Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-])=O.C(O)C>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cc2cc(N)ccc2[nH]1
Reaction time: 9 h
Yield: 85.1 %

Procedure:
A mixture of ethyl 5-nitro-1H-indole-2-carboxylate (15.0 g, 0.0641 mol), 10% palladium-on-carbon catalyst, ethanol (300 ml) and tetrahydrofuran (300 ml) is hydrogenated at an initial pressure of 47 p.s.i. for 9 h and filtered through celite. The filtrate is concentrated and the residue is digested with hot diethyl ether. Concentration of the ether extract gave the titled product (11.14 g): MS (ES) m/z 205 (M+H+), 227 (M+Na+). *Uhlig, F.; Snyder, H. R. Adv. Org. Chem. 1960, 1, 35; Parmerter, S. M.; Cook, A. G.; Dixon, W. B. J. Am. Chem. Soc. 1958, 80, 4621-2.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1.CO.[ClH:31]>[Pd]>[ClH:31].[NH2:11][C@@H:12]([CH2:20][NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14]
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)NC[C@H](N)C(=O)OC(C)(C)C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
13.1 g (33.2 mmol) of (13.8) are hydrogenated in methanol/HCl over 10% Pd/C. After 1.5 h, the mixture is filtered and the filtrate is concentrated in vacuo; 9.77 g (99%) of (13.9) are obtained as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[H-].[Na+].Cl[CH2:15][O:16][CH2:17]Cl>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:15][O:16][CH3:17])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: ClCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 88 %

Procedure:
5-Fluoro-2-nitrophenol (10 g, 63 mmol, 99%) was dissolved in anhydrous DMF (100 mL) in an oven-dried flask. The solution was stirred under an atmosphere of nitrogen and cooled in an ice-water bath. Sodium hydride (3.0 g, 75 mmol) was added with stirring, after which chloro methylether (5.3 g, 66 mmol) was added dropwise. The resulting mixture was aged at room temperature for 1 h. The reaction was quenched with MeOH, diluted with ether and washed with water and brine. The ether layer was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification of the product by silica gel chromatography (hexanes/EtOAc=1/7) gave the title compound in 88% yield. 1H NMR (500 MHz, CDCl3) δ 3.53 (s, 3H), 5.30 (d, J=2.0 Hz, 2H), 6.78 (dd, J=7.3, 9.1 Hz, 1H), 7.06 (dt, J=2.3, 10.4 Hz, 1H), 7.91 (dd, J=6.0, 9.0 Hz, 1H). 13C NMR (126 MHz, CDCl3) δ 57.0, 95.6, 105.0 (d, J=26.3 Hz), 108.8 (d, J=23.0 Hz), 127.8 (d, J=10.7 Hz), 152.8 (d, J=11.5 Hz), 165.5 (d, J=255.9 Hz). HRMS (FAB) calcd for C8H8FNNaO4 (M+Na+) 224.0330. found 224.0328.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.N12CCN(CC1)CC2.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[C:35]([CH2:36][OH:37])=[CH:34][C:33]2[C:28](=[C:29]([CH3:38])[CH:30]=[CH:31][CH:32]=2)[N:27]=1.[H-].[Na+]>CS(C)=O.O>[N:10]1[C:2]([O:37][CH2:36][C:35]2[C:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])=[N:27][C:28]3[C:33]([CH:34]=2)=[CH:32][CH:31]=[CH:30][C:29]=3[CH3:38])=[C:3]2[C:7]([NH:6][CH:5]=[N:4]2)=[N:8][CH:9]=1
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Cc1cccc2cc(CO)c(-c3ccccc3Cl)nc12
Agent: C1CN2CCN1CC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc2cc(COc3ncnc4[nH]cnc34)c(-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Prepared according to procedure L A mixture of 6-chloropurine (75 mg, 0.49 mmol) and 1,4-diazabicyclo[2.2.2]octane (109 mg, 0.97 mmol) in DMSO (0.5 mL) was stirred at rt for 5 h and was then added via cannula to a mixture of (2-(2-chlorophenyl)-8-methylquinolin-3-yl)-methanol (69 mg, 0.24 mmol) and sodium hydride, 60% dispersion in mineral oil (39 mg, 0.97 mmol) in DMSO (0.5 mL) that had been stirred at rt for 15 min prior to the addition. The mixture was stirred at rt for 3.5 h, cooled to 0° C., and H2O (5 mL) was added carefully. The mixture was extracted with EtOAc (3×10 mL), and the combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow oil was dissolved in CH2Cl2, evaporated onto silica gel (deactivated with 2M NH3 in MeOH), and purified by flash chromatography (Biotage® Si 25+M) eluting with 2M NH3 in MeOH/CH2Cl2 (5%) to provide a white solid [PI3Kδ IC50=25 nM]. MS (ESI+) m/z=402.0 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([Cl:15])=[CH:10][CH:11]=2)[C:6]1=NN(C)C.[O-:22]I(=O)(=O)=O.[Na+].C([O-])(=O)C.[Na+].C(O)(=O)C>O1CCCC1.O>[CH3:1][O:2][CH:3]([O:20][CH3:21])[CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([Cl:15])=[CH:10][CH:11]=2)[C:6]1=[O:22]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(CC1CCc2ccc(Cl)cc2C1=NN(C)C)OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COC(CC1CCc2ccc(Cl)cc2C1=O)OC
Temperature: 50 °C
Reaction time: 18 h
Yield: 34.7 %

