Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([O:31][CH2:32][CH2:33][OH:34])=[N:14][NH:15][C:16]=3[NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:11][C:6]=2[O:5][CH2:4]1.Cl[C:36]1[N:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][N:37]=1.Cl>O1CCCC1.C(OCC)(=O)C.CCOCC.CC(N(C)C)=O>[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([O:31][CH2:32][CH2:33][O:34][C:36]4[N:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][N:37]=4)=[N:14][NH:15][C:16]=3[NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:28])[CH3:29])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: CS(=O)(=O)c1cnc(Cl)nc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2[nH]nc(OCCO)c2-c2ccc3c(c2)OCO3)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2[nH]nc(OCCOc3ncc(S(C)(=O)=O)cn3)c2-c2ccc3c(c2)OCO3)cc1
Reaction time: 4 h

Procedure:
Sodium hydride (60% dispersion in oil, 20 mg) was added at 0° C. under an atmosphere of nitrogen, to a solution of N-[4-(1,3-benzodioxol-5-yl)-3-(2-hydroxyethoxy)-1H-pyrazol-5-yl]-4-(tert-butyl)benzenesulfonamide (Example 79) (50 mg) in a mixture of anhydrous tetrahydrofuran (3 ml) and anhydrous dimethylacetamide (0.8 ml). The reaction mixture was stirred for 10 minutes at 0° C. before a solution of 2-chloro-5-(methylsulfonyl)pyrimidine (42 mg) in anhydrous tetrahydrofuran (1 ml) was added. The reaction mixture was slowly allowed to room temperature and after 4 h, a solution of 2-chloro-5-(methylsulfonyl)pyrimidine (22 mg) in anhydrous tetrahydrofurane (0.5 ml) was added. The reaction was stirred overnight and then was poured into ether (10 ml) and an aqueous solution of HCl (1N, 10 ml). The remaining insoluble material was dissolved by the addition of ethyl acetate. The organic fraction was washed with water (twice 30 ml), brine (50 ml), dried on sodium sulfate and concentrated under reduced pressure. The yellow oil was purified by HPLC:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]2[CH:37]=[CH:36][C:27]3[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=3[CH:25]=2)[CH:17]=1.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C(N(CC)CC)C.O>ClCCl>[CH3:15][C:4]1[CH:5]=[C:6]([O:8][CH:9]2[CH2:10][CH2:11][N:12]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:13][CH2:14]2)[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][C:24]2[CH:37]=[CH:36][C:27]3[C@H:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH2:29][O:30][C:26]=3[CH:25]=2)[CH:17]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCNCC5)cc4C)c3)ccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cccc(-c4c(C)cc(OC5CCN(S(C)(=O)=O)CC5)cc4C)c3)ccc21
Yield: 138 %

Procedure:
(5)-Methyl 2-(6-((2′,6′-dimethyl-4′-(piperidin-4-yloxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 4a (26 mg, 0.05 mmol) was dissolved in 5 mL of dichloromethane, followed by addition of methanesulfonyl chloride (6 mg, 0.05 mmol) and triethylamine (15 mg, 0.15 mmol). The reaction solution was reacted for 1 hour. The resulting solution was mixed with 10 mL of water, and concentrated under reduced pressure to obtain the crude title compound (S)-methyl 2-(6-((2′,6′-dimethyl-4′-((1-(methylsulfonyl)piperidin-4-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 5a (40 mg) as a white solid, which was directly used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15](=[O:36])[CH2:16][C:17]([CH3:35])([CH3:34])[CH2:18][C@H:19]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:20]([OH:25])[CH2:21][N:22]=[N+]=[N-])[CH2:6]1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:37])[NH:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([C:15](=[O:36])[CH2:16][C:17]([CH3:35])([CH3:34])[CH2:18][C@H:19]([NH:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C@@H:20]([OH:25])[CH2:21][NH2:22])[CH2:6]1
Reactant: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN=[N+]=[N-])C1
Agent: [Pd]
Solvent: CO
Product: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C1
Reaction time: 2 h

