Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:33])=[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[CH:25]=2)[NH:20][C:19](=[O:34])[C:18]=1[C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[C:37]([CH3:42])[CH:36]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1.C(Cl)Cl>[Cl:33][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:35]3[CH:36]=[C:37]([CH3:42])[CH:38]=[C:39]([CH3:41])[CH:40]=3)[C:19](=[O:34])[NH:20]2)=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(-c4ccccn4)c(Cl)cc3[nH]c2=O)c1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3)c3cc(-c4ccccn4)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-(2-[7-chloro-3-(3,5-dimethylphenyl)-2-oxo-6-pyridin-2-yl-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester in 2.0 dry methylene chloride was added a few drops of anisole followed by 2.0 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 1.5 hours, the solvents were removed in vacuo and the resulting residue purified by reverse-phase mplc (C-8, methanol:0.1% aqueous trifluoroacetic acid, 55:45) to give the title compound (112 mg). MASS: 488 (M+H)
Reaction SMILES: [Br:1][C:2]1[S:23][C:5]2[C:6](=[O:22])[NH:7][CH:8]([C:18]([O:20][CH3:21])=[O:19])[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=3)[C:4]=2[CH:3]=1.O1C[CH2:27][CH2:26][CH2:25]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(Br)C=C>>[CH2:27]([N:7]1[CH:8]([C:18]([O:20][CH3:21])=[O:19])[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[C:4]2[CH:3]=[C:2]([Br:1])[S:23][C:5]=2[C:6]1=[O:22])[CH:26]=[CH2:25]
Reactant: C1CCOC1
Reactant: COC(=O)C1NC(=O)c2sc(Br)cc2C1c1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C=CCBr
Product: C=CCN1C(=O)c2sc(Br)cc2C(c2ccc(Cl)c(Cl)c2)C1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-bromo-4-(3,4-dichlorophenyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylate (0.320 g, 0.735 mmol) in tetrahydrofuran (19 mL, 230 mmol) was added lithium bis(trimethylsilyl)amide (1.103 mmol, 1.103 mmol) in tetrahydrofuran (0.956 mL, 11.8 mmol) at −78° C. under argon. The mixture was stirred for 30 min before allyl bromide (1.27 mL, 14.7 mmol) was added. The reaction mixture was warmed to rt and stirred for 3 hr. The mixture was quenched by addition of sat. NH4Cl and then extracted with EtOAc. The organic layer was separated, dried, and concentrated in vacuo. The residue was purified by silica gel chromatography to afford methyl 6-allyl-2-bromo-4-(3,4-dichlorophenyl)-7-oxo-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-5-carboxylate, the first fraction, as a white solid (58 mg, 16%). LCMS: (AA) ES−: 474, 476, 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J=8.3, 4.1 Hz, 1H), 7.17 (d, J=2.1 Hz, 1H), 6.87 (dt, J=9.8, 4.9 Hz, 1H), 6.79 (s, 1H), 5.36-5.23 (m, 1H), 5.03-4.93 (m, 2H), 4.71 (ddt, J=15.2, 5.2, 1.4 Hz, 1H), 4.63 (s, 1H), 4.18 (d, J=1.5 Hz, 1H), 3.74 (s, 3H), 3.46-3.35 (m, 1H).
Reaction SMILES: [Cl:1][C:2]([CH:5]1[O:10][CH2:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[O:6]1)([Cl:4])[Cl:3].O.[NH2:16][NH2:17].[CH2:18](O)[CH3:19]>>[C:18](=[N:16][NH2:17])([C:12]1[CH:13]=[CH:14][C:7]2[O:6][CH:5]([C:2]([Cl:1])([Cl:4])[Cl:3])[O:10][CH:9]([C:2]([Cl:4])([Cl:3])[Cl:1])[C:8]=2[CH:11]=1)[CH3:19]
Reactant: CCO
Reactant: ClC(Cl)(Cl)C1OCc2ccccc2O1
Reactant: NN
Solvent: O
Product: CC(=NN)c1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2

