Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C1C(=O)N([Cl:16])C(=O)C1>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:16])=[C:4]([CH3:8])[N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cccc(N)n1
Solvent: CN(C)C=O
Product: Cc1nc(N)ccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.5 %

Procedure:
To a stirred solution of 2-amino-6-methylpyridine (10.80 g, 100.0 mmol) in dry DMF (50 mL) was added dropwise a solution of NCS (13.35 g, 100.0 mmol) in dry DMF (60 mL) at 0° C. over 20 min. The resulting brown yellow solution was stirred at 0° C. for 1 h, and at room temperature for 3 h, then poured into ice-water (about 300 mL). The resulting mixture was extracted with EtOAc (4×100 mL). The extracts were combined, washed with brine (6×50 mL), dried (MgSO4), and rota-evaporated. To the residual viscous black oil was added hexane (200 mL) and it was heated to boiling with stirring. The hot hexane solution was decanted carefully, concentrated to about 60 ml, then allowed to stand at room temperature overnight. The resulting crystals were filtered and dried at room temperature in vacuo, giving 6.06 g (42%) of 45 as orange-colored long needles, mp 74°-5° C. (lit. 73°-4° C., Cress et al., J. Org. Chem. 93-6 (1976)). 1H NMR (CDCl3) δ 2.439 (s, 3H), 4.376 (bs, 2H), 6.302 (d, 1H, J=8.5), 7.340 (d, 1H, J=8.5).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:24])=[C:19]([F:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:24])=[C:19]([F:23])[CH:20]=[C:21]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)c(F)cc(Br)c3O2)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)c(F)cc(-c4ccccc4)c3O2)cc1
Yield: 79.6 %

Procedure:
To a solution of (±)-(7-bromo-4,5-difluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.5 g, 3.59 mmol) in dioxane (30 mL) was added phenylboronic acid (0.656 g, 5.38 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloromethane adduct (0.293 g, 0.359 mmol), and potassium carbonate (0.993 g, 7.18 mmol) and the reaction mixture was heated at reflux for 48 h. The reaction mixture was filtered (celite), rinsed (ethyl acetate), and the combined organic layers were washed with water (100 mL), aqueous sodium chloride (75 mL), dried (sodium sulfate) and the solvent was removed in vacuo to provide a crude solid. Purification by column chromatography (silica, ethyl acetate:hexane 1:9) afforded 1.19 g (80%) of (±)-(4,5-difluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.76 (silica, ethyl acetate:hexanes 1:9); 1H NMR (DMSO-d6) δH 7.69 (d, 2H); 7.50 (dd, 1H); 7.56 (d, 2H); 7.35 (m, 6H); 5.14 (m, 1H); 4.30 (dd, 1H); 4.20 (dd, 1H); 3.39 (dd, 1H); 3.05 (dd, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]([O:17]C)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][CH:9]1[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1CC(F)(F)CN1C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(F)(F)CC1C(=O)O
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a stirred solution of methyl 1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylate (885 mg, 3.34 mmol) in THF (25 ml) was added 0.25 N NaOH (26.7 ml, 6.67 mmol) and the stirring was continued for 1 h. The mixture was poured into 1 N HCl (100 ml) and extracted with CHCl3 (2×200 ml). The combined extracts were washed with brine (100 ml), dried over MgSO4, and evaporated to give 1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidine-2-carboxylic acid (775 mg, 92%) as a yellow crystalline solid. mp 113-117° C.; 1H-NMR (CDCl3) δ1.44 and 1.49 (s, each, total 9 H), 2.53-2.80 (m, 2 H), 3.71-3.90 (m, 2 H), 4.20-4.61 (m, 1 H); MS (FAB) m/z, 252 (M++1); Anal. Calcd. for C10H15F2O4: C, 47.81; H, 6.02; N, 5.58. Found: C, 48.06; H, 6.05; N, 5.45.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.[F:12][CH:13]([F:30])[C:14]1[N:19]=[CH:18][C:17]([C:20]2([CH2:28][NH2:29])[CH2:25][CH2:24][C:23]([F:27])([F:26])[CH2:22][CH2:21]2)=[CH:16][N:15]=1>>[Cl:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:29][CH2:28][C:20]1([C:17]2[CH:16]=[N:15][C:14]([CH:13]([F:30])[F:12])=[N:19][CH:18]=2)[CH2:25][CH2:24][C:23]([F:26])([F:27])[CH2:22][CH2:21]1)=[O:6]
Reactant: NCC1(c2cnc(C(F)F)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1c(Cl)cccc1Cl
Product: O=C(NCC1(c2cnc(C(F)F)nc2)CCC(F)(F)CC1)c1c(Cl)cccc1Cl

