Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2=[C:11]3[C:18]([CH3:19])=[N:17][N:16]([C:20]4[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[C:12]3=[N:13][C:14]([CH3:15])=[C:9]2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([CH:3]([N:6]1[C:10]2=[C:11]3[C:18]([CH3:19])=[N:17][N:16]([C:20]4[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[C:12]3=[N:13][C:14]([CH3:15])=[C:9]2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCc2c(C)nc3c(c(C)nn3-c3c(Cl)cc(Cl)cc3Cl)c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCC(CC)n1ccc2c(C)nc3c(c(C)nn3-c3c(Cl)cc(Cl)cc3Cl)c21
Temperature: 40 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
1-(1-Ethylpropyl)-4,8-dimethyl-6-(2,4,6-trichlorophenyl)-1,2,3,6-tetrahydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridine (70 mg, 0.160 mmol) was dissolved in toluene (7 mL). Manganese dioxide (700 mg) was added thereto, followed by stirring at 40° C. overnight. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was evaporated, and the residue was purified by silica gel column chromatography (5% ethyl acetate/hexane), to give the title compound (48 mg, 0.110 mmol) as white crystals.
Reaction SMILES: OO.[ClH:3].[CH2:4]([N:7]1[C:11]2=[C:12]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[N:13]=[CH:14][CH:15]=[C:10]2[C:9]([S:26]([CH3:28])=[O:27])=[C:8]1[CH3:29])[CH:5]=[CH2:6].C(=O)([O-])[O-:31].[K+].[K+]>C(O)(=O)C>[ClH:3].[CH2:4]([N:7]1[C:11]2=[C:12]([N:16]3[CH2:25][CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[N:13]=[CH:14][CH:15]=[C:10]2[C:9]([S:26]([CH3:28])(=[O:31])=[O:27])=[C:8]1[CH3:29])[CH:5]=[CH2:6]
Reactant: C=CCn1c(C)c(S(C)=O)c2ccnc(N3CCc4ccccc4C3)c21
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CC(=O)O
Product: C=CCn1c(C)c(S(C)(=O)=O)c2ccnc(N3CCc4ccccc4C3)c21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Hydrogen peroxide (50 wt. %, 100 μl) was added to a solution of 2-(1-allyl-3-methylsulfinyl-2-methyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (30 mg, 0.07 mmol) prepared in Example 632 in acetic acid (3 ml). The reaction mixture was stirred for 1 hour at 60° C., cooled to room temperature, basified with a potassium carbonate solution, and then extracted with dichloromethane. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography. The resulting product was dissolved in ethyl ether, saturated with hydrochloric acid gas, and then filtered to give 8 mg of the titled compound as a white solid.
Reaction SMILES: [N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([C:15]([OH:17])=O)[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.P(Cl)(OCC)(OCC)=O.[NH:34]1[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][CH:42]([CH3:48])[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:35]1>O1CCCC1.C(OCC)(=O)C>[N:1]1[C:10]2[NH:9][C:8]3[CH:11]=[C:12]([C:15]([N:34]4[CH2:39][CH2:38][CH:37]([CH2:40][CH2:41][CH:42]([CH3:48])[C:43]([O:45][CH2:46][CH3:47])=[O:44])[CH2:36][CH2:35]4)=[O:17])[CH:13]=[CH:14][C:7]=3[S:6][C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc2c(c1)Nc1nccnc1S2
Reactant: CCOC(=O)C(C)CCC1CCNCC1
Agent: CCOP(=O)(Cl)OCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)CCC1CCN(C(=O)c2ccc3c(c2)Nc2nccnc2S3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.4 %

