Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:28][CH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:30]1=[O:36].O>C(Cl)(Cl)Cl>[C:14]([NH:28][CH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][NH:31][C:30]1=[O:36])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: NC1CCCCNC1=O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1NCCCCC1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
Triethylamine (1.75 ml, 12.6 mmol) and triphenylmethyl chloride (3.50 g, 12.6 mmol) were added to a solution of 3-amino-2-azepanone (1.46 g, 11.4 mmol) in chloroform (44 ml) at room temperature and stirred overnight at room temperature. The reaction mixture was poured into water and then extracted with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/ethyl acetate) to obtain 3-(tritylamino)-2-azepanone (2.93 g, 69%).
Reaction SMILES: [C:1]([N:4]1[CH:8]([C:9]([OH:11])=[O:10])[CH2:7][S:6][CH:5]1[C:12]1[CH:17]=[C:16]([O:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:14][C:13]=1[OH:22])(=[O:3])[CH3:2].[C:23](OC1NCC(OC(=O)C)S1)(=O)C>>[CH3:23][O:10][C:9]([CH:8]1[CH2:7][S:6][CH:5]([C:12]2[CH:17]=[C:16]([O:18][C:19](=[O:21])[CH3:20])[CH:15]=[CH:14][C:13]=2[OH:22])[N:4]1[C:1](=[O:3])[CH3:2])=[O:11]
Reactant: CC(=O)OC1CNC(OC(C)=O)S1
Reactant: CC(=O)Oc1ccc(O)c(C2SCC(C(=O)O)N2C(C)=O)c1
Product: COC(=O)C1CSC(c2cc(OC(C)=O)ccc2O)N1C(C)=O

Procedure:
The procedure described above for preparation of 3-acetyl-2-(2-hydroxy-5-acetyloxyphenyl)-1,3-thiazolidine-4-carboxylic acid (4) was followed to prepare 9, except that a 2,5-diacetyloxy thiazolidine starting material was employed.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:13][C:12]=1[CH3:25].FC(F)(F)C(O)=O>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][C:12]=1[CH3:25]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1Nc1nc2ccccc2o1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CC(=O)O)ccc1Nc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 20 h
Yield: 94.6 %

Procedure:
In methylene chloride (10 ml) was dissolved tert-butyl (4-(2-benzoxazolyl)amino-3-methylphenyl)acetate (1.17 g, 3.46 mmol). To the resulting solution was added trifluoroacetic acid (10 ml). The resulting mixture was stirred at room temperature for 20 hours. The reaction mixture was poured in ice water, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from chloroform/methanol (60:1 to 50:1, v/v) eluate fractions, (4-(2-benzoxazolyl)amino-3-methylphenyl)acetic acid (924 mg, 95%) was obtained as a pale yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]2[O:18][C:19]([CH:22]=[O:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[C:12]([C:13]([F:15])([F:16])[F:14])=[CH:11][C:10]([C:17]2[O:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2cc(C(F)(F)F)n(Cc3ccccc3)n2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1ccc(-c2cc(C(F)(F)F)n(Cc3ccccc3)n2)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 g (9.36 mmol) of 1-benzyl-3-(5-formyl-2-furyl)-5-trifluoromethylpyrazole were dissolved in 80 ml of methanol, 0.35 g (9.36 mmol) of sodium borohydride were added in portions and the mixture was stirred at RT for 1 h. The mixture was subsequently concentrated, the residue was admixed with water and methylene chloride, the methylene chloride phase was separated off, dried and concentrated and the residue was chromatographed over silica gel using dichloromethane. This gave 1.6 g (53%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[C:13]2[NH:12][C:11](=S)[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])=[CH:17][CH:16]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:28]([NH:30][NH2:31])=O>C(O)C>[F:1][C:2]([F:27])([F:26])[C:3]1[C:13]2[N:12]3[CH:28]=[N:30][N:31]=[C:11]3[CH2:10][N:9]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:25])[CH2:23][CH3:24])=[CH:17][CH:16]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CCC(=O)Nc1ccc(C2=NCC(=S)Nc3c2cccc3C(F)(F)F)cc1
Reactant: NNC=O
Solvent: CCO
Product: CCC(=O)Nc1ccc(C2=NCc3nncn3-c3c2cccc3C(F)(F)F)cc1
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 9-(trifluoromethyl)-1,3-dihydro-5-[p-(propionylamino)phenyl]-2H-1,4-benzodiazepine-2-thione is heated in ethanol with formic acid hydrazide and the resulting product heated to 250° C. to give 10-(trifluoromethyl)-6-[p-(propionylamino)pheyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:33])[C:19]([CH3:32])([S:21]([CH:24]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH3:25])(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:11])[CH2:3][O:4]C1CCCCO1.CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCOCC>[OH:4][CH2:3][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:33])[C:19]([CH3:32])([S:21]([CH:24]([CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH3:25])(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:11])[CH3:1]
Reactant: CC(C1CCOCC1)S(=O)(=O)C(C)(C)C(=O)Nc1cc(C(C)(C)COC2CCCCO2)no1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C1CCOCC1)S(=O)(=O)C(C)(C)C(=O)Nc1cc(C(C)(C)CO)no1
Yield: 76.6 %

