Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][S:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([CH2:17][CH3:18])[N:13]2[CH3:16])=[C:9]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:8]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38].O>O1CCCC1>[C:37]([NH:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][S:6][C:7]1[N:15]=[C:14]2[C:10]([N:11]=[C:12]([CH2:17][CH3:18])[N:13]2[CH3:16])=[C:9]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:8]=1)(=[O:39])[CH3:38]
Reactant: CCc1nc2c(N3CCOCC3)nc(SCc3ccc(OC)c(N)c3)nc2n1C
Reactant: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nc2c(N3CCOCC3)nc(SCc3ccc(OC)c(NC(C)=O)c3)nc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
2-(3-amino-4-methoxybenzylsulfanyl)-8-ethyl-9-methyl-6-morpholino-9H-purine (100 mg, 0.24 mmol) was dissolved in tetrahydrofuran (10 ml), triethylamine (49 mg, 0.48 mmol) and acetyl chloride (38 mg, 0.48 mmol) were added and stirred at room temperature overnight. After adding water to the reaction solution and extracting twice with ethyl acetate, the organic layers were washed with a saturated saline solution and dried with MgSO4. After distilling away the solvent under reduced pressure, purification was performed by silica gel column chromatography (ethyl acetate:hexane=1:1) to obtain 77 mg (70% yield) of Compound 27.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[N:6][CH:7]=1.[BH4-].[Na+].O.[NH3:14]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:14])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: N
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(N)c1cncc(Br)c1
Temperature: 0 °C

Procedure:
To a solution of 1-(5-bromo-pyridin-3-yl)-ethanone (400 mg, 2 mmol) in methanolic ammonia (10 mL) was added Ti(O-iPr)4 (1.14 g, 4 mmol). The resulting reaction mixture was heated to reflux and stirred over night. After cooling at 0° C., NaBH4 was added into the mixture and it was allowed to warm up to room temperature and stirred for 3 hours. Water was added and the reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. It was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[N:8]=[C:9]3[N:19]([CH:20]=2)[CH2:18][CH2:17][O:16][C:15]2[C:10]3=[CH:11][CH:12]=[C:13]([C:21]([NH2:23])=[O:22])[CH:14]=2)[N:4]([CH:24]([CH3:26])[CH3:25])[N:3]=1.[CH3:27][N:28]([CH:30](OC)OC)[CH3:29]>O1CCOCC1>[CH3:27][N:28](/[CH:30]=[N:23]/[C:21]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[C:9]1[N:19]([CH:20]=[C:7]([C:5]3[N:4]([CH:24]([CH3:26])[CH3:25])[N:3]=[C:2]([CH3:1])[N:6]=3)[N:8]=1)[CH2:18][CH2:17][O:16]2)=[O:22])[CH3:29]
Reactant: COC(OC)N(C)C
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(C(N)=O)cc2OCC3)n(C(C)C)n1
Solvent: C1COCCO1
Product: Cc1nc(-c2cn3c(n2)-c2ccc(C(=O)/N=C/N(C)C)cc2OCC3)n(C(C)C)n1
Temperature: 100 °C
Yield: 77.8 %