Procedure:
A mixture of 6-acetyl-2,4-bis(trichloromethylbenzo[1,3]dioxin (2.0 g.) and 100% hydrazine hydrate (0.25 g.) in absolute ethanol (25 ml.) was heated under reflux for 16 hours, and cooled to give 6-acetyl-2,4-bis(trichloromethyl)benzo[1,3]dioxin hydrazone, m.p. 159° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][C:9]([N:11]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])[NH:5][C:4](=[O:21])[CH:3]=1.[CH3:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][N:24]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[CH2:13][CH2:12][N:11]2[C:9](=[O:10])[CH2:8][C:6]1[NH:5][C:4](=[O:21])[CH:3]=[C:2]([C:27]2[CH:26]=[CH:25][N:24]=[C:23]([CH3:22])[CH:28]=2)[N:7]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Reactant: O=C(Cc1nc(Cl)cc(=O)[nH]1)N1CCc2c(F)cccc21
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: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cc(=O)[nH]c(CC(=O)N3CCc4c(F)cccc43)n2)ccn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
120 mg of 6-chloro-2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-3H-pyrimidin-4-one, 96 mg of 2-methylpyridine-4-boronic acid pinacol ester, 45 mg of tetrakis(triphenylphosphine)palladium(0), 2.5 ml of 1,4-dioxane and 0.52 ml of an aqueous 1.5 M cesium carbonate solution are successively placed in a 5 ml microwave tube. The resulting suspension is stirred under microwave irradiation at a temperature of 100° C. for 2×1 hour. After cooling to ambient temperature, the reaction mixture is diluted with 6 ml of ethyl acetate and then filtered through Clarcel®. The solid is washed with 3 ml of ethyl acetate, and then the filtrate is treated with 12 ml of water and stirred at ambient temperature for 1.5 hours. After settling out, the organic phase is separated and the aqueous phase is extracted with 3×10 ml of ethyl acetate. The organic extracts are combined, washed with 10 ml of saturated brine, dried over magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 25 g cartridge of 15-40 μm silica, by making a solid deposit and eluting with a 95/5 v/v dichloromethane/methanol mixture at a flow rate of 25 ml/min. The fractions containing the desired product are combined and concentrated to dryness under reduced pressure. The residue is taken up twice in diethyl ether, triturated, and then concentrated to dryness under reduced pressure. 46 mg of 2-[2-(4-fluoro-2,3-dihydroindol-1-yl)-2-oxoethyl]-6-(2-methylpyridin-4-yl)-3H-pyrimidin-4-one are thus obtained in the form of a white crystalline powder, the characteristics of which are the following:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[CH:6][N:7]=1.[CH:11]([NH:13][NH:14][CH:15]=O)=O.CN(C=O)C.C(OCC)(=O)C>O>[N:13]1[N:14]=[CH:15][N:1]([C:2]2[CH:3]=[C:4]3[CH:10]=[CH:9][NH:8][C:5]3=[CH:6][N:7]=2)[CH:11]=1
Reactant: Nc1cc2cc[nH]c2cn1
Reactant: O=CNNC=O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1cc2cc(-n3cnnc3)ncc2[nH]1
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
5-Amino-1H-pyrrolo[2,3-c]pyridine (2 g, 15 mmol), diformylhydrazine (1.32 g, 15 mmol) and dry DMF (1.5 mL) were heated at 170° C. under nitrogen for 4 hours. After cooling, ethyl acetate (10 mL) and water (10 mL) were added. The mixture was stirred vigorously for 15 min. The resulting precipitate was collected by filtration, and chromatographed on silica eluting with a gradient of 5 to 7 to 10% MeOH in DCM to give a yellow solid. This was triturated with ether to give the title compound (1.65 g, 59%) as a yellow/green crystalline solid. mp 254°-257° C. 1H NMR (360 MHz, d6 -DMSO) δ 6.63 (1H, d, J=3.1Hz), 7.79 (1H, d, J=3.0Hz), 7.99 (1H, s), 8.71 (1H, s), 9.21 (2H, s) and 11.89 (1H, br s).
Reaction SMILES: [CH:1]1N=CN(C(N2C=NC=C2)=O)[CH:2]=1.[CH:13]1([N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:35])=[C:23]([C:27]4[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=4)[C:24]=3[F:26])[C:19](=[O:36])[C:18]([C:37]([OH:39])=[O:38])=[CH:17]2)[CH2:15][CH2:14]1>CN(C=O)C.C(O)C>[CH:13]1([N:16]2[C:25]3[C:20](=[CH:21][C:22]([F:35])=[C:23]([C:27]4[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=4)[C:24]=3[F:26])[C:19](=[O:36])[C:18]([C:37]([O:39][CH2:1][CH3:2])=[O:38])=[CH:17]2)[CH2:15][CH2:14]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1cc(-c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)cc(C)n1
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(-c3cc(C)nc(C)c3)c(F)cc2c1=O
Temperature: 25 °C

