Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24]I)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:26]#[N:27].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[CH2:24][C:26]#[N:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CI)N(C(=O)OCc2ccccc2)C1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CC#N)N(C(=O)OCc2ccccc2)C1

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-iodomethyl-4-t-butyldimethylsilyloxypyrrolidine (110 g) in dry dimethylformamide (300 ml), sodium cyanide (10.29 g) was added, and the resultant mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hypochlorite solution and aqueous sodium chloride solution in order and dried over magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column chromatography to give (2R,4R)-1-benzyloxycarbonyl-2-cyanomethyl-4-t-butyldimethylsilyloxypyrrolidine.
Reaction SMILES: [O-:1][O-:2].[Na+].[Na+].[C:5]([N:9]=[N:10][C:11]1(Cl)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([N:9]=[N:10][C:11]1([O:1][O:2][C:11]2([N:10]=[N:9][C:5]([CH3:8])([CH3:7])[CH3:6])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Reactant: [O-][O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)N=NC1(OOC2(N=NC(C)(C)C)CCCCC2)CCCCC1
Yield: 100.1 %

Procedure:
To a solution of 0.78 grams (.01 moles) of sodium peroxide in 30 ml. of methanol, cooled to 10° C in a 50 ml. erlenmeyer flask immersed in a cold water bath was added 4.3 grams (.0213 moles) of 1-t-butylazo-1-chlorocyclo-hexane dropwise and with rapid stirring holding the temperature at 10°-15° C. After the addition was complete, the reaction was stirred for 1 hour at 5° C. It was then poured in 250 ml. of ice cold water and the product extracted with pentane. The pentane layer was separated, washed with saturated (NH4)2SO4, water, saturated NaHCO3, water, dried, filtered and the pentane evaporated under reduced pressure to give 3.67 grams (85% yield) of crude di[1-(t-butylazo)cyclohexyl] peroxide. The infrared spectrum indicated the product was contaminated to a small extent by 1-t-butylazo-1-methoxy-cyclohexane which resulted from the chloro compound reacting to a small extent with the methanol solvent.
Reaction SMILES: CC[O-].[Na+].Cl.[CH:6]([NH2:8])=[NH:7].C[CH2:10][CH:11]([C:16](OCC)=[O:17])[C:12](OC)=[O:13]>C(O)C>[OH:13][C:12]1[C:11]([CH3:10])=[C:16]([OH:17])[N:8]=[CH:6][N:7]=1
Reactant: CCOC(=O)C(CC)C(=O)OC
Reactant: N=CN
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1c(O)ncnc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
102 ml (282 mmoles) of a solution of sodium ethylate at 21% in ethanol is added to a solution of 7.5 g (94 mmoles) of formamidine hydrochloride in 250 ml of ethanol cooled down to 0° C. and the mixture is stirred for 30 minutes; then a solution of 13 ml (94 mmoles) of diethyl methyl malonate in 50 ml of ethanol is added followed by stirring overnight at ambient temperature. The reaction mixture is evaporated to dryness under reduced pressure (2 kPa) and the residue is taken up in ethyl acetate, water and acetic acid in order to adjust the pH to 6. The precipitate is filtered then washed successively with water, isopropanol, diethyl ether and finally with pentane. 7 g (Yield=60%) of expected product is obtained in the form of a beige solid.
Reaction SMILES: [CH3:1][C:2]([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([O:28][C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)=[C:11]([O:26][CH3:27])[C:12]=2[O:24][CH3:25])[CH2:7][CH2:6]1)=[O:3].OP(O)(O)=O.[OH-].[Na+]>O>[CH3:1][C:2]([NH:4][C@@H:5]1[C:21]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[C:18]([CH:20]=2)=[O:19])[C:13]2[C:8](=[CH:9][C:10]([OH:28])=[C:11]([O:26][CH3:27])[C:12]=2[O:24][CH3:25])[CH2:7][CH2:6]1)=[O:3]
Reactant: COc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc2c(c1OC)-c1ccc(OC)c(=O)cc1[C@@H](NC(C)=O)CC2
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(O)cc2c(c1OC)-c1ccc(OC)c(=O)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.3 %

