Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([S:4][CH:5]1[N:8]([CH:9](Cl)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2].N1C(C)=CC=CC=1C.[C:33]1([P:39]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCOCC1>[C:1]([S:4][CH:5]1[N:8]([C:9](=[P:39]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Product: CC(=O)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 50 %

Procedure:
To a solution of crude p-nitrobenzyl 2-(4-acetylthio-2-oxo-1-azetidinyl)-2-chloroacetate (92.9 g., 0.249 mole) in dioxane (1200 ml.) were added in succession 2,6-lutidine (31 ml., 0.274 mole) and triphenylphosphine (71.7 g., 0.274 mole). The resulting mixture was stirred at 45°-47° for 18 hours, cooled to 23° and filtered. The filtrate was concentrated on a rotary evaporator to leave a yellow oil which was purified as follows: absorption on a column of silica gel1 and elution with petroleum ether (4000 ml.), methylene chloride (4000 ml.) and ethyl acetate (4000 ml.). The petroleum-ether fraction was discarded since it contained only impurities. The ethyl acetate fraction was concentrated on a rotary evaporator and the oily residue was triturated with diethyl ether to give the title product as a white solid (74.5 g.), m.p. 162°-165°. The methylene chloride eluate was concentrated to dryness and the oily residue again purified by chromatography as above to give 15.0 g. of title product. The combined solids were dissolved in methylene chloride, treated with activated charcoal, concentrated and recrystallized in diethyl ether to give a total of 87 g. (58%) of title product.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[OH:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([I:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][CH:5]([N:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:23])[CH2:24][NH:25][C:26](=[O:37])[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=3)[CH2:17]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Reactant: O=C1CCC(O)(c2ccc(I)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(O)(c3ccc(I)cc3)CC2)C1
Reaction time: 1 h
Yield: 36.3 %

Procedure:
To a solution of 4-hydroxy-4-(4-iodophenyl)cyclohexanone (624 mg, 2 mmol) in CH2Cl2 (10 mL) was added N-((3R)-pyrrolidin-3-ylcarbamoylmethyl)-3-trifluoromethylbenzamide (730 mg, 2 mmol) and then NaBH(OAc)3 (666 mg, 3 mmol). After stirred for 1 h, the reaction was quenched with 10% NaHCO3, and extracted with EtOAc. The organic extracts were combined, washed with saline solution, dried over sodium sulfate, concentrated in vacuo. The residue was chromatographed on silica gel, eluting with 1% NH4OH in ethyl acetate/methanol (100/0 to 10/90) to yield the major isomer (544 mg, 44.2%) and the minor isomer (446 mg, 36.3% yield). For the major isomer, LCMS: 615.2 (M+H+, 100%); 1H NMR: (CDCl3) δ 8.09, (s, 1H); 7.98, (d, 1H); 7.77, (d, 1H); 7.67, (d, 2H); 7.57, (t, 1H); 7.28, (d, 2H); 7.22, (t, 1H, NH); 6.44, (d, 1H, NH); 4.49, (m, 1H); 4.12, (m, 2H); 2.87, (m, 1H); 2.64, (m, 2H); 2.38, (m, 1H); 2.25, (m, 4H); 1.93, (m, 2H); 1.54-1.70, (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23][NH:24][S:25]([CH:28]=[CH2:29])(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:30][O-:31].[Na+].CO>CO.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23][NH:24][S:25]([CH2:28][CH2:29][O:31][CH3:30])(=[O:26])=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=CS(=O)(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCS(=O)(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-{[(ethenylsulfonyl)amino]methyl}-1,4-oxazepane-4-carboxylate (200 mg) in methanol (1 mL) was added 28% sodium methoxide-methanol (4 mL) solution at room temperature, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (132 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH:3]1[CH3:16].[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C1COCC1>[Cl:17][C:18]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:19]=1[C:20]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH:3]1[CH3:16])=[O:21]
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1Cl
Reactant: CC1CC(CNc2ccccc2)CCC1N
Solvent: C1CCOC1
Product: CC1CC(CNc2ccccc2)CCC1NC(=O)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4-Amino-3-methyl-cyclohexylmethyl)-phenyl-amine (113 mg, 0.52 mmol) in dry THF (5 mL) and TEA (105 mg, 1.04 mmol) is treated with 2-chloro-5-(trifluoromethyl)benzoyl chloride (139 mg, 0.57 mmol). After stirring at RT for 2 hours, the solvent is removed in vacuo and the residue is partitioned between water and DCM. The mixture is passed through a phase separator and the organic portion is concentrated in vacuo. Purification of the crude residue by chromatography on silica eluting with iso-hexane:EtOAc (9:1 increasing to 2:1) affords the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.47 (1H, d), 7.82 (1H, d), 7.73 (2H, m), 7.07 (2H, t), 6.56 (2H, d), 6.49 (1H, t), 5.55 (1H, m), 3.93 (1H, m), 2.86 (2H, m), 2.23 (1H, m), 1.88 (1H, m), 1.78 (1H, m), 1.70 (1H, m), 1.59 (2H, m), 1.31 (1H, m), 1.11 (1H, m), 0.92 (3H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][N:7]=[C:6]2[CH3:14].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[C:6]([CH3:14])=[N:7][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc2c(=O)[nH]nc(C)c2c1
Product: COc1ccc2c(Cl)nnc(C)c2c1
Temperature: 120 °C
Yield: 100 %

