Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].N1C2C(=CC=CC=2)C=CC=1.[CH3:16][C:17]([OH:25])([C:19]#[C:20][C:21]([CH3:24])([OH:23])[CH3:22])[CH3:18].[H][H]>CO>[CH3:16][C:17]([OH:25])(/[CH:19]=[CH:20]\[C:21]([CH3:24])([OH:23])[CH3:22])[CH3:18]
Reactant: CC(C)(O)C#CC(C)(C)O
Reactant: [H][H]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CC(C)(O)/C=C\C(C)(C)O
Yield: 99.4 %

Procedure:
1.6 g of 5% palladized calcium carbonate and 0.6 g of quinoline were added to a solution of 24 g of 2,5-dimethyl-hex-3-yne-2,5-diol [Ray et al, Am. Soc., Vol. 74 (1952), p. 1247]in 200 ml of methanol and the mixture was stirred with hydrogen until hydrogen absorption ceased. The catalyst was removed by filtration and the filtrate was evaporated to dryness under reduced pressure to obtain 24.2 g of cis 2,5-dimethyl-hex-3-ene-2,5-diol melting at 64° C. which was used as is for the next step.
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19]C3C=CC(CC(OC)=O)=CC=3)=[CH:14][C:13]=2[CH3:31])[CH2:11][CH2:10]1)[C:2]1C=CC=CC=1.[C:32](=O)([O-])[O-].[K+].[K+]>CO>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2([O:8][CH:1]([CH3:2])[CH3:32])[CH2:10][CH2:11]2)=[C:13]([CH3:31])[CH:14]=1)#[CH:19]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(OC(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-trimethylsilane (Intermediate 80, 250.0 mg, 0.87 mmol) in 8 methanol (10 mL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambient temperature. The crude alkyne (180 mg, 98%) was used directly in the next reaction.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].O[CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][C:12]([C:26]([O:28][CH3:29])=[O:27])([N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16](=[O:19])[CH2:17][CH3:18])[CH2:11][CH2:10]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][S:2]([CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][C:12]([C:26]([O:28][CH3:29])=[O:27])([N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16](=[O:19])[CH2:17][CH3:18])[CH2:13][CH2:14]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=O)N(c1ccccc1)C1(C(=O)OC)CCN(CCO)CC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCC(=O)N(c1ccccc1)C1(C(=O)OC)CCN(CCS(C)(=O)=O)CC1
Reaction time: 8 h
Yield: 44.6 %

Procedure:
A solution of methanesulfonyl chloride 0.374 g, 3.3 mmol in ethyl acetate (3 ml was added to a mixture of 1-(2-hydroxyethyl)-4-methoxycarbonyl-4-(N'-phenylpropionamido)piperidine (1.0 g, 3 mmol) and triethylamine. The resulting mixture was stirred overnight. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give an oily residue. The residue was chromatographed on silica gel (290 g; ethyl acetate/hexane: 1:4) to yield 1-(2-methanesulfonylethyl)-4-methoxycarbonyl-4-(N'-phenyl-propionamido)piperidine (0.53 g, 43%) as an oil.
Reaction SMILES: [C:1]1([N:7]2[C:11](=[O:12])[CH:10]=[C:9]([C:13]([OH:15])=O)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][O:17][C:18](=[O:30])[C@@H:19]([NH2:29])[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:30])[C@@H:19]([NH:29][C:13]([C:9]1[CH:10]=[C:11]([OH:12])[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1)=[O:15])[CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23]
Reactant: O=C(O)c1cc(=O)n(-c2ccccc2)[nH]1
Reactant: COC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(O)n(-c2ccccc2)n1