Procedure:
To a solution of 1 g of 10H-pyrazino[2,3-b][1,4]-benzothiazine-8-carboxylic acid in tetrahydrofuran (50 ml) were added under ice-cooling 0.6 ml of triethylamine and 0.55 ml of diethyl chlorophosphate. The resulting mixture was reacted at room temperature for 0.5 hour. Next, 0.66 g of ethyl 4-(piperidin-4-yl)-2-methylbutanoate was added thereto and the resulting mixture was stirred at room temperature for 12 hours. After adding ethyl acetate to the reaction mixture, the organic layer was washed with water and dried over anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with n-hexane/ethyl acetate) to thereby give 1.0 g of the title compound as a yellow oily substance.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]1([C:12]2[N:16]=[C:15](O)[O:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.N1C=CC=CC=1>>[C:6]1([C:12]2[N:16]=[C:15]([Cl:3])[O:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1nc(-c2ccccc2)no1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Clc1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 53 g of phosphorus oxychloride were added 12.6 g (18 mmol) of 3-phenyl-1,2,4-oxadiazol-5-ol, followed by the further addition of 2.8 g (35 mmol of pyridine. The resultant mixture was heated under stirring for 8 hours. The reaction mixture was allowed to cool down to room temperature and then transferred into 500 ml of ice water. The resultant liquid mixture was extracted with ether. The extract was washed successively with water, a 5% aqueous solution of sodium hydroxide and water. The organic layer was dried and the solvent was distilled off. When the residue was left over under cooling, the title compound was obtained as pale brown crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:19][C:20]1[C:21]([CH:43]2[CH2:47][CH2:46][CH2:45][N:44]2[C:48](=[O:50])[CH3:49])=[CH:22][C:23]2[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[N:25][C:24]=2[CH:42]=1.[Cl-].[NH4+]>[Cu]=O.N1C=CC=CC=1>[O:12]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:19][C:20]3[C:21]([CH:43]4[CH2:47][CH2:46][CH2:45][N:44]4[C:48](=[O:50])[CH3:49])=[CH:22][C:23]4[N:27]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[C:26]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=5)=[N:25][C:24]=4[CH:42]=3)=[CH:3][CH:4]=2)=[CH:9][N:10]=[CH:11]1
Reactant: Brc1ccc(-c2cnco2)cc1
Reactant: CC(=O)N1CCCC1c1cc2c(cc1O)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: c1ccncc1
Product: CC(=O)N1CCCC1c1cc2c(cc1Oc1ccc(-c3cnco3)cc1)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Temperature: 120 °C
Reaction time: 8 h

Procedure:
30 mg of 5-(4-bromo-phenyl)-oxazole, 56 mg of cesium carbonate and 15 mg of copper(II) oxide were added to a pyridine (1 ml) solution of 29 mg of 1-(2-(6-hydroxy-2-pyridin-2-yl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazol-5-yl)pyrrolidin-1-yl)-ethanone, and the reaction liquid was stirred overnight in a sealed tube at 120° C. After cooled, aqueous saturated ammonium chloride solution and saturated saline were added in order to the reaction liquid, and this was extracted with ethyl acetate and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=12/1) to obtain the entitled compound as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[C:5]([C:10]([O:12]C)=[O:11])=[CH:4][C:3]=1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:16][CH2:15]1.O.[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[C:5]([C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: COC(=O)c1cc(C2CCN(C(=O)OCc3ccccc3)CC2)c(F)cc1SC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CSc1cc(F)c(C2CCN(C(=O)OCc3ccccc3)CC2)cc1C(=O)O
Reaction time: 18 h
Yield: 99.7 %

Procedure:
To a solution of 4-(2-fluoro-4-methylthio-5-methoxycarbonylphenyl)-N-Cbz-piperidine (1.38 g) dissolved in 100 mL 1:1 THF:H2O was added 0.45 g LiOH. Mixture was stirred for 18 h, THF was evaporated, residue was mixed with 25 mL 1N HCl, and extracted with DCM (3×50 mL). Extracts were combined, dried over Na2SO4, and evaporated to give 1.33 g product; MS m/z 404 (M+H); 1H NMR (CDCl3) δ 8.01 (d), 7.45-7.25 (m), 6.94 (d), 5.17 (s), 4.50-4.21 (m), 2.99 (tt), 3.01-2.78 (m), 2.44 (s), 1.84 (dm), 1.69 (qd).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9](=[O:13])[NH:10][CH2:11]Cl)[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:16]=1[O:17][CH2:18][C:19]([OH:21])=[O:20].C(N(CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:9]([NH:10][CH2:11][O:21][C:19](=[O:20])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:15]=1[Cl:14])=[O:13]
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: O=C(NCCl)Oc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(COc1ccc(Cl)cc1Cl)OCNC(=O)Oc1cccc(Cl)c1
Temperature: 20 °C
Reaction time: 15 h
Yield: 71.7 %