Procedure:
A mixture of 0.37 g of [1-(7-azido-5(S)-tert-butoxycarbonylamino-6(S)-hydroxy-3,3-dimethyl-heptanoyl)-1,2,3,4-tetrahydro-quinolin-3(R,S)-yl]-carbamic acid methyl ester and 75 mg of 10% Pd/C in 15 ml of methanol is hydrogenated at room temperature for 2 hours. The solid is removed by filtration over Hyflo® and the solution is concentrated. The title compound is obtained as a yellow oil from the residue by means of flash chromatography (SiO2 60 F). Rf=0.12 (200:40:1 dichloromethane-methanol-25% conc. ammonia); Rt=3.43 (gradient I).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]([NH2:37])[CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:31]1([CH2:30][CH2:29][CH2:28][CH:27]([NH:37][C:14]([CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:16])[CH2:26][CH2:25][CH2:24][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
1-tert-Butoxycarbonyl-piperidine-2-carboxylic acid (3 g; 13.1 mmol) is dissolved in methylene chloride (100 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (4.77 g; 15.7 mmol), diisopropylethylamine (7.3 mL; 41.9 mmol), and PyBOP (8.17 g; 15.7 mmol) are added sequentially. The mixture is stirred for 17 hours at ambient temperature then concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (10%→30% ethyl acetate in hexanes) affording the desired product as an oil. ESMS: MH− 479.4
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13][CH3:14])=[N:4][N:5]([CH3:12])[C:6]=1[C:7]([O:9]CC)=O.[NH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][CH2:25][CH3:26])=[N:21][CH:22]=1>>[CH2:23]([C:20]1[N:21]=[CH:22][C:17]([CH2:16][NH:15][C:7]([C:6]2[N:5]([CH3:12])[N:4]=[C:3]([CH2:13][CH3:14])[C:2]=2[Cl:1])=[O:9])=[CH:18][CH:19]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCOC(=O)c1c(Cl)c(CC)nn1C
Reactant: CCCCc1ccc(CN)cn1
Product: CCCCc1ccc(CNC(=O)c2c(Cl)c(CC)nn2C)cn1
Temperature: 200 °C
Yield: 61.4 %

