Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=[O:24].O[CH2:27][CH2:28][NH:29][C:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:31].C1(N=C=NC2CCCCC2)CCCCC1.C(#N)C>CCOCC>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([O:25][CH2:27][CH2:28][NH:29][C:30]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[O:31])=[O:24])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: O=C(NCCO)c1cccnc1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc2c(c1)c(CC(=O)OCCNC(=O)c1cccnc1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A reaction of indomethacin (1.79 g, 5.00 mmol) and the product of Example 91 (0.830 g, 5.00 mmol) was carried out, using dicyclohexylcarbodiimide (1.10 g, 5.50 mmol) as the coupling agent and acetonitrile as the solvent. The first two reactants were dissolved completely and the solution was then cooled to 0° C. The dicyclohexylcarbodiimide was added and the mixture was stirred overnight. The reaction was allowed to continue for 48 hours. The precipitate (1.2 g) was removed by vacuum filtration. The solvent was removed from the filtrate under reduced pressure leaving an oily residue. The product was solidified by stirring with anhydrous ether. It was filtered, air-dried and recrystallized from ethanol/ether. The final product was vacuum filtered, washed with ether, and air dried. The product weighed 1.65 g, giving a 65.2% yield; mp 123°-125° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([OH:26])=O)[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:41])[O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH2:34]([O:33][C:32](=[O:41])[NH:31][CH2:30][CH2:29][NH:28][C:24](=[O:26])[C@@H:15]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: NCCNC(=O)OCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)NCCNC(=O)OCc1ccccc1

Procedure:
Preparation takes place in analogy to Example 79A from 300 mg (0.82 mmol) of N5-[(benzyloxy)carbonyl]-N-(tert-butoxycarbonyl)-L-ornithine and 246 mg (1.06 mmol) of benzyl (2-aminoethyl)carbamate hydrochloride in 6 ml of dimethylformamide with the addition of 204 mg (1.06 mmol) of EDC, 33 mg (0.25 mmol) of HOBt and 148 mg (1.15 mmol) of N,N-diisopropylethylamine.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(#N)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([CH3:11])[CH:9]=2)[N:4]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:3]=1
Reactant: Cc1cc2c(I)n[nH]c2cn1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc2c(I)nn(CC(=O)OC(C)(C)C)c2cn1
Temperature: 25 °C

Procedure:
To a suspension of 3-iodo-5-methyl-1H-pyrazolo[3,4-c]pyridine (1.00 g, 3.86 mmol), and potassium carbonate (1.28 g, 9.26 mmol) in acetonitrile (40 mL) was added tert-butyl bromoacetate (0.685 mL, 4.63 mmol) dropwise at RT and the resulting mixture was heated to reflux for 16 h. The mixture was cooled to RT and filtered, the solid was washed with acetonitrile and the filtrate was concentrated under vacuum. The residual oil was used directly in the next step without further purification. MS (LC/MS): 374.0 [M+H]+; tR (HPLC conditions k): 2.96 min.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:19][S@@](C(C)(C)C)=O)([CH2:12][C@H:13]([OH:18])[C:14]([F:17])([F:16])[F:15])[CH2:10][F:11].Cl.O1CCOCC1>ClCCl.CO>[NH2:19][C@@:9]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])([CH2:10][F:11])[CH2:12][C@H:13]([OH:18])[C:14]([F:16])([F:17])[F:15]
Reactant: CC(C)(C)[S@@](=O)N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cccc(F)c1F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@](CF)(C[C@H](O)C(F)(F)F)c1cccc(F)c1F
Reaction time: 0.17 h

Procedure:
(R)-N-((2S,4S)-2-(2,3-difluorophenyl)-1,5,5,5-tetrafluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (2.48 g, 6.34 mmol) was dissolved in dichloromethane (12.0 mL) and MeOH (4.0 mL). To this solution was added hydrogen chloride, 4M in 1,4-dioxane (12.0 mL, 48.0 mmol). After stirred for 10 min, the mixture was concentrated, diluted with dichloromethane and washed with 1N NaOH followed by brine. The organic layer was dried over Na2SO4 and then filtered. The filtrate was concentrated and dried to afford (2S,4S)-4-amino-4-(2,3-difluorophenyl)-1,1,1,5-tetrafluoropentan-2-ol as colorless oil. This crude product was dissolved in THF (60 ml) and then treated with benzoyl isothiocyanate (0.938 mL, 6.97 mmol). After stirred for 1.5 h, triethylamine (1.058 mL, 7.60 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hcl (1.336 g, 6.97 mmol) were added, and the resulted reaction mixture was brought to 70° C. for 2 h. Reaction mixture was partitioned between EtOAc and water. The separated organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (0-20% EtOAc/hexane) to afford N-((4S,6S)-4-(2,3-difluorophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (2.22 g, 5.33 mmol, 84% yield) as white solid. MS m/z=417.1 [M+H]+. Calculated for C19H14F6N2O2: 416.3