Procedure:
1,1'-Carbonyldiimidiazole (CDI) (3.9 g, 0.024 mol) was added to a suspension of (6.0 g, 0.016 mol) 1-cyclopropyl-7-(2, 6-dimethyl-4-pyridinyl )-6, 8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, described in U.S. Pat. No. 5,075,319, and incorporated herein by reference, in DMF (40 mL) and the mixture was stirred at 100° C. for 2 hr under a N2 atmosphere. The resulting solution was cooled to 25° C., diluted with and 60 mL ethanol and heated at reflux 17 h. Removal of the solvents in vacuo gave a residue that was stirred in 20 mL ethanol; after cooling in ice a solid separated and was collected (5.5 g, 86%); a 4.5 g portion of this material was recrystallized from ethanol to give 4.25 of ethyl 1-cyclopropyl-7-(2,6-dimethyl-4-pyridinyl)-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, mp 193°-195° C.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])[C:3]([OH:5])=[O:4].S(Cl)([Cl:15])=O.[CH3:17]COC(C)=O>CO.CCCCCC>[Cl-:15].[CH3:17][O:4][C:3](=[O:5])[C@H:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12])[NH3+:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccccc1[C@H](N)C(=O)O
Reactant: CCOC(C)=O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)[C@@H]([NH3+])c1ccccc1C
Product: [Cl-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.78 %

Procedure:
To a suspension of (S)-2-amino-2-(o-tolyl)acetic acid (commercially available from ACES Pharma, Princeton, N.J.) (800 mg, 4.84 mmol) in MeOH (20 mL) was added thionyl chloride (633.77 mg, 5.32 mmol) dropwise at −10° C. The resulting reaction mixture was stirred for 12 hours at reflux. After completion of the reaction (Reaction monitored by TLC, TLC system: 50% EtOAc in hexane), the reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure. The residue was crystallized with MeOH and diethyl ether to afford (S)-2-methoxy-2-oxo-1-(o-tolyl)ethanaminium chloride, (1 g, 95.78%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.97 (s, 3H), 7.39-7.28 (m, 4H), 5.34 (s, 1H), 3.70 (s, 3H), 2.43 (s, 3H). m/z (ESI) 180.1 (M+H)+.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=O.CCOCC>ClCCl>[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Fc1ccccc1-c1nc2ccccc2n1-c1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 74.9 %

Procedure:
N-phenyl-1,2-phenylenediamine (3.68 g, 20 mmol) and 40 ml of dichloromethane were charged in a 250 ml round bottle, 5 ml of triethylamine was then added, and the mixture was cooled to 0° C. 2-Fluoro-benzoyl chloride (3.16 g, 20 mmol) was dissolved in 40 ml of dichloromethane and then slowly added to the 250 ml round bottle. The reaction was conducted under a nitrogen atmosphere for 6 hours. After the reaction was complete, ether was added to form precipitation. The solid product was collected by filtration, washed with ether several times, and heated under reduced pressure to form 2-(2-fluoro-phenyl)-1-phenyl-1H-benzoimidazole (yield=4.32 g, 75%).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][C:11]=2[C:12]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:20].[OH-:21].[Na+]>C(O)CO>[C:1]1([C:7]2[O:8][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:10][C:11]=2[C:12]([OH:21])=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: [OH-]
Reactant: N#Cc1cc(-c2ccccc2)oc1-c1ccccc1
Agent: [Na+]
Solvent: OCCO
Product: O=C(O)c1cc(-c2ccccc2)oc1-c1ccccc1