Procedure:
A mixture of 2.17 g of ethyl 4-chloro-3-ethyl-1-methylpyrazole-5-carboxylate and 3.24 g of 5-aminomethyl-2-n-butylpyridine was heated at 200° C. for 4 hours under stirring. After cooling to room temperature, the reaction mixture was purified by silica gel columnchromatography to obtain 2.06 g of the compound (NO. 15) listed in Table 1.
Reaction SMILES: C(O[C@@H:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=O)C.[CH3:35][S:36][Si](C)(C)C.C(NC(C)C)(C)C>C(Cl)Cl>[C:9]([O:8][C@H:7]1[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@@H:5]([S:36][CH3:35])[C@@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=[O:11])[CH3:10]
Reactant: CS[Si](C)(C)C
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: CS[C@@H]1O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
A mixture of 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-β-D-galactose (680 mg, 1.425 mmol), methylthiotrimethylsilane (0.8 ml, 5.64 mmol), and trimethyl silyl triflate (0.32 ml, 1.66 mmol) in CH2Cl2 was stirred at room temperature for 2 days. Diisopropylamine (~1 ml) was added, diluted with CH2Cl2 (~50 ml) and washed with saturated NaHCO3 solution and water, respectively. The organic layer was dried (Na2SO4) and evaporated to dryness. Column chromatography (heptane-EtOAc) gave pure 20 (630 mg, 95%) as an amorphous powder, having [α]D24 +25° (c1, CHCl3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)#[N:23].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:22]([C:24]1[CH:29]=[C:28]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]3)[CH:3]=2)[CH:27]=[CH:26][CH:25]=1)#[N:23]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Br)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(-c3cccc(C#N)c3)c2)CC1
Temperature: 130 °C
Yield: 85.4 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(3-bromophenyl)methylidene]-1-piperidinecarboxylate (2.07 g, 5.88 mmol) in p-dioxane (30 mL) and H2O (10 mL) was added (3-cyanophenyl)boronic acid (1.036 g, 7.05 mmol), Pd(PPh3) (0.272 g, 0.235 mmol), and K2CO3 (2.436 g, 17.63 mmol) and then the reaction was heated in a microwave at 130° C. for 15 minutes. The organic layer of the reaction mixture was separated, concentrated and purified by Combiflash chromatograph to afford 1.88 g (85%) of the title compound. LC-MS m/z 749 (2M+H)+.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[S:7]1(=[O:24])=[O:23].[CH3:25][NH:26][CH3:27]>C(O)C>[F:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[N:8]1[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:6]([CH2:5]/[CH:4]=[CH:3]/[CH2:2][N:26]([CH3:27])[CH3:25])[S:7]1(=[O:24])=[O:23]
Reactant: CNC
Reactant: O=S1(=O)N(C/C=C/CBr)c2ccccc2N1c1ccc(F)cc1F
Solvent: CCO
Product: CN(C)C/C=C/CN1c2ccccc2N(c2ccc(F)cc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure V, 1-[(2E)-4-bromobut-2-en-1-yl]-3-(2,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.18 g, 0.43 mmol) was treated with 33% dimethylamine in ethanol to give (2E)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-N,N-dimethylbut-2-en-1-amine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.018 g, 10%). MS (ES) m/z 379.8 ([M+H]+).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@H:21]([C@@:39]([OH:47])([CH2:43][C:44]([OH:46])=[O:45])[C:40]([OH:42])=[O:41])/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[BH4-].[Na+]>CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:18][C:19]([C@H:21]([C@@:39]([OH:47])([CH2:43][C:44]([OH:46])=[O:45])[C:40]([OH:42])=[O:41])/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]([OH:38])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:20])[C:14]([O:16][CH3:17])=[O:15])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CC(=O)O)C(=O)O)C(=O)OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(O)CCCCCCC)[C@@](O)(CC(=O)O)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Yield: 39.9 %

Procedure:
To a mixture of No. 5153510, (S)-2-{(E)-(S)-1-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-methoxycarbonyl-ethylcarbamoyl]-10-oxo-heptadec-2-enyl}-2-hydroxy-succinic acid (20 mg, 0.0304 mmol) and methanol was added NaBH4 (7.4 mg, 0.196 mmol), and the mixture was stirred at room temperature. After confirming the consumption of the starting materials by LCMS, a saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine, and dried over anhydrous sodium sulfate. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by preparative HPLC, and then extracted with ethyl acetate. The organic layer was washed with a saturated brine, and then dried over anhydrous sodium sulfate. The organic solvent was distilled off under reduced pressure to obtain the title compound (8 mg, 40%, colorless oil).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH:9]1[CH2:12][CH:11]([OH:13])[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[C:1]([O:5][C:6]([NH:7][CH2:8][CH:9]1[CH2:10][CH:11]([O:13][C:22](=[O:23])[C:21]2[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:26][CH:25]=2)[CH2:12]1)=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CC(O)C1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1CC(OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.1 %

Procedure:
To an ice-cooled solution of (3-Hydroxy-cyclobutylmethyl)-carbamic acid tert-butyl ester (6.98 g, 34.7 mmol), 4-nitrobenzoic acid (11.59 g, 69.4 mmol) and triphenylphosphine (18.19 g, 69.4 mmol) in THF (1 L) was added a solution of DIAD (14.76 g, 69.4 mmol) in THF (10 mL). After removal of the ice bath, the mixture was stirred at RT for 15 h. The mixture was concentrated to dryness and the oily residue was purified normal phase column chromatography (elution with DCM) yielding the title intermediate as a yellow solid (9.89 g, 22.58 mmol, 65%), HPLC: FtRet=1.354; LC-MS: m/z 368.3 [M+NH4]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH2:12]([Sn](CCCC)(CCCC)C#CC)[CH2:13][CH2:14]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>[C:12]([C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1)#[C:13][CH3:14]
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC#Cc1ccc(C(=O)OC)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.9 %