Procedure:
A solution of 100 mg (0.24 mmol) of N-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-methyl-2-[1-(tetrahydro-pyran-4-yl)-ethanesulfonyl]-propionamide in DCM/ethanol (1/1, 10 mL) is treated with 145 mg (0.48 mmol) of MP-TsOH resin (loading 3.3 mmol/g) at room temperature for 18 h. The resin is removed by filtration and washed with DCM (10 mL) and methanol (10 mL). The combined filtrates are concentrated under reduced pressure and the resulting residue is slurried in heptanes/ethyl acetate (7/3) to yield 74 mg of N-[3-(2-hydroxy-1,1-dimethyl-ethyl)-isoxazol-5-yl]-2-methyl-2-[1-(tetrahydro-pyran-4-yl)-ethanesulfonyl]-propionamide. Yield 87%; ES-MS: m/z 403 [M+H].
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:4][C:5]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[NH:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23]>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[C:3]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:4][C:5]2[SH:9](=[O:10])([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:11][C:22](=[O:23])[NH:7][C:6]=2[CH:8]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: N=S(=O)(c1ccccc1)c1cc(S(N)(=O)=O)c(Cl)cc1N
Solvent: Clc1ccccc1Cl
Product: NS(=O)(=O)c1cc2c(cc1Cl)NC(=O)N[SH]2(=O)c1ccccc1

Procedure:
A stirred mixture of 34.5 g (0.1 mole) of 5-chloro-2-(phenylsulfonimidoyl)-4-sulfamylaniline and 16.2 g (0.1 mol) of 1,1'-carbonyldiimidazole in 500 ml. of o-dichlorobenzene is heated under reflux conditions for 2 hours, filtered, and cooled, yielding the product.
Reaction SMILES: [N+](=[C:3]([C:10](=O)[C@@H:11]([C@@H:13]1[C@@H:16]([C@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])[C:15](=[O:27])[NH:14]1)[CH3:12])[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])=[N-].C(N(C(C)C)CC)(C)C.C([S:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][CH:51]=[CH2:52])=[O:48])[C@H:44]([CH2:53][O:54][CH2:55][CH2:56][OH:57])[CH2:43]1)(=O)C.C[O-].[Na+]>C(OCC)(=O)C.C(#N)C.CO.C([O-])(=O)CCCCCCC.[Rh+2].C([O-])(=O)CCCCCCC>[CH2:50]([O:49][C:47]([N:45]1[CH2:46][C@@H:42]([S:41][C:10]2[C@H:11]([CH3:12])[C@H:13]3[N:14]([C:15](=[O:27])[C@@H:16]3[C@H:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:24])[CH3:25])([CH3:22])[CH3:21])[CH3:18])[C:3]=2[C:4]([O:6][CH2:7][CH:8]=[CH2:9])=[O:5])[CH2:43][C@H:44]1[CH2:53][O:54][CH2:55][CH2:56][OH:57])=[O:48])[CH:51]=[CH2:52]
Reactant: C=CCOC(=O)C(=[N+]=[N-])C(=O)[C@H](C)[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1COCCO
Agent: [Rh+2]
Agent: CCCCCCCC(=O)[O-]
Agent: C[O-]
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](COCCO)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)C(=O)N12
Reaction time: 0.33 h
Yield: 42.7 %

