Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20]([OH:22])=[O:21])=[CH:5][N:4]=1.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.CN(C1C=CC=CN=1)C.[N:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[CH2:50]O>O1CCCC1.O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([Cl:19])[CH:12]=2)[C:6]([C:20]([O:22][CH2:50][C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][N:44]=2)=[O:21])=[CH:5][N:4]=1
Reactant: OCc1ccccn1
Reactant: COc1ccc(CNc2nc(SC)ncc2C(=O)O)cc1Cl
Agent: CN(C)c1ccccn1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(CNc2nc(SC)ncc2C(=O)OCc2ccccn2)cc1Cl
Reaction time: 0.17 h

Procedure:
A mixture of 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-carboxypyrimidine (prepared in Example 79) 0.100 g and triethylamine 82 μl in tetrahydrofuran 2.0 ml is treated under room temperature with 2,4,6-trichlorobenzoyl chloride 51 μl and then dimethylaminopyridine about 1 mg is added thereto, followed by stirring for 10 minutes. After addition of 2-pyridinemethanol 31 μl, the mixture is stirred for 12 hours. Ethyl acetate and water are added thereto and the organic layer is separated, washed with sodium hydrogen carbonate solution, brine. The organic layer is dried over anhydrous sodium sulfate and in vacuo. The residue is purified with silica gel chromatography (solvent; chloroform:ethyl acetate=5:1–2:1) and recrystallized from ethyl acetate-isopropyl ether to give 2-methylthio-4-(3-chloro-4-methoxybenzylamino)-5-(2-pyridylmethoxycarbonyl)pyrimidine as a colorless needle, 0.5183 g. mp117–118° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>O1CCCC1>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (15.3 g, 99.6 mmol) in tetrahydrofuran (200 mL) was added NaH (60% dispersion in mineral oil, 4.20 g, 105 mmol) at 0° C. The resulting solution was stirred for 1 hour at 0° C. and then SEMCl (16.6 g, 100 mmol) was added dropwise. After stirring for an additional 5 hours at 25° C., the reaction was quenched by addition of 250 mL of water/ice, and extracted with ethyl acetate (×2). The organic layers were combined and dried over anhydrous sodium sulfate and concentrated in vacuo. The reaction was purified by chromatography using silica gel, eluting with 50% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine as a light yellow oil. LRMS (PSI) calc'd for C12H19N3ClOSi [M+H]+: 284. found 284.
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[C:6]([NH:5][S:2]([Cl:1])(=[O:4])=[O:3])([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:7]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: OCc1ccccc1
Solvent: ClCCl
Product: O=C(NS(=O)(=O)Cl)OCc1ccccc1

Procedure:
In dry dichloromethane (7 ml) at 0 C, chlorosulfonyl isocyanate (1.0 g, 7.06 mmol, 1 equiv) and benzyl alcohol (764 mg, 7.06 mmol, 1 equiv) were stirred for 30 min to form a 1M solution of Cbz-sulfamoyl chloride. In a separate flask, the starting material (100.0 mg, 0.22 mmol, 1 equiv) was dissolved in DCM (3.0 ml) with pyridine (88 mg, 1.1 mmol, 5 equiv) was treated with the Cbz-sulfamoyl chloride (0.55 ml, mmol, 2.5 equiv) and stirred for 5 min at room temperature. The mixture was split between ethyl acetate and water, and the organic layer was then washed with brine and dried over sodium sulfate. The residue obtained upon concentration was purified by flash silica gel chromatography (0.25% acetic acid/80→100% ethyl acetate/hexanes) to provide a white solid. This material was dissolved in 1:1 ethanol/ethyl acetate (4 ml) with 0.25% acetic acid, and was stirred under a hydrogen atmosphere with 25 mg of 10% Pd/C (wet Degussa type) for 1 hour at room temperature. The mixture was filtered and its concentrated residue purified by silica gel chromatography (0.25% acetic acid/80→100% ethyl acetate/hexanes) to give a clear white solid, Compound 44 (32 mg: 529.1 [M+H]=m/z).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-])=O)[C:3]=1[NH:15][CH3:16].[H][H]>[Ni].C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([NH2:12])[C:3]=1[NH:15][CH3:16]
Reactant: [H][H]
Reactant: CNc1c(Cl)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CNc1c(N)cc(C(F)(F)F)cc1Cl
Yield: 90.4 %

