Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[C:11]#[CH:12]>C1(C)C=CC=CC=1.C(OCC)(=O)C.[Au+].ClP(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:9]/[CH:12]=[CH:11]\[C:10]([O:14][CH2:15][CH3:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: C#CC(=O)OCC
Agent: [Au+]
Agent: Cl[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C\OC(=O)c1ccccc1
Temperature: 60 °C
Yield: 99.5 %

Procedure:
To a suspension of benzoic acid (24.4 g, 200 mmol), silver hexafluorophosphate(V) (253 mg, 1 mmol), chlorotriphenylphosphine gold(I) (495 mg, 1 mmol) in toluene (125 mL) was added ethyl prop-2-ynoate (5.1 mL, 50 mmol). The reaction mixture was stirred and heated at 60° C. for 16 hrs. The volatiles were removed to give a residue, which was dissolved in ethyl acetate (200 mL) with some trace insoluble material being removed by filtration. The filtrate was washed with saturated aqueous NaHCO3 (with gas evolved—CAUTION) until there was no further gas evolution, and evaporated to give a light brown oil. This oil was purified via flash chromatography (eluting with a gradient of 0%-100% EtOAc in heptanes) to give the title compound (10.96 g, 99% yield) as a colorless oil, which solidified to afford needle-liked crystals. 1H NMR (400 MHz, chloroform-d) δ ppm 8.24-8.32 (m, 2H) 7.85 (d, J=7.09 Hz, 1H) 7.63-7.72 (m, 1H) 7.48-7.58 (m, 2H) 5.44 (d, J=7.21 Hz, 1H) 4.29 (q, J=7.21 Hz, 2H) 1.38 (t, J=7.15 Hz, 3H). 13C NMR (101 MHz, chloroform-d) δ ppm 164.15 (s, 1C) 162.55 (s, 1C) 144.54 (s, 1C) 134.31 (s, 1C) 130.66 (s, 2C) 128.74 (s, 2C) 127.90 (s, 1C) 103.38 (s, 1C) 60.30 (s, 1C) 14.28 (s, 1C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.Cl.[SH:18][C:19]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:20]=1[NH2:21]>CO.O>[CH:12]1([O:11][C:4]2[CH:5]=[C:6]([C:7]3[S:18][C:19]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:20]=4[N:21]=3)[CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Nc1cc(F)ccc1S
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(-c2nc3cc(F)ccc3s2)cc1OC1CCCC1
Reaction time: 8 h
Yield: 72.8 %

Procedure:
A mixture of (440 mg, 2 mmoles) 4-methoxy-3-cyclopentyloxy benzaldehyde and (400 mg, 2.1 mmoles) 2-mercapto-5-fluoroaniline hydrochloride was heated on a steam bath for 15 minutes. The resulting thick orange oil was cooled and dissolved in 5 ml of 10% FeCl3 in methanol and allowed to stir overnight. The reaction was diluted with water and extracted with CH2Cl2. The CH2Cl2 layer was dried and evaporated to give 760 mg of crude product which was purified on silica gel with CH2 Cl2 to give 500 mg of product. Recrystallization from isopropanol gave 140 mg of product. M.P.: 96°-97° C. Elemental Analysis Calc'd for C19H18O2NSF : Calc'd: C, 66.45; H, 5.28; N, 4.08. Found: C, 66.44; H. 5.13; N. 4.06.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][NH:23][NH2:24])=[CH:20][CH:19]=1.C(O)(=O)C>CO>[CH3:16][O:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][NH:23]/[N:24]=[C:8](\[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:20][CH:19]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: COc1ccc(CNN)cc1
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CN/N=C(/c2ccccc2)c2ccc(C)cc2)cc1

Procedure:
To a solution of (4-methylphenyl)(phenyl)methanone (12) (1.9 g, 0.01 mol) in methanol was added 4-methoxybenzyl hydrazine (4.5 g, 0.035 mol) and acetic acid (0.5 mL). The mixture was reflux for 2 h. After cooling, the mixture was concentrated and the residue was extracted with CHCl3, washed with dil. HCl, followed by water, dried over MgSO4 and concentrated in vacuo, to give (Z)-(4-methylphenyl)(phenyl)methanone (4-methoxybenzyl)hydrazone (13). Next, a solution of above benzylhydrazone was dissolved in CH2Cl2 (50 ml) was added dropwise to a solution of Pb(OAC)4 (14.1 g, 0.03 mol) in CH2Cl2 (200 mL). After addition was completed, the mixture was reacted at 30±2° C. for 30 min, the BF3.Et2O (containing 47% of BF3 61 mL) was added. The mixture was reflux for 30 min before quenched into ice water. The organic layer was washed with water, dried over MgSO4 and evaporated. The residue was purified by column chromatography (silica gel-toluene) produce compound 24 (0.6 g). This product was confirmed by comparison of its IR and NMR spectra with that of a sample from the method A.