Procedure:
A suspension of 2,5-diphenylfuran-3-carbonitrile (0.87 g, 3.56 mmol) in ethylene glycol and 3M NaOH (10 ml) was heated at reflux for 3 days. Water was added to the reaction mixture and extracted into CH2Cl2. The organic layer was dried with MgSO4, filtered and concentrated to provide 2,5-diphenylfuran-3-carboxylic acid (intermediate XXVIf, 900 mg) as white solid.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[NH2:10][C:11]1[CH:16]=[C:15]([CH3:17])[C:14]([OH:18])=[C:13]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=1.[C:23](=[O:26])([O-])[O-].[Na+].[Na+]>CC(C)=O.O>[C:19]([C:13]1[CH:12]=[C:11]([CH:16]=[C:15]([CH3:17])[C:14]=1[OH:18])[NH:10][C:8]1[N:1]=[C:2]([NH:10][C:11]2[CH:16]=[C:15]([CH3:14])[C:23]([OH:26])=[C:13]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:12]=2)[N:4]=[C:5]([Cl:6])[N:7]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(N)cc(C(C)(C)C)c1O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(Nc2nc(Cl)nc(Nc3cc(C)c(O)c(C(C)(C)C)c3)n2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 16 h
Yield: 37.8 %

Procedure:
36.9 g of cyanuric chloride in 200 ml of boiling acetone were slowly poured into 400 ml of ice water, whilst stirring. The temperature was maintained between 0° and 5° C. by means of external cooling. 71.6 g of 4-amino-2-tert.-butyl-6-methylphenol in 100 ml of acetone and 42.4 g of sodium carbonate in 100 ml of water were simultaneously added at 10° C. The mixture was stirred at 10° C. for one hour and then at room temperature for 16 hours. The reaction mixture was then poured into ice water and the precipitate was filtered off and recrystallised from ethanol. In this way, it was possible to isolate 35.5 g of white 2,4-bis-(3-tert.-butyl-5-methyl-4-hydroxyanilino)-6-chloro-1,3,5-triazine which melts at 214° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH:12][CH3:13].C(N(CC)CC)C.C(Cl)(Cl)Cl.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:15][CH2:16][CH:17]=[C:18]([Cl:20])[Cl:19])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]([CH3:13])[C:38](=[O:39])[C:37]1[CH:41]=[CH:42][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CNCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CN(CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)C(=O)c1ccc(C(F)(F)F)cc1
Yield: 55 %

Procedure:
To a mixture of 0.42 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(methylamino)propyloxy)benzene, 0.18 ml of triethylamine and 10 ml of chloroform was added 0.18 ml of 4-(trifluoromethyl)benzoyl chloride, while stirring under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was dissolved in 50 ml of ethyl acetate, and the ethyl acetate layer was successively washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.35 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(N-methyl-4-(trifluoromethyl)benzamido)propyloxy)benzene (55% yield), nD24.5 1.5461.
Reaction SMILES: [CH3:1][C:2](=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:10][P:11]=[O:12]>CO>[OH:9][C:2]([P:11]([OH:12])[OH:10])([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC(C)=O
Reactant: O=PO
Solvent: CO
Product: CCCCCCC(C)(O)P(O)O
Temperature: 25 °C

