Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:7][CH2:8][CH2:9][CH2:10][SH:11])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Cl[C:16]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.CO>CN(C)C=O>[CH3:1][C:2]([CH3:12])([CH2:7][CH2:8][CH2:9][CH2:10][S:11][C:16]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: Clc1cc(-c2ccccc2)c2ccccc2n1
Reactant: COC(=O)C(C)(C)CCCCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)C(C)(C)CCCCSc1cc(-c2ccccc2)c2ccccc2n1
Reaction time: 2 h

Procedure:
To a solution of 4 g of methyl 2,2-dimethyl-6-mercaptohexanoate in 100 cc of dimethylformamide, is added 0.55 g of sodium hydride (50% w/w dispersion in mineral oil). The mixture is stirred for 2 hours until effervescence has stopped. A solution of 5 g of 2-chloro-4-phenylquinoline in 50 cc of dimethyl-formamide is then added. The obtained mixture is heated to 60 C. for 8 hours. After cooling, 10 cc of methanol is added and the mixture evaporated. The resultant residue is purified by flash chromatography on silica gel (30-60 mm; eluent: 8:2 hexane/ethyl acetate) to give methyl 2,2-dimethyl-6-[(4-phenyl-2-quinolyl)thio]-hexanoate is obtained as an oil.
Reaction SMILES: CN1CCCCC1.[CH3:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][O:14][C:15]([NH:17][C@H:18]([C:22]([OH:24])=O)[CH:19]([CH3:21])[CH3:20])=[O:16])=[CH:11][CH:10]=1.ClC(OCC(C)C)=O.[C:35]([C:37]1[CH:47]=[CH:46][C:40]([O:41][CH2:42][CH:43]([NH2:45])[CH3:44])=[CH:39][CH:38]=1)#[N:36]>C(Cl)Cl.O>[C:35]([C:37]1[CH:47]=[CH:46][C:40]([O:41][CH2:42][CH:43]([NH:45][C:22](=[O:24])[C@H:18]([CH:19]([CH3:20])[CH3:21])[NH:17][C:15]([O:14][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([CH3:8])=[CH:26][CH:25]=2)=[O:16])[CH3:44])=[CH:39][CH:38]=1)#[N:36]
Reactant: CC(N)COc1ccc(C#N)cc1
Reactant: Cc1ccc(COC(=O)N[C@H](C(=O)O)C(C)C)cc1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CN1CCCCC1
Product: Cc1ccc(COC(=O)N[C@H](C(=O)NC(C)COc2ccc(C#N)cc2)C(C)C)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 25.1 %

Procedure:
0.6 g of N-methylpiperidine was added to a solution containing 1.5 g of N-(4-methylbenzyloxycarbonyl)-L-valine dissolved in 100 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.8 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 1.0 g of 2-(4-cyanophenoxy)-1-methylethylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The residue, which was a crude crystal, was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of light white powder (yield: 28%).
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH2:7])[CH3:2].[C:10](N1C=CN=C1)(N1C=CN=C1)=[O:11].[C:22]1([S:28]([CH:31]2[CH2:35][CH2:34][NH:33][CH2:32]2)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[OH2:11].[CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][CH2:6][NH:7][C:10]([N:33]1[CH2:34][CH2:35][CH:31]([S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])[CH2:32]1)=[O:11])[CH3:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCN(CC)CCCN
Reactant: O=S(=O)(c1ccccc1)C1CCNC1
Solvent: C1CCOC1
Product: CCN(CC)CCCNC(=O)N1CCC(S(=O)(=O)c2ccccc2)C1
Product: O

