Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][C:19]([N:21]1[CH2:25][C@H:24]([F:26])[CH2:23][C@H:22]1[C:27](=[O:38])[NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[F:37])=[O:20])[CH:13]=[C:12]2[C:39]([NH2:41])=[O:40])C1C=CC=CC=1.C1(SC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[Cl:36][C:32]1[C:31]([F:37])=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][NH:28][C:27]([C@@H:22]1[CH2:23][C@@H:24]([F:26])[CH2:25][N:21]1[C:19](=[O:20])[CH2:18][N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[C:12]([C:39]([NH2:41])=[O:40])=[CH:13]1)=[O:38]
Reactant: NC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(OCc3ccccc3)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: NC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccc(O)cc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a suspension of 5-benzyloxy-1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-indole-3-carboxylic acid amide Example 503 (148 mg, 0.255 mmol) in TFA (2.5 mL), cooled to 0° C., was added thioanisole (0.301 mL, 2.55 mmol), and the reaction mixture was stirred at RT for 3 h. Volatiles were evaporated under reduced pressure, and the residue was suspended in a saturated aqueous NaHCO3 solution, followed by freeze-drying in vacuo. The residue was suspended in a small amount of methanol and the solid was filtered off. The filtrate was purified by preparative HPLC (Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, 20-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA). The title compound was obtained as a white solid. MS (LC/MS): 491 [M+H]+; 983 [2M+H]+; tR (HPLC, conditions b): 3.75 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[C:13]#[N:14])=[CH:9][CH:10]=[C:5]2[NH:4][C:3]1=[O:19].[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(N(CC)CC)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:20]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][CH:23]=[C:22]([N:4]2[C:5]3[C:6](=[N:7][C:8]([C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[C:13]#[N:14])=[CH:9][CH:10]=3)[N:2]([CH3:1])[C:3]2=[O:19])[CH:21]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: Cn1c(=O)[nH]c2ccc(-c3ccccc3C#N)nc21
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(=O)n(-c2cccc(-c3ccccc3)c2)c2ccc(-c3ccccc3C#N)nc21
Reaction time: 96 h

Procedure:
To a solution of 4-1 (13 mg, 0.052 mmol) in DCM (0.25 mL) was added copper (II) acetate, biphenyl-3-ylboronic acid (30 mg, 0.16 mmol) and triethylamine (0.022 mL, 16 mg, 0.16 mmol) at room temperature. After 4 days, the crude mixture was diluted in DCM (4 mL), filtered, concentrated and purified via reverse phase chromatography (1-100% Acetonitrile, 0.1% TFA in H2O) and the desired fractions were concentrated to give 76-1. MS (M+H)+: observed=403.0, calculated=403.2.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:27][CH2:28][CH:29]([OH:32])[CH:30]=[CH2:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].O>CN(C)C=O>[CH2:11]([O:27][CH2:28][CH:29]([O:32][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH:30]=[CH2:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: C=CC(O)COCCCCCCCCCCCCCCCC
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CC(COCCCCCCCCCCCCCCCC)OCc1ccccc1
Yield: 49 %

Procedure:
To stirred suspension of 3.35 g of 50% sodium hydride and 10.92 g of benzyl bromide in 75 ml of dimethylformamide was added a solution of 19 g of 1-(hexadecyloxy)-3-buten-2-ol in 75 ml of dimethylformamide. The mixture was stirred overnight, then water was added and the mixture was extracted with ether. The ether extract was dried over magnesium sulfate and activated charcoal and the solvent removed giving an oil. This oil was purified by HPLC [hexane: chloroform (8:1)] and the solvent removed giving 12 g of the desired compound as an oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[F:11])=O.[CH3:12][C:13]([S@:16]([NH2:18])=[O:17])([CH3:15])[CH3:14]>C1COCC1.[Cl-].[Na+].O.C(O[Ti](OC(C)C)(OC(C)C)OC(C)C)(C)C>[F:11][C:5]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=1/[C:2](=[N:18]\[S@@:16]([C:13]([CH3:15])([CH3:14])[CH3:12])=[O:17])/[CH3:1]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cccc(F)c1F
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C/C(=N/[S@](=O)C(C)(C)C)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 85.6 %