Procedure:
To a solution of allyl (4R)-2-diazo-4-[(2R,3S)-3-{(1R)-1-(t-butyldimethylsilyloxy)ethyl}-4-oxoazetidine-2-yl]-3-oxopentanoate (13.5 g) in ethyl acetate (65 ml) was added rhodium(II) octanoate (50 mg) under refluxing in a stream of nitrogen. After 20 minutes, rhodium(II) octanoate (50 mg) was added to the mixture at the same condition. The mixture was refluxed for 30 minutes and concentrated under reduced pressure to give a syrup. The syrup was dissolved in acetonitrile (65 ml) and cooled at 0°-5° C. under atmosphere of nitrogen. To the solution was added diphenyl phosphorochloride (7.52 ml) and N,N-diisopropyl-N-ethylamine (6.31 ml) successively and the mixture was stirred at the same condition for 18 hours (solution A). To a solution of (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(2-hydroxyethyloxymethyl)pyrrolidine (10.7 g) in acetonitrile (40.5 ml) was added a 28% solution (6.92 ml) of sodium methoxide in methanol at -10°~0° C. in a stream of nitrogen and the mixture was stirred at the same condition (solution B). To the solution A was added the solution B at -10°~0° C. in a stream of nitrogen and the mixture was stirred at -10~0° C. for one hour and then at 10°-20° C. for 3 hours. Ethyl acetate (200 ml) was added to the mixture and the mixture was washed with water (200 ml×3), dried over magnesium sulfate, and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (300 g) and eluted with ethyl acetate to give allyl (4R,5S,6S)-3-[(2S,4S)-1-allyloxycarbonyl-2-(2-hydroxyethyloxymethyl)pyrrolidin-4-yl]thio-6-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-methyl- 7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (8.80 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:7]=[CH:6]2.[CH3:21][O:22][C:23](=[O:39])[C:24]([Sn](CCCC)(CCCC)CCCC)=[CH2:25].[Cl-].[Li+].C(OCC)C>CN(C)C=O.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.[Cu]I>[CH3:21][O:22][C:23](=[O:39])[C:24](=[CH2:25])[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]=1
Reactant: C=C(C(=O)OC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: C=C(C(=O)OC)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.6 %

Procedure:
To a room temperature solution of 0.306 g of product from Example 9 in 10 ml of dimethylformamide is added 0.938 g of 2-(tributylstannyl)-2-propenoic acid methyl ester, 0.116 g of tetrakis(triphenylphosphine)palladium(0), 0.143 g of copper(1)iodide and 0.128 g of lithium chloride. The resulting reaction mixture is stirred, at room temperature, for 48 hours and then poured into 100 ml of diethyl ether. The layers are separate, the organic layer is washed with water and saturated sodium chloride, dried, filtered and concentrated in vacuo. The residue is purified by chromatography (silica gel: ethyl acetate/hexane 1/20) to give 0.171 g (71% yield) of the desired product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1.Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([NH:36][CH:37]([CH3:42])[C:38]([F:41])([F:40])[F:39])(=[O:35])=[O:34].C(Cl)Cl.C([O-])(O)=O.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([C:27]2[C:28]([S:33]([NH:36][CH:37]([CH3:42])[C:38]([F:39])([F:40])[F:41])(=[O:34])=[O:35])=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[C:19]2[CH:25]=[CH:24][NH:23][C:20]2=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc4[nH]ccc4n3)c(F)c2)OC1(C)C
Reactant: CC(NS(=O)(=O)c1ccccc1Br)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC#N
Product: CC(NS(=O)(=O)c1ccccc1-c1ccc(-c2cnc3[nH]ccc3n2)c(F)c1)C(F)(F)F
Temperature: 110 °C
Yield: 67 %