Procedure:
To a solution of methyl 5-bromopicolinate (0.60 g, 2.77 mmol) in toluene (50 mL) was added tributyl(prop-1-yn-1-yl)stannane (1.01 mL, 3.32 mmol, Sigma Aldrich) and tetrakis(triphenylphosphine)palladium (0.04 g, 0.036 mmol, Strem Chemicals, Inc.). The reaction was stirred overnight at 100° C. The reaction was allowed to cool to rt and concentrated. The residue was adsorbed onto a plug of 10% w/w KF Silica and chromatographed with a silica gel column eluting with a gradient of 10% to 100% EtOAc in hexane, to provide methyl 5-(prop-1-yn-1-yl)picolinate (0.18, 1.05 mmol, 37.8% yield). MS m/z [M+H]+=176.0. Calculated from C10H9NO2: 175.184
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.[OH-].[Na+].[CH2:17](Cl)/[CH:18]=[C:19](/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])\[CH3:20]>CO>[F:14][C:2]([F:13])([F:1])[C:3]1[CH:12]=[CH:11][C:6]2[NH:7][C:8]([S:10][CH2:17]/[CH:18]=[C:19](\[CH3:20])/[CH2:21][CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])=[N:9][C:5]=2[CH:4]=1
Reactant: FC(F)(F)c1ccc2nc(S)[nH]c2c1
Reactant: CC(C)=CCC/C(C)=C/CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)=CCC/C(C)=C/CSc1nc2cc(C(F)(F)F)ccc2[nH]1
Yield: 31 %

Procedure:
To a solution of 5-trifluoromethyl-2-mercaptobenzimidazole (1.09 g, 5 mmol) (Senn-Bilfingen, J., DE 3240298(1983)) in methanol (10 mL) was added 2N aqueous sodium hydroxide (6 mmol) and geranyl chloride (0.86 g, 5 mmol). The resultant solution was stirred for 48 hours at ambient temperature, evaporated in vacuo, dissolved in methylene chloride, washed with saturated sodium chloride, and dried over sodium sulfate. Evaporation of the solvent gave an oil which was flash chromatographed (5% MeOH (CH2Cl2) in Merck Kieselgel) and treated with charcoal. Evaporation of the solvent gave an off-white solid of the title compound (550 mg). m.p. 106°-108° C. NMR (CDCl3)δ7.83(m,1H), 7.57(m,2H), 5.43(d, J=7 Hz,1H), 5.2(m,1H), 4.03(d,J=7Hz,2H), 2.0(m,4H), 1.70(s,3H), 1.67(s,3H), 1.65(s,3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:22][C:23]1[O:24][CH:25]=[CH:26][CH:27]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:22][C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccco1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3ccccc23)CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccco3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) starting with 9.4 g (34.4 mmol) of 4-(1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 40 mL of (40 mmol) of a freshly prepared 1M solution in ethyl ether of 2-bromomethyl-furan. The reaction mixture was stirred at room temperature for 18 hours. After standard work-up, 13.2 g (100% of yield) of 4-(1-furan-2-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[S:7][C:6]=2[C:5]([O:17][CH2:18][CH2:19][CH2:20]I)=[CH:4][CH:3]=1.[NH:22]([CH2:26][CH2:27][OH:28])[CH2:23][CH2:24][OH:25]>C(#N)C>[OH:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][OH:28])[CH2:20][CH2:19][CH2:18][O:17][C:5]1[C:6]2[S:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14](=[O:16])[C:15]=2[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=c1c2ccccc2sc2c(OCCCI)ccc(Cl)c12
Reactant: OCCNCCO
Solvent: CC#N
Product: O=c1c2ccccc2sc2c(OCCCN(CCO)CCO)ccc(Cl)c12
Temperature: 50 °C
Yield: 56.1 %