Procedure:
A solution of 220.1 g (1 mole) of N-chloromethylcarbamic acid 3-chlorophenyl ester in 1 liter of anhydrous ethyl acetate was added dropwise at 0° to 10° C to a mixture of 221 g (1 mole) of 2,4-dichlorophenoxyacetic acid and 111.3 g (1.1 moles) of triethylamine in 2 liters of ethyl acetate. The mixture was stirred for a further 15 hours at 20° C and was cooled to 5° C, and the triethylammonium chloride which had precipitated was filtered off. The filtrate was washed neutral with water and was concentrated in vacuo by distilling off the solvent. The solid residue was recrystallised from ether. 290 g (71.8% of theory) of 2-(2,4-dichlorophenoxy)-acetic acid 3-chlorophenoxycarbonylaminomethyl ester were obtained in the form of white crystals of melting point 110° C.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.CCOCC.[CH2:12]([O:19][C:20]([N:22]1[CH2:26][C@H:25]([O:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][C@H:23]1[CH2:32][O:33][CH2:34][C:35](=O)[NH2:36])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>O1CCCC1.CO.C(O)C>[NH2:36][CH2:35][CH2:34][O:33][CH2:32][C@@H:23]1[CH2:24][C@@H:25]([O:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH2:26][N:22]1[C:20]([O:19][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:21]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(N)=O)N(C(=O)OCc2ccccc2)C1
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOCC
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCCN)N(C(=O)OCc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
To a suspension of sodium borohydride (3.05 g) in tetrahydrofuran (155 ml) was added boron trifluoride etherate (35.6 ml) in a nitrogen stream with stirring at 0°-5° C. for 30 minutes. The mixture was stirred at the same condition for 30 minutes. To the mixture was added a solution of (2S,4R)-1-benzyloxycarbonyl-2-(carbamoylmethyloxymethyl)-4-methanesulfonyloxypyrrolidine (15.5 g) in tetrahydrofuran (45 ml) at 0°-5° C. for 30 minutes. The reaction mixture was stirred at 0°-5° C. for 30 minutes and at ambient temperature overnight. Ethanol (46.5 ml) was added to the mixture below 10° C. After 2 hours, insoluble material was filtered off and the filtrate was concentrated under reduced pressure to give a residue. A solution of the residue in a mixture of concentrated hydrochloric acid (15.5 ml) and methanol (155 ml) was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure to give (2S,4R)-2-[(2-aminoethyl)oxymethyl]-1-benzyloxycarbonyl-4-methanesulfonyloxypyrrolidine. To a solution of the compound obtained above in a mixture of water (46.5 ml) and tetrahydrofuran (77.5 ml) was added a solution of potassium cyanate (16.3 g) in water (50 ml) at 40°-50° C., keeping the pH between 4-5 with concentrated hydrochloric acid. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give (2S,4R)-1-benzyloxycarbonyl-4-methanesulfonyloxy-2-[(2-ureidoethyl)oxymethyl]pyrrolidine (13.28 g).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]=[O:11])[C:5]#[N:6].[CH3:12][S-:13].[Na+]>CS(C)=O.O>[CH:10]([C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[S:13][CH3:12])=[O:11]
Reactant: C[S-]
Reactant: N#Cc1ccc(C=O)c(F)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1cc(C#N)ccc1C=O
Reaction time: 0.75 h

Procedure:
3-Fluoro-4-formylbenzonitrile (2.00 g, 13.4 mmol; Example 8A) was dissolved in DMSO (27 ml), and sodium methanethiolate (1.50 g, 21.5 mmol) was added with ice-bath cooling. The mixture was stirred for 45 min and then diluted with water (100 ml). The resulting precipitated product was filtered off with suction, washed with water and dried under reduced pressure. This gave 1.36 g (51% of theory) of the target compound as a yellow crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[C:46]([CH2:47][CH3:48])=[CH:45][N:44]=[C:43]([CH3:49])[CH:42]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[C:46]([CH2:47][CH3:48])=[CH:45][N:44]=[C:43]([CH3:49])[CH:42]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCc1cnc(C)cc1-c1cccc(C(=O)CC(=O)OC(C)(C)C)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: CCc1cnc(C)cc1-c1cccc(C(=O)CC(=O)Nc2cc(C(F)(F)F)c(OCC(F)(F)F)cc2NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (281 mg, 0.75 mmol) and 3-[3-(5-ethyl-2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K19) (255 mg, 0.75 mmol) according to the general procedure M. Obtained as an off-white solid (300 mg, 63%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.[ClH:17].Cl.[NH2:19][CH2:20][CH2:21][O:22][NH2:23].N1C=CC=CC=1>C(O)C>[ClH:17].[ClH:17].[NH2:19][CH2:20][CH2:21][O:22][N:23]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: NCCON
Reactant: O=C(CCn1ccnc1)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NCCON=C(CCn1ccnc1)c1ccc(F)cc1
Reaction time: 2 h
Yield: 65.9 %