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([C:8](=O)[CH:9]([F:11])[F:10])[CH:7]=1.[CH3:14][C:15]([S@@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>O1CCCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6](/[C:8](=[N:20]\[S@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])/[CH:9]([F:11])[F:10])[CH:7]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=C(c1cc(Br)ccc1F)C(F)F
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@](=O)/N=C(\c1cc(Br)ccc1F)C(F)F
Temperature: 70 °C
Reaction time: 3 h
Yield: 78 %

Procedure:
To a solution of 1-(5-bromo-2-fluorophenyl)-2,2-difluoroethanone (intermediate E1.1) (13.2 g, 52.2 mmol) and (S)-(−)-2-methyl-2-propanesulfinamide (6.96 g, 57.4 mmol) in tetrahydrofuran (104 ml) was added at 23° C. titanium(IV) ethoxide (21.4 g, 19.5 ml, 93.9 mmol). The yellow solution was stirred at 70° C. for 3 hours. The cooled reaction mixture was poured into ice water, diluted with ethyl acetate and filtered through a pad of Dicalite. The organic layer was separated and washed with brine and then dried over Na2SO4. Removal of the solvent in vacuum left a yellow oil (18.25 g), which was purified by silica column chromatography 200 g, SiO2 with dichloromethane/heptane 1:1 to give (S,E)-N-(1-(5-bromo-2-fluorophenyl)-2,2-difluoroethylidene)-2-methylpropane-2-sulfinamide (14.49 g, 40.7 mmol, 78.0% yield) as a yellow oil. MS (ISP): m/z=355.9 [M+H]+ and 357.9 [M+2+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]2[S:23][C:22]([C:24]3([O:28][CH2:29][O:30][CH3:31])[CH2:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=3[F:18])[NH:8][C:5]2=[N:6][CH:7]=1.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([C:19]2[S:23][C:22]([C:24]3([O:28][CH2:29][O:30][CH3:31])[CH2:25][CH2:26][CH2:27]3)=[N:21][CH:20]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH:15][C:35](=[O:36])[CH2:34][N:33]([CH3:38])[CH3:32])=[CH:13][C:12]=3[F:18])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)CC(=O)O
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(N)cc5F)cc34)s2)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(NC(=O)CN(C)C)cc5F)cc34)s2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-fluoroaniline (Example 60B) (68 mg, 0.148 mmol) and dimethyl glycine (15.3 mg, 0.148 mmol) in N,N-dimethylformamide (0.5 mL) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (67.6 mg, 0.178 mmol) and 4-(dimethylamino)pyridine (1.8 mg, 0.015 mmol). The reaction was stirred for 16 hours at ambient temperature. The reaction was treated with more O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (67.6 mg, 0.178 mmol) and 4-(dimethylamino)pyridine (18.1 mg, 0.148 mmol), and the reaction was stirred another 16 hours at ambient temperature. The reaction was diluted with ethyl acetate and washed with water, saturated sodium bicarbonate solution, and brine. The organic layer was dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with a gradient of 1 to 5% methanol in dichloromethane, to give the title compound. MS ESI(+) m/z 544.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15]C(=O)C)[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:21][CH:22]([CH3:24])[CH3:23].[OH-].[Na+].O.Cl>CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[NH:21][CH:22]([CH3:24])[CH3:23]
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NC(C)C)c3)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)Nc1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