Procedure:
To a mixture of (2-chloro-6-nitro-4-trifluoromethylphenyl)-methylamine (3.70 g) and ethanol (60 ml), Raney® nickel (slurry in water, 0.5 ml) was added, and stirred under about 1 atm of hydrogen at room temperature for 1.5 hours. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to give 2.95 g of 3-chloro-N2-methyl-5-trifluoromethylbenzene-1,2-diamine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35]([S:43][CH3:44])[C:14]=1[C:15]([NH:17][C:18]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH:22]([O:24]COC)[CH2:21][N:20]([CH3:28])[CH2:19]1)=[O:16].C(N(CC)CC)C>ClCCl>[CH3:11][O:12][C:13]1[CH:38]=[C:37]([C:39]([F:42])([F:40])[F:41])[CH:36]=[C:35]([S:43][CH3:44])[C:14]=1[C:15]([NH:17][C:18]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23][C:22](=[O:24])[CH2:21][N:20]([CH3:28])[CH2:19]1)=[O:16]
Reactant: COCOC1CN(C)CC(NC(=O)c2c(OC)cc(C(F)(F)F)cc2SC)(c2ccccc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1(c2ccccc2)CC(=O)CN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88.4 %

Procedure:
To a −50° C. solution of 11 ul (0.21 mmol) oxalyl chloride in 0.8 ml dichloromethane was added a solution of 17.2 ul DMSO in 0.2 ml dichloromethane over a period of 15 minutes. The reaction mixture was stirred for 10 minutes, after which a solution of 50 mg (0.11 mmol) rac-N-(5-hydroxy-1-methyl-3-phenyl-piperidin-3-yl)-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (example 51) in 0.8 ml dichloromethane was added over a period of 15 minutes. After 30 min stirring, 77 ul (0.55 mmol) triethylamine was added. The reaction mixture was stirred for 15 minutes, then allowed to warm to room temperature and quenched with water and the aqueous layer was extracted with dichloromethane. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 15%) to provide 44 mg (89%) of the title compound as a white foam. MS (m/e): 453.1 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[O:21][C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[Cl:22])[CH:14]=1)(OC(C)(C)C)=O.Cl>C(O)=O>[ClH:22].[Cl:22][C:19]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:14]=[C:13]([C@@H:9]3[CH2:10][CH2:11][CH2:12][N:8]3[CH3:1])[O:21][C:20]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1cc2nccc(Cl)c2o1
Agent: Cl
Solvent: O=CO
Product: CN1CCC[C@H]1c1cc2nccc(Cl)c2o1
Temperature: 25 °C
Yield: 15 %

Procedure:
A solution of 2-(1-BOC-2-(S)-pyrrolidinyl)-7-chlorofuro[3,2-b]pyridine, from step 51a above, in HCO2H (15.0 mL, 88%) and H2CO (15 mL, 37%) was refluxed for one hour. After cooling to room temperature and the solution was acidified to pH=2.0 with 1 N aqueous HCl and washed with Et2O (150 mL). The aqueous layer was basified with 15% NaOH and extracted with CH2Cl2 (4×400 mL). The combined CH2Cl2 extracts were dried (MgSO4) and concentrated. The crude material was chromatographed (silica gel; CH2Cl2 :MeOH, 95:5) to afford the title compound as a light yellow oil (0.036 g, 15%). The amine was dissolved in Et2O and cooled to 0° C. and a saturated solution of HCl in Et2O was added until precipitation ceased. The solvent was removed and the yellow solid was placed under vacuum to afford the title compound: [α]D≤ +26.24 (c 0.05, H2O); 1H NMR (D2O, 300 MHz) δ 2.28-2.42 (m, 2H), 2.50-2.68 (m, 2H), 2.98 (s, 3H), 3.42 (br s, 1H), 3.62 (br s, 1H), 5.00 (m, 1H), 7.38 (s, 1H), 7.59 (d, J=6.0 Hz, 1H), 8.44 (d, J=6.0 Hz, 1H); MS (DCI/NH3) m/z: 237 (M+H)+ ; Anal. Calcd for C12H13N2O.1.2 HCl.0.10H2O.0.20Et2O: C, 51.75; H, 5.56; N, 9.43. Found C, 51.40; H, 5.49; N,9.03.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:34][C:35]1([F:39])[CH2:38][NH:37][CH2:36]1.C(N(C(C)C)CC)(C)C>C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22]([N:37]4[CH2:38][C:35]([F:39])([F:34])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(S(C)(=O)=O)ncc1Br
Reactant: FC1(F)CNC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)(F)C2)ncc1Br
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Step A, 2.5 g, 4.45 mmol), and 3,3-difluoroazetidine (1.73 g, 13.34 mmol) in THF (40 mL) was added diisopropylethylamine (3.88 mL, 22.23 mmol). It was stirred at 60° C. for 15 minutes at which time complete conversion by LCMS was noted. The solvent was evaporated, and the residue was purified on a silica gel column, eluting with 50% ethyl acetate in hexanes to get the title compound (2.2 g, 86% yield) as a white solid. LCMS (M+H)+: 577.1; 575.2. 1H NMR (CDCl3, 500 MHz): δ 8.38 (s, 1H), 7.93 (s, 1H), 7.81 (s, 2H), 5.82 (d, J=8.5 Hz, 1H), 4.84 (d, J=18.0 Hz, 1H), 4.48 (m, 4H), 4.40 (m, 1H), 4.23 (d, J=18.0 Hz, 1H), 0.83 (d, J=6.5 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]([OH:15])[CH2:12][S:11](=[O:17])(=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][C:13](=[O:15])[CH2:12][S:11](=[O:16])(=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCS(=O)(=O)CC(O)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCS(=O)(=O)CC(=O)C1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
4-N-(t-Butyloxycarbonyl)-1,1-dioxo-6-hydroxy -2,3,4,5,6,7-hexahydro-1,4-thiazepine (10.0 g, 37.7 mmole) from Example 5, was dissolved in 110 mL of acetone, cooled to 0° C. and treated with 18.8 mL of freshly prepared Jones reagent. The reaction was stirred at ambient temperature for three hours and then treated with 5 mL of methanol. After 15 minutes, the reaction was filtered through magnesium sulfate and the filtrate immediately concentrated. The residue was filtered through a pad of silica gel using 3:1 chloroform-ethyl acetate to obtain the produce (9.67 g, 87%) D.C.I.M.S. 264(M+H) M.P. 172°-173° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH:10]=[CH:11][N:12]=2)[CH:9]=1)(=O)[NH2:2]>P(Cl)(Cl)(Cl)=O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([CH:10]=[CH:11][N:12]=2)[CH:9]=1)#[N:2]
Reactant: NC(=O)c1ccc2nccn2c1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc2nccn2c1
Yield: 86.6 %

