78° C. The 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (25.0 g, 133 mmol) was suspended in THF (200 mL) using gentle warming and sonication. This suspension was added dropwise to the base solution over 30 min. 50 mL more THF was used to dissolve any residue and this suspension was also added dropwise. After complete addition, the mixture was allowed to stir at −78° C. for 30 min. SEM-Cl (25 mL, 140 mmol) was added dropwise to the mixture and stirring was continued at −78° C. for 30 min. Then, the ice bath was allowed to slowly warm to rt overnight. The reaction was quenched by the addition of cold water (150 mL). EtOAc (200 mL) was added and the layers separated. The resulting aqueous layer was then extracted with EtOAc (two×200 mL). The combined organics were washed with brine (two times) and dried over MgSO4, filtered and concentrated. The orange oil was purified via gravity “plug” chromatography eluting with 80% heptanes/20% DCM eluant to afford the title compound (33.4 g, 79% yield) as an orange oil which solidified upon standing. 1H NMR (400 MHz, chloroform-D) δ ppm-0.03 (s, 9H), 0.85-0.99 (m, 2H), 3.50-3.59 (m, 2H), 5.61 (s, 2H), 6.67 (d, J=3.53 Hz, 5H), 7.38 (d, J=3.78 Hz, 1H). m/z (APCI+) for C12H17Cl2N3OSi 318.00/320.05 (M+H)+ for Cl isotopes.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(C)=O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:7][C:6]=1[N+:12]([O-:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(O)cc1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]

Procedure:
2.94 G. of 1-acetamido-4-hydroxy-2-nitrobenzene, 4.2 g. anhydrous potassium carbonate and 5.13 g. benzyl bromide were refluxed overnight with stirring in 100 ml. acetone. Evaporation and extraction of the residue with dichloromethane affords 1-acetamido-4-benzyloxy-2-nitrobenzene. This latter compound is treated with sodium hydroxide in methanol, warmed briefly on a steam bath for about 15 minutes until the reaction is complete, diluted with water and extracted with dichloromethane to afford 1-amino-4-benzyloxy-2-nitrobenzene. This latter compound is treated for 4 hours in a refluxing hydrochloric acid acidified mixture of 160 ml. methanol and 40 ml. water with 4 g. iron powder (added in two portions) and 1 g. ferrous sulfate. The mixture is poured into 150 ml. concentrated ammonia, then extracted with chloroform to afford 1,2-diamino-4-benzyloxybenzene. This latter compound is treated in accordance with the fourth paragraph of Example XV to afford 4 -benzyloxy-1,2-bis(3-methoxycarbonyl-2-thioureido)benzene.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[CH:4][N:3]=1.C1COCC1.[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([N:8]2[C:17](=[O:18])[C:16]3[C:15](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]2=[O:19])=[CH:6][N:5]=[CH:4][N:3]=1
Reactant: Nc1cncnc1Cl
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1c1cncnc1Cl
Temperature: 100 °C
Yield: 77 %

Procedure:
To a vial charged with 4-chloropyrimidin-5-amine (commercially available from Frontier Scientific, Inc., Logan Utah) (0.500 g, 3.86 mmol) were added THF (6.43 mL), toluene (6.43 mL), TEA (1.345 mL, 9.65 mmol) and phthalic anhydride (1.310 mL, 13.51 mmol). The mixture was heated to 100° C. for 72 hours. The mixture was then dried under reduced pressure and purified with a 50 g SNAP column (Biotage) ramping EtOAc in heptane from 0-45%, then isocratic at 45% to elute 2-(4-chloropyrimidin-5-yl)isoindoline-1,3-dione (0.773 g, 2.98 mmol, 77% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=9.23 (d, J=0.4 Hz, 1H), 9.09 (d, J=0.4 Hz, 1H), 8.12-8.05 (m, 2H), 8.04-7.96 (m, 2H). m/z (ESI) 260.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.N1C=CC=CC=1.Cl[C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18]>O1CCCC1>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17](=[O:18])[O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[CH:3][CH:4]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: COc1ccc(N)cn1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
To a solution of 5-amino-2-methoxypyridine (1.00 g, 8.06 mmol) and pyridine (1.96 ml, 24.2 mmol) in tetrahydrofuran (20 ml) was added 2,2,2-trichloroethyl chloroformate (1.67 ml, 12.1 mmol) with ice-cooling, the mixture was stirred for 30 minutes with ice-cooling, the reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (2.30 g, 95.4%) as a solid.
Reaction SMILES: C[O:2][C:3](=[O:21])[C:4]([CH3:20])([CH3:19])[CH:5]([C:13]1[S:14][C:15]([Br:18])=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[OH-].[K+]>CO.CS(C)=O>[Br:18][C:15]1[S:14][C:13]([CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[C:4]([CH3:20])([CH3:19])[C:3]([OH:21])=[O:2])=[CH:17][CH:16]=1
Reactant: COC(=O)C(C)(C)C(c1cccc(F)c1)c1ccc(Br)s1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: CC(C)(C(=O)O)C(c1cccc(F)c1)c1ccc(Br)s1
Temperature: 75 °C
Yield: 85.9 %