Procedure:
To a solution of 2,3-difluoroacetophenone (25.0 g, 160 mmol) in THF (500 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (38.8 g, 320 mmol) followed by tetraisopropoxytitanium (142 mL, 480 mmol). The reaction was heated to reflux for 3 days. The mixture was allowed to cool to room temperature and then treated with brine (550 ml). The resulted suspension was stirred for 15 min and filtered through celite. The filter cake was washed with EtOAc. The filtrate was extracted with EtOAc (2×). The organic extracts were washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and purified by silica gel column (10-35% EtOAc/hexane) to afford (R,Z)-N-(1-(2,3-difluorophenyl)ethylidene)-2-methylpropane-2-sulfinamide (35.6 g, 137 mmol, 86% yield) as yellow oil. MS m/z=260.1 [M+H]+ calculated for C12H15F2NOS: 259.3
Reaction SMILES: C([C:4]1[CH:9]=[C:8]([N:10]2[C:15]([CH3:16])=[CH:14][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[C:12]([Cl:27])[C:11]2=[O:28])[C:7]([CH3:29])=[CH:6][N:5]=1)(=O)C.[C:30](OC(OC(C)(C)C)N(C)C)(C)([CH3:32])[CH3:31].C(=O)([O-])[O-].[K+].[K+].Cl.[OH:51][C:52]([CH3:57])([CH3:56])[C:53]([NH2:55])=[NH:54]>CN(C=O)C>[Cl:27][C:12]1[C:11](=[O:28])[N:10]([C:8]2[C:7]([CH3:29])=[CH:6][N:5]=[C:4]([C:31]3[CH:30]=[CH:32][N:55]=[C:53]([C:52]([OH:51])([CH3:57])[CH3:56])[N:54]=3)[CH:9]=2)[C:15]([CH3:16])=[CH:14][C:13]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26]
Reactant: CC(C)(O)C(=N)N
Reactant: CC(=O)c1cc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)c(C)cn1
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cnc(-c2ccnc(C(C)(C)O)n2)cc1-n1c(C)cc(OCc2ccc(F)cc2F)c(Cl)c1=O
Temperature: 60 °C
Yield: 39 %

Procedure:
To a solution of 2′-acetyl-3-chloro-4-[(2,4-difluorobenzyl)oxy]-5′,6-dimethyl-2H-1,4′-bipyridin-2-one (0.045 g, 0.11 mmol) in DMF (0.5 mL) was added N, N dimethylformamide di-tert-butyl acetal (0.04 g, 0.2 mmol) and heated at 60° C. for 2 h. The reaction mixture was concentrated in vacuo, the residue was treated with toluene (1 mL) and concentrated in vacuo. The resulting residue was dried in vacuo for 2 h, dissolved in DMF (1 mL), and potassium carbonate (0.03 g, 0.22 mmol) and 2-hydroxy-2-methylpropiamidine hydrochloride (0.02 g, 0.14 mmol) were added. This mixture was heated at 80° C. for 12 h under nitrogen and concentrated in vacuo. The residue was partitioned between water (5 mL) and ethyl acetate (15 mL). The organic phase was washed with water, dried with magnesium sulfate, and concentrated. The resulting residue was purified by silica-gel flash chromatography using 3% methanol in ethyl acetate. Appropriate fractions were combined and concentrated under reduced pressure to give 0.022 g of the title compound. ES-MS, m/z=513 (M+H) and 535 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:12][CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:20].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:25]([Cl:41])=[CH:24][N:23]=1>>[Cl:41][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[N:27][C:22]([NH:20][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:23][CH:24]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1c(N)ccc2c1CCC(N1CCOCC1)CC2
Product: COc1c(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)C(C)C)n2)ccc2c1CCC(N1CCOCC1)CC2

Procedure:
The title compound was prepared from 1-methoxy-7-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-ylamine and (2,5-dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine in an analogous manner to Example 179 heating at 140° C. Product was isolated as a white foam (33 mg, 30%). LCMS (m/e) 586 (M+H); 1H NMR (400 MHz, CDCl3) δ12.93 (broad s, 1H), 10.32 (broad s, 1H), 8.35 (d, 1H, J=8.34 Hz), 8.00 (s, 1H), 7.91 (d, 1H, J=8.08 Hz), 7.52 (d, 1H, J=8.08 Hz), 7.41 (t, 1H, J=7.58 Hz), 7.33 (t, 1H, J=7.58 Hz), 6.90 (d, 1H, J=8.09 Hz), 4.02 (m, 4H), 3.74 (s, 3H), 3.57 (m, 2H), 3.34 (d, 2H, J=10.9 Hz), 3.20 (m, 2H), 2.94-3.08 (m, 3H), 2.82 (m, 1H), 2.40-2.50 (m, 2H), 1.50 (m, 2H), 1.31 (t, 6H, J=6.31).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:11]=[C:10]([OH:12])[N:9]=[C:8]([O:13][CH3:14])[N:7]=1>CC(O)=O>[OH:5][C:6]1[C:11]([N+:1]([O-:4])=[O:2])=[C:10]([OH:12])[N:9]=[C:8]([O:13][CH3:14])[N:7]=1
Reactant: COc1nc(O)cc(O)n1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1nc(O)c([N+](=O)[O-])c(O)n1
Yield: 68 %