Procedure:
A mixture of 2.6 g of 6-carbamoylimidazo[1,2-a]pyridine and 30 ml of phosphorus oxychloride is heated under reflux for 16 hours. The excess phosphorus oxychloride is removed under reduced pressure and the residue is poured onto ice. The mixture is neutralized with sodium carbonate and extracted with ethyl acetate. The organic layer is washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then evaporated off under reduced pressure to give 2.0 g of the above-identified compound as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[CH3:18])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:26](=[O:27])[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[CH3:18])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c(C)c1
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To a solution of 3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-amine (700 mg, 2.9 mmol) in DCM (20 mL) was added K2CO3 (4.32 mmol) and phenyl chloroformate (6.48 mmol) and the reaction stirred overnight. The solvent was decanted and the solids washed with DCM. The combined organics were concentrated and purified using silica gel chromatography eluting with an EtOAC/hexane gradient (5-20%) gave phenyl 3-tert-butyl-1-(2,4-dimethylphenyl)-1H-pyrazol-5-ylcarbamate (472 mg, 45% yield). 1H NMR (300 MHz, DMSO d6) δ 1.09 (s, 9H), 1.98 (s, 3H), 2.36 (s, 3H), 6.26 (s, 1H), 7.00 (s, 2H), 7.14 (m, 4H), 7.37 (m, 2H), 9.80 (bs, 1H); LC-MS (ESI) m/z 364 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: C1CCNC1
Reactant: O=Cc1cccc(Cl)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Clc1cccc(CN2CCCC2)c1Cl
Reaction time: 8 h
Yield: 80045 %

