Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][N:18]4C3CCCCO3)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:35][CH3:36]>Cl.CO>[Br:1][C:2]1[C:7]2[N:8]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:9]([CH:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[O:35][CH3:36]
Reactant: COc1ccc2nc([C@H](C)Nc3ncnc4c3ncn4C3CCCCO3)n(-c3ccccc3)c2c1Br
Agent: Cl
Solvent: CO
Product: COc1ccc2nc(C(C)Nc3ncnc4[nH]cnc34)n(-c3ccccc3)c2c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.2 %

Procedure:
[(S)-1-(7-Bromo-6-methoxy-1-phenyl-1H-benzoimidazol-2-yl)ethyl]-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-yl]amine (453 mg, 0.83 mmol) was dissolved in HCl in methanol (5 mL, 2.5M) and the reaction stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the resultant residue was subjected to preparative HPLC (C18 Phenomenex column, 10-90% MeCN in water 0.1% formic acid, 20 min gradient) to yield 272 as a white solid (70 mg, 18%). 1H NMR 400 MHz 6 (DMSO-d6): 8.08 (1H, br s), 8.02 (1H, s), 7.84 (1H, br s), 7.59 (1H, d, J=8.6 Hz), 7.55-7.26 (5H, m), 7.05 (1H, d, J=9.0 Hz), 5.15 (1H, br s), 3.79 (3H, s), 1.49 (3H, d, J=6.6 Hz). LCMS (Method K): RT=3.53 min, [M+H]+=464+466
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[C@H:8]([CH2:24][OH:25])[C@H:7]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH2:6]1)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.CS(C)=O>ClCCl.C(N(CC)CC)C>[C:1]([O:4][C@H:5]1[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH:21]([CH3:22])[CH3:23])=[O:19])[C@@H:8]([CH:24]=[O:25])[C@H:7]([O:26][CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][O:28]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1C[C@@H](OC2CCCCO2)[C@@H](CO)C1CCCCCCCCC(=O)OC(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)O[C@@H]1C[C@@H](OC2CCCCO2)[C@H](C=O)C1CCCCCCCCC(=O)OC(C)C

Procedure:
A solution (10 ml) of the compound (13-4)(3.18 g) in dichloromethane was subjected to Swan oxydation using oxalyl chloride(2M, CH2Cl2 solution, 8.78 ml), a solution (20 ml) of DMSO (2.49 ml) in dichloromethane and triethylamine (5.87 ml). The crude product obtained by the conventional treatment was purified by silica gel chromatography (n-hexane/ethyl acetate=7/3) to give the titled compound (13-5).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][O:15][CH3:16])[C:6]1[C:7]([NH2:12])=[CH:8][CH:9]=[CH:10][CH:11]=1.[C:17](Cl)(Cl)=[S:18].O>O1CCOCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:13][CH2:14][O:15][CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]=[C:17]=[S:18]
Reactant: COCCN(CCOC)c1ccccc1N
Reactant: S=C(Cl)Cl
Solvent: O
Solvent: C1COCCO1
Product: COCCN(CCOC)c1ccccc1N=C=S
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of N,N-bis(2-methoxyethyl)benzene-1,2-diamine (7.5 g) in dioxane (10 ml) was added to a mixture of thiophosgene (4 ml) and water (60 ml) which had been cooled to 0° C. The temperature of the mixture was allowed to rise to ambient and the mixture was stirred for 4 hours. Ice water (50 ml) was added and the mixture extracted with ether (3×20 ml). The extract was washed with water (50 ml) and brine (50 ml), dried and evaporated to give a residue which was heated at 45° C. under vacuum (100 mm/Hg) to give 2-[bis(2-methoxyethyl)amino]phenyl isothiocyanate as an oil.