Procedure:
A solution of 4.95 g (0.38 mole) of 3-diethylaminopropylamine and 6.50 g (0.040 mole) of 1,1'-carbonyldiimidazole in 400 ml of tetrahydrofuran was stirred at room temperature for 1 hr. A solution of 7.08 g (0.0336 mole) of 3-(phenylsulfonyl)pyrrolidine (free base) in 100 ml of tetrahydrofuran was added and the mixture was refluxed overnight. The tetrahydrofuran was removed in vacuo and the residue was partitioned between methylene chloride and water. The methylene chloride phase was dried over magnesium sulfate and the solvent was removed in vacuo to give the product as an oil.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].Cl[CH2:41][C:42]([N:44]1[CH2:49][CH2:48][CH:47]([CH3:50])[CH2:46][CH2:45]1)=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:41][CH2:42][N:44]2[CH2:49][CH2:48][CH:47]([CH3:50])[CH2:46][CH2:45]2)=[CH:36][CH:37]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC1CCN(C(=O)CCl)CC1
Product: CCN(Cc1ccc(OCCN2CCC(C)CC2)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 11.3 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (18.6 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (2.2 mg) was obtained.
Reaction SMILES: [CH:1]1([S:6][CH2:7][CH2:8][CH2:9][OH:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:20][S:21]([O:10][CH2:9][CH2:8][CH2:7][S:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:23])=[O:22]
Reactant: OCCCSC1CCCC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCCSC1CCCC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 3-(cyclopentylthio)-1-propanol (for example, as prepared for Intermediate 23) (1.05 g, 6.56 mmol) in dry DCM (5 ml) was added diisopropylethylamine (1.37 ml, 7.87 mmol), and then methanesulfonyl chloride (commercially available, for example, from Aldrich) (0.609 ml, 7.87 mmol) at 20° C. The reaction mixture was stirred at room temperature, under nitrogen for 2.5 h and then diluted with DCM (10 ml) and saturated sodium bicarbonate solution (20 ml). The phases were separated using a hydrophobic frit. The organic phase was concentrated in vacuo to afford the title compound (1.74 g): LCMS RT=3.13 min, ES+ve m/z 239 (M+H)+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17](OCC)=O)[N:11]=1)[CH3:8].C1C[O:25]CC1>>[CH2:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([OH:25])[CH3:17])[N:11]=1)[CH3:8]
Reactant: CCNc1cccc(CC(=O)OCC)n1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCNc1cccc(C(C)O)n1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a mechanically stirred solution of LiAlH4 in THF(1.0 M, 20 mL, 20.4 mmol) was added dropwise a solution of ethyl 2-(ethylamino)-6-pyridylacetate (1 g, 4.1 mmol) in THF (30 mL). After the addition was completed, the reaction mixture was heated to reflux. After 5 hr, the reaction was cooled to 0° C. and quenched with 10% NaOH solution. The solids were removed by filtration, and the filtrate was concentrated in vacuum. The residue was dissolved in CH2Cl2, and the solution was dried (MgSO4) and concentrated. Reconcentration from toluene (3 x) gave the title compound as a colorless oil: MS (ES) 167 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1C=C(O)[CH:5]=[CH:6][C:7]=1[OH:8].[ClH:10].[CH2:11]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH:20]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[ClH:10].[CH2:11]([N:18]1[CH2:23][CH2:22][C:21]2[C:1]3[CH:2]=[C:7]([OH:8])[C:6]([CH3:5])=[CH:29][C:28]=3[O:27][C:25](=[O:26])[C:20]=2[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: Cc1cc(O)ccc1O
Agent: Cl
Product: Cc1cc2oc(=O)c3c(c2cc1O)CCN(Cc1ccccc1)C3
Yield: 28 %

Procedure:
Prepared by the procedure of Example 1 from 3-methyl-4-hydroxyphenol and ethyl 1-benzyl-4-oxo-3-piperidinecarboxylate hydrochloride. The crude product was converted to the hydrochloride salt. Yield 28%; mp 283°-289° C.
Reaction SMILES: C(O[CH:4](OCC)[N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])C.[NH2:17][C:18]1[C:19]([CH3:24])=[CH:20][CH:21]=[CH:22][CH:23]=1.C1COCC1.O>CCOCC>[CH3:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:17]=[CH:4][N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12]
Reactant: Cc1ccccc1N
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1N=CN1CCNC1=N[N+](=O)[O-]