Procedure:
A mixture of 1-(4-fluorophenyl)-3-(1-(1H)-imidazolyl)-1-propanone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (2.46 g), 3 equivalents of pyridine and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for two hrs. The reaction mixture was partitioned between 20% sodium hydroxide solution and ethyl acetate. The layers were separated, and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and concentrated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. Diethyl ether was added. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 1.9 g (40%) of product, mp 225°-226° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]1[S:14][C:15]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:16]=2[N:17]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:25][C:22]([F:23])([F:24])[C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:13]([NH:12][C:4](=[O:5])[C:3]3[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[S:14][C:15]=2[CH:21]=1
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Reactant: O=C(Cl)c1c(F)cccc1Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(Nc1nc2ccc(C(F)(F)F)cc2s1)c1c(F)cccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.8 %

Procedure:
At 0 to 5° C., 2-chloro-6-fluorobenzoyl chloride (1.93 g) was added dropwise to a solution composed of 2-amino-6-trifluoromethylbenzothiazole (2.18 g), pyridine (30 ml) and 4-dimethylaminopyridine (0.1 g). The reaction mixture was stirred at room temperature (20 to 30° C.) for one day, and then the pyridine was evaporated. Water was added to the residue, and the mixture was stirred. The resulting crystals were collected by filtration, and thoroughly washed with water. Recrystallization from ethanol gave the desired N-(6-trifluoromethylbenzothiazol-2-yl)-2-chloro-6-fluorobenzamide (2.5 g).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[OH-].[Na+].[CH3:13]OS(OC)(=O)=O>O>[CH3:13][S:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=[N+]([O-])c1ccc(S)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ccc([N+](=O)[O-])cn1

Procedure:
4.68 gm (0.03 mol) of 2-mercapto-5-nitro-pyridine were dissolved, while gently heating, in a sodium hydroxide solution prepared by dissolving 1.32 gm (0.033 mol) of sodium hydroxide in 60 ml of water. 4.17 gm (0.033 mol) of dimethylsulfate were added to this solution, and the mixture was shaken well. The resulting precipitate was filtered off with suction, and the still moist product was recrystallized from ethanol. 2-Methylthio-5-nitro-pyridine was obtained.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([S:7](Cl)(=[O:9])=[O:8])[C:4]([CH3:11])=[N:3]1.[OH-].[NH4+:13]>C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([S:7]([NH2:13])(=[O:9])=[O:8])[C:4]([CH3:11])=[N:3]1
Reactant: [NH4+]
Reactant: Cc1nn(C)cc1S(=O)(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nn(C)cc1S(N)(=O)=O
Temperature: 25 °C
Reaction time: 64 h
Yield: 111.6 %