Procedure:
7-Chloro-1-(dimethylhydrazono)-1,2,3,4-tetrahydro-2-naphthaleneacetaldehyde dimethyl acetal (16.0 g) was dissolved under argon in 700 ml of tetrahydrofuran and 180 ml of water. The solution was treated in succession with 30.8 g of sodium (meta)periodate, 11.8 g of sodium acetate and 120 ml of acetic acid and stirred at 50° C. for 18 hours. Subsequently, 2000 ml of water were added and the mixture was extracted three times with 500 ml of ethyl acetate each time. The organic phases were washed with 500 ml of a saturated sodium chloride solution, combined, dried over MgSO4 and freed from solvent. The crude product, 18.4 g of dark brown oil, was chromatographed on 500 g of silica gel with ethyl acetate/hexane (1:3) as the eluent. There were obtained 4.8 g (35%) of 7-chloro-1,2,3,4-tetrahydro-1-oxo-2-naphthaleneacetaldehyde dimethyl acetal.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]2[CH3:19])=[C:9]([CH2:20][O:21][CH3:22])[CH:8]=1.[C:23](=[O:25])=[O:24]>CCOCC.CCOCC.CCOC(C)=O.O>[CH3:22][O:21][CH2:20][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][C:10]=1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[CH3:19])[C:23]([OH:25])=[O:24]
Reactant: O=C=O
Reactant: COCc1cc(Br)ccc1N1CCCCC1C
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COCc1cc(C(=O)O)ccc1N1CCCCC1C
Reaction time: 0.67 h

Procedure:
To anhydrous Et2O (130 mL) at −78° C. was added tert-butyllithium (63.79 mL; 1.50 M; 95.68 mmol) (solution in pentane) which was followed by the slow addition of a solution of 1-[4-bromo-2-(methoxymethyl)phenyl]-2-methylpiperidine (12.97 g; 43.49 mmol) in anhydrous Et2O (20 mL). After 40 min, the reaction mixture was poured on an excess of freshly crushed dry ice and stirred for 30 min after which time it was diluted with Et2O/EtOAc (1:1, 800 mL), water (200 mL, pH 4-5). The organic layers were combined, dried over MgSO4 and the solvents were removed under reduced pressure to give a yellow oil that was triturated in iPr2O (˜20 mL) and pentane (˜20 mL), filtered off and washed with pentane to give the title compound as a beige powder. LC/MS (Method B): 264.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4]Br.[C-:12]#[N:13].[Na+].O.CCOC(C)=O>CS(C)=O>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH2:4][C:12]#[N:13]
Reactant: [C-]#N
Reactant: COc1ccc(Br)c(CBr)c1
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(Br)c(CC#N)c1
Temperature: 90 °C

