Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCC[CH2:2]1.[CH3:6][O:7][N:8]=[C:9]1[CH2:15][C:14]([CH3:17])([CH3:16])[CH:13]([OH:18])[CH:12]([N:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:22])[CH3:21])[CH:11]=[C:10]1[CH3:30].[H-].[Na+].CI>C(O)(=O)C>[CH3:6][O:7][N:8]=[C:9]1[CH2:15][C:14]([CH3:16])([CH3:17])[CH:13]([O:18][CH3:2])[CH:12]([N:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:20](=[O:22])[CH3:21])[CH:11]=[C:10]1[CH3:30]
Reactant: CON=C1CC(C)(C)C(O)C(N(Cc2ccccc2)C(C)=O)C=C1C
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CI
Product: CON=C1CC(C)(C)C(OC)C(N(Cc2ccccc2)C(C)=O)C=C1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of tetrahydrofuran (40 ml) containing the 4-(N-acetylbenzylamino)-5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one methyloxime obtained in step 2 (9.5 g, 27.6 millimoles) there was gradually added 55% sodium hydride (3.6 g) while cooling on ice. After then adding methyl iodide (7.8 g, 55.2 millimoles) and stirring for 30 minutes, the mixture was returned to room temperature and stirring was continued for one hour. The reaction solution was poured into ice water (100 ml) containing acetic acid (1 ml), and subjected to extraction with benzene. After washing the benzene solution with water, it was dried over anhydrous magnesium sulfate. The benzene was distilled off, and the resulting residue was subjected to silica gel column chromatography with benzene-ethyl acetate (9:1) as the eluent, to obtain 8.51 g (86%) of 4-(N-acetylbenzylamino)-5-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one methyloxime as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][N:4]=1)#[N:2].[Br:10]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)Cl>[Br:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[N:4][CH:5]=1
Reactant: Cc1ccc(C#N)nc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(CBr)cn1
Temperature: 60 °C
Reaction time: 6 h
Yield: 53.3 %

Procedure:
Commercially available 2-cyano-5-methylpyridine (1.90 g, 16.1 mmol) was dissolved in chloroform (100 mL), and the mixture was stirred at 60° C. for 6 hours after adding N-bromosuccinimide (4.29 g, 24.1 mmol) and α,α-azobisisobutyronitrile (0.792 g, 4.82 mmol). After ice-cooling the reaction mixture, the precipitate was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 5-bromomethyl-2-cyanopyridine (1.69 g, 53%).
Reaction SMILES: [OH:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:13])[CH:3]=1.C1(O)C=CC=CC=1.[CH3:21][O:22][C:23](=[O:27])[CH:24](Br)[CH3:25]>>[CH:6]([C:5]1[C:4]([CH3:13])=[CH:3][C:2]([O:1][CH:24]([CH3:25])[C:23]([O:22][CH3:21])=[O:27])=[C:9]([N+:10]([O-:12])=[O:11])[CH:8]=1)=[O:7]
Reactant: COC(=O)C(C)Br
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1C=O
Solvent: Oc1ccccc1
Product: COC(=O)C(C)Oc1cc(C)c(C=O)cc1[N+](=O)[O-]