Reaction SMILES: C(N(CC)CC)C.[OH:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([I:16])[CH:13]=[C:12]1[CH:17]=[O:18].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.O>ClCCl>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([O:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([I:16])[CH:13]=[C:12]2[CH:17]=[O:18])(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1cc(I)cn1CCO
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCn2cc(I)cc2C=O)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
Triethylamine (3.3 mL, 23.8 mmol) was added to a stirred solution of 1-(2-hydroxyethyl)-4-iodo-pyrrole-2-carbaldehyde (2.1 g, 7.92 mmol) in dichloromethane (15 mL). The reaction mixture was chilled to 0° C. and 4-methyl-benzenesulfonyl chloride (1.82 g, 9.51 mmol) was added over 15 min. The reaction mixture was allowed to warm to ambient temperature and stirred overnight. Water was added, the organic phase separated and the aqueous phase extracted with dichloromethane. The combined organic layers were washed with saturated sodium bicarbonate solution, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue which was purified by washing with petroleum ether to afford 2-(2-formyl-4-iodo-pyrrol-1-yl)ethyl 4-methylbenzenesulfonate (2.4 g, 72%) as a grey solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][CH:23]=1>CN(C)C=O>[O:24]([C:21]1[N:22]=[CH:23][C:18]([CH2:17][N:1]2[CH:5]=[C:4]([C:6]3[C:7]([NH2:13])=[N:8][C:9]([NH2:12])=[CH:10][CH:11]=3)[CH:3]=[N:2]2)=[CH:19][CH:20]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Nc1ccc(-c2cn[nH]c2)c(N)n1
Reactant: ClCc1ccc(Oc2ccccc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ccc(-c2cnn(Cc3ccc(Oc4ccccc4)nc3)c2)c(N)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
To an N,N-dimethylformamide (5.00 mL) solution of 3-(1H-pyrazol-4-yl)-pyridine-2,6-diamine (30.0 mg, 0.171 mmol) described in Manufacturing Example 36-1-2 was added sodium hydride (7.52 mg, 0.188 mmol, 60% in oil) on an ice bath (0° C.) under nitrogen atmosphere, which was stirred for 10 minutes at room temperature. Thereafter, 5-chloromethyl-2-phenoxy-pyridine (59.9 mg, 0.273 mmol) described in Manufacturing Example 193-1-2 was added to the above mixture, which was stirred for 30 minutes at room temperature. The reaction mixture was partitioned into ethyl acetate and water at room temperature. The organic layer was washed with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (15.4 mg, 25.2%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[CH2:15][OH:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:13])([F:14])[CH2:10][CH:9]1[CH:15]=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1CO
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(F)(F)CC1C=O
Reaction time: 3 h
Yield: 66.9 %

Procedure:
To a stirred mixture of 1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinylmethanol (2.11 g, 8.89 mmol), Et3 N (6.2 ml, 44.5 mmol), DMSO (6.3 ml, 88.9 mmol) in CH2Cl2 (20 ml) was added SO3 pyridine (4.25 g, 26.7 mmol). After 3 h stirring, the mixture was concentrated in vacuo and diluted with Et2O (200 ml). The resulting mixture was washed with 1 N HCl (100 ml) and brine (100 ml), dried over MgSO4, and concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (4:1) as eluent to give 1-(tert-butoxycarbonyl)-4,4-difluoro-2-pyrrolidinecarbaldehyde (1.40 g, 67%) as a yellow oil. 1H-NMR (CDCl3) δ 1.45–1.52 (m, 9 H), 2.49 (m, 2 H), 3.75–3.88 (m, 2 H), 4.29–4.42 (m, 1 H), 9.54 and 9.60 (s, each, total 1 H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][C:19]([CH3:24])([CH3:23])[CH2:18]2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[Cl:25][C:26]1[C:27](B(O)O)=[CH:28][C:29]([F:32])=[N:30][CH:31]=1.C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:26]1[C:27]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([N:8]([CH2:16][CH:17]3[CH2:22][CH2:21][O:20][C:19]([CH3:23])([CH3:24])[CH2:18]3)[C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:14])[CH3:12])[N:7]=2)=[CH:28][C:29]([F:32])=[N:30][CH:31]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: CC(C)(C)OC(=O)N(CC1CCOC(C)(C)C1)c1cccc(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N(CC1CCOC(C)(C)C1)c1cccc(-c2cc(F)ncc2Cl)n1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 6-bromopyridin-2-yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate (710 mg, 1.778 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid, PdCl2(dppf).CH2Cl2 adduct (145 mg, 0.178 mmol) in DME (7 mL) and 2M aqueous Na2CO3 solution (2.3 mL, 1.778 mmol) was heated in a sealed tube at about 98° C. for 2 hr. The mixture was cooled to ambient temperature and diluted with EtOAc (˜100 mL) and saturated aqueous NaHCO3 solution. The separated organic layer was washed with saturated aqueous NaHCO3 (2×), dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, 25 min, EtOAc/heptane=0/100 to 25/75 over 25 min] providing (R/S)-tert-butyl 5′-chloro-2′-fluoro-2,4′-bipyridin-6-yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate as a highly viscous, colorless oil. Yield: 605 mg. LCMS (m/z): 394.1 {loss of tert Bu-group}/450.2 [M+H]+; Retention time=1.24 min.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1[C:25]([CH:26]=O)=[CH:24][CH:23]=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>>[N:20]1[C:25]([CH2:26][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])=[CH:24][CH:23]=[CH:22][C:21]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ccccn2)n1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccn2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with [2,2′-bipyridine]-6-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.58 min.; [M+H]+: 403.99 g/mol.