Procedure:
To a solution of 12.1 g 1-phenyl-3-carboxy-5-pyrazolone, 15 g (S)-2-amino-pentanedioic acid 5-tert-butyl ester 1-methyl ester and 22.5 g HATU in 200 ml DCM were added 34 ml triethylamine. After 2 h the mixture was extracted with water and the crude product obtained after evaporation of the solvent reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[N:10][N:11]([C:13]3[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=3[CH3:22])[C:16]([OH:18])=O)[CH:12]=2)=[CH:4][CH:3]=1.[NH2:23][C:24]1[C:25]([O:39][CH3:40])=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:30]([C:28]1[CH:27]=[C:26]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:25]([O:39][CH3:40])=[C:24]([NH:23][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][C:21]([CH3:22])=[C:13]([N:11]3[CH:12]=[C:8]([C:5]4[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=[N:10]3)[CH:14]=2)[CH:29]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccc(Cl)nc2)nn1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccc(Cl)nc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-[4-(6-Chloro-pyridin-3-yl)-1,2,3-triazol-1-yl]-4-methyl-benzoic acid (470 mg; 1.49 mmol), N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide (WO 02/083628) (488 mg; 1.79 mmol), and 0.87 mL (5.0 mmol) of DIPEA were combined in 15 ML DMF. Then 1.14 g (2.99 mmol) of HATU and 403 mg (2.99 mmol) of HOBt were added and the dark brown solution was stirred overnight at room temperature. The mixture was then partitioned between EtOAc and water. The layers were separated and the organic portion was washed with water (2×50 mL), brine (50 mL), dried (MgSO4), filtered, and concentrated. Chromatography provided 375 mg (0.66 mmol; 44%) of the title compound with 95% purity. ESI MS m/z 569 [C27H29ClN6O4S+H]+.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.O.Cl>[OH-].[K+].CO>[CH3:17][N:14]1[CH2:13][CH2:12][N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:18])=[O:2])=[CH:5][CH:6]=2)[CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C

Procedure:
HCl-salt of 4-(4-methylpiperazin-1-ylmethyl)benzoic acid methyl ester (1.25 g) was dissolved in potassium hydroxide-methanol solution (0.93 g KOH in 15 ml methanol). Water (0.75 ml) was added and the mixture was refluxed for 1 hour. The reaction mixture was allowed to cool into room temperature and the pH was tuned to 6 with 2 M HCl. The solvent was evaporated and the residue was dried under vacuum. The residue contained 4-(4-methylpiperazin-1-ylmethyl)benzoic acid and inorganic salts. It was used further without purification and the yield of title compound was assumed to be 100%. 1H NMR (400 MHz, d6-DMSO) δ: 2.27 (s, 3H), 2.44 (bs, 2H), 3.18-3.95 (m, 8H), 7.41 (d, 2H, J 8.0 Hz), 7.89 (d, 2H, J 8.1 Hz).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[O:11][CH:10]=[C:9]([CH:19]=[O:20])[C:8]2=[O:21])(=[O:3])[CH3:2].CC(C)=[O:24].OS(O)(=O)=O.O=[Cr](=O)=O.[Cr](O)(O)(=O)=O>CC(C)=O.S(=O)(=O)(O)O.O>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][C:16](=[O:18])[CH3:17])[O:11][CH:10]=[C:9]([C:19]([OH:24])=[O:20])[C:8]2=[O:21])(=[O:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(=O)Oc1cc2occ(C=O)c(=O)c2cc1OC(C)=O
Agent: O=[Cr](=O)(O)O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1cc2occ(C(=O)O)c(=O)c2cc1OC(C)=O

Procedure:
6,7-Diacetoxychromone-3-carboxaldehyde (17.8 g) were dissolved in 1 litre of acetone. To this solution were added with stirring Jones reagent (32.8 ml) which had been previously prepared by dissolving chromic acid (133.6 g) in concentrated sulfuric acid (115 ml) diluted with water to a volume of 500 ml.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6](O)[C:7](=[CH2:12])[CH2:8][O:9][CH2:10][CH3:11])[CH3:2].S(Br)([Br:20])=O.O>ClCCCl>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([NH:14][CH:15]=[O:16])[CH:6]=[C:7]([CH2:12][Br:20])[CH2:8][O:9][CH2:10][CH3:11])[CH3:2]
Reactant: O=S(Br)Br
Reactant: C=C(COCC)C(O)C(NC=O)C(=O)OCC
Solvent: ClCCCl
Solvent: O
Product: CCOCC(=CC(NC=O)C(=O)OCC)CBr
Reaction time: 1 h