Procedure:
Using 4-hydroxy-2-methyl-5-nitrobenzaldehyde as the phenol and methyl-2-bromopropanoate as the alkylating agent in the general procedure for alkylation of substituted-2-nitrophenols gives the title compound as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.82 Hz, 3 H) 2.66 (s, 3H) 3.70 (s, 3H) 5.47 (q, J=6.82 Hz, 1H) 7.26 (s, 1H) 8.36 (s, 1H) 10.11. ESI-MS: m/z 268.2 (M+H)+.
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:12]=[C:7]2/[C:6](=[C:17](\OCC)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[C:5]1=[O:27])(=O)C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]([CH3:46])[C:36](=[O:45])[CH2:37][N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[CH:31][CH:30]=1.N1CCCCC1>CN(C=O)C>[CH3:46][N:35]([C:32]1[CH:33]=[CH:34][C:29]([NH:28]/[C:17](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]2\[C:5](=[O:27])[NH:4][C:8]3[C:7]\2=[CH:12][CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[N:9]=3)=[CH:30][CH:31]=1)[C:36](=[O:45])[CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1
Reactant: CN1CCN(CC(=O)N(C)c2ccc(N)cc2)CC1
Reactant: CCO/C(=C1/C(=O)N(C(C)=O)c2nc(C(=O)OC)ccc21)c1ccccc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COC(=O)c1ccc2c(n1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN2CCN(C)CC2)cc1)c1ccccc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Step-2: To a solution of (E)-methyl 1-acetyl-3-(ethoxy(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (2.6 g, 7.10 mmol) in DMF (5 mL) was added N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (1.94 g, 7.43 mmol) at RT and the reaction mixture was heated to 110° C. and stirred for 1 h. The reaction mixture was allowed to cool to RT, treated with piperidine (3 mL) and stirred for 30 min. The reaction mixture was evaporated and the resultant residue was purified by silica gel column chromatography using 5% CH3OH in dichloromethane as eluent to afford (Z)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate as yellow solid. MS (ES+): m/z 541.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C@@H:12]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@@H:13]([CH2:17][S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:43][NH2:44]>C(Cl)Cl>[OH:43][NH:44][C:14](=[O:15])[C@H:13]([CH2:17][S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@@H:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C[Si](C)(C)ON
Reactant: COc1ccc(S(=O)(=O)[C@@H](CCCCc2ccccc2)[C@@H](CSc2ccccc2)C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)[C@@H](CCCCc2ccccc2)[C@@H](CSc2ccccc2)C(=O)NO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
(±)-(2R*,3S*)-3-(4-Methoxybenzenesulfonyl)-7-phenyl-2-(phenylsulfanylmethyl)heptanoic acid (0.42 g, 0.84 mmol) is dissolved in CH2Cl2 (3 mL) and cooled to 0° C. A solution of oxalyl chloride in CH2Cl2 (1.5 mL, 3 mmol) is added dropwise, the bath removed and the reaction allowed to warm and stir at 23° C. for 1 hour. The reaction is then concentrated in vacuo and azeotroped with CHCl3. The resulting oil is dissolved in CH2Cl2 (2 mL), cooled to 0° C. and O-(trimethylsilyl)hydroxylamine (0.3 mL, 2.6 mmol) is added dropwise. The bath is removed and the reaction is allowed to warm to 20° C. The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL). The organic layer is then separated and washed with water (10 mL), dried (MgSO4) and concentrated in vacuo to yield (±)-(2R*,3S*)-3-(4-methoxybenzenesulfonyl)-7-phenyl-2-(phenylsulfanylmethyl)heptanoic acid hydroxyamide (0.37 g, 87%) The material obtained from the reaction is analytically pure: 1H NMR (300 MHz, CD3OD) δ 7.74-7.69 (m, 2H), 7.32-7.17 (m, 1H), 7.15-7.08 (m, 1H), 7.06-7.01 (m, 4H), 3.87 (s, 3H), 3.49 (dd, J=13.8, 5.3 Hz, 1H), 3.39 (q, J=5.3 Hz, 1H), 3.21 (dd, J=13.8, 9.8 Hz, 1H), 2.98-2.85 (m, 1H), 2.43 (t, J=7.3 Hz, 2H), 1.78-1.71 (m, 2H), 1.41-1.10 (m, 4H); MS (FAB) m/e 514 (M+H)+ ; Anal. (C27H31NO5S2) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.S(=O)(=O)(O)O.CCOCC>[N+](C1C=CC=CC=1)([O-])=O>[O:14]=[C:3]1[C:2]2[N:1]=[C:20]([C:19]3[CH:23]=[CH:24][C:16]([F:15])=[CH:17][CH:18]=3)[O:21][C:11]=2[C:10](=[O:13])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)c2oc(-c3ccc(F)cc3)nc21
Reaction time: 0.17 h
Yield: 33 %

Procedure:
To a solution of 6.22 g (30 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-naphthalene in 60 mL of nitrobenzene, 18.00 mL (150 mmol) of 4-fluorobenzoic acid chloride are added with protection from light. After 10 min of stirring with reflux, 0.20 mL of concentrated sulfuric acid is added. After 12 h and complete cooling, ether is added to obtain a yellow precipitate which is filtered through fritted glass, washed with ether and purified on a flash column (support: silica; conditioning: heptane; eluant: dichloromethane/heptane, 60/40). The yellow powder obtained after evaporation of the solvent is uncolored, recrystallized in dichloromethane to produce 2.90 g of 4,9-dihydro-4,9-dioxo-2-(4-fluorophenyl)-naphtho[2,3-d]oxazole in the form of yellow crystals.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:7]2=[N:6][C:5]=1[CH3:16].C(N(C(C)C)CC)(C)C.[F:26][C:27]1[CH:41]=[CH:40][C:30]2[C:31]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[N:32][O:33][C:29]=2[CH:28]=1>CO>[CH3:16][C:5]1[N:6]=[C:7]2[N:8]([CH2:11][CH2:12][CH2:13][CH:14]2[OH:15])[C:9](=[O:10])[C:4]=1[CH2:3][CH2:2][N:37]1[CH2:36][CH2:35][CH:34]([C:31]2[C:30]3[CH:40]=[CH:41][C:27]([F:26])=[CH:28][C:29]=3[O:33][N:32]=2)[CH2:39][CH2:38]1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O
Temperature: 62.5 °C
Reaction time: 16 h