Reaction SMILES: C(=O)([O-])O.[Na+].[N+:6]([C:9]1[CH:10]=[N:11][N:12]([CH2:14][C:15]([OH:17])=[O:16])[CH:13]=1)([O-:8])=[O:7].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O[C:43]1[CH:44]=[N:45][C:46]2[C:51]([C:52]=1[CH:53]=O)=[CH:50][C:49]([O:55][CH3:56])=[CH:48][CH:47]=2.N12CCCN=C1CCCCC2>CN(C)C=O.O>[CH3:56][O:55][C:49]1[CH:50]=[C:51]2[C:46](=[CH:47][CH:48]=1)[N:45]=[CH:44][C:43]1[O:16][C:15](=[O:17])[C:14]([N:12]3[CH:13]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=[N:11]3)=[CH:53][C:52]2=1
Reactant: COc1ccc2ncc(O)c(C=O)c2c1
Reactant: O=C(O)Cn1cc([N+](=O)[O-])cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2ncc3oc(=O)c(-n4cc([N+](=O)[O-])cn4)cc3c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.1 %

Procedure:
Sodium hydrogen carbonate (4.96 g, 59.06 mmol, 3.0 eq) is added at room temperature to a stirred solution of (4-nitro-pyrazol-1-yl)-acetic acid (3.77 g, 21.65 mmol, 1.1 eq) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (14.97 g, 39.37 mmol, 2.0 eq) in N,N-dimethylformamide (200 mL). After 1 h 30 stirring at room temperature 3-hydroxy-6-methoxy-quinoline-4-carbaldehyde (4.0 g, 19.69 mmol, 1.0 eq) is added and the resulting mixture is stirred at room temperature for 3 hours before the addition of 1,8-diazabicyclo[5,4,0]undec-7-ene (11.8 mL, 78.74 mmol, 4.0 eq). After 48 hours stirring at room temperature, the reaction mixture is poured into water (1000 mL) and the resulting solid is collected by filtration to afford 6-methoxy-3-(4-nitro-pyrazol-1-yl)-1-oxa-9-aza-phenanthren-2-one as a yellow solid (4.0 g, 57% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.CC(=CC)C.P([O-])(O)(O)=[O:15].[Na+].Cl([O-])=O.[Na+].Cl>CC(O)(C)C.O>[CH3:1][C:2]1[O:6][C:5]([C:7]([OH:15])=[O:8])=[CH:4][CH:3]=1
Reactant: O=P([O-])(O)O
Reactant: Cc1ccc(C=O)o1
Agent: CC=C(C)C
Agent: Cl
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24 %

Procedure:
5-Methylfuran-2-carbaldehyde (2.20 g, 20.0 mmol) obtained in Step 1 was dissolved in a mixed solvent of 2-methyl-2-propanol (150 mL) and water (40 mL), and 2-methyl-2-butene (10.6 mL, 100 mmol) and sodium dihydrogenphosphate (2.40 g, 20.0 mmol) were added thereto, followed by stirring at room temperature for 15 minutes. 79% sodium chlorite (8.01 g, 70.0 mmol) was added to the reaction mixture little by little, followed by stirring at room temperature for 1 hour. 4 mol/L hydrochloric acid was added to the reaction mixture to adjust the pH to 3, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=17:3) to afford 5-methylfuran-2-carboxylic acid (606 mg, 24%).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:25](=[O:26])[N:5]2[C:6]([C:22]([OH:24])=[O:23])=[C:7](/[CH:10]=[CH:11]/[CH2:12][N+:13]3[CH:18]=[CH:17][C:16]([C:19](=[O:21])[NH2:20])=[CH:15][CH:14]=3)[CH2:8][S:9][C@H:4]12.C([O-])(O)=O.[Na+].N1([CH2:41][O:42][N:43]=[C:44]([C:48]2[N:52]=[C:51]([NH2:53])[S:50][N:49]=2)[C:45]([O-])=[O:46])C2C=CC=CC=2N=N1.Cl>CN(C=O)C.CC(C)=O>[NH2:53][C:51]1[S:50][N:49]=[C:48]([C:44](=[N:43][O:42][CH3:41])[C:45]([NH:2][CH:3]2[C:25](=[O:26])[N:5]3[C:6]([C:22]([O-:24])=[O:23])=[C:7]([CH:10]=[CH:11][CH2:12][N+:13]4[CH:14]=[CH:15][C:16]([C:19](=[O:21])[NH2:20])=[CH:17][CH:18]=4)[CH2:8][S:9][C@H:4]23)=[O:46])[N:52]=1