Procedure:
3.70 g (15.1 mmol) of 5-ethoxy-2-formylamino-3-hydroxy-4-methylene-pentanoic acid ethyl ester are dissolved in 100 ml of 1,2-dichloroethane, and 1.8 ml (22.8 mmol) of thionyl bromide are added dropwise at room temperature. After one hour, 100 ml of water are added and the mixture is stirred vigorously for 15 minutes. The organic phase is separated off, washed in succession with 1N potassium hydrogen carbonate solution and with brine, dried over sodium sulfate, filtered and concentrated by evaporation. 5-ethoxy-4-bromomethyl-2-formylamino-pent-3-enoic acid ethyl ester is obtained in the form of a yellowish-brown oil which is reacted further in the crude state.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([C:19]1([CH2:22][N:23]2[CH:27]=[N:26][CH:25]=[N:24]2)[CH2:21][O:20]1)([CH3:18])[CH3:17]>C(O)CC>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH2:15][C:16]([CH3:18])([CH3:17])[C:19]([CH2:22][N:23]1[CH:27]=[N:26][CH:25]=[N:24]1)([OH:20])[CH2:21][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(Cc1ccc(Cl)cc1Cl)C1(Cn2cncn2)CO1
Reactant: c1nc[nH]n1
Agent: [Na]
Solvent: CCCO
Product: CC(C)(Cc1ccc(Cl)cc1Cl)C(O)(Cn1cncn1)Cn1cncn1
Yield: 18.8 %

Procedure:
3.7 g (52.5 millimoles) of 1,2,4-triazole are added to a solution of 0.11 g (47 millimoles) of sodium in 30 ml of n-propanol at room temperature, while stirring. The mixture is heated to the reflux temperature and a solution of 15.4 g (47 millimoles) of 2-(2,4-dichlorophenyl-tert.-butyl)-2-(1,2,4-triazol-1-yl-methyl)-oxirane in 20 ml of n-propanol is added. The reaction mixture is heated under reflux for 15 hours and then cooled and poured onto water. The mixture is extracted with methylene chloride and the organic phase is dried over sodium sulphate and concentrated. The residue is purified by column chromatography (silica gel; ethyl acetate:cyclohexane=3:1). 3.5 g (18.8% of theory) of 4-(2,4-dichlorophenyl)-3,3-dimethyl-2-(1,2,4-triazol-1-yl-methyl)-1-(1,2,4-triazol-1-yl)-2-butanol of melting point 126° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11](Cl)=[O:12])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:16][NH2:17]>O1CCCC1.O>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH:7]2[CH2:10][N:9]([C:11]([NH:17][CH3:16])=[O:12])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)N1CC(Oc2ccc(Br)cc2)C1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2ccc(Br)cc2)C1
Reaction time: 18 h
Yield: 85.9 %

Procedure:
A stirred solution of 5.8 g (0.02 mole) of 3-(4-bromophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4.7 g (0.06 mole) of 40% aqueous monomethylamine and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the solid which separated was collected by filtration, 5.7 g. Recrystallization from ethanol-water yielded 4.9 g (85.9%) of fine white crystals, m.p. 135°-137° C.
Reaction SMILES: C(N(CC)CC)C.[N:8]1([CH2:17][C:18]([OH:20])=O)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.ClC(OCC)=O.[CH3:27][NH:28][C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>O1CCCC1>[CH3:27][N:28]([C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]1[N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[C:18](=[O:20])[CH2:17][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Reactant: O=C(O)Cn1ccc2ccccc21
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)Cn1ccc2ccccc21)[C@@H]1CCCC[C@H]1N1CCCC1
Reaction time: 0.08 h
Yield: 29.5 %

