Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.Br[C:36]1[CH:37]=[C:38]([CH:42]([N:46]([C:48](OC(C)(C)C)=O)[CH3:47])[C:43]([OH:45])=[O:44])[CH:39]=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C.C1COCC1>[CH3:48][N:46]([CH:42]([C:38]1[CH:39]=[CH:40][CH:41]=[C:36]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:12]3=[N:13][CH:14]=2)[CH:37]=1)[C:43]([OH:45])=[O:44])[CH3:47]
Reactant: CN(C(=O)OC(C)(C)C)C(C(=O)O)c1cccc(Br)c1
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: Cl
Solvent: CC#N
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(C(=O)O)N(C)C)c3)cc12

Procedure:
To a mixture of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (0.545 g, 1.1 mmol) and (3-bromo-phenyl)-(tert-butoxycarbonyl-methyl-amino)-acetic acid (0.29 g, 1.1 mmol) in a 20 mL microwave reaction flask was added THF (3 mL), acetonitrile (3 mL), and sodium carbonate (1 N in water, 3 mL, 6 mmol). The resulting suspension was purged with nitrogen for 1 minute. Dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct (39 mg, 48 μmol) was added and the purging was continued for another minute. The flask was sealed and was irradiated in a microwave reactor to 90° C. for 10 minutes. The reaction mixture was adjusted to pH 4 using 1 N hydrochloric acid, extracted with ethyl acetate (10 mL×3). The combine organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel using a gradient of methanol in dichloromethane to afford dimethylamino-{3-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-acetic acid as a off white solid (280 mg, 48%). MS: m/z 533 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[C:10]1[C:11]([CH3:22])=[CH:12][C:13]([C:16]([NH:18][CH2:19][CH2:20][OH:21])=[O:17])=[N:14][CH:15]=1.ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:23]([C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)=[O:39])[C:10]1[C:11]([CH3:22])=[CH:12][C:13]([C:16]([NH:18][CH2:19][CH2:20][OH:21])=[O:17])=[N:14][CH:15]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C(=O)NCCO)ncc1C(Sc1ccc(F)cc1)c1cc(F)ccc1F
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCO)ncc1C(c1cc(F)ccc1F)S(=O)c1ccc(F)cc1
Reaction time: 3 h
Yield: 47.7 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)thio]methyl]-N-(2-hydroxyethyl)-4-methylpyridine-2-carboxamide (478 mg, 1.11 mmol) in methylene chloride (15 ml), 3-chloroperbenzoic acid (293 mg, 1.11 mmol) was added at 0° C. After stirring for 3 hours at the same temperature, the reaction mixture was washed with 1 N aqueous sodium hydroxide, the organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=1:2 was concentrated under reduced pressure. The resulting residue was washed with hexane, and then the residue was dried under reduced pressure, to obtain the title compound (238 mg, 0.53 mmol, 48%) as a colorless foamy substance.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[O:19][C:20]1[C:21]([F:42])=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]([O:31]C1C=CC([N+]([O-])=O)=CC=1)=O)[C:24]([CH3:41])=[CH:23]2>CN(C)C=O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17][CH3:18])[N:13]=[CH:12][N:11]=[C:10]2[O:19][C:20]1[C:21]([F:42])=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25]([C:29]([NH:4][CH2:1][CH2:2][CH3:3])=[O:31])[C:24]([CH3:41])=[CH:23]2
Reactant: CCCN
Reactant: COc1cc2ncnc(Oc3ccc4c(cc(C)n4C(=O)Oc4ccc([N+](=O)[O-])cc4)c3F)c2cc1OC
Solvent: CN(C)C=O
Product: CCCNC(=O)n1c(C)cc2c(F)c(Oc3ncnc4cc(OC)c(OC)cc34)ccc21
Reaction time: 0.67 h
Yield: 7 %