Procedure:
A solution of 6-methoxy-4-methyl-2H-phthalazin-1-one (6) (2.0 g, 10.5 mmol) in POCl3 (20 mL) is heated at reflux (120° C.) for 4 h and then cooled to room temperature. Unreacted POCl3 is removed at reduced pressure, followed by azeotroping with toluene (2×10 mL). The residue is diluted with sat. NaHCO3 (75 mL) and extracted with dichloromethane (150 mL, 2×60 mL, and 50 mL). The extract is washed (brine) and dried. After solvent removal at reduced pressure, the residue is dried under high vacuum to give 2.2 g (100%) of 7 as a yellow solid, mp 123-126° C. IR 2991, 1611, 1403, 1290, 1234 cm−1; 1H NMR (CDCl3) δ 2.95 (s, 3H, CH3), 4.05 (s, 3H, CH3O), 7.25 (d, J=1.2 Hz, 1H, 5-PhthH), 7.55 (dd, J=6.0, 1.2 Hz, 1H, 7-PhthH), 8.21 ppm (d, J=6.0 Hz, 1H, 8-PhthH).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[OH:14].[NH4+].OO>C(#N)C.O>[O:14]1[CH2:1][CH:2]1[C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: C=Cc1ccc(S(N)(=O)=O)cc1
Reactant: O=C([O-])O
Agent: OO
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(C2CO2)cc1
Reaction time: 0.25 h
Yield: 26100.9 %

Procedure:
To a suspension of 4-sulfonamidostyrene (1.83 g, 0.01 mmol) and ammonium hydrogencarbonate (1.6 g, 0.02 mol) in acetonitrile/water (60 mL/30 mL) was added hydrogen peroxide (30% solution, 10 mL, 0.09). The mixture was kept in dark without stirring for 72 hours during which two portion of hydrogen peroxide (5 mL each) were introduced slowly. While HPLC showed all of the starting 4-sulfonamidostyrene was consumed, sodium thiosulfate solution (10%, 60 mL) was added slowly and stirred for 15 minutes. The mixture was extracted with dichloromethane (3×80 mL). The organic phases were combined, washed with brine and dried over magnesium sulfate. The solution was concentrated to give the crude title compound (0.52 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[OH:22][N:23]=[C:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.FC(F)(F)C([O-])=O.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:27]2[CH2:28][CH2:29][C:24](=[N:23][OH:22])[CH2:25][CH2:26]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: ON=C1CCNCC1
Agent: O=C([O-])C(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1c(F)c(N2CCC(=NO)CC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 80 °C
Reaction time: 6 h
Yield: 38.2 %