Procedure:
Triethylamine (139 μl, 1 mmol) was added to a solution of 1H-indole-1-acetic acid (175 mg, 1 mmol) in tetrahydrofuran (10 ml) at -15° C. with vigorous stirring. Ethyl chloroformate (96 μl, 1 mmol) was added, and the mixture stirred for five minutes. A solution of trans-(±)-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine (182 mg, 1 mmol) in tetrahydrofuran (2 ml) was added, and stirring continued for 30 minutes at -15° C., then 30 minutes at room temperature. The reaction was evaporated to small volume, the residue dissolved in ethyl acetate (50 ml), and washed with saturated sodium biocarbonate solution (3×50 ml). The organic extract was drige (MgSO4), evaporated under reduced pressure, and recrystallized from diethyl ether/methylene chloride to yield the amide (100 mg, 32%); Vmax C=0 1635 cm-1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.N1C=CN=C1.[C:18]([Si:22](Cl)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:21])([CH3:20])[CH3:19].O>CN(C)C=O>[Si:22]([O:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCOc1ccc(C=O)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-hydroxyethoxy)benzaldehyde (0.50 g) and imidazole (0.41 g) in N,N-dimethylformamide (6 mL) was added tert-butylchlorodiphenylsilane (0.94 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give 4-[2-(tert-butyl-diphenylsilyloxy)ethoxy]benzaldehyde (1.21 g). The title compound was prepared in a similar manner to that described in Reference Example 45 using this material instead of 4-isobutylbenzaldehyde.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:13][CH3:14])[CH:11]=2)[C:6]([C:15]([OH:17])=O)=[CH:5]1)([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:54][C:55]1[S:56][CH:57]=[CH:58][N:59]=1>C(Cl)Cl>[S:56]1[CH:57]=[CH:58][N:59]=[C:55]1[NH:54][C:15]([C:6]1[C:7]2[C:12](=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)=[O:17]
Reactant: Nc1nccs1
Reactant: CSc1ccc2c(C(=O)O)cn(C(C)C)c2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CSc1ccc2c(C(=O)Nc3nccs3)cn(C(C)C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
A solution of 1-isopropyl-6-methylsulfanyl-1H-indole-3-carboxylic acid (275 mg, 1.10 mmol) and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (585 mg, 1.32 mmol) in methylene chloride (5 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.44 mL, 2.54 mmol). The reaction was stirred at 25° C. for 30 min. At this time, the reaction was treated with 2-aminothiazole (254 mg, 2.54 mmol). The reaction was stirred at 25° C. for 18 h. At this time, the reaction was partitioned between water (40 mL) and ethyl acetate (40 mL) and was treated with a 1N aqueous hydrochloric acid solution (25 mL). The layers were shaken and separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×25 mL), water (1×25 mL), and a saturated aqueous sodium chloride solution (1×25 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 1-isopropyl-6-methylsulfanyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (155 mg, 42%) as light yellow solid: mp 172-176° C.; (ES)+-HRMS m/e calcd for C16H17N3OS2 (M+Na)+ 354.0705, found 354.0709.
Reaction SMILES: [Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:13])[C:3]=1[N:14]1[CH2:19][CH2:18][N:17]([S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([F:20])([F:32])[F:33])(=[O:30])=[O:29])[CH2:16][CH2:15]1
Reactant: O=C1C(Cl)=C(N2CCNCC2)C(=O)c2ccccc21
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Product: O=C1C(Cl)=C(N2CCN(S(=O)(=O)c3ccccc3C(F)(F)F)CC2)C(=O)c2ccccc21

Procedure:
A 1.5 g portion of 3-chloro-2-piperazinyl-1,4-naphthoquinone and 1.26 g of 2-trifluoromethylbenzenesulfonyl chloride were reacted as described in Example 56, giving 1.53 g of the desired product, mp 122°-124° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:10][CH:9]=1.[NH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1.C(P(C#N)(CC)=O)C.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11](/[CH:12]=[CH:13]/[C:14]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:16])=[CH:17][CH:18]=1
Reactant: NCc1cccnc1
Reactant: COCCOCOc1ccc(C=CC(=O)O)cc1
Agent: CCP(=O)(C#N)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOCOc1ccc(/C=C/C(=O)NCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
3.74 g of 4-[(2-methoxyethoxy)methoxy]cinnamic acid and 1.68 g of 3-(aminomethyl)pyridine were dissolved in 30 ml dimethylformamide, and stirred with 2.7 ml diethylphosphoryl cyanide and subsequently with 2.5 ml triethylamine on ice, followed by further stirring at room temperature for 1 hour. Saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with ethyl acetate, washed with water, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give a residue, which was then purified via column chromatography on silica gel (chloroform:methanol=50:1) to provide (E)-3-[4-[(2-methoxyethoxy)methoxy]phenyl]-N-(3-pyridylmethyl)-2-propenoic acid amide as a pale yellow oil (4.54 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@H:12]([O:24][CH2:25][O:26][CH3:27])[C@H:13]([OH:23])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[CH3:9].[CH3:28][O:29][C:30](=[O:46])[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[O:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:28][O:29][C:30](=[O:46])[C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1[O:38][C:39]1[CH:40]=[CH:41][C:42]([O:23][C@H:13]([C@@H:12]([C:5]2[CH:6]=[C:7]([O:10][CH3:11])[C:8]([CH3:9])=[C:3]([O:2][CH3:1])[CH:4]=2)[O:24][CH2:25][O:26][CH3:27])[CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:43][CH:44]=1
Reactant: COC(=O)c1ccc(C)cc1Oc1ccc(O)cc1
Reactant: COCO[C@H](c1cc(OC)c(C)c(OC)c1)[C@H](O)CCCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCO[C@H](c1cc(OC)c(C)c(OC)c1)[C@H](CCCc1ccccc1)Oc1ccc(Oc2cc(C)ccc2C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.9 %