Procedure:
A mixture of 2.0 g of of 1-diethoxymethyl-2-nitroiminoimidazolidine, 0.92 g of o-toluidine, 5 ml of THF and 0.12 g of a boron trifluoride ether complex was heated under reflux for 1 hour. The reaction mixture was poured into water, extracted with ethyl acetate, washed with water, dried and condensed. Ether was added to the resultant oily residue and the resultant crystals were separated by filtration and dried to give 1.2 g of 1-(2-methylphenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][OH:13].CCN(CC)CC.[Cl:21][C:22](OC(Cl)(Cl)Cl)=[O:23]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][O:13][C:22]([Cl:21])=[O:23]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cccc(F)c1CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Cl)OCCc1c(F)cccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of 2-(2-fluoro-6-nitrophenyl)ethanol (500 mg, 2.7 mmol) and Et3N (273 mg, 2.7 mmol, dist. over KOH) in THF (6.75 ml, dist. over CaH2) was dropped into a solution, cooled to 0° C., of trichloromethyl chloroformate (641 mg, 3.24 mmol) in THF (6.75 ml, see above) for 5 min. It was stirred for 1 h while cooling in an ice bath and then stirred for 1 h at room temperature. The mixture was filtered over Celite. Rewashing the filter cake with THF and removing the solvent and excess reagent from the pooled filtrates by distillation at 30° C. in a high vacuum yielded 2-(2-fluoro-6-nitrophenyl)ethoxycarbonyl chloride (620 mg, 93%) as a light-brown oil.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([I:14])[C:8]=3[N:7]=[N:6]2)[CH2:3][CH2:2]1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:16]([O:15][C:12]1[CH:11]=[CH:10][C:9]2[N:5]([CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:6]=[N:7][C:8]=2[C:13]=1[I:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccc2c(nnn2CC2CC2)c1I
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Ic1c(OCc2ccccc2)ccc2c1nnn2CC1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(Cyclopropylmethyl)-4-iodo-1H-benzotriazol-5-ol (9-2, 9.01 g, 28.6 mmol) was suspended in degassed N,N-dimethylformamide (75 mL) and treated with benzylbromide (3.74 mL, 31.5 mmol, 1.1 equiv) and potassium carbonate (19.8 g, 143 mmol, 5 equiv). The mixture was placed into a preheated oil bath at 50° C. for 30 minutes, cooled to ambient temperature, and diluted with water (500 mL). The mixture was extracted with dichloromethane (2×500 mL) and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound 9-3.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:4]=2[N:5]=[CH:6][N:7]=1.C(O)C.[CH3:22][NH2:23]>C1(C)C=CC=CC=1>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:23][CH3:22])[C:3]=2[N:10]=[N:9]1
Reactant: Fc1ccccc1Cn1nnc2c(Cl)ncnc21
Reactant: CN
Solvent: CCO
Solvent: Cc1ccccc1
Product: CNc1ncnc2c1nnn2Cc1ccccc1F
Reaction time: 15 h

Procedure:
A solution of 9.22 g (35 mmol) of crude 7-chloro-3-(2-fluorobenzyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine in 150 ml of toluene is added dropwise, while stirring, to a mixture of 750 ml of ethanol and 200 ml of 40% aqueous methylamine solution. The whole is left to stand for 15 hours at room temperature and then the solvent is distilled off under reduced pressure. 500 ml of water are added to the residue. The precipitated product is filtered off with suction and recrystallised from methanol. In this manner 3-(2-fluorobenzyl)-7-(N-methylamino)-3H-1,2,3-triazolo[4,5-d]pyrimidine having a melting point of 180°-182° is obtained.
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])C.C[C:7]([CH3:10])([O-])[CH3:8].[K+]>C1COCC1.O>[CH2:4]=[CH:1][CH:3]=[CH:10][CH2:7][CH2:8][CH2:8][CH2:7][CH:10]=[CH:3][CH:1]=[CH2:4]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC=CCCCCC=CC=C
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
The latter compound (2.0 g) was dissolved in 50 mL of 1:4 THF:tert-butanol and added dropwise to an ice cold solution of potassium tert-butoxide (3.00 g) in 100 mL of 1:4 THF:tert-butanol. The reaction mixture was stirred in ice for 0.5 hours and at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with pentane. The combined organic layer was washed with water. The organic layer was separated, dried with anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to give an oil. Distillation gave 0.34 g (48% yield) of 1,3,9,11-dodecatetraene as established by proton and carbon-13 NMR and IR analysis.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:30]=[C:29]([CH3:31])[O:28][N:27]=1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:25][C:26]2[CH:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reactant: Cc1cc(N)no1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)no1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.3 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared as in Example 38A, 70.7 mg, 0.25 mmol) in oxalyl chloride (215 μL, 2.46 mmol) was cooled to 0° C. and then treated with 1 drop of dry N,N-dimethylformamide. The reaction mixture was stirred at 0° C. for 30 min and then stirred at 25° C. for 3 h. The reaction mixture was concentrated in vacuo to afford a yellow oil. This yellow oil was dissolved in a small amount of methylene chloride and then slowly added to a solution of 3-amino-5-methylisoxazole (48.3 mg, 0.49 mmol) and triethylamine (68 mL, 0.49 mmol) in methylene chloride (1.2 mL). The resulting reaction mixture was stirred at 25° C. for 14 h. The reaction mixture was concentrated in vacuo to remove methylene chloride. The resulting residue was diluted with ethyl acetate (100 mL) and then washed with a 10% aqueous hydrochloric acid solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 3/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-methyl-isoxazol-3-yl)-propionamide (78.3 mg, 87%) as a yellow glass: mp 84-86° C.; FAB-HRMS m/e calcd for C18H20Cl2N2O2 (M+H)+ 367.0981, found 367.0982.
Reaction SMILES: [OH:1][C@@H:2]([CH3:6])[C:3](N)=O.F[B-](F)(F)F.C([O+](CC)CC)C.[NH2:19][C:20]1[C:21]([NH:29][C@@H:30]2[CH2:35][O:34][C@@H:33]([CH2:36][OH:37])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>C1COCC1.C(O)C.CO>[OH:37][CH2:36][C@@H:33]1[O:34][CH2:35][C@@H:30]([N:29]2[C:21]3=[C:22]4[S:28][CH:27]=[CH:26][C:23]4=[N:24][CH:25]=[C:20]3[N:19]=[C:3]2[C@@H:2]([OH:1])[CH3:6])[CH2:31][CH2:32]1
Reactant: C[C@H](O)C(N)=O
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)OC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)OC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.9 %