N-(6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (123.6 mg, 342.5 μmol) was suspended in MeOH (2.2 ml) and sodium hydroxide (89.90 mg, 2248 μmol) and water (0.44 ml) were added. The reaction flask was fit with a reflux condenser and placed in a preheated oil bath (80° C.), and the reaction was stirred for 1 hour. The reaction was cooled to room temperature, treated with 5 N HCl to neutralize the solution, and allowed to stand overnight. It was then extracted with 10:1 DCM/MeOH, and the organic extracts were combined, concentrated, and purified on a silica gel column (20:1 DCM/MeOH to 15:1 DCM/2 N ammonia in MeOH). Fractions with product collected, concentrated, and treated with Et2O and MeOH. The MeOH washings were decanted, and the solid was collected and dried under high vacuum to afford 6-(6-chloro-5-(isopropylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (18.2 mg, 17% yield). MS (ESI pos. ion) m/z: 319. Calculated exact mass for C15H15ClN4S 318.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:34][C:31]3[CH:32]=[CH:33][C:28]([CH:25]([CH3:27])[CH3:26])=[CH:29][CH:30]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)c1ccc(O)cc1
Product: CC(C)c1ccc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)cc1
Yield: 73.8 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 4-isopropyl phenol (36 mg, 0.26 mmol) to give the title compound (46 mg, 73%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[C:28](O)(=[O:31])[CH2:29][CH3:30]>ClCCl>[CH3:1][CH:2]1[N:6]([C:28](=[O:31])[CH2:29][CH3:30])[CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[S:3]1
Reactant: CCC(=O)O
Reactant: CC1NCC2(CCN(C)CC2)S1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCC(=O)N1CC2(CCN(C)CC2)SC1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
To a stirred solution of 2,8-dimethyl-1-thia-3,8-diaza-spiro[4.5]decane (Example 1) (0.86 g, 4.62 mmol) in dichloromethane (90 ml) at room temperature was added dicyclohexylcarbodiimide (DCC) (1.28 g, 6.2 mmol) followed by addition of propionic acid (0.41 ml, 5.5 mmol). The resulting solution was stirred at room temperature overnight. During the reaction a white solid precipitated. After filtration the solvent was evaporated and the crude product was purified by flash chromatography (silica, CH2Cl2/MeOH/NH4OH 90/10/1) to give the title compound (0.5 g) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ 5.51, 5.19 (2q, J=6.15 and J=6.22 Hz, 1H, CHCH3), 4.63, 3.74 (2d, J=11.88 and J=11.57 Hz, 1H, CHHNCO), 3.44, 3.08 (2d, J=11.55 and J=12.09 Hz, 1H, CHHNCO), 2.8-2.6 (m, 2H), 2.5-2.2 (m, 7H, CH2, CH2CH3, NCH3), 2.2-2.0 (m, 1H), 2.0-1.8 (m, 3H) 1.52, 1.48 (2d, J=6.30 and J=6.18 Hz, 3H, CH3—CH), 1.19-1.12 (m, 3H, CH3) ppm; 13C NMR (CDCl3, 300 MHz) δ 171.6 (C), 57.5, 57.2 (CH), 55.5 (C), 54.7, 54.3 (CH2), 53.2, 53.0 (CH2), 46.3 (CH3), 38.4, 37.7 (CH2), 37.0, 36.4 (CH2), 28.8, 26.8 (CH2), 25.6, 23.6 (CH3), 9.6, 9.4 (CH3) ppm.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][OH:15])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:16][CH2:17][C:18](O)=[O:19].C1(C)C=CC(S([O-])(=O)=O)=CC=1.CN(C)C1C=C[NH+]=CC=1.C1CCC(N=C=NC2CCCCC2)CC1>ClCCl>[Br:16][CH2:17][C:18]([O:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:19]
Reactant: O=C(O)CBr
Reactant: OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1cc[nH+]cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: ClCCl
Product: O=C(CBr)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, 9-fluorenemethanol (99%, 0.694 g, 3.5 mmol), bromoacetic acid (99%, 0.406 g, 2.9 mmol), DPTS (0.130 g, 0.44 mmol) and DCC (99%, 0.729 g, 3.5 mmol) were combined in dichloromethane (9 mL), stirred at 0° C. for 1 h, and the precipitate of dicyclohexylurea was filtered off from the cold mixture. The filtrate was diluted with cold ethyl acetate (30 mL), washed twice with cold 5% aqueous solution of NaH2PO4 (60 mL, acidified with H3PO4 to pH=3), freed of water droplets, and the solvents were distilled off in vacuo. The residue was extracted with cold pentane to remove the excess of DCC, and purified by flash chromatography (silica-gel, hexane-CHCl3, 5:1 to 1:1) followed by crystallization from cold hexane. Yield of 8: 0.795 g (87%). The purity was confirmed by TLC (SiO2, heptane-ethyl acetate, 9:1).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][C:7]([CH2:8][CH:9]2[S:13][C:12](=[O:14])[NH:11][C:10]2=[O:15])=[CH:6][CH:5]=1.Cl[CH2:19][C:20]1[N:21]=[C:22]([C:25]2([CH3:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[O:23][CH:24]=1.O>CN(C)C=O>[CH3:31][C:25]1([C:22]2[O:23][CH:24]=[C:20]([CH2:19][O:3][C:4]3[CH:17]=[CH:16][C:7]([CH2:8][CH:9]4[S:13][C:12](=[O:14])[NH:11][C:10]4=[O:15])=[CH:6][CH:5]=3)[N:21]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: O=C1NC(=O)C(Cc2ccc(O)cc2)S1