Procedure:
From 2,6-dichlorobenzoic acid and (1-(2-(difluoromethyl)pyrimidin-5-yl)-4,4-difluorocyclohexyl)methanamine. LCMS (MH+): m/z=450.1, tR (minutes, Method F)=2.93
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][S:39]([CH2:42][CH2:43][NH2:44])(=[O:41])=[O:40]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:44][CH2:43][CH2:42][S:39]([CH3:38])(=[O:41])=[O:40])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-methanesulfonylethylamine according to conditions described in general procedure C. Mp: 102-104° C.; 1H NMR (400 MHz, CDCl3) δ 1.62-1.71 (m, 6 H), 2.54-2.64 (m, 5 H), 3.27 (t, J=5.5 Hz, 4 H), 3.50 (s, 2 H), 5.66 (bs, 1 H), 6.31 (d, J=5.5 Hz, 1 H), 6.76 (d, J=11.1 Hz, 1 H), 6.98 (d, J=8.5 Hz, 1 H), 7.23 (d, J=8.0 Hz, 1 H), 7.30 (s, 1 H), 7.47-7.56 (m, 2 H), 7.80-7.91 (m, 3 H), 8.17 (d, J=5.5 Hz, 1 H), 8.25 (s, 1 H).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:11](N(CC)CC)C>>[N:4]1[C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:10])[O:9][CH:11]=1
Reactant: Nc1ccccc1C(=O)O
Reactant: CCN(CC)CC
Product: O=c1ocnc2ccccc12

Procedure:
involves reacting anthranilic acid derivative of Formula (1) with appropriately substituted anhydrides (2), in this case trifluoroacetate anhydride, in the presence of tertiary bases like triethylamine at elevated temperatures preferably at the reflux for 1-6 hours, preferably 2 hours. The volatile components are removed under reduced pressure and the residue treated with an ethereal solvent like diethyl ether and water. The ethereal layer was separated, dried over MgSO4 and concentrated to give the appropriate benzo[d][1,3]oxazin-4-one derivative as the product.
Reaction SMILES: C([O-])(=O)C.[K+].C(O)C.[NH2:9][NH:10][C:11]([NH2:13])=[S:12].Cl[CH2:15][C:16](=O)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>O>[NH:10]([C:11]1[S:12][CH:15]=[C:16]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:13]=1)[NH2:9]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: NNC(N)=S
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1csc(NN)n1

Procedure:
Potassium acetate (1.3 g., 12.5 mmoles) was dissolved in 40 ml. of an aqueous ethanol mixture (1:1). With stirring, thiosemicarbazide (1.1 g., 12.5 mmoles) and ethyl 4-chloroacetoacetate (2.0 g., 12.5 mmoles) were introduced. After 3 hours of stirring at room temperature a red oil settled out. The reaction mixture was diluted with water and extracted several times with methylene chloride (total 100 ml.). Combined extracts were dried (calcium chloride), filtered, and concentrated under reduced pressure to approximately 2.0 g. of oily residue. Thin layer chromatography (chloroform) revealed the presence of two compounds. This oil was then chromatographed on a silica gel column using methylene chloride as the eluent. Compound IVA (see Example 12) was in the first few fractions while the latter fractions contained a single component (0.6 g.) characterized as Compound IIA by pmr. Although Compound IIA was chromatographically pure, it would not crystallize; ir (mull): 3450-3200 (N--H), 1725 (C=O), 1620, 1580 (C=N) cm-1 : pmr (deuteriochloroform): δ1.20 (t, 3H, CH3), 3.55 (s, 2H, CH2CO), 4.15 (q, 2H, OCH2), 5.80-6.20 (s-broad, 3H, NH), 6.30 (s, 1H, vinyl); ms: (m/e)201(M+).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]>C(O)C.[C].[Pd]>[F:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[C:4]1[NH:3][CH:2]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:5]=1
Reactant: CCOC(=O)c1cc(-c2c(F)cccc2F)[nH]c1Cl
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(-c2c(F)cccc2F)c1
Temperature: 40 °C
Reaction time: 72 h
Yield: 44 %