Reaction SMILES: [CH2:1]([N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=O)[CH3:2].COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:19]2)=CC=1>C1C=CC=CC=1>[CH2:1]([N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=[S:19])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCn1ccccc1=O
Solvent: c1ccccc1
Product: CCn1ccccc1=S
Yield: 187 %

Procedure:
Under an inert atmosphere, 1.23 g of 1-ethyl-2-pyridone and 25 ml of benzene were mixed together and then under vigorous stirring, 2.02 g of 2,4-bis-(4-methoxyphenyl)-2,4-dithioxo1,3,2,4-dithiadiphosphetane (Lawesson's reagent) were added all at once with stirring at reflux for 2 hours. After cooling and filtering, the filtrate was taken to dryness by distilling under reduced pressure, and the 3.8 g of residue were chromatographed on silica and eluted with a mixture of methylene chloride and ethyl acetate (8/2) to obtain 1.3 g of the expected product melting at about 50° C.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH:16]([C:21](=[O:23])[NH2:22])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[OH:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH:16]([C:21](=[O:23])[NH2:22])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][C:13]=2[O:24][CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)C1CCCc2c1c1c(O)cccc1n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(n2Cc2ccccc2)CCCC1C(N)=O
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of 80 mg (0.25 mmol) of 9-benzyl-4-carbamoyl-5-hydroxy-1,2,3,4-tetrahydrocarbazole in 2.5 mL of DMF was treated with 61 mg (0.30 mmol) of Cs2CO3 followed by 26 mg (0.30 mmol) of methyl bromoacetate. The mixture was stirred at room temperature until tlc indicated complete consumption of starting material (2 hours). The reaction was diluted with H2O (10 mL) and was extracted with EtOAc (3×10 mL). The combined organic layers were washed with H2O (3×20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by radial chromatography (SiO2; 2.5% MeOH in CH2Cl2) to afford 50 mg (0.13 mmol; 51%) of [9-benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbazole-5-yl]oxyacetic acid, methyl ester as an oil. 1H NMR (CDCl3) δ 7.33-7.21 (m, 3H), 7.05-6.98 (m, 3H), 6.98 (d, 1H, J=7.4 Hz), 6.46 (br s, 1H), 6.37 (d, 1H, J=7.7 Hz), 5.52 (br s, 1H), 5.23 (d, 1H, J=4.9 Hz), 4.79-4.70 (m, 2H), 4.20-4.15 (m, 1H), 3.81 (s, 3H), 2.79-2.69 (m, 1H), 2.63-2.49 (m, 1H), 2.43-2.35 (m, 1H), 2.25-2.09 (m, 1H), and 1.99-1.78 (m, 2H). IR (CHCl3, cm−1) 1759, 1670, 1497, 1453, 1440, and 1132. MS (ES) m/e 393 (M+1).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].CO[C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11](I)[CH:10]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C@@H:24]2[C@:26]3([C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[NH:28][C:27]3=[O:35])[CH2:25]2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([C@H:24]2[C@@:26]3([C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([C:11]4[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=4)[C:8]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[O:16])[C:27]3=[O:35])[CH2:25]2)=[CH:22][CH:23]=1
Reactant: CS(N)(=O)=O
Reactant: COC(=O)c1cccc(I)c1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@@H]2c1ccc(Cl)cc1
Product: CS(=O)(=O)NC(=O)c1cccc(N2C(=O)[C@@]3(C[C@H]3c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 85 starting from methylsulfonamide, methyl-3-iodobenzoate (commercially available), (1R,2S) and (1S,2R)-2-(4-chlorophenyl)spiro[cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1. LC/MS m/e calcd. for C24H19ClN2O4S: 466, observed (M+H)+: 467.2 1H NMR (400 MHz, DMSO-d6) δppm 2.15 (dd, J=9.09, 4.80 Hz, 1 H) 2.44 (dd, J=8.08, 4.80 Hz, 1 H) 3.25 (t, J=8.59 Hz, 1 H) 3.41 (s, 3 H) 6.21 (d, J=7.58 Hz, 1 H) 6.79-6.88 (m, 2 H) 7.10-7.17 (m, 1 H) 7.37-7.45 (m, 4 H) 7.75 (t, J=7.83 Hz, 1 H) 7.80-7.85 (m, 1 H) 8.04 (d, J=7.83 Hz, 1 H) 8.11-8.16 (m, 1 H) 12.29 (br. s., 1 H).