Procedure:
n-Propylamine (210 μL, 2.55 mmol) was added to a solution of Compound 12 in dry N,N-dimethylformamide and the reaction stirred for 40 minutes. The solvent was removed by rotary evaporator and the crude residue suspended in saturated aqueous NaHCO3. Precipitate was filtered and washed with additional NaHCO3 (20 mL×2) and diethyl ether (20 mL). Solids were dissolved in a minimal amount of methylene chloride and precipitated from diethyl ether. Precipitate was filtered and purified by reverse phase HPLC to give 27 mg of Compound 13 (two-step yield=7%) as a tan solid. m/z 439.2 (M+H, 100%) (positive ionization mode). 1H-NMR (CDCl3, 400 MHz): δ 1.06 (3H, t); 1.74 (2H, m); 2.60 (3H, s); 4.08 (6H, d); 5.69 (1H, t); 6.47 (1H, s); 7.12 (1H, dd); 7.35 (1H, s); 7.48 (1H, d); 7.63 (1H, s); 8.61 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[C:15]([CH:20]=[CH:21][N:22]=2)[C:16]([O:18][CH3:19])=[O:17])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].[ClH:23]>CO.[Pt](=O)=O>[ClH:23].[F:12][C:6]1[CH:5]=[C:4]([CH:13]2[CH2:14][CH:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:20][CH2:21][NH:22]2)[CH:3]=[C:2]([F:1])[C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: COC(=O)c1ccnc(-c2cc(F)c(C(F)(F)F)c(F)c2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)C1CCNC(c2cc(F)c(C(F)(F)F)c(F)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.4 %

Procedure:
Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)isonicotinate (3.147 g, 9.92 mmol) was dissolved in MeOH (20 mL) and hydrogen chloride (1.25 M in MeOH, 23.81 mL, 29.76 mmol) was added. The reaction was stirred at room temperature for 2 h and evaporated. Methanol (20 mL) and platinum(IV) oxide (0.113 g, 0.50 mmol) was added and the solution hydrogenated in a Büchi hydrogenator at 5 bar and room temperature for 4.5 h. Platinum(IV) oxide (0.113 g, 0.50 mmol) was added and hydrogenation continued for 4 h. The catalyst was filtered off and washed with MeOH. The filtrate was evaporated in vacuo to yield methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)piperidine-4-carboxylate hydrochloride (3.12 g, 87%) as a white solid. MS m/z 324 (M+H)+
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=3[N+:19]([O-:27])=[N:18][C:17]2=[O:28])[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.NC1CCN(CCN2C3C(=CC(C#N)=CC=3)N=CC2=O)CC1>>[NH2:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][N:16]2[C:21]3[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=3[N+:19]([O-:27])=[N:18][C:17]2=[O:28])[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1
Agent: N#Cc1ccc2c(c1)ncc(=O)n2CCN1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(CCn2c(=O)n[n+]([O-])c3ccc(Cl)cc32)CC1

Procedure:
tert-Butyl{1-[2-(6-chloro-1-oxido-3-oxo-1,2,4-benzotriazin-4(3H)-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 206, 0.65 g) was deprotected with TFA as described for Intermediate 197 to give the crude free base of the product, 0.517 g.
Reaction SMILES: CC([NH:4][C:5]1[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][N:6]=1)=O.[OH-].[K+]>Cl>[NH2:4][C:5]1[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[N:7][N:6]=1
Reactant: CC(=O)Nc1nnc(S(N)(=O)=O)s1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Nc1nnc(S(N)(=O)=O)s1
Temperature: 100 °C
Yield: 72.9 %

Procedure:
Acetazolamide (2.03 g, 9.13 mmol) was combined with 1N HCl (20 mL) and then heated at 100° C. The initial suspension became a clear solution within 3 h. After cooling to 0° C. the reaction mixture was carefully neutralized by the addition of solid KOH. Upon standing precipitates had formed and were collected by filtration. The solids were dried under high vacuum to afford 5-amino-[1,3,4]thiadiazole-2-sulfonic acid amide (1.2 g, 70%) as a colorless solid; 1H NMR (DMSO-d6): δ 8.06 (s, 2H), 7.82 (s, 2H). Acetazolamide (2.03 g, 9.13 mmol) was combined with 1N HCl (20 mL) and then heated at 100° C. The initial suspension became a clear solution within 3 h. After cooling to 0° C. A. The title compound was prepared from 5-amino-[1,3,4]thiadiazole-2-sulfonic acid amide in a manner similar to that described in Example 1D; 1H NMR (DMSO-d6): δ 8.09 (s, 2H), 7.82 (d, J=8 Hz, 1H), 7.73 (t, J=8 Hz, 1H), 7.63 (t, J=8 Hz, 1H), 7.32 (d, J=8 Hz, 1H), 6.74 (s, 1H), 1.98 (s, 3H), 1.67 (s, 3H); MS (ESI) m/z 446 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:25]2[N:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[O:11])=[C:13]([N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)[CH:14]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1
Reactant: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-n2nccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-n2nccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 464.4 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 8.80-6.65 (m, 8H), 4.95-2.70 (m, 5H), 1.95-0.65 (m, 8H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22](Cl)=[N:21][CH:20]=[CH:19][N:18]=2)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:25][NH2:26]>CCO>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:17]3[C:22](=[N:21][CH:20]=[CH:19][N:18]=3)[NH:26][N:25]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1nccnc1Cl
Solvent: CCO
Solvent: O
Product: c1ccc(COc2ccc(-c3n[nH]c4nccnc34)cc2)cc1