Procedure:
To a tetrahydrofuran (4 ml) solution of (±)-(1R*,2R*)-1-(3,5-dimethoxy-4-methylphenyl)-1-(methoxymethoxy)-5-phenylpentan-2-ol (142 mg) and methyl2-(4-hydroxyphenoxy)-4-methylbenzoate (249 mg), triphenylphosphine (262 mg) and diethyl azodicarboxylate (0.47 ml) were added, followed by stirring at room temperature overnight. The reaction mixture was concentrated, and the residue was purified with silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the title compound (128 mg) having the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([CH:10](S(C)=O)SC)[CH:7]=[C:6]([F:16])[C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:18].O>C1COCC1>[F:1][C:2]1[CH:9]=[C:8]([CH:10]=[O:18])[CH:7]=[C:6]([F:16])[C:3]=1[C:4]#[N:5]
Reactant: CSC(c1cc(F)c(C#N)c(F)c1)S(C)=O
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(F)cc(C=O)cc1F
Reaction time: 72 h

Procedure:
2,6-Difluoro-4[(methylsulfinyl)(methylthio)methyl]benzonitrile (2.17 g, 8.32 mmol; see step (i) above) was dissolved in 90 mL of THF and 3.5 mL of concentrated sulfuric acid was added. The mixture was left at room temperature for 3 days and subsequently poured into 450 mL of water. Extraction three times with EtOAc followed and the combined ethereal phase was washed twice with aqueous sodium bicarbonate and with brine, dried (Na2SO4) and evaporated. Yield: 1.36 g (98%). The position of the formyl group was established by 13C NMR. The signal from the fluorinated carbons at 162.7 ppm exhibited the expected coupling pattern with two coupling constants in the order of 260 Hz and 6.3 Hz respectively corresponding to an ipso and a meta coupling from the fluorine atoms.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([OH:15])=O)[C:7](=[O:16])[N:6]2[CH3:17].[NH2:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:13]([NH:18][C:19]1[NH:23][N:22]=[N:21][N:20]=1)=[O:15])[C:7](=[O:16])[N:6]2[CH3:17]
Reactant: Nc1nnn[nH]1
Reactant: COc1ccc2nc(C(=O)O)c(=O)n(C)c2c1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2nc(C(=O)Nc3nnn[nH]3)c(=O)n(C)c2c1

Procedure:
3,4-Dihydro-6-methoxy-4-methyl-3-oxo-2-quinoxalinecarboxylic acid (1.2 g) and N,N'-carbonyldiimidazole (0.8 g) in tetrahydrofuran (25 ml) and dimethylformamide (20 ml) were heated under reflux for 1 hour. 5-Amino-1H-tetrazole (0.5 g) in dimethylformamide (5 ml) was added and the solution was heated under reflux for 1 hour and allowed to cool. The solid was collected and dried, m.p. 295°-296° (d) (70%).
Reaction SMILES: C(O)C.[NH2:4][C:5]1([CH3:11])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.Cl[C:13]1[N:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>O>[NH2:4][C:5]1([CH3:11])[CH2:10][CH2:9][N:8]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:7][CH2:6]1
Reactant: CC1(N)CCNCC1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC1(N)CCN(c2ncccn2)CC1
Yield: 65.1 %

Procedure:
2 ml of an ethanol suspension containing 260 mg of 4-amino-4-methylpiperidine (synthesized according to a method described in U.S. Pat. No. 5,821,240), 237 mg of 2-chloropyrimidine and 858 mg of potassium carbonate was stirred at 50° C. for 12 hours. The reaction mixture was poured into water, and extracted with chloroform. The extract was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography [solvent: chloroform-methanol-aqueous ammonia (300:10:1)] to obtain 259 mg of 4-amino-4-methyl-N-(2-pyrimidinyl)piperidine (Reference Example 8-1 in Table 9).