Reactant: CC1(c2nc(CCl)co2)CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(c2nc(COc3ccc(CC4SC(=O)NC4=O)cc3)co2)CCCCC1
Reaction time: 0.5 h

Procedure:
60% sodium hydride in oil (1.32 g) was added to solution of 5-(4-hydroxybenzyl)-2,4-thiazolidinedione (3.35 g) in N,N-dimethylformamide (30 ml), and the mixture was stirred for 30 minutes. Then, solution of 4-chloromethyl-2-(1-methylcyclohexyl)oxazole (3.85 g) in N,N-dimethylformamide (5 ml) was added dropwise thereto at room temperature. After being stirred at 60° C. for 1 hour, the reaction solution was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The oily residue was chromatographed on a column of silica gel (70 g). Elution with hexaneethyl acetate (2:1, V/V) gave 5-{4-[2-(1-methylcyclohexyl)-4-oxazolylmethoxy]benzyl}-2,4-thiazolidinedione as an oily substance. A solution of sodium 2-ethylhexanoate in isopropanol (2N, 3 ml) was added to the oily substance, and treated with ether. The crystals which separated out were collected by filtration to give 5- {4-[2-(1-methylcyclohexyl)-4-oxazolylmethoxy]benzyl}-2,4-thiazolidinedione.sodium salt (2.3 g, 36.3%). Recrystallization from methanol afforded colorless plates. m.p. 285°-287° C. (decomp.) Elemental analysis for C21H23N2O4SNa, Calcd.: C, 59.70; H, 5.49; N, 6.63. Found: C, 59.76; H, 5.56; N, 6.82.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[Li]CCCC.C1(O[C:21]#[N:22])C=CC=CC=1>CCOCC>[CH:4]1([CH2:1][C:2]#[C:3][C:21]#[N:22])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: C#CCC1CCCC1
Reactant: N#COc1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Product: N#CC#CCC1CCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
Prop-2-ynyl-cyclopentane (46.2 mmol) was dissolved in 100 mL of anhydrous Et2O under N2 and the reaction was cooled to −78° C. A 2.5 M solution of BuLi in hexanes (55.5 mmol) was added dropwise to the reaction over 30 minutes. The reaction was stirred for an additional 20 minutes and phenyl cyanate (55.5 mmol) was then added in solution with 20 mL of Et2O dropwise over 20 minutes. The resultant solution was allowed to slowly warm to rt and stir for 3 hours. The reaction material was then diluted in 200 mL of fresh Et2O and washed with three 100 mL portions of 1 N aqueous NaOH solution. The organics were then washed with 200 mL of brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified through flash chromatography on silica gel to give 4-cyclopentyl-but-2-ynenitrile (21.7 mmol).
Reaction SMILES: S(C)C.[CH3:4][Li].[C:6]([NH:25][C@@H:26]([CH2:29][CH3:30])[CH:27]=[O:28])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH4+].[Cl-]>CCOCC>[C:6]([NH:25][C@@H:26]([CH2:29][CH3:30])[C@H:27]([OH:28])[CH3:4])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CSC
Product: CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O
Temperature: 25 °C

Procedure:
To a stirred suspension of CuBr.SMe2 (3 g, 14.6 mmol) in anhydrous ether (100 ml) under an argon atmosphere at −78° C., was added methyl lithium (1.6M in ether, 16.5 ml, 4.0 eq, 26.5 mmol) dropwise and the solution allowed to warm to room temperature over 1 h. The mixture was recooled to −78° C., and a solution of (S)-2-(trityl-amino)-butyraldehyde (2.2 g, 6.62 mmol) in ether (25 ml) was added dropwise with stirring. The reaction mixture was stirred at this temperature for 2 h then allowed to warm to room temperature over 1 h. A saturated aqueous solution of NH4Cl (50 ml) was added and the two layers separated. The organic phase was washed with brine (50 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash silica gel column chromatography, eluted with hexane:ethyl acetate (80:20) to afford (2R,3S)-3-(trityl-amino)-pentan-2-ol as a light yellow oil; Yield: 1.5 g (66%). (75% de 2R, 3S: 25% de 2S, 3S). 