Procedure:
To a solution of [4-(benzyloxy)phenyl](3-chloropyrazin-2-yl)methanone (1.23 g) in EtOH (20 mL) was added hydrazine hydrate (0.37 mL) at room temperature, and the mixture was refluxed for 2 h. The mixture was concentrated under reduced pressure. The residue was partitioned between AcOEt/THF (1/1) and saturated NaHCO3 aqueous solution. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residual crystals were recrystallized from THF/AcOEt to give the title compound (0.60 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>O>[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:6]2[CH:5]=[CH:4][C:3]([N+:8]([O-:10])=[O:9])=[CH:2][CH:7]=2)[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN1CCCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Yield: 94.5 %

Procedure:
Fluoronitrobenzene (10.3 g, 0.073 mol) is dissolved in water and then potassium carbonate (12.1 g, 0.0876 mol) is added. 1-Methyl[1,4]diazepane (10 g, 0.0876 mol) is introduced and then the reaction medium is heated under reflux (≅100° C.) for 5 hours. The medium is cooled. A precipitate forms, which is filtered and washed with water. A yellow solid is recovered, which is dried at 45° C. in a vacuum oven (16.21 g, yield=94.5%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:20]([C:24]1[CH:25]=[C:26]([CH2:35][CH2:36][C:37](O)=[O:38])[CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])([CH3:23])([CH3:22])[CH3:21].P(Cl)(Cl)Cl>N1C=CC=CC=1>[C:31]([C:28]1[CH:27]=[C:26]([CH2:35][CH2:36][C:37]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]3[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=3)[CH2:2][CH2:3]2)=[O:38])[CH:25]=[C:24]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:29]=1[OH:30])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Reactant: CCOC(=O)c1ccc(CCN2CCNCC2)cc1
Solvent: c1ccncc1
Solvent: ClP(Cl)Cl
Product: CCOC(=O)c1ccc(CCN2CCN(C(=O)CCc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)CC2)cc1
Yield: 62 %

Procedure:
This is prepared analogously to Example 12 from ethyl 4-[2-(piperazin-1-yl)-ethyl]-benzoate, 3-(3,5-di-tert.-butyl-4-hydroxyphenyl)-propionic acid, phosphorus trichloride and pyridine. Yield 62% of theory; m.p. 105°-107° C. (recrystallised from ethyl acetate/ligroin).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:27]=[C:28]([O:32][CH3:33])[CH:29]=[CH:30][CH:31]=1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: COc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4cccnc4F)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12i and 3-bromoanisole
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[Si:19]([N:26]1[CH:29]([C:30]([CH3:34])([CH3:33])[CH:31]=[CH2:32])[CH2:28][C:27]1=[O:35])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].[C:36](N1C=CN=C1)(=[O:38])[CH3:37]>O1CCCC1>[Si:19]([N:26]1[CH:29]([C:30]([CH3:34])([CH3:33])[CH:31]=[CH2:32])[CH:28]([C:36](=[O:38])[CH3:37])[C:27]1=[O:35])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: C=CC(C)(C)C1CC(=O)N1[Si](C)(C)C(C)(C)C
Reactant: CC(=O)n1ccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C=CC(C)(C)C1C(C(C)=O)C(=O)N1[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium in hexane (4.10 mmol) is added by syringe to a solution of diisopropylamine (4.10 mmol) in anhydrous tetrahydrofuran (16 ml) at -78° C. The resulting solution is stirred at -78° C. for 15 min. prior to the addition of a solution of 1-(t-butyldimethylsilyl)-4-(1,1-dimethyl-prop-2-enyl)-azetidin-2-one 3 (2.0 mmol) in anhydrous tetrahydro uran (2 ml). After an additional 15 min. at -78° C., the reaction mixture is added via a Teflon tube to a mixture of N-acetylimidazole (4.1 mmol) in anhydrous tetrahydrofuran (16 ml) at -78° C. The resulting yellow reaction mixture is stirred at -78° C. for 15 min., then quenched by addition of saturated aqueous ammonium chloride solution (10 ml). The reaction mixutre is diluted with ether (100 ml) and washed with 2.5N hydrochloric acid solution (25 ml) water (25 ml) and brine. The organic phase is dried over magnesium sulfate and concentrated in vacuo to yield crude products. This material is chromatographed on silica gel (2:1 petroleum ether:ether) to yield 4.
Reaction SMILES: C([O-])(=O)C.[NH4+].[N+:6]([C:9]1[C:24]([C:25](=[O:27])[CH3:26])=[CH:23][C:12]2[O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:11]=2[CH:10]=1)([O-])=O.C1(C)C=CC=CC=1>[Fe].O>[NH2:6][C:9]1[C:24]([C:25](=[O:27])[CH3:26])=[CH:23][C:12]2[O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][C:11]=2[CH:10]=1
Reactant: CC(=O)c1cc2c(cc1[N+](=O)[O-])OCCOCCOCCO2
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cc2c(cc1N)OCCOCCOCCO2