Procedure:
A mixture of 250 mg of colchicoside and 2 ml of 85-86% H3PO4 is stirred at 25° C. for 24 hours. The yellow solution is diluted with 10 ml of water, adjusted to pH 5 by addition of 2N NaOH and extracted with methylene chloride. The extracts are dried (Na2SO4), evaporated and chromatographed on Al2O3 (basic, Alfa Division, CH2C12 /MeOH=95:5). The appropriate fractions after evaporation of solvent and crystallization from acetone afford 180 mg (89%) of 3-demethylcolchicine: mp 176°-177° C. (resolidification at 205°-210° C. and 2nd mp 270° C. (dec.), [α]D =-151° (solvate crystal, CHCl3).
Reaction SMILES: O.C(O)(=O)C.[Cl:6][C:7]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:8]=1[CH:9]([OH:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17].CO.O.C>O.[O-2].[Cr+6].[O-2].[O-2]>[Cl:6][C:7]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:8]=1[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH3:17])=[O:18]
Reactant: COc1ccccc1C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1ccccc1C(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 1 h

Procedure:
A solution of chromium(VI) oxide (91.0 g, 0.919 mol) in a water/acetic acid solution (1:4) is added portionwise to 2-chloro-2'-methoxy-5-nitrobenzhydrol (64.2 g, 0.219 mol) while maintaining the reaction mixture temperature at 25° C. to 35° C. The reaction mixture is then stirred at 25° C. to 35° C. for one hour, cooled, diluted with water, and concentrated in vacuo to obtain a residue. The residue is diluted with water, and extracted with methylene chloride. The organic extracts are combined, dried over anhydrous sodium sulfate, mixed with silica gel (10 g), and filtered. The filtrate is concentrated in vacuo to obtain an oil. A solution of the oil in a methanol/water solution is decolorized with charcoal and concentrated in vacuo to yield a residue. Column chromatography of the residue using silica gel and methylene chloride/hexanes solutions gives the title product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[S:11][C:10]([C:12]#[N:13])=[C:9]([OH:14])[C:7]=3[S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]3[S:11][C:10]([C:12]#[N:13])=[C:9]([O:14][CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:7]=3[S:8][C:4]=2[CH:3]=1
Reactant: N#Cc1sc2c(sc3cc(Cl)ccc32)c1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1c(C#N)sc2c1sc1cc(Cl)ccc12
Yield: 90 %

Procedure:
A solution of 6-chloro-3-hydroxythieno[3,2-b][1]benzothiophene-2-carbonitrile (200 mg, 0.8 mmol), potassium carbonate (156 mg, 1.5 eq), methyl bromoacetate (110 μL, 1.5 eq) in DMF was heated at 60° C. for 1.5 h. The solution was diluted with ethyl acetate, washed with water and brine, dried, filtered, evaporated, and flash chromatographed (20-30% ethyl acetate/hexanes) to provide methyl [(6-chloro-2-cyanothieno[3,2-b][1]benzothien-3-yl)oxy]acetate (230 mg, 90%) as a white, fibrous solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22])[C:6]([CH2:12]Cl)=[N:7]2.[I:26][C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[NH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH2:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([CH2:12][C:6]3[N:5]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:21]([F:24])([F:23])[F:22])[C:4](=[O:25])[C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[Br:1])[N:7]=3)[N:28]=[C:27]([I:26])[C:35]=12
Reactant: O=c1c2c(Br)cccc2nc(CCl)n1Cc1ccccc1C(F)(F)F
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(I)nn2Cc1nc2cccc(Br)c2c(=O)n1Cc1ccccc1C(F)(F)F

Procedure:
To a solution of the quinazolinone, obtained as described above, (100 g, 90% pure, 210 mmol) and 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50.4 g, 193 mmol) in DMF (600 mL) at RT was added potassium carbonate (80.0 g, 580 mmol) and after 18 hr the reaction mixture was poured into water (1.2 L). The resulting precipitate was collected by filtration, and was washed sequentially with water (500 mL), with EtOAc (600 mL) and finally with Et2O (400 mL). The resulting cake was dried in vacuo to afford the title compound, Intermediate A, as an off white solid (115 g, 89%); Rt 2.28 min, m/z 656/658 (M+H)+ (ES+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=2)[CH2:7][CH2:6]1.[H-].[Na+].Cl[C:21]1[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=1>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:11]2[N:16]=[CH:15][N:14]=[C:13]([NH:17][C:21]3[S:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=3)[CH:12]=2)[CH2:9][CH2:10]1
Reactant: N#Cc1cnc(Cl)s1
Reactant: COCCN1CCN(c2cc(N)ncn2)CC1
Agent: [H-]
Agent: [Na+]
Product: COCCN1CCN(c2cc(Nc3ncc(C#N)s3)ncn2)CC1