Procedure:
298 mg (1 mmol) of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was dissolved in 5 ml of dimethyl sulfoxide, and 570 mg (2.5 mmol) of 4-hydroxyiminopiperidine-trifluoroacetate and 404 mg (4 mmol) of triethylamine were added thereto. The mixture was stirred at 80° C. for 6 hours. After cooling, the precipitate thereby formed was collected by filtration and washed with water, isopropanol and diethyl ether to give 150 mg of the desired product as yellow powder.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][N:7]=1.I[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][OH:15])=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>[Cu].CCOC(C)=O>[OH:15][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]2=[O:8])=[CH:11][CH:12]=1
Reactant: Cc1nccnc1O
Reactant: OCc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1nccn(-c2ccc(CO)cc2)c1=O

Procedure:
3-Methyl-2-hydroxypyrazine (1.10 g, 10.0 mmol), 4-Iodobenzyl alcohol from Example 1, Step 1 (4.0 g, 17.0 mmol), K2CO3 (1.52 g, 110 mmol), and copper (15 mg , 0.2 mmol) were heated under argon for 40 hours. The dark residue was partitioned between CHCl3 and saturated NaHCO3. The aqueous layer was back extracted twice with CHCl13. The organic layers were combined, washed with brine, dried (MgSO4,), filtered and concentrated to give a light brown solid. Flash chromatography (EtOAc) yielded the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:19])[C:6]=2[CH:20]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[C:21]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[CH2:8][N:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N+:14]=3[O-:19])[C:6]=2[CH:20]=1)(=[O:23])[CH3:22]
Reactant: CC1(C)CN(c2cccc[n+]2[O-])c2cc(N)ccc2O1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc2c(c1)N(c1cccc[n+]1[O-])CC(C)(C)O2
Temperature: 25 °C
Reaction time: 63 h

Procedure:
To a solution of 0.474 g of 2-(6-amino-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-4-yl)pyridine N-oxide in 5 ml of acetic anhydride was added 3 drops of pyridine and the mixture was stirred at room temperature for 63 hours. After concentration, the residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution, dried and concentrated. The residue was recrystallized from chloroform-ether to give 0.285 g of 2-(6-acetamido-3,4-dihydro-2,2-dimethyl-2H-1,4-benzoxazin-4-yl)pyridine N-oxide.
Reaction SMILES: Cl.[NH2:2][NH2:3].CCN(C(C)C)C(C)C.[CH2:13]([O:15][C:16](=[O:28])/[C:17](=[CH:24]/OCC)/[C:18](=O)[C:19]([F:22])([F:21])[F:20])[CH3:14]>CCO>[CH2:13]([O:15][C:16]([C:17]1[CH:24]=[N:2][NH:3][C:18]=1[C:19]([F:22])([F:21])[F:20])=[O:28])[CH3:14]
Reactant: NN
Reactant: CCO/C=C(/C(=O)OCC)C(=O)C(F)(F)F
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn[nH]c1C(F)(F)F
Reaction time: 0.17 h
Yield: 43 %