Procedure:
A Mixture of iron powder (477 mmol, 27 g), ammonium acetate (500 mmol, 31 g), 1-(3-Nitro-6,7,9,10,12,13-hexahydro-5,8,11,14-tetraoxa-benzocyclododecen-2-yl)-ethanone (120 mmol, 36 g), toluene (500 ml) and water (500 ml) was refluxed overnight, or until completion. The mixture was filtered through celite and washed with EtOAc. The organic layer was washed with water and Sat. NaCl, dried over Na2SO4, and concentrated to afford the product, 90%. 1HNMR (400 MHz, DMSO) δ 7.82 (s, 1H), 7.61 (s, 1H), 5.45 (s, 2H), 4.35 (s, 4H), 3.87 (d, 4H), 3.62 (s, 4H), 2.71 (s, 3H). LC/MS Calcd for (M+H)+282.3. found 282.5.
Reaction SMILES: [CH3:1][C:2]1[N:7]([CH2:8][C:9]([F:12])([F:11])[F:10])[C:6](=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=1[F:22]>CO.[Pt](=O)=O>[CH3:1][CH:2]1[N:7]([CH2:8][C:9]([F:12])([F:10])[F:11])[C:6](=[O:13])[CH2:5][CH2:4][CH:3]1[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[C:15]=1[F:22]
Reactant: Cc1c(-c2cc(F)cc(F)c2F)ccc(=O)n1CC(F)(F)F
Agent: O=[Pt]=O
Solvent: CO
Product: CC1C(c2cc(F)cc(F)c2F)CCC(=O)N1CC(F)(F)F
Reaction time: 2 h

Procedure:
A mixture of 6-methyl-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)pyridin-2(1H)-one (3.73 g, 11.6 mmol) and platinum(IV) oxide (659 mg, 2.90 mmol) in MeOH (200 mL) was shaken on a Parr hydrogenation apparatus under an atmosphere of hydrogen (ca. 45 psi) for 2 h. The reaction mixture was filtered through a pad of Celite®, washing with MeOH, and the filtrate was concentrated in vacuo to give a crude solid. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:Et2O—100:0 to 0:100, to give the title compound. MS: m/z=326.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([C:32]([O:34]CC)=[O:33])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4]1[CH:14]=[C:13]([CH2:15][C:16]([NH:18][CH:19]([C:32]([OH:34])=[O:33])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:17])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOC(=O)c1ccc(CC(=O)NC(C(=O)OCC)c2ccccc2N2CCCCC2)cc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc(CC(=O)NC(C(=O)O)c2ccccc2N2CCCCC2)ccc1C(=O)O

Procedure:
Ethyl 2-ethoxy-4-[N-(α-ethoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl]-benzoate (0.45 g, 0.9 mmol) in ethanol (5 ml) is stirred together with 1N sodium hydroxide solution (2.7 ml) for 2 hours at 50° C. Then 1N hydrochloric acid (2.7 ml) is added and the mixture is concentrated by evaporation in vacuo. The evaporation residue is partitioned between water and chloroform. The combined chloroform extracts are shaken once with water, then the organic phase is dried, filtered and evaporated down in vacuo. The evaporation residue is crystallized with ether.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH3:13]>>[Cl:1][C:2]1[N:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)c1ccc(Cl)nc1Cl
Reactant: N
Product: Nc1ccc(C(F)(F)F)c(Cl)n1
Temperature: 93 °C
Yield: 46 %