Procedure:
To a solution of 4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-12-carboxamide (200 mg, 0.568 mmol) in dioxane (20 mL) was added DMF-DMA (0.2 mL, 1.7 mmol). The reaction mixture was heated at 100° C. for 1 h. The solvent was removed under reduce pressure and the resultant residue was triturated with hot diethyl ether. The solid was collected by filtration, washed with diethyl ether, and dried in vacuo to afford N-[(1E)-(dimethylamino)methylidene]-4-[3-methyl-1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-12-carboxamide (180 mg, 78% yield) as a brown solid. LCMS (ESI) m/z: 408.3 [M+H+].
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=1.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>O1CCCC1.CCCCCC.O.C(OCC)(=O)C>[Br:13][C:14]1[C:15]([Si:23]([CH3:26])([CH3:25])[CH3:24])=[C:16]([F:21])[C:17]([F:20])=[CH:18][CH:19]=1
Reactant: C[Si](C)(C)Cl
Reactant: Fc1ccc(Br)cc1F
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)c1c(Br)ccc(F)c1F
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Under nitrogen atmosphere, to a solution of 18.2 mL of N,N-diisopropylamine in 200 mL of tetrahydrofuran was added 66.0 mL of 1.57 M n-butyllithium in hexane at 0° C., and stirred at this temperature for 10 minutes. After cooling to −78° C., a solution containing 20.0 g of 1-bromo-3,4-difluorobenzene in 100 mL of tetrahydrofuran was added dropwise and stirred at this temperature for 30 minutes, stirred at this temperature for 30 minutes, added dropwise with 32.9 mL of chlorotrimethylsilane, and the reaction solution was allowed to warm gradually to room temperature, and stirred for a day. After diluting with water and ethyl acetate, the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (n-hexane)-, to afford 20.3 g of the title compound as a colorless oil.
Reaction SMILES: O[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:35]>>[Cl:35][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:13])[N:5]=[C:4]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)Cc1c(C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1O
Solvent: CN(C)c1ccccc1
Product: COC(=O)Cc1c(C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1Cl
Temperature: 25 °C
Yield: 32.2 %

Procedure:
A solution of methyl [4-hydroxy-6-methyl-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (1.59 g, 5.0 mmol) and N,N-dimethylaniline (0.56 mL, 4.4 mmol) in POCl3 (2.33 mL, 25 mmol) was refluxed for 14 hours. After cooling to room temperature, the reaction mixture was poured into ice-cold saturated K2CO3. The resulting aqueous layer was extracted with EtOAc and the combined organic extracts was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained was chromatographed over silica gel eluting with 20% EtOAc in n-hexane to afford methyl [4-chloro-6-methyl-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (0.54 g, 32% yield) as a white powder.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([C@@H:10]1[CH2:14][C@@H:13]([C@@H:15]([N:24]=[N+:25]=[N-:26])[CH2:16][C@H:17]([C:21](O)=[O:22])[CH:18]([CH3:20])[CH3:19])[O:12][C:11]1=[O:27])([CH3:9])[CH3:8].CN(C)C=O.[NH4+].[Cl-]>C1(C)C=CC=CC=1.O1CCCC1.COCCOCCOC.C(OCC)C.C(O)(=O)C>[CH:7]([C@@H:10]1[CH2:14][C@@H:13]([C@@H:15]([N:24]=[N+:25]=[N-:26])[CH2:16][C@@H:17]([CH:18]([CH3:19])[CH3:20])[CH:21]=[O:22])[O:12][C:11]1=[O:27])([CH3:8])[CH3:9]
Reactant: CC(C)[C@H](C[C@H](N=[N+]=[N-])[C@@H]1C[C@@H](C(C)C)C(=O)O1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)[C@@H]1C[C@@H]([C@H](C[C@H](C=O)C(C)C)N=[N+]=[N-])OC1=O
Temperature: 37 °C
Reaction time: 2 h