Procedure:
To glacial HOAc (860 mL) was added red fuming HNO3 (300 mL) with cooling and stirring, at such a rate that the temperature was kept below 20° C. This stirred mixture was cooled in an ice bath and the foregoing material prepared in Example 134 (200 g, 78% pure, 1.1 mol) was added in portions over a period of 1 hr such that the temperature was maintained between 18°-20° C. The reaction was then stirred overnight. The precipitate which formed was filtered off and washed with HOAc (50 mL). This solid was then slurried with ice-H2O (400 mL), filtered off and dried to constant weight in vacuo at 60° C. to yield 141 g (0.75 mol, 68% yield) of the title compound; nmr (d6 -DMSO) d: 3.95 (s); mass spectrum showed m/e 187 (M+). A separate synthesis gave an analytical sample.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[N:11]([CH3:10])[S:12]([CH3:15])(=[O:14])=[O:13])#[N:5]
Reactant: N#Cc1ccccc1F
Reactant: CNS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(c1ccccc1C#N)S(C)(=O)=O
Temperature: 80 °C

Procedure:
To a round bottom flask was added 2-fluoro-benzonitrile (1.0 g, 8.2 mmol), N-Methyl-methanesulfonamide (1.0 g, 9.2 mmol), potassium carbonate (1.7 g, 12 mmol) and N,N-dimethylformamide (5 mL). The mixture was heated at 80° C. for 18 hours. The mixture was cooled to room temperature and water (50 mL) was added. The mixture was extracted with ethyl acetate (75 mL). The organic layer was washed with water (2×25 mL) and saturated aqueous sodium chloride (25 mL), dried over magnesium sulfate, filtered and evaporated to a waxy solid. The recovered solid was triturated with hexane, filtered and dried. N-(2-Cyano-phenyl)-N-methyl-methanesulfonamide was isolated as a pale yellow solid (0.74 g, 42%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.72 (d, J=7.7 Hz, 1H), 7.70-7.64 (m, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 3.40 (s, 3H), 3.13 (s, 3H). MS=211 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][S:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CN(C)[CH:51]=[O:52]>C1(C)C=CC=CC=1.CCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH2:22][S:23][C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:14]([CH:51]=[O:52])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(Br)c(CSC(c4ccccc4)(c4ccccc4)c4ccccc4)nc3N21
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(C=O)c(CSC(c4ccccc4)(c4ccccc4)c4ccccc4)nc3N21
Reaction time: 0.25 h

Procedure:
To a solution of 0.39 g product of step 2 in 10 ml toluene was dropwise added 1.0 ml of a 1.7 M solution of tert-butyllithium in pentane at −78 C. The resulting orange solution was stirred at −78 C. for 15 min. to the resulting orange solution was added 1.00 ml dimethylformamide at −78 C. The initially read but soon bright yellow solution was stirred at −78 C. for 15 min and was then allowed to thaw to room temperature over 30 min. The reaction mixture was quenched with 10% aqueous ammonium chloride, the phases were separated and the organic phase was purified by chromatography on silica gel with dichloromethane:ethyl acetate=19:1. to yield 0.21 g of the title compound as colorless foam (MS: 606.4(M+H+)).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([C:16](=[O:19])[CH2:17][CH3:18])[C:9](=[N:12][N+:13]([O-:15])=[O:14])SC)=[CH:5][N:6]=1.[CH3:20][NH2:21].CO.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:8]([C:16](=[O:19])[CH2:17][CH3:18])[C:9]([NH:21][CH3:20])=[N:12][N+:13]([O-:15])=[O:14])=[CH:5][N:6]=1
Reactant: CCC(=O)N(Cc1cnc(Cl)s1)C(=N[N+](=O)[O-])SC
Reactant: CN
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CO
Product: CCC(=O)N(Cc1cnc(Cl)s1)C(=N[N+](=O)[O-])NC
Reaction time: 3 h
Yield: 40.9 %