Procedure:
To a mixture of 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5H-pyrrolo[2,3-b]pyrazine (32 mg, 0.09 mmol), racemic 2-bromo-N-(1,1,1-trifluoropropan-2-yl)benzenesulfonamide (38 mg, 0.11 mmol) and Pd(dppf)Cl2.CH2Cl2 (6 mg, 0.007 mmol) in a microwave vial were added acetonitrile (2.0 mL) and sat. NaHCO3 (2.0 mL). The mixture was sparged with nitrogen for 5 min and then the vial capped and heated at 110° Celsius for 90 min. After cooling, the reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL) and brine (25 mL). The organic layer was dried (Na2SO4) and concentrated to dryness. The crude product was purified by HPLC to give the title compound (28 mg, 64%). MS (ESI): mass calcd. C21H16F4N4O2S, 464.09; m/z found, 465.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.81 (s, 1H), 8.47 (s, 1H), 8.27-8.17 (m, 1H), 7.75-7.41 (m, 5H), 7.40-7.32 (m, 2H), 7.20 (d, J=12.6, 1H), 6.74-6.67 (m, 1H), 4.12-3.94 (m, 1H), 1.39-1.19 (m, 3H).
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=2)=[CH:5][CH:4]=[C:3]([OH:14])[CH:2]=1.[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>N1C=CC=CC=1>[CH3:15][O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([O:14][C:3]2[CH:2]=[CH:1][C:6]([C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=3)=[CH:5][CH:4]=2)=[O:22])=[CH:19][CH:18]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Oc2ccc(-c3ccc(O)cc3)cc2)cc1
Temperature: -15 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
3.72 g of 4,4'-hydroxybiphenyl was put in an 100 ml two-necked. flask and dissolved by the addition of 60 ml of pyridine. The flask was set up in an ice bath. 3.41 g of 4-methoxybenzoyl chloride was added over 1.5 hours while maintaining the reaction mixture at -15° C. The mixture was reacted in the ice bath for 3 hours and then at an ambient temperature for 2 hours. The reaction mixture was poured into chipped ice to obtain a white precipitate. This precipitate was filtered, dried and re-crystallized with acetone. The yield was 63% and 1HNMR and IR spectra of the product were as follows.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([O:29][C:30](=[O:42])[NH:31][CH:32]([C:34]1[S:35][CH:36]=[C:37]([C:39]([OH:41])=O)[N:38]=1)[CH3:33])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)CC)(C)C.[NH:52]1[C:61]2[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=2)[CH2:55][CH2:54][CH2:53]1>CN(C=O)C>[C:25]([O:29][C:30](=[O:42])[NH:31][CH:32]([C:34]1[S:35][CH:36]=[C:37]([C:39]([N:52]2[C:61]3[C:56](=[CH:57][CH:58]=[CH:59][CH:60]=3)[CH2:55][CH2:54][CH2:53]2)=[O:41])[N:38]=1)[CH3:33])([CH3:26])([CH3:27])[CH3:28]
Reactant: c1ccc2c(c1)CCCN2
Reactant: CC(NC(=O)OC(C)(C)C)c1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(NC(=O)OC(C)(C)C)c1nc(C(=O)N2CCCc3ccccc32)cs1
Reaction time: 18 h
Yield: 63.6 %