Procedure:
2-Bromo-5-methoxybenzyl bromide (2 g, 7.1 mmol) and sodium cyanide (0.526 g, 10.7 mmol) were combined in DMSO (20 mL) and heated to 90° C. for 3 hours. Once no starting material was seen by analytical tlc, the mixture was worked-up with H2O and EtOAc to give the desired product as a colorless oil.
Reaction SMILES: [O:1]1[CH2:15][CH:2]1[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH:11]2[O:13][CH2:12]2)[C:5]=1[OH:14].[OH-].[Na+].F[C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>CC(N(C)C)=O.C(OCC)(=O)C>[C:23]([C:22]1[CH:25]=[CH:26][C:19]([O:14][C:5]2[C:4]([CH2:3][CH:2]3[O:1][CH2:15]3)=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:10][CH:11]2[O:13][CH2:12]2)=[CH:20][CH:21]=1)#[N:24]
Reactant: Oc1c(CC2CO2)cccc1CC1CO1
Reactant: N#Cc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2c(CC3CO3)cccc2CC2CO2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
2,6-Diallylphenol (3.8 gm, 0.02 mol) was oxidized with m-chloroperbenzoic acid as described in Example 1 to give 2,6-di(2,3-epoxypropyl)phenol. MS m/z 206 (M+ calcd for C12H14O3=206). H NMR (300 MHz, CDCl3) d 2.65 (d, 2, CH2 epoxypropyl) 2.75–2.96 (CH2 epoxypropyl), 3.12 (d, 2, CH epoxypropyl), 3.25–3.35(m, 2, CH epoxypropyl), 6.80 (t, 1, aromatic), 7.10 (d, 2, aromatic). The product 2,6-di(2,3-epoxypropyl)phenol was diluted with dimethylacetamide (50 ml) and neutralized with sodium hydroxide. 4-Fluorobenzonitrile (1 equivalent of the phenol) was added and the mixture heated and stirred overnight at 50° C. After cooling, the reaction was diluted with ethyl acetate and washed with water (4×), dried over MgSO4 and evaporated to give 2,6-di(2,3epoxypropyl)phenyl 4-cyanophenyl ether. MS m/z 307 (M+ calcd for C19H17O3N=307). H NMR (300 MHz, CDCl3) d 2.50, (d, 2, CH2 epoxypropyl CH2), 2.65–2.90 (m, 4, CH2 epoxypropyl), 3.15–3.30 (m, 2, CH2 epoxypropyl), 3.45–3.75 (m, 2, epoxypropyl CH), 6.75–7.06 (m, 3, aromatic), 7.00–7.75 (m, 4, aromatic).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([C:14]2[O:18][N:17]=[C:16]([Br:19])[CH:15]=2)[O:7][C@H:6]1[N:20]1[CH:28]=[N:27][C:26]2[C:21]1=[N:22][CH:23]=[N:24][C:25]=2[NH:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[F:37])(=O)C.C(N)(C)(C)C>CO>[Br:19][C:16]1[CH:15]=[C:14]([C@@H:8]2[C@@H:9]([OH:10])[C@@H:5]([OH:4])[C@H:6]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[F:37])[O:7]2)[O:18][N:17]=1
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](c2cc(Br)no2)O[C@H]1n1cnc2c(Nc3ccc(Cl)cc3F)ncnc21
Solvent: CC(C)(C)N
Solvent: CO
Product: O[C@@H]1[C@H](O)[C@@H](c2cc(Br)no2)O[C@H]1n1cnc2c(Nc3ccc(Cl)cc3F)ncnc21
Yield: 110.9 %