Procedure:
A mixture of (2S)-2-hydroxypropanamide (86.6 mg, 0.972 mmol) and triethyloxonium tetrafluoroborate (185 mg, 0.972 mmol) in THF (2 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (0.50 mL) and added to a suspension of {(2R,5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl}methanol (65.0 mg, 0.233 mmol) in ethanol (1.8 mL). The mixture was stirred at 80° C. for 1 h. The mixture was cooled to room temperature, diluted with methanol, and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product as white solid (45 mg, 58%). LCMS calculated for C16H20N3O3S (M+H)+: m/z=334.1. Found: 334.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1)#[N:2].N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:32][C@H:33]1[C@@H:40]2[N:36]([C:37](=[O:54])N(C3C4CCCCC=4C(C#N)=CC=3)[C:39]2=[O:41])[CH2:35][CH2:34]1>>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[C:3]([C:1]#[N:2])=[CH:9][CH:8]=[C:6]([N:7]3[C:39](=[O:41])[C@@H:40]4[C@H:33]([OH:32])[CH2:34][CH2:35][N:36]4[C:37]3=[O:54])[CH:5]=2)=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(N)cc1-c1ccc(F)cc1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)cc1-c1ccc(F)cc1

Procedure:
The title compound was prepared from compound 48A by procedures analogous to those described in Experiment 2E and 2F. HPLC: 99% at 3.32 min (retention time) (Conditions: YMC S5 C18 (4.6×50 mm); Eluted with 0% to 100% B, 8 min gradient, 3 min hold. (A=90% H2O-10% MeOH-0.1% H3PO4 and B=10% H2O-90% MeOH-0.1% H3PO4); Flow rate at 2.5 mL/min. UV detection at 220 nm.). LC/MS m/z 352 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:14][CH2:15][OH:16])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([CH2:17][N:13]([CH:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:14][CH2:15][OH:16])=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(CCO)Cc2ccc(Cl)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OCCN(Cc1ccc(Cl)cc1)C1CCNC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-[(4-chloro-benzyl)-(2-hydroxy-ethyl)-amino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.22 g, 0.6 mmol) in dichloromethane cooled at 0° C. was treated with trifluoroacetic acid (20%). The resulting mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate and free based with 10% aqueous sodium bicarbonate. The combined organics were dried over sodium sulfate. The product was used without any further purification. ESI-MS m/z: 255 (M+1), UV retention time: 0.34 min.
Reaction SMILES: COC([O:7][CH3:8])N(C)C.[NH2:9][C:10]1[N:14]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:18]([OH:20])=O)[N:13]=[CH:12][C:11]=1[C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([I:32])[CH:27]=1.C[N:35](C=O)C>>[NH2:9][C:10]1[N:14]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:18]([NH:35][O:7][CH3:8])=[O:20])[N:13]=[CH:12][C:11]=1[C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([I:32])[CH:27]=1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)O)cc1-n1ncc(C(=O)c2cccc(I)c2)c1N
Reactant: COC(OC)N(C)C
Product: CONC(=O)c1ccc(C)c(-n2ncc(C(=O)c3cccc(I)c3)c2N)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
N,N-Dimethylformamide dimethyl acetal (10 mL) was added to the solution of 3-(3-benzyloxy-phenyl)-3-oxo-propionitrile 3 (2.5 g, 10 mmoL) in DMF (20 mL, dry) and the mixture was stirred at 100° C. for 3 hr. Solvent was removed and the residue was purified by silica gel column chromatography (EtOAc as eluent). Product 2-(3-benzyloxy-benzoyl)-3-dimethylamino-acrylonitrile 4 was obtained as a light yellow solid (2.6 g, 90%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:25][CH2:26][S:27](Cl)(=[O:29])=[O:28].O>C1COCC1.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:25][CH2:26][S:27](=[O:29])(=[O:28])[N:8]=2
Reactant: Nc1ncc(F)cc1-c1ccc(Oc2ccccc2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=C(F)C=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-fluoro-3-(4-phenoxyphenyl)pyridin-2-amine (124 mg) in THF (dry) (5 mL) was added to a suspension of NaH (60%, 88.0 mg) and 2-chloroethanesulfonyl chloride (0.139 mL) in THF (dry) (5 mL) at 0° C. The mixture was stirred at room temperature overnight. Water and hexane were added to give a white precipitate. The precipitate was collected by filtration and washed with water and EtOAc, then recrystallized from EtOAc-EtOH to give the title compound (29.0 mg) as a white solid.
Reaction SMILES: [O:1]1[CH2:4][C:3](=O)[CH2:2]1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])C=CC=CC=1>C(Cl)Cl>[O:1]1[CH2:2][C:3](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4]1
Reactant: O=C1COC1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=C1COC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.6 %