Procedure:
1.45 ml of oxalyl chloride are added dropwise at 0° C., with stirring, within a period of 10 minutes, to a solution of 1.7 g of 3(S)-isopropyl-5(S)-(1(S)-azido-3(S)-carboxy-4-methyl-pentyl)-tetrahydrofuran-2-one in 20 ml of toluene. 0.03 ml of dimethylformamide is then added, and the temperature is then increased to 37° C. within a period of 30 minutes. The reaction mixture is stirred for 2 hours at 37° C. and is then clarified by filtration and concentrated by evaporation under reduced pressure at a bath temperature of 30° C. The residue is twice dissolved in 10 ml of toluene and concentrated by evaporation again in the same manner. The crude acid chloride so obtained is dissolved in 5 ml of tetrahydrofuran, and 16 ml of a 0.34M solution of NaAlH(O-tert-bu)3 in diglyme (H. C. Brown et al., J. Org. Chem. (1992) 58.472) are added thereto at -75° C. within a period of 30 minutes. The reaction mixture is stirred for 70 minutes at -75° C., and then a solution of 0.385 ml of glacial acetic acid in 1 ml of tetrahydrofuran is added dropwise at the same temperature, followed by 2.1 ml of saturated NH4Cl solution and then 20 ml of diethyl ether. The reaction mixture is brought to room temperature and is partitioned between diethyl ether and water/saturated sodium chloride solution. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation, and the residue is purified by means of FC (hexane/ethyl acetate=95:5), yielding the title compound: Rf (hexane/ethyl acetate=2:1)=0.55; HPLC Rt =16.41 minutes.
Reaction SMILES: [CH2:1]([NH:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH3:15])[C:8]([CH3:17])([CH3:16])[CH2:7]1)[CH2:2][CH2:3][CH3:4].[Cl:18][CH2:19][C:20](Cl)=[O:21]>ClCCl.C(OCC)C>[CH2:1]([N:5]([CH:6]1[CH2:7][C:8]([CH3:16])([CH3:17])[N:9]([O:14][CH3:15])[C:10]([CH3:13])([CH3:12])[CH2:11]1)[C:20](=[O:21])[CH2:19][Cl:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC1CC(C)(C)N(OC)C(C)(C)C1
Reactant: O=C(Cl)CCl
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCN(C(=O)CCl)C1CC(C)(C)N(OC)C(C)(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
A solution of 48.5 g (0.200 mol) of 4-butylamino-1-methoxy-2,2,6,6-tetramethylpiperidine in 150 ml of dichloromethane is added over a one hour interval at -10° C. to a solution of 11.3 g (0.100 mol) of chloroacetyl chloride in 100 ml of dichloromethane. The reaction mixture is then stirred at ambient temperature for 1 hour. The mixture is diluted with diethyl ether (500 ml), and solids are removed by filtration. The filtrate is washed with 1N hydrochloric acid (2×75 ml) and saturated sodium bicarbonate (100 ml), then dried over magnesium sulfate and concentrated to afford 27.8 g (87% yield) of the title compound, a pale yellow oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:19]=[C:18]([CH:20]=O)[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])[CH:2]=[CH2:3].CN.[C:24]([BH3-])#[N:25].[Na+].[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>CO.C(O)(=O)C>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH2:1]([C:4]1[CH:19]=[C:18]([CH2:20][NH:25][CH3:24])[CH:17]=[CH:16][C:5]=1[O:6][C:7]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])[CH:2]=[CH2:3]
Reactant: [BH3-]C#N
Reactant: C=CCc1cc(C=O)ccc1Oc1cc(Cl)ccc1C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CCc1cc(CNC)ccc1Oc1cc(Cl)ccc1C#N
Yield: 80.8 %

Procedure:
2-(2-Allyl-4-formyl-phenoxy)-4-chlorobenzonitrile (0.09 g, 0.30 mmol), methylamine (33% in ethanol, 0.3 mL, 2.4 mmol) and sodium cyanoborohydride (40 mg, 0.64 mmol) were stirred at ambient temperature in a solution of glacial acetic acid (0.5 mL) in methanol (25 mL) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (36 mg, 0.30 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 2-(2-allyl-4-methylaminomethyl-phenoxy)-4-chlorobenzonitrile fumarate (104 mg, 80%) as a white solid.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][CH:26]=2)[C:6](=[O:24])[C:7]2[CH:13]=[CH:12][C:11]([NH:14]CC3C=CC(OC)=CC=3)=[N:10][C:8]=2[N:9]=1)[CH3:2].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>>[NH2:14][C:11]1[CH:12]=[CH:13][C:7]2[C:6](=[O:24])[N:5]([C:25]3[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:29][CH:30]=3)[C:4]([S:3][CH2:1][CH3:2])=[N:9][C:8]=2[N:10]=1
Reactant: CCSc1nc2nc(NCc3ccc(OC)cc3)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCSc1nc2nc(N)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Yield: 60 %