Reaction SMILES: CI.[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]([C:13]3[N:18]=[C:17]([NH:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]4)[C:16]([F:27])=[CH:15][N:14]=3)=[CH:11][N:10]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])[C:7]2=[N:8][CH:9]=1.Cl[C:39]1C=C2C(C3N=C(NC4(O)CCCCC4)C(F)=CN=3)=CN(S(C3C=CC(C)=CC=3)(=O)=O)C2=NC=1.S([O-])([O-])(=O)=O.[Ca+2]>[Ag]=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:12]([C:13]3[N:18]=[C:17]([NH:19][C@H:20]4[CH2:25][CH2:24][CH2:23][CH:22]([O:26][CH3:39])[CH2:21]4)[C:16]([F:27])=[CH:15][N:14]=3)=[CH:11][N:10]([S:28]([C:31]3[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=3)(=[O:30])=[O:29])[C:7]2=[N:8][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCC(O)C4)n3)c3cc(Cl)cnc32)cc1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4(O)CCCCC4)n3)c3cc(Cl)cnc32)cc1
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CI
Product: COC1CCC[C@H](Nc2nc(-c3cn(S(=O)(=O)c4ccc(C)cc4)c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of methyl iodide (0.20 g, 0.41 mmol) and 3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]-cyclohexanol, 27a, (0.47 g, 2.04 mmol) was added silver oxide (0.578 g, 4.07 mmol and calcium sulfate (0.28 g, 2.04 (mmol). The reaction mixture was stirred at room temperature for 18 h. The mixture was filtered through celite and the resulting filtrate was concentrated in vacuo. The resulting crude mixture was purified by silica gel chromatography to afford 120 mg of the desired product, 27b.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([O:33]CC3C=CC=CC=3)=[C:12]([CH:32]=2)[C:13]([NH:15][C:16]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[O:14])[CH2:4][CH2:3][CH2:2]1.O1CCOCC1>C(OCC)(=O)C.CO.[C].[Pd]>[N:1]1([CH2:5][CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([OH:33])=[C:12]([CH:32]=2)[C:13]([NH:15][C:16]2[CH:25]=[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:23]=[CH:22][C:17]=2[C:18]([O:20][CH3:21])=[O:19])=[O:14])[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCC2)ccc1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
To a solution mixture of the obtained methyl 2-(5-(2-(azetidin-1-yl)ethoxy)-2-(benzyloxy)benzamido)-4-phenylbenzoate (0.088 g) in ethyl acetate (1.5 mL), methanol (1.5 mL), and dioxane (1.5 mL), 10% palladium-carbon (0.088 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours. To the reaction mixture, 10% palladium-carbon (0.088 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 3 hours. The insoluble substance was removed by filtration, and then the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue, and the solid substance was collected by filtration to obtain 0.033 g of methyl 2-(5-(2-(azetidin-1-yl)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoate as a light yellow solid.