Procedure:
HBTU (306 mg, 0.81 mmol) was added to a solution of tert-butyl(1-(4-carboxythiazol-2-yl)ethyl)carbamate (200 mg, 0.73 mmol) in DMF (5 ml) at room temperature. Diisopropylethylamine (0.26 ml, 190 mg, 1.5 mmol) and 1,2,3,4-tetrahydroquinoline (0.11 ml, 117 mg, 0.88 mmol) were added and the mixture was stirred for 18 h. The mixture was partitioned between ethyl acetate and 1N hydrochloric acid and separated. The organic layer was washed with water and brine, dried and reduced. Chromatography (45% EtOAc/55% hexanes) afforded tert-butyl(1-(4-(1,2,3,4-tetrahydroquinoline-1-carbonyl) thiazol-2-yl)ethyl)carbamate (180 mg, 63%).
Reaction SMILES: [CH3:1][N:2]([CH3:34])[CH2:3][CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:19][CH:18]=3)[C:13]2=[O:30])=[CH:8][C:7]=1[N+:31]([O-])=O>ClCCl.C(O)(=O)C.[Zn]>[NH2:31][C:7]1[CH:8]=[C:9]([N:12]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:19][CH:18]=3)[C:13]2=[O:30])[CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][CH2:3][N:2]([CH3:34])[CH3:1]
Reactant: CN(C)CCNc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(C)CCNc1ccc(-n2ccn(-c3ccc(Oc4ccccc4)cc3)c2=O)cc1N
Reaction time: 0.17 h

Procedure:
Zinc dust (250 mg) was added to a solution of 1-[4-(2-dimethylamino-ethylamino)-3-nitrophenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in dichloromethane (10 ml) and glacial acetic acid (1 ml). After 10 minutes, solids were removed by filtration and the filtrate was washed with saturated sodium carbonate solution. The organic phase was dried over magnesium sulfate and concentrated. The product with the molecular weight of 429.53 (C25H27N5O2); MS (ESI): 430 ([M+H]+), was obtained in this way.
Reaction SMILES: C[C@H]1P(CCP2[C@H](C)CC[C@H]2C)[C@H](C)CC1.[CH3:17][O:18][C:19]1[CH:32]=[CH:31][C:22]2[C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][O:25][C:21]=2[CH:20]=1.[H][H]>CO>[CH3:17][O:18][C:19]1[CH:32]=[CH:31][C:22]2[CH:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])[CH2:24][O:25][C:21]=2[CH:20]=1
Reactant: [H][H]
Reactant: COC(=O)Cc1coc2cc(OC)ccc12
Agent: C[C@@H]1CC[C@@H](C)P1CCP1[C@H](C)CC[C@H]1C
Solvent: CO
Product: COC(=O)CC1COc2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.3 %

Procedure:
To a mixture of (1,5-cyclooctadiene)rhodium trifluoromethanesulfonate (12 mg) and (R,R)-Me-BPE (6.5 mg) was added methanol (2.5 mL) sufficiently substituted by argon gas, and the mixture was stirred at room temperature for 15 min. This was added to methyl (6-methoxy-1-benzofuran-3-yl)acetate (55 mg), and the mixture was stirred at 70° C. for 3 hr under 0.7 MPa hydrogen atmosphere. The reaction mixture was quantified by HPLC. As a result, the enantiomeric excess was 52.8%, and the yield was 24.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[CH:25]([CH3:32])[N:26]([OH:31])[CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:33]([F:36])([F:35])[F:34]>Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[CH:25]([CH3:32])[N:26]([OH:31])[CH:27]=[CH:28][C:29]=3[CH3:30])=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:33]([F:36])([F:34])[F:35]
Reactant: COCN(c1cc(Cl)cnc1C(=O)C1=C(C)C=CN(O)C1C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: CC1=C(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)C(C)N(O)C=C1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
A solution of 4-Chloro-N-[5-chloro-2-(1-hydroxy-2,4-dimethyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (21 mg) in 6 ml of HCl (4M in dioxane) and 2 mL of water was refluxed for 2 hours. After cooling to rt the mixture was concentrated and was added 3 mL of water. Sodium bicarbonate was added until the final pH was 6. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was further purified via short flash column (8% methanol in DCM) to afford 7.9 mg of title compound as an off white solid. MS: (M+H)/z=520.0.
Reaction SMILES: Br[CH:2]([C:4]1[NH:13][C:12](=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:3].[CH:15]1([NH2:18])[CH2:17][CH2:16]1>CN(C)C=O.O>[CH:15]1([NH:18][CH:2]([C:4]2[NH:13][C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH3:3])[CH2:17][CH2:16]1
Reactant: CC(Br)c1nc2ccccc2c(=O)[nH]1
Reactant: NC1CC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(NC1CC1)c1nc2ccccc2c(=O)[nH]1
Reaction time: 18 h