Procedure:
(2R,3 R,4R,5S)-4-(acetyloxy)-5-(3-bromoisoxazol-5-yl)-2-[6-(4-chloro-2-fluoroanilino)-9H-purin-9-yl]tetrahydrofuran-3-yl acetate (16.8 mg) was treated with t-butylamine (0.08 ml) in methanol (0.8 ml) at 0° C. for 1.5 h, and the mixture was evaporated to dryness to give the title compound (16 mg).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>CN(C=O)C.CCOC(C)=O>[Si:22]([O:1][CH:2]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[CH2:3]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: O=C(OCc1ccccc1)C1CCC(O)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC1CCC(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of benzyl 3-hydroxycyclopentanecarboxylate (1.0 g, 4.54 mmol) in 9 ml of degassed DMF was added imidazole (0.34 g, 4.99 mmol) and tert-butyldimethylsilyl chloride (0.75 g, 4.99 mmol). The mixture was stirred at ambient temperature for 4 hours, and then poured into 70 mL of water, and extracted with ethyl acetate. The combined ethyl acetate extracts were washed with water and brine and then dried over sodium sulfate. Filtration and concentration afforded the crude product which was subjected to chromatography on silica gel eluting with 5% EtOAc in hexanes to give benzyl 3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentanecarboxylate.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:4][N:5](S(C2C=NC=CC=2)(=O)=O)[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[OH-].[Na+]>O1CCCC1.CC(O)C>[F:1][C:2]1[C:3]([CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccnc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 108 %

Procedure:
tert-Butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (1.0 g) was dissolved in tetrahydrofuran (8 mL) and 2-propanol (2 mL), and 1 mol/L aqueous sodium hydroxide solution (5 mL) was added under ice-cooling. After stirring at room temperature for 18 hr, the solvent evaporated under reduced pressure, water was added to the residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 752 mg, quantitative).
Reaction SMILES: [OH-].[Na+].O.[C:4]1([C:10]2([CH2:15][NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:17](=S)=[S:18]>>[C:4]1([C:10]2([CH2:15][N:16]=[C:17]=[S:18])[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCC1(c2ccccc2)CCCC1
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: S=C=NCC1(c2ccccc2)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 parts of sodium hydroxide and 300 parts of water is cooled to ±10° C. and there are added successively 41.8 parts of carbon disulfide and then dropwise 95 parts of 1-phenyl-cyclopentylmethylamine (exothermic reaction). Upon completion, the cooling-bath is removed and the whole is stirred at 30 minutes at room temperature. Then there are added dropwise at 30° C., 54.25 parts of ethyl chloroformate (exothermic reaction: cooling is necessary). The whole is stirred for 3 hours at 50° C. The reaction mixture is cooled and the product is extracted with benzene. The extract is dried, filtered and evaporated. The oily residue is distilled, yielding 86 parts of (1-phenylcyclopentylmethyl)isothiocyanate; bp. 125° C. at 0.2 mm pressure; nD20 :1.5848; d2020 :1.0910.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:12][CH:11]=1.C(O)(=O)C.C1C(=O)N([Br:38])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:38][C:18]1[S:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:6]3[S:7][CH:8]=[CH:9][C:5]=3[CH2:4][C:3]([O:2][CH3:1])=[O:26])=[CH:11][CH:12]=2)=[C:20]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=1
Reactant: COC(=O)Cc1ccsc1-c1ccc(-c2sccc2CC(=O)OC)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)Cc1ccsc1-c1ccc(-c2sc(Br)cc2CC(=O)OC)cc1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Intermediate R (1.13 g, 2.92 mmol) was dissolved in CHCl3 (5 ml), acetic acid (5 ml) was added and the solution was cooled to 0° C. NBS (0.53 g, 2.92 mmol) was added and the mixture was left to slowly reach ambient temperature. After 14 hrs, the reaction mixture was diluted with CH2Cl2 (20 ml), washed with water/brine (30:1-60 ml), dried with MgSO4 (s), filtered and evaporated to dryness to obtain the crude product. The residue was purified by flash chromatography using toluene/EtOAc 100:1→40:1) as eluent. Yield: 0.54 g (40%); off-white solid. 1H NMR (400 MHz, CDCl3): δ 3.63 (s, 2H), 3.69 (s, 2H), 3.73 (s, 3H), 3.74 (s, 3H), 7.06 (s, 1H), 7.09 (d, J 5.3 Hz, 1H), 7.30 (d, J 5.3 Hz, 1H), 7.45-7.48 (m, 2H), 7.51-7.54 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:16](=[O:17])[N:15]([CH3:18])[C:13](=[O:14])[C:12]=2[O:19][CH3:20])=[CH:3]1.[Na+].[I-].[C:23](OCC)(=O)[CH3:24]>>[CH3:23][CH2:24][CH2:20][O:19][C:12]1[C:13](=[O:14])[N:15]([CH3:18])[C:16](=[O:17])[C:11]=1[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: COC1=C(c2cn(C)c3ccccc23)C(=O)N(C)C1=O
Agent: [I-]
Agent: [Na+]
Product: CCCOC1=C(c2cn(C)c3ccccc23)C(=O)N(C)C1=O