Procedure:
6-[4-(2-methoxyethyl)piperazin-1-yl]pyrimidin-4-amine 5-3 (0.25 g, 1.05 mmol), sodium hydride (0.842 g, 2.11 mmol), and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.15 g, 1.05 mmol) were treated as in Scheme 4 above. The product 5-4 was purified on a C18 preparative hplc and isolated via lyophilization from dioxane. Hi-Res MS: calc: 346.1445 found: 346.1445. 1H-NMR (DMSO): 9.97 ppm (s, 1H); 8.51 ppm (s, 1H); 8.28 ppm (s, 1H); 6.32 ppm (s, 1H); 4.35 ppm (m, 2H); 3.68 ppm (m, 2H); 3.59 ppm (m, 2H); 3.37 ppm (m, 7H); 3.12 ppm (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[OH:14][C:15]1[CH:30]=[CH:29][C:18]([CH2:19][C:20]2[C:21](=[O:28])[NH:22][C:23](SC)=[N:24][CH:25]=2)=[CH:17][CH:16]=1>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:23]2[NH:22][C:21](=[O:28])[C:20]([CH2:19][C:18]3[CH:29]=[CH:30][C:15]([OH:14])=[CH:16][CH:17]=3)=[CH:25][N:24]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1CCCCN
Reactant: CSc1ncc(Cc2ccc(O)cc2)c(=O)[nH]1
Solvent: c1ccncc1
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2ccc(O)cc2)c(=O)[nH]1
Yield: 40.6 %

Procedure:
5-Bromo-2-(4-aminobutyl)-3-methylpyridine, (0.875 g) and 5-(4-hydroxybenzyl)-2-methylthio-4-pyrimidone (0.745 g) were refluxed in pyridine (3 ml) for 24 hours. The pyridine was evaporated in vacuo. Residual pyridine was removed from the residue by azeotroping with water in vacuo and dried by azeotroping with ethanol. Water (20 ml) was added and the pH lowered to 6 with dilute hydrochloric acid. The solid obtained was recrystallised from ethanol/water, dimethylformamide/water and finally acetic acid/water to give 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(4-hydroxybenzyl)-4-pyrimidone (0.54 g) m.p. 232°-4° C.
Reaction SMILES: [C:1]([C@H:3]1[CH2:7][N:6]([CH3:8])[CH2:5][C@@H:4]1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[C:10]=1[C:11]([O:13][CH3:14])=[O:12])#[N:2].C(N1C[C@@H](C#N)[C@H](C2C=CC(Cl)=CC=2C(OC)=O)C1)C1C=CC=CC=1>>[NH2:2][CH2:1][C@H:3]1[CH2:7][N:6]([CH3:8])[CH2:5][C@@H:4]1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:21])[F:22])[C:10]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1c(OC(F)(F)F)cccc1[C@H]1CN(C)C[C@@H]1C#N
Agent: COC(=O)c1cc(Cl)ccc1[C@@H]1CN(Cc2ccccc2)C[C@H]1C#N
Product: COC(=O)c1c(OC(F)(F)F)cccc1[C@H]1CN(C)C[C@@H]1CN

Procedure:
The title compound was prepared according to the procedure outlined in Example 45C substituting the product obtained from Example 110A for the product obtained from Example 45B. In this instance, the aminoester did not cyclize. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.42 (s, 1H) 2.10-2.21 (m, 1H) 2.32-2.48 (m, 4H) 2.55-2.63 (m, 1H) 2.73 (t, J=8.48 Hz, 1H) 2.79-2.87 (m, 3H) 3.87 (s, 3H) 7.28-7.36 (m, 1H) 7.55-7.64 (m, 3H); MS (DCI+) m/z 333.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:15]=[C:16]([SH:21])[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16]([S:21][C:2]2[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)c(Cl)c2)s1

Procedure:
Prepared according to the procedure described as in Step B for example 1 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.502 g, 2.45 mmol) and 3,4-dichlorobenzenethiol (0.438 g, 2.45 mmol). The title compound was obtained as an off-white solid (0.631 g, 74.6% yield). 1H NMR (300 MHz, CDCl3) δ: 8.10 (1H, s), 7.80 (1H, s), 7.70 (1H, d), 7.50 (1H, d), 2.50 (3H, s).
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[NH2:8][CH2:9][CH2:10][CH2:11][OH:12]>C(O)C>[OH:12][CH2:11][CH2:10][CH2:9][NH:8][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1
Reactant: O=C1NC(=S)CS1
Reactant: NCCCO
Solvent: CCO
Product: O=C1N=C(NCCCO)CS1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
To a solution of 4-thioxothiazolidin-2-one (2.66 g) in ethanol (50 mL) was added 3-aminopropan-1-ol (1.50 g) at room temperature. The reaction mixture was stirred at room temperature for 4 hr, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, methanol/ethyl acetate) to give the title compound (2.70 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.C1C(=O)N([Br:19])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: Cc1ccc2nccnc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2nccnc2c1
Yield: 77.5 %

