Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[CH2:13]([O:20][C@H:21]1[C@H:25]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:24]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:23][C@@H:22]1Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[Cl:3][C:4]1[C:5]2[CH:12]=[CH:11][N:10]([C@@H:22]3[O:23][C@H:24]([CH2:34][O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C@@H:25]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@@H:21]3[O:20][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: Cl[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A suspension of 240 mg of sodium hydride, 1.54 g of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine, and 6 ml of dry dimethyl-formamide (DMF) is stirred at 50° C. for 15 minutes, cooled, and added to 4.83 g of 2,3,5-tri-O-benzyl-α-D-arabinofuranosyl chloride in 4 ml of DMF. The solution is stirred at ambient temperature for two hours, concentrated in vacuo, and distributed between a mixture of ethyl acetate-water. Chromatography of the dried ethyl acetate layer over silica gel with 4:1 benzene-ethyl acetate provides 3.3 g of yellow, syrupy 4-chloro-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=O.P(Cl)(Cl)(Cl)=O>ClCCCl.ClCCl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3]1[CH:32]=[CH:31][CH:30]=[CH:29][C:4]=1[C:5]1[N:15]2[C:10]([CH:11]=[N:12][C:13]([NH:16][C:17]3[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=3)=[N:14]2)=[C:8]([CH3:9])[N:7]=1
Reactant: COc1ccccc1C(=O)NC(C)c1cnc(Nc2cc(OC)c(OC)c(OC)c2)nn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccccc1-c1nc(C)c2cnc(Nc3cc(OC)c(OC)c(OC)c3)nn12
Temperature: 25 °C
Yield: 19.8 %

Procedure:
To a solution of 2-methoxy-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (Intermediate 25) (27 mg, 0.06 mmol) in 1,2-dichloroethane (4 mL) was added phosphorus oxychloride (45 microL, 0.5 mmol). The mixture was heated to reflux for 4 hours. After cooling to room temperature, the mixture was diluted with DCM (150 mL) and aqueous (saturated) Na2CO3 (25 mL). The aqueous layer was extracted with dichloromethane (DCM) and the combined organic layers were washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by reverse-phase HPLC to give 7-(2-methoxyphenyl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.005 g) as a yellow solid. 1H NMR (CDCl3): δ8.80 (s, 1H), 7.59 (dd J=7.51, 1.65 Hz, 1H), 7.44 (m, 1H), 7.00-7.07 (m, 3H), 6.84 (s, 1H), 3.78 (s, 6H), 3.59 (s, 6H), 2.63 (s, 3H). MS m/z 421 (M+1).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1)(=O)=O.[F-:20].[Cs+].C(O)(C)(C)C.C(OCC)C>CCCCCC.C(OCC)(=O)C>[F:20][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CS(=O)(=O)OCCCOc1ccc2ccccc2c1
Reactant: [F-]
Agent: [Cs+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: FCCCOc1ccc2ccccc2c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
280 mg (1.0 mmol) of 2-(3-methanesulfonyloxypropoxy)naphthalene and 456 mg (3.0 mmol) of cesium fluoride are added to a solvent of 4.0 mL of t-butanol. The reaction mixture is stirred for 6 hrs at 80° C. 7 mL of ethyl ether is added to the reaction mixture to remove metal salts. After filtration, the filtrate is concentrated by reduced pressure distiller. 188 mg (92% yield) of 2-(3-fluoropropoxy)naphthalene is obtained by column chromatography (ethyl acetate:n-hexane=1:20).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[CH2:15][NH2:16].C(N(C(C)C)CC)(C)C.COC([N:32]1[C:40]2[C:35](=[C:36]([NH:41][C:42](ON3C(=O)CCC3=O)=[O:43])[CH:37]=[CH:38][CH:39]=2)[CH:34]=[N:33]1)=O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:6]=1[CH2:15][NH:16][C:42]([NH:41][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:35]=1[CH:34]=[N:33][NH:32]2)=[O:43]
Reactant: CC(C)(C)CCc1cc(C(F)(F)F)ccc1CN
Reactant: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CCc1cc(C(F)(F)F)ccc1CNC(=O)Nc1cccc2[nH]ncc12
Reaction time: 1 h