Procedure:
3-(2-chloroethyl)-9-hydroxy-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (formula-7) (5.2 grams) and diisopropyl ethyl amine (12.56 grams) was added to 6-fluoro-3-(piperidin-4-yl)benzo[d]isoxazole (formula-8) (5.0 grams) in methanol (75 ml) taken in autoclave and then heated to 60-65° C., 0.8 Kg pressure was applied and stirred for 16 hours. The reaction mixture cooled and then distilled under reduced pressure. Isopropyl alcohol was added to the obtained residue and stirred for 15 minutes and then distilled off under reduced pressure to get the title compound. Added methanol and heated the reaction mixture to reflux temperature and stirred for 2.0 hrs at same temperature. Cooled the reaction mixture to 20° C. and stirred for 90 minutes at the same temperature. Filtered the solid precipitated. Washed the solid with chilled methanol and dried the compound.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:41])[CH2:21][NH:22][C:23]2([CH2:26][CH2:27][N:28]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[C:31]([CH3:39])([CH3:38])[O:30][C:29]3=[O:40])[CH2:25][CH2:24]2)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:41][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[CH2:21][NH:22][C:23]1([CH2:26][CH2:27][N:28]2[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[C:31]([CH3:39])([CH3:38])[O:30][CH:29]2[OH:40])[CH2:25][CH2:24]1
Reactant: CC1(C)OC(=O)N(CCC2(NCC(O)c3cc(OCc4ccccc4)cc4c3OCC(=O)N4)CC2)c2ccccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1(C)OC(O)N(CCC2(NCC(O)c3cc(O)cc4c3OCC(=O)N4)CC2)c2ccccc21

Procedure:
590 mg (1.06 mmol) of 1-(2-{1-[2-(6-benzyloxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-2-hydroxyethlamino]cyclopropyl}ethyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one is dissolved in 30 mL of methanol and hydrogenated in the presence of palladium on charcoal (10%) at ambient temperature and 3 bar hydrogen pressure. Yield: 180 mg (36%); mass spectroscopy: [M+H]+=468.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=1.CC([O-])(C)C.[K+]>CC#N.C1COCC1>[N:9]1[C:8]2[CH:7]=[C:6]3[N:14]([C:13]=2[CH:12]=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5]3
Reactant: Nc1cccnc1C#CCCCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: c1cnc2cc3n(c2c1)CCCC3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
A solution of 2-(6-chlorohex-1-ynyl)pyridin-3-amine (300 mg) in CH3CN (3 ml) was added a solution of KOtBu (387 mg) in THF (3.5 mL) at 0.0° C. The mixture was stirred at 0° C. for 30 min. The mixture was quenched with water at 0° C. and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (170 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[O:12][CH3:13])[CH2:3][OH:4].[C:14]([N:18]=[C:19]=[S:20])([CH3:17])([CH3:16])[CH3:15]>C(O)C>[C:14]([NH:18][C:19]([NH:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[O:12][CH3:13])[CH2:3][OH:4])=[S:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)N=C=S
Reactant: COc1cnccc1CC(N)CO
Solvent: CCO
Product: COc1cnccc1CC(CO)NC(=S)NC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h