Procedure:
NaHB(OAc)3 (15.1 g, 0.0714 mmol) was added under vigorous stirring in portions to a solution of 2,3-dichlorobenzaldehyde (10 g, 0.057 mmol) and pyrrolidine (5.97 mL, 0.0714 mmol) in CH2Cl2 (200 mL). The reaction mixture was vigorously stirred overnight. Then 5N NaOH (50 mL) was added, and the layers were separated. The product was extracted from the aqueous layer with CH2Cl2 (2×50 mL). The combined extracts were washed with 5N NaOH (50 mL), water, brine, dried with anhydrous Na2SO4, and evaporated. The residue was distilled in vacuum to give title compound (10.5 g, 90%) as a colorless liquid (bp 80-84° C./0.5 mmHg). LC/MS data: 229.9, 230.9, 231.9 (M+H) (calculated for C11H13Cl2N 230.14). 1H NMR data (DMSO-d6): δ 7.52 (dd, 1H, J1=1.5 Hz, J2=7.8 Hz), 7.46 (dd, 1H, J1=1.5 Hz, J2=7.8 Hz), 7.33 (t, 1H, J=7.8 Hz), 3.70 (s, 2H), 2.46-2.52 (m, 4H), 1.66-1.75 (m, 4H).
Reaction SMILES: ClCI.[Br:4][C:5]1[CH:6]=[N:7][C:8]([OH:22])=[C:9]([CH:21]=1)[C:10]([NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)=[O:11].[C:23]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:4][C:5]1[CH:6]=[N:7][C:8]2[O:22][CH2:23][N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=3)[C:10](=[O:11])[C:9]=2[CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(NCc1ccc(F)cc1)c1cc(Br)cnc1O
Agent: ClCI
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2cc(Br)cnc2OCN1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 9 %

Procedure:
Chloroiodomethane (897 mg, 5.1 mmol) was slowly added to a mixture of 5-bromo-N-(4-fluorobenzyl)-2-hydroxynicotinamide (1.5 g, 4.6 mmol) and Cs2CO3 (6.0 g, 18.4 mmol) in DMF (20 mL) at 100° C. The mixture was stirred at 100° C. for 2 h. Water was added and the mixture was extracted with EtOAc. After being concentrated, the residue was purified by column chromatography (PE:EtOAc=2:1) to give the product of 6-bromo-3-(4-fluorobenzyl)-2H-pyrido[3,2-e][1,3]oxazin-4(3H)-one (140 mg, yield: 9%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.46 (d, J=2.4 Hz, 1H), 8.44 (d, J=2.4 Hz, 1H), 7.40 (dd, J=5.6, 8.8 Hz, 2H), 7.09 (t, J=8.8 Hz, 2H), 5.40 (s, 2H), 4.74 (s, 2H). MS (M+H)+: 337/339.
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:19](/[CH:20]=[CH:21]/[C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][CH2:16][C:15]1=[O:31]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:32])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15](=[O:31])[CH2:16][CH2:17][CH2:18][CH:19]1/[CH:20]=[CH:21]/[CH:22]([OH:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)CCCCCCN1C(=O)CCCC1/C=C/C(=O)Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)CCCCCCN1C(=O)CCCC1/C=C/C(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
Sodium borohydride (36 mg, 0.96 mmol), followed by MeOH (0.25 mL), was added to a solution of 7-[2-oxo-6-((E)-3-oxo-4-phenyl-but-1-enyl)-piperidin-1-yl]-heptanoic acid methyl ester (37 mg, 0.096 mmol) in CH2Cl2 (0.75 mL) at 0° C. The mixture was allowed to warm to rt. After 1.5 h at rt, the reaction was quenched with HCl (1.0 M aqueous) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL) then dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→3% MeOH/CH2Cl2, gradient) afforded 32 mg (86%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC([O-])(C)C.[Na+].C1(P(C2C=CC=CC=2)C2C=CC=C3C=2C(C2C4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C=CC=2)=CC=C3)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CNc1ncccc1N
Reactant: Ic1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CNc1ncccc1Nc1ccccc1

Procedure:
N2-methylpyridine-2,3-diamine (11.95 g, 97 mmol), iodobenzene (16.22 ml, 146 mmol), sodium 2-methylpropan-2-olate (13.99 g, 146 mmol), 8,8′-bis(diphenylphosphino)-1,1′-binaphthalene (BINAP) (60.4 g, 97 mmol) with toluene (400 mL) were added to a three necked 1 L round bottom flask. The reaction was degassed with N2 for 20 minutes. Pd2(dba)3 (1.777 g, 1.941 mmol) was added and the reaction mixture was refluxed for 20 h. The reaction mixture was concentrated to dryness. Residue was dissolved in EtOAc. It was not clear solution, but a suspension was obtained and then filtered through a silica gel plug. The desired product was concentrated and recrystallized from DCM/hexanes providing a yield of 6.45 g, 33.3%.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)C(=O)[O:19][N:18]=2)=[N:14][O:15][N:16]=1.[S:31](N)([NH2:34])(=[O:33])=[O:32].[OH-].[Na+]>N1C=CC=CC=1.O>[NH2:34][S:31]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13]([C:17](=[N:18][OH:19])[NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=2)=[N:14][O:15][N:16]=1)(=[O:33])=[O:32]
Reactant: NS(N)(=O)=O
Reactant: NCCCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NS(=O)(=O)NCCCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 85.4 %