Procedure:
Into ethyl acetate was dissolved IM-8 (42 g) which was obtained as described above. NaI (42.5 g) was added. This mixture was refluxed for three hours. The reaction mixture was concentrated, and then refined with silica gel column chromatography (ethyl acetate/hexane) to obtain 36.3 g of IM-9.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([Si:9]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32]C)[CH:27]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24]C)[CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.[OH-].[Na+].[Na+].[Cl-]>C(Cl)Cl>[OH:16][C:12]1[CH:11]=[C:10]([Si:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=2)([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COc1cccc([Si](c2cccc(OC)c2)(c2cccc(OC)c2)c2cccc(OC)c2)c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc([Si](c2cccc(O)c2)(c2cccc(O)c2)c2cccc(O)c2)c1
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of tetrakis (3-methoxyphenyl) silane (4.5 g, 0.001 mol) in CH2Cl2 (80 ml) was added BBr3 (50 ml of 1M CH2Cl2 solution) dropwise at −78° C. The mixture was allowed to room temperature and stirred overnight. The reaction mixture was poured into 2N NaOH 50 ml), and extracted with CH2Cl2. The aqueous layer was acidified with 5N HCl, and extracted with ethyl acetate. The organic layer was dried with MgSO4 and evaporated to give brown solid. Yield 95%. 1 H NMR (acetone) 6.95 ppm (CH aromatic), 6.98 ppm (CH aromatic), 7.2 ppm (CH aromatic), 7.4 ppm (CH aromatic), 8.4 (OH). IR (NaCl plate) 3300 cm−1, 3600 cm−1 (O—H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5](=[O:8])[CH2:6][CH3:7].C(O)C.[CH3:13][NH:14][CH3:15]>>[CH3:13][N:14]([CH3:15])[C:3](=[O:2])[CH2:4][C:5](=[O:8])[CH2:6][CH3:7]
Reactant: CNC
Reactant: CCC(=O)CC(=O)OC
Solvent: CCO
Product: CCC(=O)CC(=O)N(C)C
Temperature: 100 °C
Reaction time: 24 h

Procedure:
0.8 mol (100 ml) methyl-3-oxovalerate (3-oxo-pentanoic acid methylester) and 250 ml 33% dimethylamine solution in ethanol (approx. 1.4 mol dimethylamine) was stirred for 4 hours at 110° C. in a pressure reactor. After cooling off, the solvents were distilled off on a rotavap, the raw products were taken up in 40 ml water, 30 ml 32% HCl and 40 ml ethanol and stirred for 24 hours at 100° C. The mixture was again concentrated to dryness by evaporation, taken up again in 300 ml acetic ester and filtrated. The filtrate was concentrated to dryness by evaporation and the product was completely dried under an oil-pump vacuum. 25.8 g of the title compound was obtained.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].Cl[SiH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([F:32])[CH:23]=3)[CH2:18][CH2:17]2)[CH2:8][CH2:7]1>C1COCC1>[F:32][C:24]1[CH:23]=[C:22]([C@H:19]2[CH2:20][CH2:21][C@H:16]([CH2:15][CH2:14][CH2:13][CH2:12][C@H:9]3[CH2:8][CH2:7][Si@H:6]([CH2:1][CH3:2])[CH2:11][CH2:10]3)[CH2:17][CH2:18]2)[CH:27]=[CH:26][C:25]=1[O:28][CH:29]([F:30])[F:31]
Reactant: Fc1cc([C@H]2CC[C@H](CCCCC3CC[SiH](Cl)CC3)CC2)ccc1OC(F)F
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CC[Si@H]1CC[C@H](CCCC[C@H]2CC[C@H](c3ccc(OC(F)F)c(F)c3)CC2)CC1