Procedure:
To a solution of 0.3 g of 2-amino-3-(3-methoxy-pyridin-4-yl)-1-propanol in 50 mL of absolute ethanol, about 0.337 mL of tert-butylisothiocyanate is added then the reaction medium is stirred under an inert atmosphere at a temperature of about 20° C. for 18 hours. About 0.337 mL of tert-butylisothiocyanate is added again and the reaction mixture is heated at a temperature of about 60° C. for 4 hours. After cooling, the reaction medium is concentred under reduced pressure (2 kPa) at a temperature of about de 40° C. The oil obtained is purified by chromatography under argon pressure (50 kPa), in a column of silica gel (particle size 40-63 μm; diameter 4 cm; height 22 cm), eluting with a 20% dichloromethane/methanol/aqueous ammonia mixture (90/10/0.5 by volume) and obtaining fractions of 10 mL. The fractions containing the expected product are collected and concentred under reduced pressure (2 kPa) at a temperature of about 40° C. About 0.4 g of N-(tert-butyl)-N′-[2-hydroxy-1-(3-methoxy-pyridin-4-yl-methyl)ethyl]-thiourea is obtained, under the form of an yellow oil. [Infrared spectrum CH2Cl2: 3620; 3411; 2972; 1614; 1561; 1532; 1400; 1319; 1161; 1041 and 815 cm−1].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[S:14][CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(C=CC=1)C(OO)=[O:20].C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[S:14](=[O:20])[CH2:13][CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc(C2COCCS2)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S1CCOCC1c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
A stirred solution of 3-(3,4-dichlorophenyl)-1,4-oxathiane (1 g, 4 mmol) in dichloromethane (10 ml) at 0° C. was treated with a solution of meta-chloroperoxybenzoic acid (85%, 860 mg, 4 mmol) in dichloromethane (10 ml) and stirred at 0° C. for 30 mins then at room temperature for 3 hrs. The mixture was shaken with aqueous sodium bicarbonate solution and the organic phase separated, dried (MgSO4) and evaporated to give a solid which was triturated with hexane/toluene (1:1) to give 3-(3,4-dichlorophenyl)-1,4-oxathiane 4-oxide (860 mg), as a colourless crystalline solid, m.p. 100°-103° C.;
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[C:9](C(O)=O)=[CH:8][CH:7]=[CH:6][C:5]=2[C:4](=[O:15])[CH2:3]1>N1C2C(=CC=CC=2)C=CC=1.CC(=O)OCC.[Cu]>[CH3:1][C:2]1([CH3:16])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:15])[CH2:3]1
Reactant: CC1(C)CC(=O)c2cccc(C(=O)O)c2C1
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CC1(C)CC(=O)c2ccccc2C1
Yield: 34.4 %

Procedure:
2.2 g (10 mmol) of 7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid were heated to 180° C. for 5 h with 2.2 g of copper powder in 22 g of quinoline. After cooling, the mixture was diluted with EA, and the copper was filtered off and then washed several times with dil. hydrochloric acid. After concentration of the organic phase in a rotary evaporator and purification by chromatography on silica gel using cyclohexane/EA 6:1, 0.6 g of 3,3-dimethyl-3,4-dihydro-2H-naphthalen-1-one was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[CH3:32][S:33]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)(=[O:35])=[O:34].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:42][CH:39]4[CH2:40][CH2:41][N:36]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:37][CH2:38]4)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: C=C(C)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C(C)C1N(CC(=O)NC2CCN(S(C)(=O)=O)CC2)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 34.3 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.2 g, 0.433 mmol) prepared in example 116d was reacted with 1-methylsulfonyl-piperidin-4-yl-amine (0.15 g, 0.86 mmol), N-methylmorpholine (90 mg, 0.86 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-isopropenyl-1′-[(1-methylsulfonyl-piperidin-4-yl)aminocarbonyl-methyl]spiro[3H-indole-3,3′ piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 92 mg, 38.3%).
Reaction SMILES: [CH3:1][CH:2]1[CH:9]2[CH2:10][CH:5]([C:6]([CH3:11])=[CH:7][CH2:8]2)[CH:4]([OH:12])[CH2:3]1.[Na].[CH3:14]I>O1CCCC1>[CH3:14][O:12][CH:4]1[CH2:3][CH:2]([CH3:1])[CH:9]2[CH2:10][CH:5]1[C:6]([CH3:11])=[CH:7][CH2:8]2
Reactant: CC1=CCC2CC1C(O)CC2C
Reactant: CI
Agent: [Na]
Solvent: C1CCOC1
Product: COC1CC(C)C2CC=C(C)C1C2
Temperature: 40 °C
Yield: 71.9 %

Procedure:
To a solution of 10 g (60.2 mmol) of 4,8-dimethylbicyclo[3.3.1]nona-7-en-2-ol [IA] in 60 ml of tetrahydrofuran were added 1.3 g (56.5 mmol) of sodium and the resulting mixture was heated with stirring at 40° C. After the sodium was dissolved, 12.8 g (90 mmol) of methyl iodide were added dropwise and the resulting mixture was heated with stirring at 40° C. for 10 hours. After cooling, the tetrahydrofuran was distilled off under reduced pressure, the residue was subjected to column chromatography and eluate with toluene gave 7.8 g of the title compound, which had a refrigerant and camphor-like smell.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][N:8]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:9]1([C:17](O)=[O:18])[CH2:15][CH:14]2[O:16][CH:11]([CH2:12][CH2:13]2)[CH2:10]1)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:40])=O.CN(C)C=O>ClCCl>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][CH2:7][N:8]([C:9]1([C:17]([Cl:40])=[O:18])[CH2:15][CH:14]2[O:16][CH:11]([CH2:12][CH2:13]2)[CH2:10]1)[S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH3:2]
Reactant: CCOC(=O)CCN(C1(C(=O)O)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C1(C(=O)Cl)CC2CCC(C1)O2)S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Reaction time: 8 h