Procedure:
To the product of Example 1B dissolved in DMF (80 mL) was added diisopropylethylamine (5.6 mL, 32.1 mmol, 1.2 eq), followed by the addition of the product of Example 1C (8.82 g, 26.5 mmol, 1 eq). The mixture was stirred for 1 hour, diluted with ethyl acetate (600 mL) and the resulting solution washed sequentially with H2O (1×250 mL) and saturated aqueous NH4Cl (1×250 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was taked up in 2:1 methanol:THF (90 mL) and 1 N NaOH (30 mL) was added. The solution was stirred 45 minutes, concentrated under reduced pressure to remove the organic solvents. The residue was diluted with ethyl acetate (600 mL), washed sequentially with H2O (2×200 mL), brine (1×200 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude solid was filtered through SiO2 (80 mL) with 4% ethanol in ethyl acetate, stirred over charcoal, filtered and concentrated under reduced pressure, triturated with 4:1 hexane and ethyl ether (150 mL). The solid was recrystallized from methanol and water, filtered and dried under reduced pressure to provide the title compound. 1H-NMR (DMSO-d6) δ 12.99 (brs, 1H), 8.79 (brs, 1H), 8.08 (s, 1H), 7.61 (d, 1H), 7.50-7.59 (m, 3H), 7.20 (t, 1H), 7.02 (d, 1H), 6.81 (t, 1H), 4.45 (d, 2H), 2.70 (ddd, 2H), 1.45 (ddd, 2H), 0.97 (s, 9H).
Reaction SMILES: [H-].[K+].C1(S)C=CC=CC=1.[CH3:10][N:11]([CH2:13][C@H:14]1[C@:19]([OH:28])([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH3:12]>C(O)COCCO>[CH3:12][N:11]([CH2:13][C@@H:14]1[C@@:19]([OH:28])([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1)[CH3:10]
Reactant: COc1cccc([C@]2(O)CCCC[C@H]2CN(C)C)c1
Agent: Sc1ccccc1
Agent: [H-]
Agent: [K+]
Solvent: OCCOCCO
Product: CN(C)C[C@H]1CCCC[C@]1(O)c1cccc(O)c1

Procedure:
First, O-desmethyl tramadol was prepared as set forth hereinafter. Diethylene glycol (125 mL) was added with cooling to potassium hydride (9.5 g) with the temperature being maintained at <50° C. To the solution was added thiophenol (10 mL) dissolved in diethylene glycol (25 mL), and then (-)-tramadol as the free base (9.3 g) in diethylene glycol (50 mL) was added. The final reaction mixture was heated slowly to reflux for 45 minutes. The mixture was cooled and quenched with water. The pH was adjusted to about 3, and the mixture was extracted with ethyl ether. The pH was readjusted to about 8 and the resulting mixture was extracted 5 more times with methylene chloride. The extract was dried and the methylene chloride was evaporated to yield 4.6 g of the title compound. The title compound (4.6 g) was distilled (Kugelrohr), was dissolved in tetrahydrofuran and treated with an ethanol/HCl solution to give 2.3 g of the hydrochloride salt. The salt was recrystallized from ethanol/ethyl ether and dried to yield 1.80 g of the salt of the (-) enantiomer of O-desmethylated tramadol (mp. 242°-3° C.), [α]D25 =-32.9 (C=1, EtOH).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[F:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[N:13][CH:14]=1.I[CH2:27][C:28]([NH2:30])=[O:29]>O>[F:8][C:9]1[CH:10]=[CH:11][C:12](=[N:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[N:13]([CH2:27][C:28]([NH2:30])=[O:29])[CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(F)cn2)cc1
Reactant: NC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N=c2ccc(F)cn2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.43 g, 0.018 mol) was mixed with N,N-Dimethylformamide (67.4 mL) and N-(5-fluoropyridin-2-yl)-4-methylbenzenesulfonamide 1 (4.0 g, 0.015 mol) was added. The reaction was stirred at room temperature for 10 minutes. Iodoacetamide (3.3 g, 0.018 mol) was added and the mixture was stirred at room temperature for 24 hours. The reaction was poured into water (100 mL) and extracted with ethyl acetate (4×75 mL). Organic layers were combined then dried with magnesium sulfate and the solvent removed. The crude product was chromatographed on silica using 5% methanol in dichloromethane to give 2-(5-fluoro-2-(tosylimino)pyridin-1(2H)-yl)acetamide 2 Rf 0.26, 5% methanol.dichloromethane; MS m/z 324 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[CH2:13][CH2:12][N:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[CH2:36][NH2:37].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:26]([F:29])([F:27])[F:28])[CH2:13][CH2:12][N:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:37][CH2:36][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][N:30]=4)=[O:20])=[C:16]([N+:23]([O-:25])=[O:24])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: O=C(O)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Reactant: NCc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1ccccn1)c1ccc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 54.4 %