Procedure:
To a suspension of 2-(1-bromoethyl)quinazolin-4(3H)-one (2.53 g) in N,N-dimethylformamide (30 mL) was added cyclopropylamine (3.46 mL), and the mixture was diluted with N,N-dimethylformamide (20 mL) and water (1 mL), and then stirred for 18 hours. The reaction solution was concentrated under reduced pressure, and to the residue was added aqueous sodium hydrogen carbonate solution, and then the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was triturated with diisopropyl ether/ethyl acetate (20:1) to give 2-[1-(cyclopropylamino)ethyl]quinazolin-4(3H)-one [REx(33-1)] (1.71 g) as a colorless powder.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[S:15]([NH2:18])(=[O:17])=[O:16]>C(O)=O>[S:15]1(=[O:17])(=[O:16])[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[NH:8][CH:1]=[N:18]1
Reactant: Nc1ccncc1S(N)(=O)=O
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=S1(=O)N=CNc2ccncc21

Procedure:
3.3 cm3 of formic acid and 6.6 cm3 of acetic anhydride are kept stirring at 50° C. for 15 minutes. 1 g of 4-aminopyridine-3-sulfonamide (Preparation 2) is added to this solution and the reaction mixture is brought to reflux for 2 hours. After cooling, the crystals obtained are collected on a filter, washed with a small amount of acetic acid and then with diethyl ether and dried.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][C:5]([N+:13]([O-])=O)=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=2)[O:2]1.[CH3:16]N>C(O)C>[CH3:16][NH:13][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:9][C:8]2=[CH:7][C:6]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])OCO2
Reactant: CN
Solvent: CCO
Product: CNc1cc2c(cc1[N+](=O)[O-])OCO2

Procedure:
0.05 mol (10.6 g) of 4,5-methylenedioxy-1,2-dinitrobenzene is added to 40 ml of a 33% strength solution of methylamine in absolute ethanol to which 20 ml of 96° strength ethanol have been added. The reaction edium is heated under reflux for 30 minutes. After dilution with 150 ml of ice-cold water, the expected product precipitates. After being drained and washed with water, it is recrystallized from a mixture of ethanol and acetone. It melts at 170° C. (literature 171° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3](C(N)=O)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[C:19](=[O:31])[N:20]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:21]([CH3:24])[C:22]=2[CH3:23])=[O:17])=[CH:11][C:10]=1[F:32].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.CC#[N:53]>CCOC(C)=O.O>[NH2:53][C:3]1[C:2]([Cl:1])=[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][C:10]=2[F:32])[CH:6]=[CH:5][N:4]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3Cl)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: CC#N
Solvent: Ic1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3Cl)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
To a suspension of 3-chloro-4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2-fluorophenoxy)picolinamide (437 mg, 0.88 mmol) in EtOAc (5 mL), CH3CN (5 mL) and H2O (2.5 mL) was added iodobenzene diacetate (341 mg, 1.06 mmol) at 0° C. The reaction was stirred at 0° C. for 30 minutes, then warmed up to rt and continued to stir for 3 hours. The mixture was concentrated in vacuo, and the residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=1/3) to give the title compound as a yellow solid (290 mg, 70.6%).