Procedure:
A solution of 15.1 mmoles of the product from Step E in 73 mL of dichloromethane is treated with 1.4 mL (17 mmol, 1.1 equivalents) of oxalyl chloride and 0.02 mL (0.3 mmol, 0.02 equivalents) of dimethylformamide at ambient temperature, causing some bubbling, and is stirred overnight. The resulting solution of the title compound is used in step G without isolation.
Reaction SMILES: C([C:3]1[CH:18]=[C:17]([C:19](=[NH:22])[NH:20][OH:21])[CH:16]=[C:15]([CH3:23])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.[OH:24][C:25]1C(C)=CC(C#N)=CC=1OC>>[OH:12][CH2:11][C:10]([NH:9][CH2:8][C@H:7]([OH:14])[CH2:6][O:5][C:4]1[C:15]([CH3:23])=[CH:16][C:17]([C:19](=[NH:22])[NH:20][OH:21])=[CH:18][C:3]=1[O:24][CH3:25])=[O:13]
Reactant: COc1cc(C#N)cc(C)c1O
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Product: COc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO

Procedure:
The title compound is obtained as a reddish oil (1.3 g) in analogy to N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide starting from 4-hydroxy-3-methoxy-5-methyl-benzonitrile; LC-MS: tR=0.49 min, [M+H]+=327.98.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][C:10]2[C:11]([F:35])=[C:12]([CH2:17][NH:18][C:19]([C:21]3[N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:24]=[N:23][C:22]=3[Cl:34])=[O:20])[CH:13]=[CH:14][C:15]=2[Cl:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:36](O)[CH2:37]C>>[Cl:34][C:22]1[N:23]=[CH:24][N:25]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:21]=1[C:19]([NH:18][CH2:17][C:12]1[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([O:9][C:4]2[CH:3]=[C:2]([CH:36]=[CH2:37])[CH:7]=[C:6]([Cl:8])[CH:5]=2)[C:11]=1[F:35])=[O:20]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1F
Reactant: CCCO
Product: C=Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a solution of N-({3-[(3-bromo-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (320 mg, 0.513 mmol), potassium vinyl trifluoroborate (69.2 mg, 0.513 mmol) and TEA (0.214 ml, 1.539 mmol) in n-propanol (3 ml) was added 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (84 mg, 0.103 mmol) and the reaction mixture was stirred at 100° C. for 4 hours. The mixture was adsorbed onto silica gel and the crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (246 mg, 0.431 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.74 (t, 1H), 7.95 (s, 1H), 7.40-7.55 (m, 1H), 7.22-7.39 (m, 2H), 6.99 (s, 1H), 6.72-6.81 (m, 1H), 6.64 (dd, 1H), 5.89 (d, 1H), 5.46 (s, 2H), 5.32 (d, 1H), 4.45 (d, 2H), 3.35 (t, 2H), 0.72 (t, 2H), −0.12 (s, 9H).
Reaction SMILES: OS(O)(=O)=O.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.[CH3:19][C@H:20]1[C@H:25]([OH:26])[CH2:24][C@@H:23]2[CH2:27][C@H:21]1[C:22]2([CH3:29])[CH3:28]>O.CC(C)=O>[CH3:19][C@H:20]1[C:25](=[O:26])[CH2:24][C@@H:23]2[CH2:27][C@H:21]1[C:22]2([CH3:28])[CH3:29]
Reactant: C[C@H]1[C@H](O)C[C@@H]2C[C@H]1C2(C)C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: C[C@H]1C(=O)C[C@@H]2C[C@H]1C2(C)C
Yield: 93.3 %

Procedure:
add a mixture of 9 ml of H2SO4 and 40 ml of H2O to a solution of Cr2O3 (15.0 g, 0.15 mol) in H2O (20 mL) at 0° C. Add dropwise the above Jones reagent to a solution of (1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-ol (23.1 g, 0.15 mol) in acetone (100 mL) over a period for 2 hours at 0° C. Stir the resultant mixture for additional 1 hour. Dilute the mixture with 100 mL of water and then extract the aqueous mixture with ether (50 mL×3). The combined organic layers are washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give crude (1R,2R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-one as pale yellow oil (21.3 g, yield: 93.4%), MS (m/z): 151 (M−1).