Procedure:
To a solution of ethyl 2-chloro-5-(2,6-difluorophenyl)-1H-pyrrole-3-carboxylate (9.82 g) in ethanol (200 mL) was added 10% palladium carbon (50% containing water, 4.91 g), and the mixture was stirred under a hydrogen atmosphere at 40° C. for 72 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as colorless crystals (yield 3.80 g, 24%).
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([NH:16][CH:17]1[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:27][CH2:28]Cl)[C:18]1=[O:30])=[O:15])=[CH:8]2>CN(C=O)C.CCOC(C)=O>[Cl:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([NH:16][CH:17]1[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]([CH2:27][CH2:28][S:2][CH3:1])[C:18]1=[O:30])=[O:15])=[CH:8]2
Reactant: C[S-]
Reactant: O=C(NC1Cc2ccccc2N(CCCl)C1=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCCN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Temperature: 80 °C
Yield: 37.1 %

Procedure:
Sodium thiomethoxide (280 mg, 4.00 mmol) and KI (10 mg, 0.06 mmol) were added to a soluton of 5-chloro-N-[1-(2-chloroethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-1H-indole-2-carboxamide (Method 3; 1.07 g, 2.67 mmol) in DMF (10 mL) under an inert atmosphere and heated at 80° C. for 2 hours. On cooling the mixture was diluted with EtOAc (100 mL), washed with water (20 mL), dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:THF (2:23)) to give a white solid. The solid was triturated with refluxing Et2O (20 mL) and the solid filtered, washed with Et2O (10 mL) then hexane (10 mL) to afford the title compound (410 mg, 37%) as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[N:10][C:9]([Cl:12])=[C:8]2[C:4]=1[C:5]([C:13](=[O:17])[C:14]([O-:16])=O)=[CH:6][NH:7]2.[K+].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26]>>[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:14](=[O:16])[C:13]([C:5]2[C:4]3[C:8](=[C:9]([Cl:12])[N:10]=[CH:11][C:3]=3[O:2][CH3:1])[NH:7][CH:6]=2)=[O:17])[CH2:29][CH2:28]1)=[O:26]
Reactant: O=C(c1ccccn1)N1CCNCC1
Reactant: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)[O-])c12
Agent: [K+]
Product: COc1cnc(Cl)c2[nH]cc(C(=O)C(=O)N3CCN(C(=O)c4ccccn4)CC3)c12

Procedure:
Precursor 51, 1-picolinoyl-4-[(4-methoxy-7-chloro-6-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a starting from Potassium (4-methoxy-7-chloro-6-azaindol-3-yl)oxoacetate, Precursor 4d, and picolinoyl-piperazine. 1H NMR (500 MHz, DMSO-d6) δ 8.63-7.45 (m, 7H), 3.94 (s, 3H), 3.82-2.50 (m, 8H). MS m/z: (M+H)+ Calc'd for C20H19ClN5O4: 428.11; Found 428.11. HPLC retention time: 1.09 minutes (column A).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=3)[N:9]=[CH:10][C:3]=12.CC1(C)C(C)(C)[O:25][B:24](B2OC(C)(C)C(C)(C)O2)[O:23]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:18][C:17]([F:20])([F:19])[C:16]1[C:11]([N:8]2[C:4]3=[N:5][CH:6]=[CH:7][C:2]([B:24]([OH:25])[OH:23])=[C:3]3[CH:10]=[N:9]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: FC(F)(F)c1cccnc1-n1ncc2c(I)ccnc21
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccnc2c1cnn2-c1ncccc1C(F)(F)F