Procedure:
To a suspension of hydrazine hydrochloride (10 g, 147 mmol) in EtOH (500 mL), DIPEA (45.3 mL, 267 mmol) was added slowly at −20° C. and stirred for 10 mins. Then 2-[1-Ethoxy-meth-(E)-ylidene]-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (Preparation 135, 32 g, 133.33 mmol) was added to above solution and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and residue was partitioned between EtOAc (200 mL) and water (50 mL). The organic layer was washed with water (25 mL), dried (Na2SO4) and evaporated in vacuo. The crude material was purified by column chromatography on silica gel (Hexane:EtOAc 90:10) to afford the title compound as off white solid in 43% yield, 13 g.
Reaction SMILES: [ClH:1].Cl.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[CH:6][CH:5]=1.[N:12]12[CH2:20][CH2:19][CH:16]([CH2:17][CH2:18]1)[C:15](=O)[CH2:14][CH2:13]2>C(O)(=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:15]3[CH:16]4[CH2:19][CH2:20][N:12]([CH2:13][C:14]=3[C:6]=2[CH:5]=1)[CH2:18][CH2:17]4.[ClH:1]
Reactant: NNc1ccc(Br)cc1
Reactant: O=C1CCN2CCC1CC2
Agent: Cl
Solvent: CC(=O)O
Product: Brc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of HCl in acetic acid (1 M, 30 mL) was added under nitrogen to a mixture of 4-bromophenylhydrazine hydrochloride (4.33 g, 19.37 mmol; Aldrich) and 1-azabicyclo[3.2.2]nonan-4-one (2.70 g, 19.37 mmol; Example 2A). The mixture was stirred at room temperature for 16 hours, then heated at 75° C. for 3 hours. The mixture was cooled to room temperature and concentrated under vacuum to remove most of the acetic acid. Anhydrous ethanol (100 mL) was added to the residue, and the mixture was heated at reflux for 10 minutes, then cooled to room temperature. The precipitate was collected by filtration, washed with ethanol (25 mL) and dried under vacuum to provide the title compound as its HCl salt (3.02 g). A portion of this salt (400 mg) was partitioned between 20% NaOH (25 mL) and chloroform (50 mL) and the organic phase was dried (sodium sulfate) and concentrated. The residue was crystallized from ethyl acetate-ethanol (5:1) to provide the free base of title compound: 1H NMR (300 MHz, methanol-d4) δ 2.14-2.36 (m, 4H), 3.17-3.25 (m, 1H), 3.33-3.45 (m, 2H), 3.45-3.65 (m, 2H), 4.54 (s, 2H), 7.18 (dd, J=8.8, 1.8 Hz, 1H), 7.24 (d, J=9.1 Hz, 1H), 7.51 ppm (d, J=2.4 Hz, 1H); MS(DCI) m/z 291/293 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8](=[O:12])[C:7]2([CH3:14])[CH3:13].C([O-])(=O)C.[Na+].[Br:20]Br>C(Cl)Cl>[Br:20][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[N:9]([CH3:11])[C:8](=[O:12])[C:7]2([CH3:14])[CH3:13]
Reactant: BrBr
Reactant: CN1C(=O)C(C)(C)c2cccc(F)c21
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN1C(=O)C(C)(C)c2cc(Br)cc(F)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 82 %

Procedure:
7-Fluoro-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one (0.10 g, 0.52 mmol) was dissolved in 5 mL of CH2Cl2 and sodium acetate (47 mg, 0.56 mmol) was added followed by bromine (0.029 mL, 0.56 mmol). The mixture was stirred at 25° C. for 16 h then loaded directly onto a silica gel column. The column was eluted with 250 mL of CH2Cl2 and 250 mL 5% Acetone/CH2Cl2 to provide the title compound (116 mg) as a white solid (82%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CN(C=O)C>[F:15][C:12]1[CH:13]=[CH:14][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: Nc1ccccc1
Reactant: O=C(CBr)Nc1ccc(F)cc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1ccc(F)cc1C(=O)O
Temperature: 120 °C
Yield: 74.9 %