Procedure:
130 ml (0.13 moles) of a THF solution of 1M of ethylmagnesium bromide was dropped in a mixed solution of 43.3 g (10 mmols) of 1-chloro-4-(4-(trans-4-(3-fluoro-4-difluoromethoxyphenyl)cyclohexyl)butyl)-1-silacyclohexane and 30 ml of THF. The resultant product was found to be a mixture of trans and cis isomers with respect to the silacyclohexane ring. The product was subjected to ordinary aftertreatments, followed by isolation through chromatography to obtain 42.7 g (yield: 87%) of the intended trans isomer product.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])[N:5]=[CH:4][C:3]=1[NH:16][C@@H:17]1[CH2:22][C@@H:21]2[CH2:23][C@@H:19]([C:20]2([CH3:25])[CH3:24])[C@H:18]1[CH3:26].[OH-].[Na+].C(OCC)(=O)C>O1CCOCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[N:5]=[CH:4][C:3]=1[NH:16][C@@H:17]1[CH2:22][C@@H:21]2[CH2:23][C@@H:19]([C:20]2([CH3:25])[CH3:24])[C@H:18]1[CH3:26]
Reactant: CCOC(=O)CCn1ncc(N[C@@H]2C[C@@H]3C[C@H]([C@H]2C)C3(C)C)c(Br)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCC(=O)O)c(=O)c1Br)C2(C)C
Yield: 74.4 %

Procedure:
Ethyl 3-{5-bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}propanoate (453 mg, 1.06 mmol) in 1,4-dioxane (4 mL) was stirred with 1 M aqueous sodium hydroxide (2.93 mL, 2.93 mmol) at room temperature for 1 hour. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with 1 M hydrochloric acid and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give the desired product (314 mg, 80% yield).
Reaction SMILES: [CH:1]([CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5]1=[O:14])=[O:2].S(=O)(O)[O-].[Na+].[C-:20]#[N:21].[Na+]>O.CCOCC>[C:20]([CH:1]([OH:2])[CH2:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[C:5]1=[O:14])#[N:21]
Reactant: CN1C(=O)C(CC=O)c2ccccc21
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CN1C(=O)C(CC(O)C#N)c2ccccc21
Temperature: 25 °C

Procedure:
89 Grams of 3-formylmethyl-1-methyloxindole and 54 g of sodium bisulfite was dissolved in a mixed solvent of 75 ml of water with 150 ml of ether, then to the resultant mixture was added dropwise a solution of 28 g of sodium cyanide with 60 ml of water, under stirring at a room temperature. The reaction mixture was stirred for 1 hour, then water was added to the reaction mixture until the crystals formed were dissolved, the whole reaction mixture was further stirred for 1 hour. The crystals formed were collected by filtration, washed with water, dried and recrystallized from benzene to obtain 30 g of 3-(2-cyano2-hydroxyethyl)-1-methyloxindole in the form of white powdery substance. Melting point: 136°-138°C.)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CN(C)[C:12](=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>O.CCOCC>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:21])=[CH:14][CH:15]=1
Reactant: COc1ccc(C(=O)N(C)C)cc1
Reactant: c1ccc2[nH]ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C(=O)c2c[nH]c3ccccc23)cc1
Yield: 56 %

Procedure:
2.6 g of indole and 8.6 g of N,N-dimethylanisamide were added to 2.6 ml of phosphorus oxychloride. The mixture was heated at 80°-85° C. for 3 hours. After cooling,50 ml of ether was added to the mixture. The reaction mixture was then poured into water and pH value was adjusted to 10 with aqueous solution of sodium hydroxide. The resulting precipitate was filtered out and then recrystallized from ethanol to obtain compound 1 in the form of white crystals. (Yield: 56%)