Procedure:
To the solution of 4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-nitrobenzoic acid (0.3 g) and 2-picolylamine (0.07 g) in DMF was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.13 g) and 1-hydroxybenzotriazole monohydrate (0.01 g), and the mixture was stirred for 6 hour at room temperature. The reaction solution was poured into water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent, was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 4-[3(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-nitro-N-(pyridine-2-ylmethyl)benzamide (0.19 g). 1H-NMR (CDCl3) δ: 2.54-2.65 (1H, m), 2.89-2.97 (1H, m), 3.51-3.67 (2H, m), 3.83 (1H, d), 4.13 (1H, d), 4.74 (2H, d), 6.75 (1H, dd), 7.08 (1H, d), 7.15-7.23 (2H, m), 7.28 (2H, br s), 7.37 (1H, d), 7.41 (1H, t), 7.49 (1H, d), 7.70 (1H, td), 8.52 (1H, d).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[OH:29][CH2:30][C:31]([CH3:36])([CH3:35])[C:32](O)=[O:33].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[OH:33][CH2:32][C:31]([CH3:36])([CH3:35])[C:30]([O:19][C@H:18]1[CH2:20][CH2:21][C@@:22]2([CH3:23])[C:16](=[CH:15][CH2:14][C@@H:13]3[C@@H:24]2[CH2:25][CH2:26][C@@:27]2([CH3:28])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C@H:7]([CH3:8])[CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH2:17]1)=[O:29]
Reactant: CC(C)(CO)C(=O)O
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)C(C)(C)CO)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 4 h
Yield: 13 %

Procedure:
A solution of 11.6 g of cholesterol and 3.6 g of hydroxypivalic acid in 80 ml of toluene is treated with 1 g of p-toluenesulphonic acid and boiled for 4 hours. The reaction mixture is treated with water and extracted with ether. The organic phase is dried and concentrated and the residue is purified over silica gel with petroleum ether/ether (4:1). There are obtained 1.9 g of cholest-5-en-3β-yl 3-hydroxy-2,2-dimethyl-propionate, m.p. 174°-176° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][C:10]1([CH3:14])[CH2:13][O:12][CH2:11]1.[OH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][C:10]1([CH2:9][O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=2)[CH2:13][O:12][CH2:11]1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CC1(COCCCCCCBr)COC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCCCCCCOCC2(C)COC2)cc1
Yield: 80.6 %