Procedure:
Crude 1-chloro-4-(3-iodopropoxy)-9H-thioxanthen-9-one (10.0 g; 23.22 mmol) from the previous step was slowly charged into a solution of diethanolamine (14.65 g; 139.3 mmol) in acetonitrile (100 mL) heated to 50° C. The reaction mixture was stirred vigorously and heated to 50° C. for 60 h. The solvent was removed in vacuo and water (500 mL) was added. The mixture was extracted with dichloromethane (3×250 mL). The aqueous phase was discarded and the organic phase was extracted with hydrochloric acid (2M, 3×100 mL). The pH of the strongly acidic aqueous phase was adjusted to 12-13 by slow addition of 50% aq. NaOH to reprecipitate the product. The aqueous phase was reextracted with dichloromethane (4×100 mL), the organic phase dried (MgSO4), evaporated to give 4-{3-[bis(2-hydroxyethyl)amino]propoxy}-1-chloro-9H-thioxanthen-9-one (5.31 g; 56% yield).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][C:15]#[N:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC#N)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.5 %

Procedure:
A solution of trans (4-cyanomethyl-cyclohexyl)-carbamic acid tert-butyl ester (0.71 g, 3.00 mmol) in DCM (15 mL) was treated with trifluoroacetic acid (2 mL) and the mixture was stirred at ambient temperature for 2.5 hours, then concentrated under vacuum. The residue was purified by column chromatography using Isolute SCX-2 cartridge (eluting with MeOH then 2M NH3 in MeOH). The relevant fractions were combined and concentrated under vacuum to afford 0.40 g (97%) of trans (4-amino-cyclohexyl)-acetonitrile that was used without further purification. 1H NMR (400 MHz, CDCl3) δ: 3.52-3.42 (m, 2H), 2.69-2.60 (m, 1H), 2.26 (d, 2H), 1.94-1.83 (m, 4H), 1.70-1.57 (m, 1H), 1.24-1.06 (m, 4H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:4]1([CH:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Product: CC(O)c1ccccc1
Yield: 90 %

Procedure:
Under the same conditions, the reduction of acetophenone using tetra-n-butylammonium hydrogensulphate as catalyst gave racemic 1-phenylethanol in 90% yield.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([F:14])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[F:15].C(=O)([O-])[O-].[K+].[K+].[CH:22](B)=[CH2:23]>COCCOC.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>[CH:22]([C:2]1[C:11]2[C:6](=[C:7]([F:14])[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[F:15])=[CH2:23]
Reactant: COc1cc(F)c2ncc(F)c(Br)c2c1
Reactant: BC=C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: C=Cc1c(F)cnc2c(F)cc(OC)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90 %

Procedure:
4-Bromo-3,8-difluoro-6-(methoxy)quinoline (0.63 g, 2.3 mmol) in DME (26 mL) under argon, was treated with tetrakis(triphenylphosphine)palladium(0) (0.13 g, 0.115 mmol) and the mixture stirred at room temperature for 20 minutes. Anhydrous potassium carbonate (0.32 g, 2.3 mmol), water (7 mL), and vinylborane:pyridine complex (see F. Kerins and D O'Shea J. Org. Chem. 2002, 67, 4968-4971) (0.22 g, 0.92 mmol) were added and the mixture was heated at 100° C. for 2 hr. It was cooled, diluted with water and extracted with ether, dried over magnesium sulfate and evaporated to dryness. After work-up the product was chromatographed on silica gel, eluting with 10% methanol in DCM to afford a white solid (0.46 g, 90%). MS (+ve ion electrospray) m/z 221 (MH+).