Procedure:
A mixture of octan-2-one (3.76 g, 0.29M) and hypophosphorus acid (91.5%, 2.09 g, 0.029M) is heated at 100° C. for 12 hours in the presence of Dowex 50W x 2 ion exchange resin (1 ml, aqueous slurry). The mixture is cooled to room temperature, methanol (50 ml) is added and the Dowex is removed by filtration. The filtrate is evaporated to an oily residue, which is dissolved in ethyl acetate, washed with water, brine, then dried (MgSO4). Removal of the solvent gives 1-hydroxy-1-methylheptylphosphonous acid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)[N:6]=1.O1CCCC1.CO.[OH-].[Na+]>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)[N:6]=1
Reactant: COC(=O)c1ccc(-c2csc(N)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1nc(-c2ccc(C(=O)O)cc2)cs1
Reaction time: 1 h

Procedure:
At room temperature, methyl 4-(2-aminothiazol-4-yl)benzoate (300 mg) was suspended in a mixed solvent of tetrahydrofuran (5 ml) and methanol (5 ml), followed by the addition of a 1N aqueous sodium hydroxide solution (10 ml). The resulting mixture was stirred for one hour. To the reaction mixture, N,N-dimethylformamide (5 ml) was added, followed by heating under reflux for 6 hours. After completion of the reaction, the solvent was distilled off. To the residue, water and 1N hydrochloric acid were added successively and the pale yellow solid so precipitated was collected by filtration, whereby the title compound (229 mg, 69%) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C@@H:7]([N:14]1[C:18](=[O:19])[C:17]2([CH2:24][CH2:23][N:22](C(OCC3C=CC=CC=3)=O)[CH2:21][CH2:20]2)[N:16]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.C(O)C.[Pd]>[O:19]=[C:18]1[C:17]2([CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)[N:16]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:15][N:14]1[C@@H:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:41]
Reactant: CC(C)(C)OC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](c1ccccc1)N1CN(c2ccccc2)C2(CCNCC2)C1=O
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A solution of (S)-benzyl 3-(2-tert-butoxy-2-oxo-1-phenylethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (1.88 g, 3.39 mmol, 1 equiv) in a mixture of ethyl acetate and ethanol was charged with 10% palladium on carbon (1 g, 20%/wt) and the resulting mixture was hydrogenated at atmospheric pressure for 2 h. The reaction was filtered over Celite and the filtrate was concentrated and dried in vacuo to afford the title compound as a dark grey foam (1.24 g, 93%); MS for C25H31N3O3 m/z 422.24 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][C@@H:5]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH2:4][CH2:3]1.[Cl:17][C:18]1[CH:23]=[C:22](Cl)[N:21]=[C:20]([NH2:25])[N:19]=1.C([O-])(O)=O.[Na+].O>O1CCOCC1.CCOC(C)=O.ClC1C=C(Cl)N=C(N)N=1>[NH2:25][C:20]1[N:21]=[C:22]([N:7]2[C@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]([C:8]([NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:9])[CH2:6]2)[CH:23]=[C:18]([Cl:17])[N:19]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: C[C@@H]1CC[C@H](C(=O)Nc2ccccc2)CN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: C[C@@H]1CC[C@H](C(=O)Nc2ccccc2)CN1c1cc(Cl)nc(N)n1
Yield: 116.8 %

Procedure:
To a solution of (3S,6R)-6-methyl-N-phenyl-3-piperidinecarboxamide (12 g, 55 mmol) in 1,4-dioxane (250 mL) was added 4,6-dichloro-2-pyrimidinamine (8.11 g, 49.5 mmol) and sat. aqueous NaHCO3 (125 mL), and the reaction mixture was then refluxed overnight. The reaction was not completed. The reaction mixture was cooled, added 4,6-dichloro-2-pyrimidinamine (0.9 g, 5.5 mmol), and refluxed overnight. When the reaction was completed, the mixture was cooled down. To the mixture was added about 500 mL of H2O to form a precipitate, and then filtered to obtain a gummy solid. The gummy solid was then dissolved in EtOAc (˜800 mL). The organic solution was washed with water (2×200 mL), brine (200 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford the crude title compound (20 g). LC-MS (ES) m/z=346 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]([CH3:33])[S:7]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:20](=[O:21])[C:19]([CH:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][C:24]([O-:26])=O)=[CH:18][NH:17]3)=[N:14][CH:15]=2)(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[F:43][C:44]([F:48])([F:47])[CH2:45][NH2:46].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH:1]1([N:6]([CH3:33])[S:7]([C:10]2[CH:11]=[CH:12][C:13]([N:16]3[C:20](=[O:21])[C:19]([CH:22]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:23][C:24]([NH:46][CH2:45][C:44]([F:48])([F:47])[F:43])=[O:26])=[CH:18][NH:17]3)=[N:14][CH:15]=2)(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C1CCCC1)S(=O)(=O)c1ccc(-n2[nH]cc(C(CC(=O)[O-])c3ccccc3)c2=O)nc1
Reactant: NCC(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C1CCCC1)S(=O)(=O)c1ccc(-n2[nH]cc(C(CC(=O)NCC(F)(F)F)c3ccccc3)c2=O)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 13.5 %