Procedure:
To a solution of 6-methylquinoxaline (10.0 g, 69.4 mmol) in CCl4 (80 mL) was added NBS (13.5 g, 76.3 mmol) and benzoyl peroxide (BP, 1.7 g, 6.9 mmol) at room temperature. The mixture was heated at reflux for 2 hours. After cooling, the mixture was evaporated under vacuum to give a yellow solid, which was extracted with Petroleum Ether (50 mL×5). The extracts were concentrated under vacuum. The organics were combined and concentrated to give crude 6-bromomethylquinoxaline (12.0 g), which was used directly in the next step. 1H NMR (300 MHz, CDCl3) δ 8.85-8.87 (m, 2 H), 8.10-8.13 (m, 2 H), 7.82 (dd, J=2.1, 8.7 Hz, 1 H), 4.70 (s, 2 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:15]([CH3:23])([CH3:22])[C:14]4[C:9]3=[C:10]([CH:11]=[C:12](Br)[CH:13]=4)[C:4]=2[CH:3]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C(O)C>[CH3:23][C:15]1([CH3:22])[C:14]2[C:9]3=[C:10]([C:4]4[CH:3]=[C:2]([C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:7]=[CH:6][C:5]=4[N:8]3[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=3)[CH:11]=[C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH:13]=2
Reactant: OB(O)c1ccccc1
Reactant: CC1(C)c2ccccc2-n2c3ccc(Br)cc3c3cc(Br)cc1c32
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-n2c3ccc(-c4ccccc4)cc3c3cc(-c4ccccc4)cc1c32

Procedure:
19.8 g (45 mmol) of 3,6-dibromo-8,8-dimethyl-8H-indolo[3,2,1-de]acridine, 11.4 g (94 mmol) of phenylboronic acid and 164 ml of saturated NaHCO3 solution are suspended in 1500 ml of toluene and 150 ml of ethanol. 1.9 g (1.6 mmol) of Pd(PPh)3 are added to this suspension, and the reaction mixture is heated under reflux for 16 h. After cooling, the organic phase is separated off, filtered through silica gel, washed three times with 200 ml of water and subsequently evaporated to dryness.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2[C:16]#[C:17][S:18][CH2:19][C@@H:20]([O:26][Si](C(C)(C)C)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[CH3:44].C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2[C:16]#[C:17][S:18][CH2:19][C@@H:20]([OH:26])[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[CH3:44]
Reactant: COC(=O)C[C@@H](CSC#Cc1c(C)cc(C)cc1-c1ccc(F)c(C)c1)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)C[C@H](O)CSC#Cc1c(C)cc(C)cc1-c1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.4 %

Procedure:
A solution of (S)-4-[[[4'-fluoro-3,3',5-trimethyl[1,1'-biphenyl]-2-yl]ethynyl]thio]-3-(t-butyldiphenylsilyloxy)butanoic acid, methyl ester (1.2 g, 1.9 mM) in dry tetrahydrofuran (10 ml) was treated with glacial acetic acid (0.43 ml, 7.70 mM, 4.0 eq) followed by a 1.0M tetrabutylammonium fluoride solution in tetrahydrofuran (5.78 ml, 5.78 mM, 3.0 eq) and the dark reaction mixture stirred overnight at room temperature under argon. The mixture was diluted with 10 ml of ice water and extracted with ethyl acetate (2×). The organic phase was washed with saturated NaHCO3 and brine, then dried over anhydrous Na2SO4 and evaporated to give a dark oily residue. The crude oil was purified by flash chromatography (Merck Silica gel, 20% ethyl acetate/hexane) affording the title compound as a dark oil (0.53 g, 71.6%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1([CH3:35])[CH2:34][O:33][CH2:32]1>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:30][C:31]2([CH3:35])[CH2:34][O:33][CH2:32]2)[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CCOc1ccc(-c2cccc3c2CCC3=O)c(O)c1OC
Reactant: CC1(CBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(-c2cccc3c2CCC3=O)c(OCC2(C)COC2)c1OC
Temperature: 80 °C
Yield: 19.5 %

Procedure:
To a stirring solution of 4-(4-ethoxy-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.268 mmol) in acetonitrile (7 mL) was added potassium carbonate (111 mg, 0.80 mmol) and 3-(bromomethyl)-3-methyloxetane (132 mg, 0.80 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-25% ethyl acetate in pet ether) afforded title compound as a solid (20 mg, 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[F:9][C:10](Br)([F:12])[F:11].O>N1C=CC=CC=1.[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:10]([F:12])([F:11])[F:9])=[CH:4][N:3]=1
Reactant: Clc1ccc(I)cn1
Reactant: FC(F)(F)Br
Agent: [Cu]
Solvent: O
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc(Cl)nc1
Yield: 13.6 %