Procedure:
A reaction mixture comprising 84 g of 3-[(6-bromohexyloxy)methyl]-3-methyloxetane, 50 g of ethyl 4-hydroxybenzoate, 50 g of potassium carbonate and 600 ml of dimethylformamide was stirred at 90° C. for 4 hours. Water was added to the reaction mixture and the reaction was stopped. This was extracted with ethyl acetate, and the organic layer was washed with aqueous 2 N-sodium hydroxide solution and water in that order, and then dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the resulting residue was purified through silica gel chromatography (elution solvent:toluene/ethyl acetate=8/2), and 85 g of ethyl 4-[6-(3-methyloxetan-3-ylmethoxy)hexyloxy]benzoate was obtained.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH2:12]([Mg]Br)[CH:13]=[CH2:14]>C1COCC1>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH2:14][CH:13]=[CH2:12]
Reactant: O=C(CCCl)c1ccccc1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)(CCCl)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 3-chloro-1-phenylpropan-1-one (170 g, 1.01 mol) in anhydrous THF (1200 mL) was added allylmagnesium bromide (1.2 L, 1 mol/L) at −78° C. under nitrogen. The formed mixture was stirred for 30 min at −78° C. The reaction was quenched with aqueous NaHCO3 solution. The organic phase was separated, dried over Na2SO4 and concentrated to give the crude product, which was purified by column chromatography (petroleum ether/EtOAc=100:1) to afford 1-chloro-3-phenylhex-5-en-3-ol (180 g, 86%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([Cl:9])=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)=[N:22][CH:23]=2)O1.C([O-])([O-])=O.[Cs+].[Cs+].C(Cl)Cl>O1CCOCC1.CCOC(C)=O.O>[NH2:8][C:6]1[N:7]=[C:2]([C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)=[N:22][CH:23]=2)[CH:3]=[N:4][C:5]=1[Cl:9]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1nc(Br)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(Cl)c(N)n3)cn2)CC1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a mixture of 6-bromo-3-chloropyrazin-2-amine (2.00 g, 9.60 mmol), tert-butyl 4-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)piperazine-1-carboxylate (3.74 g, 9.60 mmol), Cs2CO3 (7.82 g, 24.0 mmol), and Pd(dppf)2.CH2Cl2 (786 mg, 0.959 mmol) in 1,4-dioxane (40 mL) was added water (20 mL). The resulting mixture was stirred at 90° C. for 16 h and then cooled to rt. The reaction mixture was diluted with EtOAc (300 mL), then washed with water (2×50 mL) and brine (50 mL). Removal of the solvent under reduced pressure followed by purification by flash column chromatography on silica gel (0-3% MeOH/DCM) gave compound 87a as a yellow solid. 1H-NMR (CDCl3; 400 MHz) δ 8.75 (d, J=2.2 Hz, 1H), 8.01-8.09 (m, 2H), 6.70 (d, J=9.0 Hz, 1H), 5.02 (br. s., 2H), 3.60-3.69 (m, 4H), 3.57 (br. s., 4H), 1.49 (s, 9H). Mass spectrum (LCMS, ESI pos.): Calcd. for C18H23ClN6O2, 391.1 (M+H). found 391.1.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]#[CH:15])(=O)=O)=CC=1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CC(=O)CC.O>[CH2:12]([N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[CH2:13][C:14]#[CH:15]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CCC(C)=O
Product: C#CCCn1ccnc1
Yield: 89.9 %

Procedure:
A mixture of but-3-ynyl 4-methylbenzenesulfonate (1.04 g), imidazole (573 mg) and K2CO3 (3.88 g) in 2-butanone (10 mL) was heated to reflux overnight. Work-up (DCM, H2O), drying (Na2SO4) and concentration gave 1-(but-3-ynyl)-1H-imidazole (501 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:19]=[O:20])[CH:5]=[C:6]2[C:14]=1[CH:13]([CH2:15][OH:16])[C:12]1([OH:18])[O:17][N:7]2[CH2:8][CH:9]2[CH:11]1[NH:10]2.[C:21](OC(=O)C)(=[O:23])[CH3:22]>CO>[C:21]([N:10]1[CH:9]2[CH:11]1[C:12]1([OH:18])[O:17][N:7]([CH2:8]2)[C:6]2[C:14](=[C:2]([OH:1])[CH:3]=[C:4]([CH:19]=[O:20])[CH:5]=2)[CH:13]1[CH2:15][OH:16])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=Cc1cc(O)c2c(c1)N1CC3NC3C(O)(O1)C2CO
Solvent: CO
Product: CC(=O)N1C2CN3OC(O)(C(CO)c4c(O)cc(C=O)cc43)C21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6,9-dihydroxy-8-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carbaldehyde (98 mg) in methanol (3 ml) was added acetic anhydride (40 μl). The mixture was stirred for 1 hour at ambient temperature and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (10:1, v/v) to afford 11-acetyl-6,9-dihydroxy-8-hydroxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-triene-4-carbaldehyde (71 mg).
Reaction SMILES: C[Mg]I.[Mg].[CH3:5]I.[CH:7]([CH:9]1[C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[S:12][CH2:11][CH2:10]1)=[O:8].[Cl-].[NH4+]>CCOCC.C1C=CC=CC=1>[OH:8][CH:7]([CH:9]1[C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[S:12][CH2:11][CH2:10]1)[CH3:5]
Reactant: CI
Reactant: O=CC1CCSc2[nH]c3ccccc3c21
Agent: C[Mg]I
Agent: [Cl-]
Agent: [Mg]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CC(O)C1CCSc2[nH]c3ccccc3c21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl magnesium iodide prepared from reaction of magnesium (2.4 g) and methyl iodide (13.9 g) in absolute ether is dissolved in absolute benzene (50 ml) and a solution of 4-formyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole (5.5 g) in absolute benzene (60 ml) is added dropwise thereto during 3 hours. The mixture is stirred at room temperature for 1 hour, poured slowly into an ice water containing ammonium chloride (10 g) and extracted with ether. The extract is evaporated. The oily residue is chromatographed on a column of silica gel and eluted with ether-benzene (1:50). The eluate is evaporated. The residue is again chromatographed on a column of silica gel and eluted with benzene and ether-benzene (1:20). The title compound is obtained from the latter eluate as an oil (4.58 g).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH2:16]([O:18][C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[C:21]([CH3:31])[CH:20]=1)[CH3:17]>ClCCl.CN(C=O)C.C(OCC)(=O)C>[CH2:16]([O:18][C:19]1[N:24]=[C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:29][CH2:30]2)[CH:22]=[C:21]([CH3:31])[CH:20]=1)[CH3:17]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: CCOc1cc(C)cc(N2CCNCC2)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1cc(C)cc(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 30 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (17 mg, 0.12 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (11 μl, 0.12 mmol) was added and the resulting solution was stirred at room temperature for 10 minutes. This solution was added to a solution of 1-(6-ethoxy-4-methyl-2-pyridyl)piperazine (26 mg, 0.12 mmol) and TEA (42 μl, 0.3 mmol) in anhydrous DMF (0.5 ml) and the resulting mixture was stirred at room temperature for one hour. The mixture was diluted with ethyl acetate, washed with sat. sodium bicarbonate solution, brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 12 mg of a solid (0.036 mmol, yield 30%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([C:11]2[S:12][C:13](S(C)(=O)=O)=[N:14][N:15]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])[CH3:3].CN.[CH2:27]([N:29](CC)CC)C>C(O)C>[CH3:21][C:20]([C:7]1[CH:8]=[C:9]([C:11]2[S:12][C:13]([NH:29][CH3:27])=[N:14][N:15]=2)[CH:10]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[C:6]=1[OH:24])([CH3:22])[CH3:23]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)c1cc(-c2nnc(S(C)(=O)=O)s2)cc(C(C)(C)C)c1O
Agent: CN
Solvent: CCO
Product: CNc1nnc(-c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)s1
Reaction time: 8 h
Yield: 46.4 %