Procedure:
A solution of 2-(bromoacetamido)-5-fluorobenzoic acid from Example 19 (22.36 g, 91 mmol) and aniline (21 mL, 230 mmol) in dry DMF (150 mL) was heated at 85° C. for 5 hours. TLC showed indicated the presence of unreacted starting. Additional aniline (5 mL, 52 mmol) was added, and the solution was heated at 120° C. for 30 hours. After cooling, the reaction mixture was poured into ice-water (800 mL) and aqueous 5% KOH (100 mL) was added to adjust the pH to 10-11. The excess aniline was removed by extraction with CH2Cl2 (3×400 mL) and the aqueous layer was separated and acidified with aqueous 20% HBr. The resulting precipitate was collected, washed with water and dried, yielding 19.64 g (74.6%) of the title compound as white crystals, mp 194°-195° C.; 1H NMR (acetone-d6) δ 11.87 (s, 1H), 8.88 (dd, J=5.2, J=9.6, 1H), 7.71 (dd, J=3.2, J=9.2, 1H), 7.45-7.39 (m, 1H), 7.14-7.10 (m, 2H), 6.68-6.64 (m, 3H), 3.92 (s, 2H); 13C NMR (acetone-d6) δ 171.30, 168.14, 163.22, 157.97 (d, J=241.3), 148.97, 138.66, 129.82, 122.60 (d, J=7.1), 121.90 (d, J=21.9), 118.63, 117.78 (d, J=24.0), 113.67, 50.07; MS (EI, m/z) 288.1 (M+).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:13])[C:6](=[O:12])[O:7]2.[H-].[Na+].Cl[CH2:17][O:18][CH3:19]>CN(C)C=O>[CH3:13][C:5]1[C:6](=[O:12])[O:7][C:8]2[C:3]([CH:4]=1)=[C:2]([O:1][CH2:17][O:18][CH3:19])[CH:11]=[CH:10][CH:9]=2
Reactant: COCCl
Reactant: Cc1cc2c(O)cccc2oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccc2oc(=O)c(C)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
To a solution of 5-hydroxy-3-methyl-2H-chromen-2-one (Intermediate 112, 2.225 g) in dry N,N-Dimethylformamide (60 ml) cooled to 0° C. was added sodium hydride (60%, 0.532 g, 13.89 mmol) followed by the addition of chloro(methyloxy)methane (1.919 ml, 25.3 mmol). The reaction mixture was warmed to room temperature and stirred for 30 minutes under nitrogen. It was then quenched by the addition of a saturated solution of NH4Cl, the product was extracted with diethyl ether, washed with brine, dried over sodium sulphate, filtered and concentrated under vacuum. The residue obtained was purified by silica gel chromatography (Biotage system, with a gradient from pure cyclohexane to cyclohexane/ethyl acetate 5/1) to give the title compound as a white solid (2.15 g). 1H NMR (400 MHz, CDCl3): δ ppm 7.94 (1H, s), 7.38 (1H, t), 6.93-7.05 (2H, m), 5.33 (2H, s), 3.55 (3H, s), 2.26 (3H, s); UPLC_ipqc: 0.94 min, 221 [M+H]+.
Reaction SMILES: [C:1](=O)([O:33]C1C=CC([N+]([O-])=O)=CC=1)[O:2][CH:3]([CH3:32])[C:4](=[C:13]1[CH2:16][N:15]([CH:17]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1.[CH:44]([NH2:47])([CH3:46])[CH3:45]>C(Cl)Cl>[CH:44]([NH:47][C:1](=[O:33])[O:2][CH:3]([CH3:32])[C:4](=[C:13]1[CH2:14][N:15]([CH:17]([C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:16]1)[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[CH:6]=1)([CH3:46])[CH3:45]
Reactant: CC(C)N
Reactant: CC(OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Solvent: ClCCl
Product: CC(C)NC(=O)OC(C)C(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 45 mg (0.073 mmol) of 2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-2-(3,5-difluorophenyl)-1-methylethyl 4-nitrophenyl carbonate in 3 mL of methylene chloride was added 0.3 mL of isopropylamine and the reaction was stirred for 4 h at rt, followed by concentration and purification of the residue by silica gel chromatography with hexanes/ethyl acetate=4:1 to afford the title compound as white solid. Mass Spectrum: m/e=545 (M+1 35Cl, 35Cl) and 547 (M+1 35Cl, 37Cl).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][C:12]4[CH2:24][C:19]5(OCC[O:20]5)[CH2:18][CH2:17][CH2:16][C:13]=4[CH:14]=3)[CH:9]=[N:8]2)=[CH:3][CH:2]=1.O.CC1C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][C:12]4[CH2:24][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][C:13]=4[CH:14]=3)[CH:9]=[N:8]2)=[CH:3][CH:2]=1
Reactant: c1cc(-n2ncc3cc4c(cc32)CCCC2(C4)OCCO2)ccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCCc2cc3c(cnn3-c3ccncc3)cc2C1
Temperature: 60 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
1-(Pyridin-4-yl)-5,7,8,9-tetrahydro-1H-spiro[cyclohepta[f]indazole-6,2′-[1,3]dioxolane] (31.8 g, 99 mmol) and 4-methylbenzenesulfonic acid hydrate (23.8 g, 125 mmol) were added to a round bottom flask followed by the addition of acetone (250 mL). The mixture was heated to about 60° C. for about 2 h, then about 45° C. for about 16 h. The reaction mixture was cooled to rt, filtered and the resulting solids were collected. The solids were taken into EtOAc/MeOH and neutralized with sat. aq. NaHCO3. The mixture was extracted with EtOAc (3×100 mL) and any solids that would not dissolve were collected. The organics were dried over MgSO4 and concentrated in vacuo. The collected solids and extracted material were combined to provided 1-(pyridin-4-yl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (26.2 g, 95%); LC/MS, method 1, Rt=1.25 min MS m/z 278 (M+H)+, 1H NMR (400 MHz, DMSO) δ 8.73-8.68 (m, 2H), 8.43-8.41 (m, 1H), 8.03 (s, 1H), 7.95-7.90 (m, 2H), 7.73 (s, 1H), 3.19 (d, J=5.5 Hz, 2H), 3.17 (d, J=4.1 Hz, 2H), 2.54-2.48 (m, 2H), 2.00-1.87 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][S:8][C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=1[NH:11][C:12]([NH:14][O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[S:13]>C(Cl)Cl>[CH3:7][S:8][C:9]1[CH:25]=[CH:24][CH:23]=[CH:22][C:10]=1[N:11]1[C:2](=[O:3])[C:1](=[O:5])[N:14]([O:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]1=[S:13]
Reactant: CCOC(=O)CONC(=S)Nc1ccccc1SC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)CON1C(=O)C(=O)N(c2ccccc2SC)C1=S
Yield: 33.2 %