Procedure:
3-[4-(3-Aminopropyl)-1,2,5-oxadiazol-3-yl]-4-(3-chloro-4-fluorophenyl)-1,2,4-oxadiazol-5(4H)-one trifluoroacetate (7.8 mg, 0.017 mmol) and sulfamide (9.4 mg, 0.98 mol) was dissolved in pyridine (1.0 mL). The solution was heated at 120° C. for 3 minutes in a microwave. A solution of sodium hydroxide in water (0.5 mL, 1.0; N) was added and the mixture stirred at room temperature for 16 hrs. Acidification with acetic acid and purification by preparative LCMS gave the desired product (5.7 mg, 84%). 1H NMR (400 MHz, CD3OD): δ 7.02 (t, 1H), 6.95 (m, 1H), 6.7 (m, 1H), 3.1 (m, 2H), 2.9 (m, 2H), 2.0 (m, 2H). MF=C12H14ClFN6O4S. LCMS calculated for C12H15ClFN6O4S (M+H)+: m/z=393.0.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]([F:24])([F:23])[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[O:16][CH2:17][CH2:18][OH:19].O>C(Cl)Cl>[F:11][C:12]([F:23])([F:24])[C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][CH:22]=1)[O:16][CH2:17][CH:18]=[O:19]
Reactant: OCCOc1cccc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: O=CCOc1cccc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of oxalyl chloride (0.49 ml; 5.821 mmol) in anhydrous DCM (25 ml) was treated dropwise with a solution of dimethyl sulfoxide (0.91 ml; 11.641 mmol) in anhydrous DCM (4 ml). After 10 min., a solution of 2-(3-trifluoromethyl-phenoxy)-ethanol (0.800 g; 3.880 mmol) in DCM (8 ml) was added dropwise, and the reaction mixture was further stirred at −78° C. for 30 min. TEA (2.70 ml; 19.402 mmol) was then added dropwise, and after 10 min. the resulting mixture was allowed to warm-up to 0° C. before a mixture of water (2.5 ml) and DCM (25 ml) was added. The aq. layer was extracted with DCM (2×25 ml), and the mixed organic layers were then washed with aq. sat. NaHCO3 (20 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give (3-trifluoromethyl-phenoxy)-acetaldehyde as a yellow oil (0.792 g; 99%). This aldehyde was used for the next step without additional purification.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.C(N(CC)CC)C.Cl[C:21]([O:23][CH3:24])=[O:22]>ClCCl>[CH3:24][O:23][C:21]([NH:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1)=[O:22]
Reactant: COC(=O)Cl
Reactant: CCOC(=O)c1sc(N)nc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1sc(NC(=O)OC)nc1C
Reaction time: 6 h
Yield: 81 %

Procedure:
2.0g of ethyl 2-amino-4-methyl-thiazole-5-carboxylate and 2.7ml of triethylamine were dissolved in 40ml of dichloromethane and then 1.1ml of methyl chloroformate was added thereto at 0° C. The reaction mixture was stirred for 6 hours at normal temperature, evaporated to remove the solvent and then extracted with 10% aqueous sodium hydroxide solution and ethylacetate. The organic layer was separated, dried over anhydrous magnesium sulfate and then evaporated to obtain 2.1g (Yield 81%) of ethyl 2-methoxycarbonylamino-4-methyl-thiazole-5-carboxylate as a pale yellow solid. The resulting product was hydrolyzed according to the same procedure as PREPARATION 1 to obtain 1.4g (Yield 75%) of the title compound as a pale yellow solid.
Reaction SMILES: [OH-].[Na+].CO.[C:5]([NH:13][C:14]1[CH:23]=[C:22]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O1CCCC1>[C:5]([NH:13][C:14]1[CH:23]=[C:22]([C:24]#[C:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])(=[O:12])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(C#Cc2ccccc2)cc1NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1cc(C#Cc2ccccc2)ccc1C(=O)O)c1ccccc1
Reaction time: 0.5 h

Procedure:
0.24 mL of 2.0 mol/L aqueous sodium hydroxide was added dropwise to a mixed solution of 1 mL of methanol and 2 mL of tetrahydrofuran containing 0.13 g of methyl 2-(benzamido)-4-(phenylethynyl)benzoate at room temperature and stirred at the same temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure and water was added and pH was adjusted to pH 4.0 while ice-cooled with 1.0 mol/L hydrochloric acid. A solid substance was separated by filtration to obtain 0.11 g of 2-(benzamido)-4-(phenylethynyl)benzoic acid as white solid.