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[C:18]([O-:21])(=[S:20])[CH3:19].[K+]>CN(C)C=O>[C:18]([S:20][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])(=[O:21])[CH3:19]
Reactant: CC(C)(Br)C(=O)O
Reactant: CC([O-])=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC(C)(C)C(=O)O
Temperature: -45 °C
Reaction time: 22 h
Yield: 82 %

Procedure:
Dimethylformamide (DMF), 100 ml, was poured into a 4 l indented 3 neck round bottom flask equipped with a nitrogen bubbler and an overhead stirrer (glass shaft, teflon Paddle). The hot 2-bromo-2-methylpropionic acid was then added to the flask through a powder funnel. The flask and the funnel were rinsed with 4×100 ml portions of DMF and were added to the reaction flask. A thermometer was placed in the third neck and the stirred solution was cooled under an atmosphere of nitrogen to -45° C. by placing it in a methanol/water 50:50 dry ice bath. The thermometer was removed and potassium carbonate 250.21 g (1.810 mol, 100 M %) was added through a powder funnel over a 5 minute period. The reaction mixture warmed to -40° C. but there was no apparent reaction and the carbonate did not dissolve. The solution was diluted with 200 ml DMF and potassium thioacetate 407.10 g (3.564 mol, 196.9 M %) was added through a powder funnel over a 5 minute period. The powder funnel was rinsed with 300 ml DMF which was added to the reaction solution which had warmed to -30° C. The reaction was allowed to slowly warm up as the dry ice was consumed. When the reaction temperature reached -10° C. the reaction began to bubble. The reaction was allowed to warm slowly to room temperature and was stirred under nitrogen for 22 hours. Water, 2 1, and 500 ml concentrated hydrochloric acid were mixed and cooled to 9° C. in an ice bath. The tan colored reaction mixture was slowly poured into the stirred acid solution over a 25 minute period. The reaction flask was washed with 2×100 ml portions of deionized water which was added to the acid solution (10° C., pH 1.5). The acid solution was poured into a 4 l separatory funnel and was extracted sequentially with 3×500 ml and 1×250 ml ethyl acetate. Each organic extract was washed with a separate 100 ml portion of saturated sodium chloride solution. The organic extracts were combined and dried over 400 g of anhydrous sodium sulfate. The solution was filtered through a fluted filter paper into a 2,000 ml round bottom flask and the solvent was removed in two portions under reduced pressure on the rotary evaporator. The sodium sulfate was washed with 3×100 ml portions of ethyl acetate which were filtered into the 2,000 ml round bottom. After all the solvent was removed, the rotary evaporator was connected to the high-vacuum pump and the water bath was heated to 100° C. The product was removed after 1.5 hour to afford 241.07 g of the crude brown oily product which crystallized on cooling. The crystalline mass was placed under high vacuum at 22° C. for 16 hours to afford 240.51 g (82% yield) of the crude crystalline 2-acetylthio-2-methylpropanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([CH2:8][C@H:9]([OH:11])[CH3:10])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:22][S:23]([O:11][C@H:9]([CH3:10])[CH2:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[CH3:12])(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(F)cc1C[C@@H](C)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(F)cc1C[C@@H](C)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (R)-1-(5-fluoro-2-methylphenyl)propan-2-ol (6.1 g, 36.3 mmol) and DIEA (12.6 mL, 72.6 mmol) in 200 mL anhydrous DCM was cooled in ice-water bath. Then methylsulfonyl chloride (3.4 mL, 43.5 mmol) was added slowly and the mixture was stirred for 30 min at rt. And then, saturated NaHCO3 solution (30 mL) was added to the solution and extracted with DCM, dried over anhydrous MgSO4, concentrated, passed through silicagel pad to give crude (R)-1-(5-fluoro-2-methylphenyl)propan-2-yl methanesulfonate (F-2).