Procedure:
To a solution of N-(2-chloro-5-thiazolylmethyl)-S-methyl-N'-nitro-N-propionylisothiourea (310 mg) in toluene (5 ml) was added 40% methylamine-methanol solution (75 mg) below -10° C. and the mixture was stirred at the same temperature for 3 hours. After addition of 2N hydrochloric acid (5 ml) under ice-cooling, the mixture was extracted with AcOEt (10 ml). The organic layer was washed with an aqueous saturated sodium bicarbonate solution, dried over MgSO4 and concentrated in vacuo. The resulting residue was applied to column chromatography on silica gel. The column was eluted with AcOEt. The fractions containing the desired compound were concentrated and the residue was dissolved in toluene. Crystallization by addition of n-hexane gave 120 mg of 1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitro-1-propionylguanidine (Compound No. 32) as a white crystal, m.p. 89°-90° C.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[C:8]1([N:14]2[C:22](=[O:23])[C:21]3[C@@H:20]4[C:24]([CH3:26])([CH3:25])[C@@:17]([CH3:27])([CH2:18][CH2:19]4)[C:16]=3[NH:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>[OH-].[Na+].O>[CH3:5][N:15]1[C:16]2[C@@:17]3([CH3:27])[C:24]([CH3:26])([CH3:25])[C@H:20]([CH2:19][CH2:18]3)[C:21]=2[C:22](=[O:23])[N:14]1[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1.[CH3:5][O:23][C:22]1[N:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:15]=[C:16]2[C:21]=1[C@@H:20]1[C:24]([CH3:26])([CH3:25])[C@@:17]2([CH3:27])[CH2:18][CH2:19]1
Reactant: COS(=O)(=O)OC
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3)c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c2c(nn1-c1ccccc1)[C@]1(C)CC[C@H]2C1(C)C
Product: Cn1c2c(c(=O)n1-c1ccccc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %
Yield: 20 %

Procedure:
Dimethyl sulfate (0.4 mL, 4.1 mmol) was added to (4S,7R)-2-phenyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 6; 1.00 g, 3.7 mmol) in 1 M NaOH (10 mL). The mixture was stirred at room temperature overnight and then diluted with water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an Analogix Intelliflash 280 system (Analogix, Inc., Burlington, Wis.) with an RS-12 column, eluting with 0-16% ethyl acetate/hexanes to give (4S,7R)-1,7,8,8-tetramethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (213 mg, 20%) as a white solid, (4S,7R)-3-methoxy-7,8,8-trimethyl-2-phenyl-4,5,6,7-tetrahydro-2H-4,7-methano-indazole (243 mg, 23%) as a yellow solid and unreacted starting material (243 mg, 24%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[Cl:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][S:20][C:18]1[N:17]=[C:16]([OH:21])[CH:15]=[C:14]([CH3:13])[N:19]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2ccc([N+](=O)[O-])cc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
1-(bromomethyl)-2-chloro-4-nitrobenzene, 6-methyl-2-sulfanylpyrimidin-4-ol (425 mg, 3 mmol), and potassium carbonate (420 mg, 3 mmol) were mixed in DMF (10 mL). The mixture was stirred at room temperature for 2 hours. To the mixture, water (100 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide pure titled product (500 mg, 54% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 4.55 (s, 2H), 6.03 (s, 1H), 7.92 (d, 1H), 8.19 (d, 1H), 8.31 (s, 1H); M+312.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])CC)C.[CH2:8]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C1COCC1>[CH2:8]([O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:3][CH2:6][CH:7]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[CH3:8])=[O:20])=[CH:17][CH:16]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCN(CC)CC
Reactant: CCCCCCOc1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(C(=O)NCC2CCCCC2C)cc1
Reaction time: 0.08 h

Procedure:
To a suspension of title B compound (213 mg, 1.30 mmol) in THF (6 mL) was added triethylamine 0.42 mL, 3.0 mmol). After stirring for 5 minutes, 4-hexyloxybenzoyl chloride (0.223 mL, 1.00 mmol) was added. After stirring for 4 hours, the reaction was filtered through a Celite pad. The pad was rinsed with ether (4×5 mL) and the combined filtrates were concentrated in vacuo. Purification by RP-HPLC (YMC SH-365-10 120A S-110 30×500 mm column, 40 mL/minute, 90:10 methanol/water containing 0.1% TFA)) afforded the title compound as a 1:1 mixture of cis- and trans- isomers (43 mg). MS: (ESI) (m/z) 332.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[S:20])[N:15]=[CH:16]N(C)C)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Br[CH2:29][C:30](=[O:33])[CH2:31][CH3:32]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[S:20][C:29]([C:30](=[O:33])[CH2:31][CH3:32])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC(=O)CBr
Reactant: CN(C)C=NC(=S)N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 90 °C
Yield: 72 %