Procedure:
To a solution of 200 mg (0.43 mmol) of 3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-3-phenylpropanoate, 0.3 mL (1.7 mmol) of DIEA and 30 μL (0.43 mmol) of 2,2,2-trifluoroethylamine in 1 mL of DCM are added, at 0° C., 207 mg (0.64 mmol) of TBTU. The medium is stirred for 12 hours at room temperature. A further 0.3 mL of 2,2,2-trifluoroethylamine is then added and the medium is heated at 40° C. for 6 hours. The medium is taken up in 20 mL of DCM, washed successively with water (2×10 mL) and brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure, and then purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 10% EtOAc. 32 mg of 3-(2-{5-[cyclopentyl(methyl)sulfamoyl]pyridin-2-yl}-3-oxo-2,3-dihydro-1H-pyrazol-4-yl)-3-phenyl-N-(2,2,2-trifluoroethyl)propanamide are thus obtained in the form of a powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[N:17]=[CH:16][CH:15]=[N:14]2)=[CH:9][CH:8]=1.CCN(CC)CC.[CH:26]1([CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=2)[CH2:28][CH2:27]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:18])[CH2:4][N:5]([S:37]([C:34]1[CH:33]=[CH:32][C:31]([O:30][CH2:29][CH:26]2[CH2:27][CH2:28]2)=[CH:36][CH:35]=1)(=[O:39])=[O:38])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[N:14]=[CH:15][CH:16]=[N:17]2)=[CH:11][CH:12]=1
Reactant: COC(=O)CNCc1ccc(-n2nccn2)cc1
Reactant: O=S(=O)(Cl)c1ccc(OCC2CC2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CN(Cc1ccc(-n2nccn2)cc1)S(=O)(=O)c1ccc(OCC2CC2)cc1
Reaction time: 1 h

Procedure:
To a solution of 79.5 g (323.2 mmol) of the compound of stage 3.2, 80.9 ml (581.6 mmol) of Et3N and 1.97 g (16.1 mmol) of DMAP in 1000 ml of CH2Cl2, a solution of 99.6 g (404 mmol) of 4-cyclopropylmethoxy-benzenesulfonyl chloride in 150 ml of CH2Cl2 is added and stirred for 60 min. at 0–5° C. After stirring for additional 18 h at r.t., the reaction mixture is quenched with ice water and extracted with CH2Cl2. The combined extracts are washed with H2O, brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by CC on silica gel (n-Hexane:AcOEt=4:1˜2:1) to give the title compound as colorless solid; 1H-NMR (400 MHz, CDCl3): 0.35–0.45 (m, 2H), 0.65–0.75 (m, 2H), 1.25–1.35 (m, 1H), 3.58 (s, 3H), 3.87 (d, 2H, J=7.04 Hz), 3.94 (s, 2H), 4.52 (s, 2H), 6.99 (d, 2H, J=7.04 Hz), 7.37 (d, 2H, J=8.56 Hz), 7.81 (s, 2H), 7.82 (d, 2H, J=7.04 Hz), 8.02 (d, 2H, J=8.56 Hz).