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[H-].[Na+].I[CH3:20].O>CN(C)C=O>[CH3:20][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2]1=[O:1]
Reactant: CCOC(=O)c1nc2ccccc2[nH]c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1nc2ccccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
4.0 g (18.3 mmol) of ethyl 2-oxo-1,2-dihydroquinoxaline-3-carboxylate was dissolved in N,N-dimethylformamide (100 mL), and under a nitrogen stream, 0.81 g (20.3 mmol) of 60% sodium hydride (oily) was added thereto, while maintaining the liquid temperature in the range of 5° C. to 10° C. After stirring the mixture for one hour at room temperature, 3.9 g (27.5 mmol) of iodomethane was added dropwise to the reaction solution. The mixture was stirred for a day at room temperature, and then the reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The inorganic matter was separated by filtration, and then the solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel chromatography (developing solvent: ethyl acetate:hexane=3:2), to obtain 3.0 g (yield: 71%) of ethyl 1-methyl-2-oxo-1,2-dihydroquinoxaline-3-carboxylate as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[I-:11].[Na+]>CC(=O)CC>[NH2:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([I:11])=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: N#Cc1nc(Cl)ccc1N
Agent: [Na+]
Solvent: CCC(C)=O
Product: N#Cc1nc(I)ccc1N

Procedure:
A stirred suspension of 12.0 grams (0.08 mole) of 3-amino-6-chloro2-cyanopyridine [prepared by the method of Colbry, Elslager, and Werbel; previously cited] and 26.9 grams (0.18 mole) of sodium iodide in 300 mL of n-butanone is heated at reflux for about 3 days. After this time, the reaction mixture is concentrated under reduced pressure to a residue. The residue is then stirred with about 50 mL of water. The resultant solid is collected by filtration and washed with water. The solid is dried, yielding 3-amino-2-cyano-6-iodopyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][N:14]=1)[C:10]#[N:11].[C:21]([C:23]1[CH:24]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:26]=[CH:27][C:28]=1[F:29])#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([S:30]([N:6]([C:7]2[CH:8]=[C:9]([C:10]#[N:11])[CH:12]=[CH:13][N:14]=2)[CH2:5][C:4]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:3]=2[O:2][CH3:1])(=[O:32])=[O:31])[CH:26]=[CH:27][C:28]=1[F:29])#[N:22]
Reactant: COc1ccc(CNc2cc(C#N)ccn2)c(OC)c1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Product: COc1ccc(CN(c2cc(C#N)ccn2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1

Procedure:
The title compound was prepared according to the method described for Preparation 18 using 2-((2,4-dimethoxybenzyl)amino)isonicotinonitrile (Preparation 35) and 3-cyano-4-fluorobenzene-1-sulfonyl chloride. The residue was purified by reverse phase chromatography eluting with 0-100% MeCN in water/0.1% formic acid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]5[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=5)=[CH:33][CH:32]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]4[N:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[N:50]=[C:24]34)[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>C(OCC)(=O)C>[O:13]1[C:17]2([CH2:18][CH2:19][CH:20]([N:23]3[C:28](=[O:29])[C:27]([CH2:30][C:31]4[CH:32]=[CH:33][C:34]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=5[C:43]5[NH:3][C:4](=[O:7])[O:5][N:44]=5)=[CH:35][CH:36]=4)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]4[N:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[N:50]=[C:24]34)[CH2:21][CH2:22]2)[O:16][CH2:15][CH2:14]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C(F)(F)F)nn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C(F)(F)F)nn12
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (396 mg), sodium hydrogen carbonate (638 mg) and dimethyl sulfoxide (3 mL) was stirred at 60° C. for 30 min, 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-2-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (220 mg) was added, and the mixture was stirred at 90° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (3 mL). N,N′-Carbonyldiimidazole (75 mg) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (70 mg) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=70/30→30/70 (volume ratio)] to give the title compound as a colorless amorphous compound (162 mg, 67%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][F:12])=[CH:6][CH:5]=1.O.[NH2:15][NH2:16]>C(O)C>[F:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:15][NH2:16])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCF)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ccc(OCF)cc1
Yield: 1010.6 %

Procedure:
4-Fluoromethoxy-benzoic acid methyl ester (573 mg, 0.31 mmol) was dissolved in ethanol (10 ml) and heated under reflux with hydrazine monohydrate (0.8 ml, 1.55 mmol, 5 eq.) for 60 hrs. The volatiles were completely evaporated and the product was dried overnight under high vacuum at 40° C., to afford the title compound (577 mg, 100% yield) as a light brown solid. MS: m/e=184 (M+).