Procedure:
Oxalyl chloride (10.2 g; 0.08 mol) was added dropwise to the solution of ethyl 2-[({[2-(methylsulfanyl)anilino]carbothioyl}amino)oxy]acetate (12 g, 0.04 mol) in methylene chloride (100 mL). The mixture was heated at reflux for 1 hour then evaporated to dryness. The residue was treated with ethanol (100 mL) and the mixture was heated at reflux for 1 hour. The mixture was evaporated to dryness. The residue was chromatographed on silica gel (20%ethyl acetate in hexane). Ethyl 2-({3-[2-(methylsulfanyl)phenyl]-4,5-dioxo-2-thioxo-1-imidazolidinyl}oxy)acetate (4.7 g) was obtained as a solid, m.p. 112–114° C. Mass spectrum; (El, M.+) m/z 354. 1H-NMR (DMSO-d6; 300 MHz): δ 7.56–7.46 (m, 2H), 7.34 (m, 2H), 4.94 (q, 2H), 4.19 (q, 2H), 2.43 (s, 3H), and 1.23 ppm (t, 3H).
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>C(O)(C)(C)C>[C:8]([O:7][C:1](=[O:12])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: Nc1ccccn1
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)Nc1ccccn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.8 %

Procedure:
To a solution of tert-butyl alcohol (650 mL) and di-tert-butyl carbonate (24 g) was added 2-aminopyridine (9.4 g) slowly. This mixture was stirred for 24 hours at room temperature. This reaction solution was concentrated under a reduced pressure, and the residue was purified by silica gel chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (18 g).