Procedure:
2-(Ethylsulfanyl)-7-[(4-methoxybenzyl)amino]-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidin-4(3H)-one (63 mg) and anisole (26 μl) were added to trifluoroacetic acid (1 ml), and the mixture was heated under reflux for 1 hr and 30 min. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (29 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]([N:16]=[C:17]=S)([CH3:15])[CH3:14]>C(OCC)(=O)C>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9](=[O:11])(=[O:10])[N:12]=[C:17]([NH:16][CH:13]([CH3:15])[CH3:14])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(F)ccc1S(N)(=O)=O
Reactant: CC(C)N=C=S
Solvent: CCOC(C)=O
Product: CC(C)NC1=NS(=O)(=O)c2ccc(F)cc2N1
Temperature: 140 °C
Yield: 13.8 %

Procedure:
A mixture of 2-amino-4-fluorobenzenesulfonamide (1.9 g, 10 mmol) and isopropyl isothiocyanate (6.4 ml, 60 mmol) was heated at 140° C. for 2.5 h. The mixture was cooled to room temperature and stirred with 50 ml of ethyl acetate for 20 min. The precipitate was isolated by filtration and washed with ethyl acetate to give 355 mg (14%) of the title compound; m.p. 266-269° C.; 1H-NMR (DMSO-d6): δ 1.18 (d, 6H, CH(CH3)2), 3.91 (m, 1H, CH(CH3)2), 7.00-7.13 (m, 2H, ArH), 7.16 (br.s, 1H, NH), 7.73 (dd, 1H, ArH), 10.4 (br.s, 1H, NH); MS: m/e 257 (M+, 25%); (C10H12N3F1O2S1) calc. C, 46.68; H, 4.70; N, 16.33; found C, 46.84; H, 4.88; N, 16.13.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([Cl:26])[CH:24]=4)[CH:19]=[N:18]3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-n3ncc4ccc(Cl)cc43)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-n3ncc4ccc(Cl)cc43)nc12
Reaction time: 15 h
Yield: 56.9 %

Procedure:
To a stirred solution of N-tert-butyl-2-(6-chloro-1H-indazol-1-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (120 mg, 240 μmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 15 h, the mixture was concentrated in vacuo then 25 mL of a Jan. 10, 1960 mixture of ammonium hydroxide/methanol/dichloromethane added. After 1 h the mixture was concentrated in vacuo. Purification by chromatography (silica, 24 g Analogix column, 0 to 5% of a solution of methanol containing 10% ammonium hydroxide in dichloromethane) gave 2-(6-chloro-indazol-1-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid tert-butylamide (50.4 mg, 57%). MS: (M+H)+=369; 1H NMR (DMSO-d6) δ: 8.97 (s, 1H), 8.57 (s, 2H), 8.43 (s, 1H), 8.00 (dd, J=8.5, 0.5 Hz, 1H), 7.61 (s, 1H), 7.41 (dd, J=8.5, 1.8 Hz, 1H), 1.50 (s, 9H).
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[NH:5][CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)=[CH2:15].C(OCC)(=O)C>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[N:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH:14]=[CH2:15])=[CH:17][CH:18]=1)(=[O:24])=[O:23])[CH3:2]
Reactant: C=Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1ccccc1NCC(C)C
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=Cc1ccc(S(=O)(=O)N(CC(C)C)c2ccccc2CC)cc1