Procedure:
To a solution of 3-(5-bromo-thiophen-2-yl)-3-(3-fluoro-phenyl)-2,2-dimethyl-propionic acid methyl ester (419 mg, 1.128 mmol) in MeOH (4 ml) and DMSO (2 ml) was added a 40% aqueous solution of potassium hydroxide (4 ml). The reaction mixture was heated at 75° C. for 6 hours. After removal of methanol, the solution was adjusted to pH 2 and was extracted with ethyl ether. The ether layer was washed, dried and evaporated to give 3-(5-bromo-thiophen-2-yl)-3-(3-fluoro-phenyl)-2,2-dimethyl-propionic acid (1a) as a white glass (346.2 mg, 86% yield). 1H NMR (400 MHz, CDCl3): δ 1.06 (s, 3H), 1.15 (s, 3H), 3.21 (s, 1H), 6.75 (d, 1H, J=3.8 Hz), 6.82 (d, 1H, J=3.8 Hz), 6.87 (td, 1H, J=8.1, 2.6 Hz), 7.02 (m, 1H), 7.10 (br d, J=8.1 Hz), 7.20 (m, 1H). HPLC Rt: 3.695 min.
Reaction SMILES: [CH:1]1([CH2:5][C@H:6]([C:21]2[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[C:23]([CH3:29])[CH:22]=2)[C:7](N([C@H](C)[C@H](O)C2C=CC=CC=2)C)=[O:8])[CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)[OH:31]>O1CCOCC1.O>[CH:1]1([CH2:5][C@H:6]([C:21]2[CH:26]=[CH:25][C:24]([S:27][CH3:28])=[C:23]([CH3:29])[CH:22]=2)[C:7]([OH:8])=[O:31])[CH2:2][CH2:3][CH2:4]1
Reactant: O=S(=O)(O)O
Reactant: CSc1ccc([C@@H](CC2CCC2)C(=O)N(C)[C@H](C)[C@H](O)c2ccccc2)cc1C
Solvent: C1COCCO1
Solvent: O
Product: CSc1ccc([C@@H](CC2CCC2)C(=O)O)cc1C
Temperature: 110 °C
Yield: 77 %

Procedure:
A solution of (R)-3-cyclobutyl-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-methyl-4-methylsulfanyl-phenyl)-propionamide (300 mg, 0.73 mmol) in dioxane (4 mL) was treated with a 9 N aqueous sulfuric acid solution (2 mL). The resulting solution was then heated at 110° C. for 16 h. The reaction was then cooled and diluted with water (75 mL) and extracted with a chloroform/methanol solution (3:2, 2×50 mL) and then concentrated. The resulting residue was then dissolved in methylene chloride and concentrated with silica gel (2 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 80% ethyl acetate/hexanes) to afford (R)-3-cyclobutyl-2-(3-methyl-4-methylsulfanyl-phenyl)-propionic acid (148 mg, 77%): [α]30589=−48.3° (c=0.18, methylene chloride); EI-HRMS m/e calcd for C15H20O2S (M+) 264.1184, observed 264.1183; 1H NMR (300 MHz, DMSO-d6) δ 1.47-2.14 (m, 9H, CH and 4×CH2), 2.21 (s, 3H, ArCH3), 2.43 (s, 3H, SCH3), 3.30 (t, J=7.4 Hz, 1H, ArCHCO), 7.05-7.15 (m, 3H, Ar), 12.28 (s, 1H, CO2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-])=O)[CH:29]=3)=[C:7]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[C:24]([F:27])([F:26])[F:25])=[O:15])[C:8](=[O:12])[O:9]2)=[CH:4][C:3]=1[CH3:37]>C(O)C.C1COCC1.[Ni]>[NH2:34][C:30]1[CH:29]=[C:28]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[C:3]([CH3:37])[CH:4]=3)[O:9][C:8](=[O:12])[C:7]=2[CH2:13][C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:24]([F:26])([F:27])[F:25])=[O:15])[CH:33]=[CH:32][CH:31]=1
Reactant: Cc1cc2c(-c3cccc([N+](=O)[O-])c3)c(CC(=O)Nc3ccc(Cl)cc3C(F)(F)F)c(=O)oc2cc1Cl
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc2c(-c3cccc(N)c3)c(CC(=O)Nc3ccc(Cl)cc3C(F)(F)F)c(=O)oc2cc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.5 %