Reactant: NC(=O)c1cc[n+](C/C=C/C2=C(C(=O)O)N3C(=O)C(N)[C@H]3SC2)cc1
Reactant: Nc1nc(C(=NOCn2nnc3ccccc32)C(=O)[O-])ns1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CC[n+]3ccc(C(N)=O)cc3)CS[C@H]12)c1nsc(N)n1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a mixture of 7-amino-3-[3-(4-carbamoylpyridinio)-1-(E)-propenyl]-3-cephem-4-carboxylic acid hydrochloride (XXII-H, 397 mg, 1 mmole) and NaHCO3 (168 mg, 2 mmoles) in aqueous DMF (water, 3.5 ml and DMF, 7.5 ml) was added benzotriazol-1-yl-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetate (479 mg, 1.5 mmoles) (from Preparation No. 28). The mixture was stirred at room temperature for 3.5 hours. The reaction mixture was adjusted to pH 3-4 with 3N HCl and diluted with 200 ml of acetone to give a precipitate, which was collected by filtration. The crude product was dissolved in a small volume of aqueous THF and the solution was adjusted to pH 6.8 with NaHCO3, treated with decolorizing carbon, concentrated to ca. 1 ml and seeded with a few pieces of crystalline I-1H. After stirring overnight, the crystalline precipitate was collected by filtration to afford the title compound I-1H (zwitterion form). Yield 83 mg (16%). Mp. >185° C. (dec.). Physico-chemical data of this product were identical to those of the compound in Example 10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH:11]2[CH2:13][CH2:12]2)=O)[CH:6]=[CH:7][CH:8]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:15]3[N:14]([CH:18]=[CH:17][N:16]=3)[CH2:12][CH2:13][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=O)C2CC2)c1
Reactant: c1c[nH]cn1
Solvent: ClCCl
Product: COc1cccc(C2=CCCn3ccnc32)c1

Procedure:
Combine 35 g of crude cyclopropyl 3-methoxyphenyl ketone with 60 g of imidazole, and heat to 200° C. for 18 hr. Dissolve the reaction mixture in 500 ml of methylene chloride, and wash with three 300 ml portions of water to remove the excess imidazole, further wash with two 100 ml portions of 10% sodium hydroxide. Dry the methylene chloride portion over magnesium sulfate, and remove the solvent in vacuo. Crystallize the residue from ether to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])[C:3]=1[NH2:16].[C:17](C1NC=CN=1)(C1NC=CN=1)=[O:18]>O1CCCC1>[F:1][C:2]1[C:3]2[NH:16][C:17](=[O:18])[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1c(F)cccc1Nc1ccccc1F
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: O=c1[nH]c2c(F)cccc2n1-c1ccccc1F

Procedure:
3-fluoro-N1-(2-fluorophenyl)benzene-1,2-diamine (0.44 g, 2 mmol) and carbonyl diimidazole (0.29 g, 1.8 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature overnight. Upon disappearance of the starting material, the reaction was partitioned between 1 N hydrochloric acid (100 mL) and ethyl acetate (100 mL). The organics were dried over sodium sulfate and concentrated to give 4-fluoro-1-(2-fluorophenyl)-1,3-dihydro-2H-benzimidazol-2-one as a white solid in near quantitative yield. MS (ES) m/z 247.0
Reaction SMILES: [CH2:1]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:21][C:22]1[CH2:23][C:24](=[C:36]=O)[C:25]2[O:32][C:29]3([CH2:31][CH2:30]3)[CH2:28][C:27]([CH3:34])([CH3:33])[C:26]=2[CH:35]=1.C(OCC)(=O)C>CCCCCC>[Br:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH2:1])[C:25]2[O:32][C:29]3([CH2:31][CH2:30]3)[CH2:28][C:27]([CH3:34])([CH3:33])[C:26]=2[CH:35]=1