Procedure:
A solution of 1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (232 mg, 1.192 mmol) in THF (10.0 mL) was cooled to 0° C. and to it was added dropwise ammonium hydroxide (0.650 mL, 16.69 mmol). The reaction mixture was allowed to warm to RT and left to stir over the weekend (ca. 64 hours). The reaction mixture was concentrated in vacuo. The residues were taken up in water, then neutralized with 1M aqueous HCl (dropwise addition) to pH 5-6 and extracted with ethyl acetate (3×50 mL). The combined organics were dried over MgSO4, filtered and evaporated to dryness, producing the title compound (233 mg). LCMS (A): m/z (M+H)+ 176, C5H9N3O2S requires 175 (acidic).
Reaction SMILES: [C:1]1([CH2:7][NH:8][C@@H:9]([CH3:12])[CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:20][C:21](Cl)=[O:22].[OH-].[Na+]>C1COCC1.O>[CH3:12][C@@H:9]1[N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21](=[O:22])[CH2:20][O:11][CH2:10]1
Reactant: O=C(Cl)CCl
Reactant: C[C@@H](CO)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1COCC(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of (2S)-2-[(phenylmethyl)amino]-1-propanol (10.52 g, 63.67 mmol) in THF (65 mL) was added a solution of K2CO3 (26.40 g, 191.0 mmol) in water (65 mL). The vigorously stirred mixture was cooled to 0° C., and chloroacetyl chloride (7.10 mL, 89.14 mmol) was added dropwise over 20 min. The mixture was stirred for 1 h, and then an additional portion of chloroacetyl chloride (0.500 mL, 6.278 mmol) was added dropwise. The mixture was stirred for 1 h, and then the mixture was adjusted to pH>13 with 50% aq. NaOH (ca. 20 mL). The mixture was stirred and warmed to room temperature overnight, and then extracted with DCM (250 mL). The organic phase was washed with 1 N aq. HCl, followed by water. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give (5S)-5-methyl-4-(phenylmethyl)-3-morpholinone (12.74 g, 97%) as a colorless oil. LCMS: (M+H)+: 206.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]2[C:12]([C:13](=[O:17])[C:14]=1[CH2:15]Br)=[CH:11][CH:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[N:8]=2)=[O:4].[N-:28]=[N+:29]=[N-:30].[Na+].CN(C=O)C>O>[CH3:1][O:2][C:3]([C:5]1[N:6]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:7]2[C:12]([C:13](=[O:17])[C:14]=1[CH2:15][N:28]=[N+:29]=[N-:30])=[CH:11][CH:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[N:8]=2)=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1c(CBr)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(CN=[N+]=[N-])c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
In a 25 mL pear-shaped flask, 3-bromomethyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (150.6 mg, 0.341 mmol) and sodium azide (66.6 mg, 1.02 mmol) were combined with DMF (2 mL) to give a light yellow solution. The reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with H2O (25 mL) and extracted with ethyl acetate (3×30 mL). The organic layers were combined, washed with brine (2×25 mL), dried over MgSO4, and concentrated in vacuo to give 3-azidomethyl-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]naphthyridine-2-carboxylic acid methyl ester (134.7 mg, 97.8%) as a yellow oil which contained DMF as an impurity. 1H NMR (DMSO-d6) δ ppm 8.89 (d, J=8.2 Hz, 1H) 7.78-8.27 (m, 1H) 7.26-7.76 (m, 5H) 4.30 (s, 2H) 3.52 (s, 2H). MS calcd. for C18H12F3N5O3 [(M+H)+] 404.0, obsd. 404.0, [(M+H-N2)+] 376.0, obsd. 376.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=2)[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][CH2:24][C@:25]([CH3:31])([CH:29]=[CH2:30])[C:26]([OH:28])=[O:27].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(N(C)C2CCCCC2)CCCCC1.S([O-])(O)(=O)=O.[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1.C(#N)C>[C:1]([O:5][C:6]([NH:7][C@@H:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][C:14](/[CH:30]=[CH:29]/[C@:25]([CH2:24][O:23][CH3:22])([CH3:31])[C:26]([OH:28])=[O:27])=[CH:15][CH:16]=2)[N:11]=1)[CH3:9])=[O:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C[C@@](C)(COC)C(=O)O
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(Br)cc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CC#N
Solvent: C1COCCO1
Product: COC[C@](C)(/C=C/c1ccc2ccc([C@@H](C)NC(=O)OC(C)(C)C)nc2c1)C(=O)O
Yield: 21.2 %

Procedure:
To a vial charged with [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-carbamic acid tert-butyl ester (706 mg, 2 mmol), (S)-2-methoxymethyl-2-methyl-but-3-enoic acid (290 mg, 2 mmol), tri-(o-tolyl)phosphine (610 mg, 2 mmol) and N,N-dicyclohexyl-methyl-amine (0.85 mL, 4 mmol), was added acetonitrile (2 mL) and 1,4-dioxane (6 mL). The vial was purged with nitrogen. Palladium(II) acetate (450 mg, 2 mmol) was added. The vial was sealed and irradiated by microwave at 130° C. for 1 h. The mixture was then treated with saturated solution of potassium hydrogen sulfate. The aqueous layer was extracted with ethyl acetate (2×) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated. The crude residue was purified by silica gel chromatography using a Biotage KP-Sil 100 g cartridge eluting with a gradient of ethyl acetate/methanol 1:0 to 41:9 to give the title product (0.176 g, 21%) as an amber oil. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.54 (s, 3H), 1.57 (d, J=6.5 Hz, 3H), 3.47 (s, 3H), 3.62 (d, J=8.7 Hz, 1H), 3.77 (d, J=8.7 Hz, 1H), 4.90-5.10 (m, 1H), 6.60-6.85 (m, 2H), 7.34 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 8.06-8.17 (m, 2H). LCMS (m/z) 415.3 [M+H], Tr=2.11 min.