Procedure:
To a solution of 0.83 mmol 4-(dimethylaminomethylene-thiocarbamoyl)-piperazine-1-carboxylic acid tert-butyl ester in 6 ml ethanol were added 2.50 mmol triethylamine and 1.00 mmol 1-bromo-2-butanone. The mixture was heated at 90° C. for 16 h. The reaction mixture was then concentrated in vacuo and the residue was purified by chromatography (SiO2, ethyl acetate/heptane) to afford the title compound as a white crystalline solid (yield 72%). MS (m/e): 326.1 (M+H+, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:17])=[CH:4][C:5]2[C:6]([CH3:16])([CH3:15])[CH2:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.[CH3:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][C:3]=1[O:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH3:23])=[CH:21][CH:20]=1)[C:6]([CH3:15])([CH3:16])[CH2:7][CH:8]=[C:9]2[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)C1=CCC(C)(C)c2cc(O)c(Br)cc21
Reactant: Cc1ccc(CBr)cc1
Product: Cc1ccc(COc2cc3c(cc2Br)C(C(C)C)=CCC3(C)C)cc1

Procedure:
Following General Procedure O, 3-bromo-5-isopropyl-8,8-dimethyl-7,8-dihydronaphthalen-2-ol (Compound 97, 0.14 g, 0.49 mmol) was reacted with 4-methylbenzylbromide to afford 0.19 g (1 00%) of the title compound as ayellow oil. PNMR (300 MHz, CDCl3) δ 1.22 (d, 6H, J=4.5 Hz), 1.28 (s, 6H), 2.22 (d, 2H, J=4.7 Hz), 2.45 (s, 3H), 5.22 (s, 2H), 5.78 (t, 1H, J=4.5 Hz), 7.02 (s, 1H), 7.22 (d, 2H, J=8.8 Hz), 7.38 (d, 2H, J=9.3 Hz), 7.60 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[C:9]2[C:4](=[C:5]3[CH2:26][CH2:25][CH2:24][C:6]3=[C:7](B3OC(C)(C)C(C)(C)O3)[CH:8]=2)[N:3]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].Br[C:36]1[C:37]([CH:42]2[O:46][CH2:45][CH2:44][O:43]2)=[N:38][O:39][C:40]=1[CH3:41].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:46]1[CH2:45][CH2:44][O:43][CH:42]1[C:37]1[C:36]([C:7]2[CH:8]=[C:9]3[C:4](=[C:5]4[CH2:26][CH2:25][CH2:24][C:6]=24)[N:3]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:2]([CH3:1])([CH3:34])[C:11](=[O:12])[C:10]3([CH3:13])[CH3:14])=[C:40]([CH3:41])[O:39][N:38]=1
Reactant: Cc1onc(C2OCCO2)c1Br
Reactant: CC(C)(C)OC(=O)N1c2c(cc(B3OC(C)(C)C(C)(C)O3)c3c2CCC3)C(C)(C)C(=O)C1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1onc(C2OCCO2)c1-c1cc2c(c3c1CCC3)N(C(=O)OC(C)(C)C)C(C)(C)C(=O)C2(C)C
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.6 %

Procedure:
To a solution of tert-butyl 2,2,4,4-tetramethyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one-1-carboxylate (1.2 g) obtained in Example 1, 9) in isopropanol (11 ml) were added 4-bromo-3-[1,3]dioxolan-2-yl-5-methylisoxazole (500 mg), 2.0 M aqueous potassium carbonate solution (3.2 ml) and tetrakis(triphenylphosphine)palladium(0) (250 mg), and the mixture was stirred at 80° C. for 16 hr. The reaction solution was diluted with water and ethyl acetate, the mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to normal phase chromatography (elution solvent hexane-ethyl acetate=6:1) to give tert-butyl 6-(3-[1,3]dioxolan-2-yl-5-methylisoxazol-4-yl)-2,2,4,4-tetramethyl-2,3,4,7,8,9-hexahydro-1H-cyclopenta[h]quinolin-3-one-1-carboxylate (410 mg, 32%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[NH:9][C:10](=[O:13])[CH2:11][O:12][C:7]=2[CH:6]=1)=[O:4].[H-].[Na+].I[CH:19]([CH3:21])[CH3:20].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]2[N:9]([CH:19]([CH3:21])[CH3:20])[C:10](=[O:13])[CH2:11][O:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2c(c1)OCC(=O)N2
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(c1)OCC(=O)N2C(C)C
Temperature: 25 °C
Yield: 24.9 %

Procedure:
To a solution of 7-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.00 g) in dimethylformamide (10 ml) were added 60% sodium hydride (in oil) (0.25 g) and 2-iodopropane (1.00 g) and the mixture was stirred at room temperature for a day. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give 7-methoxycarbonyl-4-(2-propyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (0.30 g).