Reactant: CC1(C)CC2(CC2)OC2=C1C=C(Br)CC2=C=O
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=Cc1cc(Br)cc2c1OC1(CC1)CC2(C)C

Procedure:
Following general procedure N and using A solution of methylidene triphenyl phosphorane [generated from methyl triphenylphosphonium bromide (7 g, 20 mmol) and 1.6M solution of n-butyl lithium in hexanes (11.8 mL, 19 mmol) ], 6-bromo-8-carbonyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane] (Intermediate 40, 2.06 g, 7 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, the title compound was obtained as a clear oil (1.36 g, 66%).
Reaction SMILES: C(O)(=O)C.OO.[C:7]([C:10]1[C:11]([CH3:24])=[C:12]2[C:17](=[C:18]([Cl:20])[CH:19]=1)S[CH2:15][C:14]([CH3:22])([CH3:21])[C:13]2=[O:23])(=[O:9])[CH3:8].[S:25]([O-:28])(O)=[O:26].[Na+]>O>[C:7]([C:10]1[C:11]([CH3:24])=[C:12]2[C:17](=[C:18]([Cl:20])[CH:19]=1)[S:25](=[O:28])(=[O:26])[CH2:22][C:14]([CH3:21])([CH3:15])[C:13]2=[O:23])(=[O:9])[CH3:8]
Reactant: CC(=O)c1cc(Cl)c2c(c1C)C(=O)C(C)(C)CS2
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c2c(c1C)C(=O)C(C)(C)CS2(=O)=O
Reaction time: 2.5 h
Yield: 88 %

Procedure:
4 Milliliters of acetic acid and 2.12 g (18.71 mmol) of a 30 wt % hydrogen peroxide aqueous solution were added to 2.20 g (7.79 mmol) of 6-acetyl-8-chloro-3,3,5-trimethylthiochroman-4-one in a 100-ml round-bottomed flask, and the mixture was reached at 80° C. for 2.5 hours. The reaction mixture was diluted with about 50 ml of water, and a sodium hydrogensulfite aqueous solution was added to decompose excess hydrogen peroxide. Then, the reaction mixture was extracted with ethyl acetate. An organic layer was washed with a saturated sodium hydrogencarbonate aqueous solution and with a saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 2.16 g (yield 88%) of 6-acetyl-8-chloro-3,3,5-trimethylthiochroman-4-one-1,1-dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=O)[CH:3]=1.Cl.[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][NH2:33])=[CH:28][CH:27]=1.CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:33][O:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:3]=1
Reactant: NOc1ccc(F)cc1
Reactant: O=C(c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F)C1CCCCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(Nc1ccc(Cl)cc1C(=NOc1ccc(F)cc1)C1CCCCC1)C(F)(F)F
Yield: 37.6 %

Procedure:
A solution of N-(4-chloro-2-cyclohexanecarbonylphenyl)trifluoromethanesulfonamide 29E (410 mg, 1.11 mmol), O-(4-fluorophenyl)hydroxylamine hydrochloride (200 mg, 1.22 mmol) and anhydrous NaOAc (100 mg, 1.22 mmol) in EtOH (20 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum and the residue purified by column chromatography (eluting with CH2Cl2/PE, 3:7 to CH2Cl2) to afford N-{4-chloro-2-[(4-flurophenoxyimino)cyclohexylmethyl]phenyl}trifluoromethanesulfonamide 169 (200 mg, 38%), as a white solid. 1H n.m.r. (200 MHz, CDCl3) δ 7.54, d, J=8.8 Hz, 1H; 7.43, dd, J=2.2 and 8.8 Hz, 1H; 7.24, d, J=2.2 Hz, 1H; 7.12-6.95, m, 5H; 2.56, m, 1H; 2.14, m, 1H; 1.93-1.65, m, 5H; 1.29, m, 4H.