Procedure:
In an autoclave were placed 2.9 g of 2-chloro-5-iodopyridine, 2.5 g of trifluoromethyl bromide dissolved in 100 ml of pyridine and 1.6 g of copper dust, and the mixture was reacted at 170° C. for 18 hours. After cooling the system, the reaction mixture was added to a suitable amount of water and extracted with methylene chloride. The extract was washed successively with water, 10% dilute hydrochloric acid, and water. After drying over anhydrous sodium sulfate, the extract was distilled to remove the methylene chloride and obtain 300 mg of 2-chloro-5-trifluoromethylpyridine.
Reaction SMILES: [CH2:1]([C:3]1([OH:14])[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1)[CH3:2].[C:15]([OH:21])([C:17]([F:20])([F:19])[F:18])=[O:16]>C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[C:15]([OH:21])=[O:16].[CH2:1]([C:3]1([OH:14])[CH2:6][NH:5][CH2:4]1)[CH3:2]
Reactant: CCC1(O)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1(O)CNC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 3-ethyl-3-hydroxyazetidine-1-carboxylate (2.3 g, 11.43 mmol) was dissolved in DCM (10 mL) and TFA (15 mL) was added. The reaction mixture was stirred at RT for 2.5 h and then the mixture was evaporated. Ethanol was added and the mixture was again evaporated to afford 3.0 g (100%) of 70A. 1H NMR (500 MHz, CDCl3): δ 0.96 (t, 3H), 1.81 (q, 2H), 3.94 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]1[CH2:11][CH:12]3[N:17]([CH3:18])[CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3.[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[N:25][CH:26]=1)#[CH:20]>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7](/[CH:20]=[CH:19]/[C:21]1[CH:26]=[N:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:6]1[CH2:11][CH:12]3[N:17]([CH3:18])[CH:16]([C:5]2=1)[CH2:15][CH2:14][CH2:13]3
Reactant: Cc1ccc2[nH]c3c(c2c1)C1CCCC(C3)N1C
Reactant: C#Cc1ccc(C)nc1
Product: Cc1ccc2c(c1)c1c(n2/C=C/c2ccc(C)nc2)CC2CCCC1N2C

Procedure:
The coupling of 2,12-dimethyl-6,7,8,9,10,11-hexahydro-5H-7,11-epiminocycloocta[b]indole (110 mg, 0.458 mmol; Example 114A) and 5-ethynyl-2-methylpyridine (107 mg, 0.915 mmol; prepared as described in International Publication No. WO2005090333) was performed according to the procedure described in Example 20 to give the title compound as the minor of two alkene isomers: 1H NMR (300 MHz, methanol-d4) δ ppm 1.30-1.53 (m, 2H), 1.73-1.88 (m, 2H), 1.97-2.17 (m, 2H), 2.43 (s, 3H), 2.53 (s, 3H), 2.55 (s, 3H), 2.88 (d, J=18 Hz, 1H), 3.40-3.51 (m, 1H), 3.56 (br. s, 1H), 4.41 (s, 1H), 6.88 (d, J=15 Hz, 1H), 7.10 (dd, J=8, 1 Hz, 1H), 7.24 (s, 1H), 7.30 (d, J=8 Hz, 1H), 7.67 (d, J=8 Hz, 1H), 7.74 (d, J=15 Hz, 1H), 7.97 (dd, J=8, 2 Hz, 1H), 8.53 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 358 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][N:3]=1.N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].Cl>C(#N)C>[C:17]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[N:3]1)(=[O:19])[CH3:18]
Reactant: Cc1n[nH]c2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)n1nc(C)c2ccccc21
Temperature: 20 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
290 g (2.20 mol) of 3-methylindazole and an acetonitrile solution (400 ml) of pyridine (4.34 mol) were stirred as the mixture was cooled on a water bath, and 310 ml (3.30 mol) of acetic anhydride was added dropwise thereto. Upon addition, the reaction temperature rose from 15° C. to 43° C. After the conclusion of the dropwise addition, the reaction solution was warmed to from 55° to 60° C., and stirred at this temperature for one hour. After cooling to 20° C., the reaction solution was poured into 1.5 kg of ice-cold water containing 500 ml of aqueous hydrochloric acid. The crystals deposited were filtered off, and washed with water. Thus, 328 g (1.89 mol) of 1-acetyl-3-methylindazole was obtained.