Procedure:
A mixture solution of 2-[7-chloro-6-methyl-4-(3-nitrophenyl)-2-oxo-2H-chromen-3-yl]-N-[4-chloro-2-(trifluoromethyl)phenyl]acetamide (300 mg) in ethanol (2 ml) and THF (5 ml) was combined with Raney-nickel (50 mg), and stirred under hydrogen atmosphere at room temperature for 5 hours. After catalyst was filtered off, the reaction solution was concentrated. The resultant residue was purified by a silica gel chromatography (eluent: hexane-ethyl acetate=2:1), and further recrystallized from THF-ethyl acetate to obtain the title compound as a colorless crystal (166 mg, yield: 59%). Melting point: 206-207° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:9](=[S:25])[NH:8][C:7]=2[N:26]=1.[C:27](=O)([O-])O.[Na+].IC.CN(C)C=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=3)[C:9]([S:25][CH3:27])=[N:8][C:7]=2[N:26]=1
Reactant: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(=S)[nH]c2n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(SC)nc2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 7-methoxy-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (1.2 g), 1M aqueous sodium hydrogen carbonate solution (3.1 ml), iodomethane (0.98 ml) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 1 hr. The reaction mixture was allowed to be cooled, diluted with ethyl acetate (100 ml), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.24 g).
Reaction SMILES: [O:1]=[C:2]1[N:6]=[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4](=[O:15])[NH:3]1.[H-].[Na+].[CH3:18][O:19][CH2:20]Cl>CN(C=O)C.CCOCC.C(OCC)(=O)C>[CH3:18][O:19][CH2:20][N:3]1[C:4](=[O:15])[C:5]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[N:6][C:2]1=[O:1]
Reactant: CCOP(=O)(OCC)C1=NC(=O)NC1=O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOP(=O)(OCC)C1=NC(=O)N(COC)C1=O
Reaction time: 0.08 h

Procedure:
To a solution of diethyl 2,5-dioxo-4-imidazolylphosphonate (3.61 g, 0.015 moles) in DMF (10 mL), under N2, is added sodium hydride (80% dispersion in oil) (0.55 g, 0.018 moles) and stirred for 5 minutes. Chloromethyl methyl ether (tech. grade 85%) (1.9 mL, 0.021 moles) is added. This mixture is stirred at room temperature for 4 hours, diluted with ether and ethyl acetate (300 mL) and then washed with water and brine before drying over MgSO4. The aqueous layer is back extracted with methylene chloride and combined with the previous organic fraction. Evaporation of solvents and chromatography (eluant 1% methanol in chloroform) and evaporation under high vacuum affords the required product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([CH3:20])[C:17]([NH2:21])=[C:16]([N+:22]([O-])=O)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H].[I:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([O:34][CH3:35])[C:29]=1[CH:36]=O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[C:16]3[C:17]([N:21]=[C:36]([C:29]4[C:30]([O:34][CH3:35])=[N:31][CH:32]=[CH:33][C:28]=4[I:27])[NH:22]3)=[C:18]([CH3:20])[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COc1nccc(I)c1C=O
Reactant: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)nc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: Ic1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: COc1nccc(I)c1-c1nc2c(C)nc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2[nH]1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-(5-amino-4-methyl-6-nitro-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (3.18 g, 9.4 mmol) in methanol (200 mL) and 10% palladium on carbon (180 mg) were added methanol (10 mL) under nitrogen. The reaction mixture was stirred under hydrogen atmosphere (hydrogen balloon) for 18 hours. The solution was filtered through a pad of celite and the filtercake was washed with a small amount of MeOH. This solution was cooled to 0° C. and the 4-iodo-2-methoxy-pyridine-3-carbaldehyde (2.47 g, 9.4 mmol) in methanol (50 mL) was added to the reaction mixture and stirred at 23° C. for 18 hours. Then iodobenzene diacetate (3.03 g, 9.4 mmol) was added and the reaction mixture was stirred at 23° C. for 5 hours. MeOH was evaporated in vacuo and the crude material was purified on silica gel column using EtOAc:Hex (1:2 to 1:1 gradient) to give the title compound as a yellow solid. (2.75 g, 53%). HPLC 98%. LCMS (+ESI, M+H+) m/z 552; IR (KBr, cm−1) 3177, 2976, 1699, 1558, 1223; 1H NMR (400 MHz, DMSO) δ 12.92 (s, 1H), 8.0 (d, J=5.1 Hz, 1H), 7.64 (d, J=5.6 Hz, 1H), 3.81 (s, 3H), 3.73 (br s, 4H), 3.43 (br s, 4H), 2.57 (s, 3H), 1.44 (s, 9H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=O)=[N:6]1)[CH:2]([CH3:4])[CH3:3].[NH2:17][C:18]1[S:19][CH:20]=[CH:21][N:22]=1>>[S:19]1[CH:20]=[CH:21][N:22]=[C:18]1[NH:17][C:14]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:6]=1)=[O:16]
Reactant: CC(C)Cn1nc(C(=O)O)c2ccccc21
Reactant: Nc1nccs1
Product: CC(C)Cn1nc(C(=O)Nc2nccs2)c2ccccc21
Yield: 36.6 %

Procedure:
1-(Isobutyl)-indazole-3-carboxylic acid (340 mg) was obtained from methyl indazole-3-carboxylate (0.5 g, 2.84 mmol) and 1-iodo-2-methylpropane (0.33 mL, 2.84 mmol) following general procedures G and E. 1-(Isobutyl)-indazole-3-carboxylic acid thiazol-2-ylamide (66 mg) was prepared from 1-(isobutyl)-indazole-3-carboxylic acid (130 mg, 0.60 mmol) and 2-aminothiazole (150 mg,1.5 mmol) following the general procedure H.