1H-NMR (d6-DMSO, 250 MHz): δ 0.0.47+0.55 (2×t, J=7.50+7.26 Hz —NHCH(CH2CH3)CH(CH3)OH), 0.99-1.12 (m, 5 H, —NHCH(CH2CH3)CH(CH3)OH), 2.01 (1 H, m, —NHCH(CH2CH3)CH(CH3)OH), 3.22-3.43 (m, 1H, —NHCH(CH2CH3)CH(CH3)OH), 4.41 [1 H, d, J=3.3, NHCH(CH2CH3)CH(CH3)OH], 7.14-7.56 (15 H, m, ArH). δC (250 MHz, CDCl3) 146.88 (C), 128.97 (6×CH), 127.83 (6×CH), 126.43 (3×CH), 71.03 (C), 68.13 (CH), 58.77 (CH), 23.09 (CH2), 17.88 (CH3), 10.47 (CH3)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[NH:26][C:27](=[O:35])[C:28]2[CH:33]=[C:32]([CH3:34])[S:31][C:29]=2[N:30]=1.[H-].[Na+]>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:24][C:25]4[NH:26][C:27](=[O:35])[CH:28]5[CH:33]=[C:32]([CH3:34])[S:31][CH:29]5[N:30]=4)[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1
Reactant: Cc1cc2c(=O)[nH]c(CCl)nc2s1
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC4=NC5SC(C)=CC5C(=O)N4)C3=O)CC2)cc1
Temperature: 70 °C
Yield: 88.5 %

Procedure:
To a solution of 3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (0.165 mmol, 50 mg) and 2-chloromethyl-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one (0.165 mmol, 33 mg) in THF (2 mL) was added sodium hydride (60%, 0.331 mmol, 23 mg) and heated to 70° C. for 1 hour. The reaction was allowed to cool to ambient temperature, diluted with 10 mL of ether, and the resulting solid in suspension was filtered and dried under vacuum provided the title compound as an off-white solid (70.5 mg, 95.4% yield). HRMS calculated for C25H28N4O4S 480.5903. found (ESI, [M+H]+) 481.1907. 1H NMR (400 MHz, MeOD) δ ppm 1.66-1.93 (m, 4H) 2.05-2.30 (m, 2H) 2.51-2.63 (m, 1H) 2.79-2.90 (m, 1H) 2.90-2.98 (m, 1H) 3.03-3.18 (m, 1H) 3.33-3.54 (m, 4H) 3.65-3.75 (m, 1H) 3.87 (s, 3H) 4.20-4.31 (m, 1H) 4.51-4.62 (m, 1H) 6.94-7.06 (m, 3H) 7.98 (d, J=9.03 Hz, 2H), analytical RP-HPLC retention time=3.22 min
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([N:23]([CH2:25][C:26]([O:28]CC)=O)[CH3:24])=[O:22])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CC(C)([O-])C.[K+].Cl>C1COCC1.CN(C=O)C>[CH3:24][N:23]1[CH2:25][C:26]([OH:28])=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=2)[C:21]1=[O:22]
Reactant: CCCCCCCCCCCCOc1ccc(CC(=O)N(C)CC(=O)OCC)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCOc1ccc(C2=C(O)CN(C)C2=O)cc1
Reaction time: 1 h
Yield: 64.3 %

Procedure:
In a mixture of THF (50 ml) and DMF (10 ml) was dissolved ethyl N-(4-dodecyloxyphenylacetyl)-N-methylaminoacetate (4.0 g, 0.01 mol.). To the solution was added at room temperature potassium tertiary butoxide (1.8 g, 1.6 mol.) and the mixture was stirred for one hour, to which was then added 2N HCl (20 ml), followed by extraction with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure to give crude crystals. The crude crystals were recrystallized from IPE - ethyl acetate to give N-methyl-3-(4-dodecyloxyphenyl)-4-hydroxy-3-pyrrolin-2-one (4-b, 2.4 g, 71%).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][C:13]1[C:18](Cl)=[N:17][C:16]([N:20]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]([CH3:23])[CH3:22])=[CH:15][N:14]=1)[CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O>CN(C=O)C>[CH2:24]([N:20]([CH:21]([CH3:23])[CH3:22])[C:16]1[CH:15]=[N:14][C:13]2[CH2:12][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10][O:11][C:18]=2[N:17]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)N(Cc1ccccc1)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(Cc1ccccc1)c1cnc2c(n1)OCCN(Cc1ccccc1)C2
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 2-[benzyl({5-[benzyl(1-methylethyl)amino]-3-chloropyrazin-2-yl}methyl)amino]ethanol (3.32 g) in DMF (12 mL) was added potassium tert-butoxide (1.05 g) at 0° C., and the mixture was stirred for 2 hr. Water (10 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→30% ethyl acetate/hexane) to give the title compound (2.55 g, 84%) as a pale-yellow oil.