Procedure:
To a 48 mL pressure bottle containing Intermediate 73A (495 mg, 1.269 mmol) was added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (569 mg, 2.241 mmol), potassium acetate (571 mg, 5.82 mmol) and anhydrous DMSO (10 mL). The reaction mixture was purged with argon, treated with PdCl2(dppf).CH2Cl2 (56 mg, 0.077 mmol), and heated to 85° C. for 2 h 15 min to give conversion to the desired product. LC/MS (Condition B): ret. T=2.5 min, (M+H)+ 309.07.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]2[C:14]3[CH:20]=[CH:19][C:18]([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=4)(=[O:23])=[O:22])=[CH:17][C:15]=3[O:16][CH:10]2[CH2:9]1)=O)(C)(C)C.Br[CH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[O:36]1[CH2:37][CH2:38][CH:33]([CH2:32][O:30][C:26]2[CH:25]=[C:24]([S:21]([C:18]3[CH:19]=[CH:20][C:14]4[CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH:10]5[O:16][C:15]=4[CH:17]=3)(=[O:23])=[O:22])[CH:29]=[CH:28][CH:27]=2)[CH2:34][CH2:35]1
Reactant: BrCC1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(S(=O)(=O)c4cccc(O)c4)cc3OC2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=S(=O)(c1cccc(OCC2CCOCC2)c1)c1ccc2c(c1)OC1CNCCC21
Temperature: 60 °C
Reaction time: 2 h

Procedure:
7-(3-Hydroxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester (enantiomer 2, 42 mg, 0.097 mmol) and 4-bromomethyl-tetrahydropyran (26 mg, 0.15 mmol) were dissolved in acetonitrile (1 ml). Cesium carbonate (95 mg, 0.29 mmol) was added, and the mixture was heated to 60° C. overnight. The solvent was evaporated and the residue purified by preparative TLC (30% EtOAc/hexane). The residue was dissolved in 1 mL of 4N HCl in dioxane (1 mL) and stirred for 2 h. The solvent was evaporated and the mixture was triturated with ether. The resulting solid was filtered, washed with ether (twice) and dried at 90° C. for 2 h. MS m/z 430 [M+H]+. 1H-NMR (400 MHz, CDCl3): δ 1.28-1.40 (m, 2H), 1.46-1.58 (m, 1H), 1.63-1.71 (m, 2H), 1.95-2.07 (m, 1H), 2.09-2.18 (m, 1H), 2.92-3.00 (m, 2H), 3.28-3.46 (m, 4H), 3.52-3.61 (m, 2H), 3.82-3.94 (m, 4H), 4.90-4.96 (m, 1H), 7.22-7.28 (m, 1H), 7.45 (s, 1H), 7.49-7.61 (m, 4H), 8.98 (s, 1H).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[Cl:16][C:17]1[N:18]=[C:19]([CH:22](O)[CH2:23][CH2:24][N:25]2[C:33]([C:34]3[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=3)[C:37]#[N:38])=[C:32]3[C:27]([N:28]([CH3:45])[C:29](=[O:44])[N:30]([CH3:43])[C:31]3=[O:42])=[CH:26]2)[S:20][CH:21]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:16][C:17]1[N:18]=[C:19]([CH:22]2[C:26]3[N:25]([C:33]([C:34]4[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=4)[C:37]#[N:38])=[C:32]4[C:31](=[O:42])[N:30]([CH3:43])[C:29](=[O:44])[N:28]([CH3:45])[C:27]4=3)[CH2:24][CH2:23]2)[S:20][CH:21]=1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCC(O)c3nc(Cl)cs3)cc2n(C)c1=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(c1nc(Cl)cs1)CC3
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Trifluoromethanesulfonic anhydride (0.445 mL, 2.63 mmol) was added to a solution of 3-(6-(3-(4-chlorothiazol-2-yl)-3-hydroxypropyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (600 mg, 1.316 mmol) and triethylamine (0.550 mL, 3.95 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 90 mins. Further portions of triethylamine (0.550 mL, 3.95 mmol) and trifluoromethanesulfonic anhydride (0.445 mL, 2.63 mmol) were added to allow the reaction to run to completion. The reaction mixture was quenched with saturated NaHCO3(aq) and extracted with DCM (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum. Purification by chromatography on silica, eluting with 20-80% EtOAc/hexane gave a crude material which was triturated with DCM/diethyl ether/hexane to afford the title compound.
Reaction SMILES: [S:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[C:15]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([NH:23][C:24]1[N:29]=[CH:28][C:27]([C:30](Cl)=[O:31])=[CH:26][CH:25]=1)=[O:22]>>[S:1]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:30]([C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:16]4[C:15]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:22])=[N:29][CH:28]=3)=[O:31])[CH2:6][CH2:5][C:4]=2[CH:3]=[CH:2]1
Reactant: c1ccc2c(c1)NCCc1ccsc1-2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2-c2ccccc2)nc1
Product: O=C(Nc1ccc(C(=O)N2CCc3ccsc3-c3ccccc32)cn1)c1ccccc1-c1ccccc1