Procedure:
To a solution of 2,6-bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-thiadiazole-2-yl]phenol (2.0 g, 0.0054 mole) in ethanol (10 ml) is added 25% ethanolic methylamine solution (15 ml), followed by triethylamine (0.6 g, 0.006 mole). The resulting mixture is heated to reflux for three hours. An additional amount of 25% ethanolic methylamine (15 ml) solution is added and the mixture is stirred overnight at reflux. The solution is cooled and the volatiles removed under reduced pressure. The residue is purified by flash chromatography (SiO2) using 30% ethyl acetate/hexane eluent. Recrystallize from ethyl acetate/hexane to obtain 0.8 g (1.7 g theor., 48%) of 2,6-bis(1,1-dimethylethyl)-4-[5-(methylamino)-1,3,4-thiadiazol-2-yl]phenol, mp 207.5°-208° C.
Reaction SMILES: [H-].[Na+].[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[I-].[Na+].[CH2:20]([O:22][CH2:23][CH2:24]Cl)[CH3:21]>C(O)(C)(C)C>[C:14]([O:13][C:3]([CH:4]([CH2:21][CH2:20][O:22][CH2:23][CH3:24])[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Reactant: CCOCCCl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CCOCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C

Procedure:
A 55% dispersion of sodium hydride in mineral oil (5.46 g) was added by portions to a solution of di-t-butyl malonate (25.8 g) in t-butanol (100 ml) under argon. The reaction mixture was stirred at ambient temperature for 1 hour before sodium iodide (1.53 g) and 2-ethoxyethyl chloride (13.1 ml) were added. The resultant mixture was heated to reflux for 48 hours and then evaporated to dryness. The residue was partitioned between water and ether, the organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The resultant oily residue was purified by flash chromatography on silica by elution with 10% ethyl acetate/hexane to give t-butyl 2-t-butoxycarbonyl-4-ethoxybutyrate (21 g) as a colourless oil: NMR Spectrum (CDCl3) 1.19 (3H, t), 1.45 (18H, s), 2.07 (2H, m), 3.34 (1H, t), 3.45 (4H, m); Mass Spectrum m/Z 289 (M+H)+.