Procedure:
2,6-Dichloro-3-(trifluoromethyl)pyridine (5.00 g, 23.2 mmol) and 28% aqueous ammonia (150 mL) were placed in a 250 mL autoclave. The mixture was heated at 93° C. for 21 h. The reaction was cooled to rt and extracted with EtOAc (100 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give the crude product, which was purified by column chromatography on silica gel (2-20% EtOAc in petroleum ether as eluant) to give 6-chloro-5-(trifluoromethyl)pyridin-2-amine (2.1 g, 46% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.69 (d, J=8.4 Hz, 1H), 7.13 (br s, 2H), 6.43 (d, J=8.4 Hz, 1H). MS (ESI) m/z (M+H)+ 197.2
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([S:21]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=O)(=[O:23])=[O:22])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1>O1CCOCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[C:16]([S:21]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]2[O:28][CH:29]=[N:2][N:3]=2)(=[O:23])=[O:22])[CH:15]=[CH:14]3)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ccccc1-c1nnco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.1 %

Procedure:
Hydrazine hydrate (2.25 mL, 46 mmol) was added to a solution of methyl 2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}benzoate (Example 38, 0.42 g, 1.0 mmol) in 1,4-dioxane (1 mL), stirred for 1 hour at room temperature then heated at 90° C. overnight. Solvent was removed in vacuo and the residue azeotroped using toluene. Triethyl orthoformate (10 mL) and a catalytic quantity of (±)-10-camphorsulfonic acid were added to the resultant crude hydrazide then stirred and heated at 90° C. overnight. Solvent was removed in vacuo, water (100 mL) added and extracted with ethyl acetate (2×75 mL). Extracts were washed with water and saturated brine then dried (MgSO4), filtered and evaporated to a yellow residue. Purification by flash column chromatography eluting with a 20-60% ethyl acetate/isohexane gradient gave 2-(2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}phenyl)-1,3,4-oxadiazole (0.22 g, 51%). 1H NMR (500 MHz, d6-DMSO) δ 9.46 (1H, s), 8.59 (1H, s), 8.40 (1H, dd, J=1.0, 8.0 Hz), 8.37 (1H, s), 8.30 (1H, d, J=8.7 Hz), 8.20 (1H, d, J=8.8 Hz), 8.05 (1H, dd, J=1.7, 8.6 Hz), 8.00-7.96 (1H, m), 7.93-7.91 (3H, m), 7.87-7.85 (2H, m), 7.42-7.33 (2H, m); m/z (ES+) 431 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:35][CH2:34][CH2:33][C@H:9]3[S:10](=[O:32])(=[O:31])[C:11]([CH3:30])([CH3:29])[C:12]([N:14](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:13][C@:8]3([CH2:36][F:37])[C:6]=2[CH:7]=1.[Cl:38][C:39]1[CH:40]=[N:41][C:42]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[N:44][C:43]=2Cl.C(O)(C)C.OS(O)(=O)=O>[OH-].[Na+].C(Cl)Cl.CO>[NH2:14][C:12]1[C:11]([CH3:29])([CH3:30])[S:10](=[O:31])(=[O:32])[C@@H:9]2[CH2:33][CH2:34][O:35][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:43]4[N:44]=[CH:45][CH:46]=[C:47]5[C:42]=4[N:41]=[CH:40][C:39]([Cl:38])=[CH:48]5)=[CH:7][C:6]=3[C@@:8]2([CH2:36][F:37])[N:13]=1
Reactant: Clc1cnc2c(Cl)nccc2c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(CF)c3cc(N)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CO
Product: CC1(C)C(N)=N[C@]2(CF)c3cc(Nc4nccc5cc(Cl)cnc45)ccc3OCC[C@H]2S1(=O)=O
Temperature: 90 °C
Yield: 81.6 %

Procedure:
To a 15-mL reaction vial was added tert-butyl N-[(4aR,11bS)-10-amino-11b-(fluoromethyl)-3,3-dimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (103 mg, 0.190 mmol), 3,8-dichloro-1,7-naphthyridine (41.6 mg, 0.209 mmol), isopropanol (3 mL) and a couple of β-drops of H2SO4. The vial was closed and heated at 90° C. for 1 h. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with 1N NaOH (5 mL) and extracted with DCM (8 mL×3). The organic extracts were dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 2% 2M NH3.MeOH in DCM, to provide (4aR,11bS)-2-amino-10-((3-chloro-1,7-naphthyridin-8-yl)amino)-11b-(fluoromethyl)-3,3-dimethyl-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazine 4,4-dioxide (78 mg, 0.155 mmol, 81% yield) as yellow solid. MS m/z=503.9 (M+H).