Reaction SMILES: O=[C:2]1[CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][CH2:8][C:3]21[CH2:7][CH2:6][CH2:5][CH2:4]2.C([O-])(=O)C.[NH4+].[BH3-]C#[N:23].[Na+]>CO>[NH2:23][CH:2]1[CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:10][CH2:9][CH2:8][C:3]21[CH2:7][CH2:6][CH2:5][CH2:4]2
Reactant: [BH3-]C#N
Reactant: COC(=O)C1CCCC2(CCCC2)C1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCC2(CCCC2)C1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a flask containing methyl 6-oxospiro[4.5]decane-7-carboxylate, 60, (4.10 g, 19.50 mmol) in MeOH (35 mL) was added ammonium acetate (10.52 g, 136.50 mmol) and NaCNBH3 (1.47 g, 23.40 mmol). The mixture was stirred at room temperature for 24 hrs. GCMS showed conversion to product SM (Rt=12.3 min, E+=211), product (Rt=12.6 min, ES+=212 [major] and Rt=12.45 min, ES+=212 [minor]). The solvent was evaporated, HCl (1N) was added and the aqueous phase was extracted with EtOAc. The organic phase was neutralized with NaOH (6N) to pH ˜10. The aqueous phase was extracted three times with EtOAc and twice with dichloromethane, dried over Na2SO4 to yield 1.6 g of product.
Reaction SMILES: [CH3:1][C:2]([CH3:59])([CH3:58])[C@H:3]([N:44]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[N:51]=2)[C:45]1=[O:57])[C:4]([NH:6][C@@H:7]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@@H:8]([OH:36])[CH2:9][CH:10]([NH:25]C(=O)OCC1C=CC=CC=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)=[CH:14][CH:13]=1)=[O:5].Cl>CO.[OH-].[OH-].[Pd+2]>[NH2:25][CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][N:19]=2)=[CH:14][CH:13]=1)[CH2:9][C@H:8]([OH:36])[C@@H:7]([NH:6][C:4](=[O:5])[C@@H:3]([N:44]1[CH2:48][CH2:47][N:46]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([CH3:56])[N:51]=2)[C:45]1=[O:57])[C:2]([CH3:1])([CH3:58])[CH3:59])[CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: Cc1ccc(-c2ccc(CC(C[C@H](O)[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4cccc(C)n4)C3=O)C(C)(C)C)NC(=O)OCc3ccccc3)cc2)nc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-c2ccc(CC(N)C[C@H](O)[C@H](Cc3ccccc3)NC(=O)[C@@H](N3CCN(Cc4cccc(C)n4)C3=O)C(C)(C)C)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 128E (0.127 g, 0.159 mmol) in methanol (2 mL) was treated with Pd(OH)2 on carbon (0.035 g, 20% Pd by wt.) and HCl solution (0.12 mL, 4N in dioxane), stirred under a hydrogen atmosphere (balloon pressure) at 25° C. for 16 hours, filtered through a bed of celite® and rinsed with methanol. The solvent was concentrated to give the title compound as the hydrochloride salt, which was used without further purification.