Procedure:
2-ethyl-N-isobutylaniline (83 mg, 0.468 mmol) was dissolved in pyridine (3 mL) add 4-vinylbenzene-1-sulfonyl chloride (114 mg, 0.562 mmol) added. Reaction stirred for over the weekend. Ethyl acetate (10 mL) was added to the solution and the organic phase was washed with water (10 mL), sodium hydroxide solution (2M, 2×10 mL) and brine (10 mL), then dried and concentrated under vacuum to provide the product, 129 mg. LCMS [LCMS1] Rt 1.43 min, m/z (ES+) 344 (M+H).
Reaction SMILES: [OH-].[K+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH2:8][C:9]#[N:10].[N+:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-])=[O:12].C(O)(=O)C>CO.O>[OH:12][N:11]=[C:14]1[CH:19]=[CH:18][C:17](=[C:8]([C:4]2[S:3][CH:7]=[CH:6][CH:5]=2)[C:9]#[N:10])[CH:16]=[CH:15]1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: N#CCc1cccs1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: N#CC(=C1C=CC(=NO)C=C1)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
9.5 g of KOH are dissolved in 50 ml of methanol. To the solution are added 5 g (41 mmol) of thiophene-2-acetonitrile followed by 4.2 ml (41 mmol) of nitrobenzene. After the reaction mixture is stirred at room temperature for 2 hrs, 200 ml of water are added with stirring. The resulting solution is acidified by addition of 30 ml of acetic acid in 25 ml of water, leading to a dark orange precipitate. The mixture is then filtered, and the solid is washed with a mixture of methanol and water, and methanol. The crude product is dried in air and recrystallized from toluene. 4.7 g (50%) of (4-Hydroxyimino-cyclohexa-2,5-dienylidene)-thiophen-2-yl-acetonitrile are obtained in the form of a dark orange powder having a melting point of 151-155° C. (dec.).
Reaction SMILES: COC([C@@]12C(C)(C)[C@@H](CC1)C=C2[C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22]([CH3:30])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:23])=[CH:16][C:15]=1[O:31][CH3:32])=O.FC(F)(F)S(O[C:39]1[C@@H:40]2[C:45]([CH3:47])([CH3:46])[C@:43]([CH3:48])([CH:44]=1)[CH2:42][CH2:41]2)(=O)=O>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>[CH3:32][O:31][C:15]1[CH:16]=[C:17]([C:22]([CH3:23])([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:30])[CH:18]=[C:19]([O:20][CH3:21])[C:14]=1[C:39]1[C@@H:40]2[C:45]([CH3:47])([CH3:46])[C@@:43]([CH3:48])([CH2:42][CH2:41]2)[CH:44]=1
Reactant: CCCCCCC(C)(C)c1cc(OC)c(C2=C[C@@H]3CC[C@@]2(C(=O)OC)C3(C)C)c(OC)c1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C=C2OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCCCCCC(C)(C)c1cc(OC)c(C2=C[C@]3(C)CC[C@H]2C3(C)C)c(OC)c1

Procedure:
The title compound was prepared by the general procedure described for compound 11a (HU-911), using pinacol arylboronate 3 (mixed with 4-alkyl resorcinol dimethylether 1) 0.755 g, enol triflate 19a 0.17 g (0.598 mmol), Pd(PPh3)4 0.041 g (0.036 mmol) and t-BuNF 0.9 ml (0.9 mmol, 1M solution in THF). The product was purified by silica gel column chromatography (petroleum ether/ether) to give oil 0.185 g (78%), which solidified upon standing at −20° C. mp 33-34° C.; 1H NMR (300 MHz, CDCl3) δ ppm 6.50 (s, 2H), 5.79 (d, J=3.00 Hz, 1H), 3.76 (s, 6H), 2.60 (d, J=3.51, 1H), 1.81 (m, 1H), 1.64 (m, 1H), 1.60 (m, 1H), 1.55 (m, 2H), 1.31 (m, 1H), 1.28 (s, 6H), 1.17-1.25 (m, 8H), 1.08 (s, 3H), 0.99 (s, 3H), 0.86 (t, J=6.69 Hz, 3H), 0.81 (s, 3H). Exact mass calculated for C27H42O2 m/e 398.32. found 398.82. Anal. calcd. for C27H42O2: C, 81.35; H, 10.62. Found: C, 81.50; H, 10.71.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].C[O:17][C:18]([C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19]>>[CH:7]([Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[O:5][CH2:4][CH2:3][CH2:2][N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[C:20]1[C:18]([OH:19])=[O:17])([CH3:9])[CH3:8]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Reactant: CC(C)[Si](OCCCBr)(C(C)C)C(C)C
Product: CC(C)[Si](OCCCn1c(C(=O)O)cc2ccccc21)(C(C)C)C(C)C