Procedure:
To a solution of oxetan-3-one (500 mg, 6.938 mmol) in DCM (15.00 mL) at 0° C. was added ethyl 2-triphenylphosphoranylideneacetate (2.659 g, 7.632 mmol). The solution was allowed to warm to room temperature and stirred for 15 minutes. The reaction mixture was then filtered through a pad of silica (washing with 30% EtOAc:Petrol ether), and the solvent removed under reduced pressure to give ethyl 2-(oxetan-3-ylidene)acetate as a colourless viscous oil (815 mg, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH2:22][CH3:23].CC[O:28]CC>>[C:21]([N:11]1[CH2:12][CH2:13][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:10]1=[O:28])(=[O:24])[CH2:22][CH3:23]
Reactant: COc1cccc(C2CCNC2)c1
Reactant: CCC(=O)Cl
Reactant: CCOCC
Solvent: CCN(CC)CC
Product: CCC(=O)N1CCC(c2cccc(OC)c2)C1=O
Temperature: 0 °C
Yield: 100 %

Procedure:
3-(3-methoxyphenyl)pyrrolidine (8.86 g, 0.050 mol) and triethylamine (5.57 g, 0.055 mol) was dissolved in 500 ml of dry ether. The solution was cooled to 0° C. and propionyl chloride (5.09 g, 0.055 mol) was added dropwise with stirring. The reaction mixture was then allowed to acquire ambient temperature, whereafter it was refluxed for 30 minutes. Triethylamine hydrochloride was filtered off, and the filtrate was evaporated leaving 11.7 g (100%) of crude N-propionyl-3-(3-methoxyphenyl)pyrrolidone, which was used in the next reaction step without further purification. The crude amide (11.7 g, 0.050 mol) was reduced with LiAlH4 (2.85 g, 0.075 mol) in refluxing ether (200 ml) for 24 hours. Workup of the reaction mixture afforded 10 g of product, which upon distillation in vacuo yielded 9.1 g (83%) of N-propyl-3-(3-methoxyphenyl)-pyrrolidine b.p. 85°-86°C./0.1 mm Hg. MS: m/e 219 (M +, 12%) 190 (M-C2H5, 100%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH2:8](OC(OCCC)OCCC)[CH2:9][CH3:10]>ClC1C=CC=CC=1>[CH2:8]([O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH2:9][CH3:10].[CH2:2]=[CH2:3]
Reactant: CCCOC(OCCC)OCCC
Reactant: O=C1CCOCC1
Solvent: Clc1ccccc1
Product: C=C
Product: CCCOC1CCOCC1

Procedure:
reacting tetrahyro-4H-pyran-4-one with tripropylorthoformate and chlorobenzene to form 4-propoxytetrahydro-2H-pyran-ethene;