Procedure:
As described for Example 12, 4,5-dihydro-6H-thieno[3,2-d][1]benzazepine is reacted with 6-[([1,1'-biphenyl]-2-ylcarbonyl)amino]-3-pyridinecarbonyl chloride to give the product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[C:13]([F:21])=[C:14]([F:20])[C:15]4[N:16]=[CH:17][O:18][C:19]=4[C:11]=3[N:10]([S:22]([CH:25]3[CH2:27][CH2:26]3)(=[O:24])=[O:23])C2=O)=[C:4]([F:29])[CH:3]=1.[K].F[C:32]1C2N=COC=2C(NS(C2CC2)(=O)=O)=C(NC2C=CC(I)=CC=2F)C=1F>>[F:20][C:14]1[C:15]2[N:16]=[C:17]([CH3:32])[O:18][C:19]=2[C:11]([NH:10][S:22]([CH:25]2[CH2:27][CH2:26]2)(=[O:23])=[O:24])=[C:12]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:29])[C:13]=1[F:21]
Reactant: O=S(=O)(Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ncoc12)C1CC1
Reactant: O=c1n(-c2ccc(Br)cc2F)c2c(F)c(F)c3ncoc3c2n1S(=O)(=O)C1CC1
Agent: [K]
Product: Cc1nc2c(F)c(F)c(Nc3ccc(Br)cc3F)c(NS(=O)(=O)C3CC3)c2o1

Procedure:
Compound 1G was prepared from 6-(4-bromo-2-fluoro-phenyl)-8-cyclopropanesulfonyl-4,5-difluoro-6,8-dihydro-imidazo[4′,5′:3,4]benzo[1,2-d]oxazol-7-one (I-25a: 120 mg, 0.245 mmol) and potassium trimethylsilonolate (46 mg, 0.368 mmol) using procedures analogous to those described above for Compound 1A to afford 20 mg of the product (17.8% yield). H1NMR (DMSO-d6, 300 MHz): δ 9.75 (s, 1H), 8.90 (s, 1H), 7.80 (s, 1H), 7.52 (dd, 1H), 7.17 (d, 1H), 6.80-6.68 (m, 1H), 2.68-2.60 (m, 1H), 0.90-0.82 (m, 2H), 0.80-0.70 (m, 2H). LCMS: 96.25%, m/z=460.0 (M−2). HPLC: 96.94%
Reaction SMILES: CC1(C)O[C:6](=O)[CH2:5][C:4](=O)[O:3]1.[NH2:11][C:12]1[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=1>>[OH:3][C:4]1[C:13]2[C:12](=[CH:22][CH:21]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:14]=2)[N:11]=[CH:6][CH:5]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: CCOC(=O)c1ccc2nccc(O)c2c1