Procedure:
(3-Bromo-propoxy)-triisopropyl-silane (prepared from the corresponding alcohol, Greene, T. W. Protective Groups in Organic Chemistry; John Wiley & Sons, Inc.: New York, 1991) was reacted with 1H-indole-2-carboxylic acid methyl ester using procedures similar to Example 11 to give 1-(3-triisopropylsilanyloxy-propyl)-1H-indole-2-carboxylic acid as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1)#[N:2].C([S:14]P(CC)(=S)O)C.[ClH:20]>C(OCC)(=O)C>[ClH:20].[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([C:1](=[S:14])[NH2:2])=[CH:4]1
Reactant: N#Cc1c[nH]c2ccccc12
Reactant: CCSP(O)(=S)CC
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=S)c1c[nH]c2ccccc12

Procedure:
To a solution of 1.0 g of 3-cyanoindole in 30 ml of ethyl acetate was added 1.1 ml of diethyldithiophosphonic acid. The solution was then saturated with gaseous hydrogen chloride and stirred at room temperature for 18 hours. The thioamide was isolated from the reaction mixture as a tan precipitate and used directly in the following reaction.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:25][C:21]1[CH:20]=[C:19]([CH2:18][CH2:17][CH2:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])[CH:24]=[CH:23][CH:22]=1
Reactant: Clc1cccc(CCCCc2ccccc2OCc2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccccc1CCCCc1cccc(Cl)c1
Yield: 80.6 %

Procedure:
Following a procedure similar to that described in the final part of Preparation 15, a solution of 3.04 g of this 1-(2-benzyloxyphenyl)-4-(3-chlorophenyl)butane in 18 ml of methylene chloride was treated with 8.67 ml of a 1M solution of boron tribromide in methylene chloride to eliminate the benzyl group. The resulting crude product was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.82 g (yield 80%) of the title compound as a colorless oil.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]1([C:13]2[C:21]3[C:16](=[CH:17][C:18]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][CH:20]=3)[NH:15][C:14]=2B2OC(C)(C)C(C)(C)O2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH2:35]([O:42][C:43]1[C:48](Br)=[CH:47][CH:46]=[CH:45][N:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[Li+].[Cl-]>C(O)C.C1(C)C=CC=CC=1.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>[CH2:35]([O:42][C:43]1[C:48]([C:14]2[NH:15][C:16]3[C:21]([C:13]=2[CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:20][CH:19]=[C:18]([C:22]([O:24][CH3:25])=[O:23])[CH:17]=3)=[CH:47][CH:46]=[CH:45][N:44]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: Brc1cccnc1OCc1ccccc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(B3OC(C)(C)C(C)(C)O3)[nH]c2c1
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: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3cccnc3OCc3ccccc3)[nH]c2c1
Temperature: 80 °C
Yield: 70.4 %

Procedure:
2M Na2CO3 (1.25 mL, 2.5 mmol) aqueous solution was added to a suspension of methyl 3-cyclohexyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-6-carboxylate (383 mg, 1.0 mmol), 2-(benzyloxy)-3-bromopyridine (317 mg, 1.2 mmol) and LiCl (84.8 mg, 2.0 mmol), in ethanol (3 mL) and toluene (3 mL). The mixture was degassed by evacuating the reaction flask and then flushing with N2. Pd(PPh3)4 (58 mg, 0.05 mmol) was then added, and the reaction mixture was heated at 80° C. for 6 hr. The reaction mixture was then filtered and concentrated in vacuo, and the resultant residue was purified by silica gel flash chromotagraphy using hexanes to 50% ethyl acetate in hexanes as eluent to afford the title compound as a yellowish solid, (310 mg, 70% yield). MS m/z 441(MH+); 1H NMR (500 MHz, CDCl3) δ ppm 1.32-1.46 (m, 3 H) 1.78-1.93 (m, 5 H) 2.05-2.16 (m, 2 H) 2.96 (m, 1H) 3.92 (s, 3 H) 5.25 (s, 2 H) 6.39 (t, J=6.87 Hz, 1 H) 7.31-7.41 (m, 6 H) 7.60 (dd, J=7.17, 1.98 Hz, 1 H) 7.71 (d, J=8.55 Hz, 1 H) 7.84 (d, J=8.55 Hz, 1 H) 8.07 (s, 1 H) 10.32 (s, 1 H).