Procedure:
In a manner similar to that described in Example 58, Part A., 10 g (69 mmol) of 2,2-dimethyl-1,3-dioxan-4,6-dione and 11.4 g (69 mmol) of ethyl 4-aminobenzoate were tranformed into the title product: yield 10.86 g (72%); m.p. 233°-234° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18](Br)[CH:17]=3)[NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][C:27]1[C:31](B(O)O)=[C:30]([CH3:35])[O:29][N:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:31]4[C:27]([CH3:26])=[N:28][O:29][C:30]=4[CH3:35])[CH:17]=3)[NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)N=C(c1cccc(Br)c1)NC2=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1noc(C)c1-c1cccc(C2=NC3(CCN(C(=O)OC(C)(C)C)CC3)C(=O)N2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester (100 mg, 0.245 mmol), 3,5-dimethyl-isoxazole-4-boronic acid (51.8 mg, 0.367 mmol), tetrakis-(triphenylphosphine)palladium(0) (28 mg, 0.0245 mmol) and K3PO4 (104 mg, 0.490 mmol) in dioxane (1.2 mL) was heated with stirring at 100° C. for one hour in a nitrogen atmosphere. The reaction mixture was cooled, and then quenched with water and extracted with ethyl acetate (×3). The organic layers were combined and sequentially washed with water (×2) and saturated brine, and then dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to give 2-[3-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-carboxylic acid tert-butyl ester as a pale yellow solid (88.3 mg, 85%).
Reaction SMILES: [F:1][C@H:2]1[C@H:7]2[NH:8]C(=O)[O:10][C@H:6]2[CH2:5][C@H:4]([CH2:12][OH:13])[C@H:3]1[OH:14].[Li+].[OH-]>O.CO>[NH2:8][C@@H:7]1[C@H:2]([F:1])[C@H:3]([OH:14])[C@@H:4]([CH2:12][OH:13])[CH2:5][C@@H:6]1[OH:10]
Reactant: O=C1N[C@@H]2[C@H](F)[C@H](O)[C@@H](CO)C[C@@H]2O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N[C@@H]1[C@H](F)[C@H](O)[C@@H](CO)C[C@@H]1O
Yield: 78.9 %

Procedure:
A mixture of (3aS,4S,5R,6R,7aS)-4-fluoro-5-hydroxy-6-(hydroxymethyl)hexahydrobenzo[d]oxazol-2(3H)-one (704 mg, 3.43 mmol) and LiOH (2.71 g, 113 mmol) in water (35 mL) and MeOH (26 mL) was stirred at reflux for 2 h. The solvents were evaporated to give the crude product. This was purified by SiO2 column, eluted with 20%-30% 2 M NH3 MeOH solution in DCM give (1S,2S,3S,4R,5R)-2-amino-3-fluoro-5-(hydroxymethyl)cyclohexane-1,4-diol (485 mg, 80%) as a white solid. 1H NMR (400 MHz, MeOD) δ 4.74 (d, J=52.0 Hz, 1H), 3.96-3.99 (m, 1H), 3.65-3.73 (m, 2H), 3.49 (ddd, J=28.0 Hz, 10.5 Hz, 1.6 Hz, 1H), 3.05 (d, J=31.0 Hz, 1H), 2.09-2.19 (m, 1H), 1.96 (dt, J=14.5 Hz, 3.7 Hz, 1H), 1.46-1.53 (m, 1H).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH:8]([C:10]1[C:11](=[O:22])[N:12]([CH3:21])[C:13]2[C:18]([N:19]=1)=[CH:17][C:16]([Cl:20])=[CH:15][CH:14]=2)[NH2:9].C(N(CC)CC)C>O1CCOCC1>[CH3:21][N:12]1[C:13]2[C:18](=[CH:17][C:16]([Cl:20])=[CH:15][CH:14]=2)[N:19]=[C:10]([NH:8][NH:9][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[C:11]1=[O:22]
Reactant: Cn1c(=O)c(NN)nc2cc(Cl)ccc21
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCC(=O)NNc1nc2cc(Cl)ccc2n(C)c1=O

Procedure:
Pentanoyl chloride (52.6 mmol) is added dropwise to a solution of 3-hydrazino-1-methyl-6-chloro-1H-quinoxalin-2-one (43.8 mmol) and triethylamine (52.6 mmol) in 500 ml. of dioxane and stirred at room temperature for 2 hours. The dioxane is removed under vacuum and the residue washed with water and ether, filtered and dried under high vacuum at 65° for 3 hours to give crude product.