Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].N1C=CC=CC=1.[Br:14][C:15]1[C:24]([CH:25]([O:28][C:29]([CH3:35])([CH3:34])[C:30]([F:33])([F:32])[F:31])[CH2:26][OH:27])=[C:23]([CH3:36])[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2>C(Cl)Cl>[C:3]([O:27][CH2:26][CH:25]([C:24]1[C:15]([Br:14])=[C:16]2[C:21](=[CH:22][C:23]=1[CH3:36])[N:20]=[CH:19][CH:18]=[CH:17]2)[O:28][C:29]([CH3:35])([CH3:34])[C:30]([F:31])([F:33])[F:32])(=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc2ncccc2c(Br)c1C(CO)OC(C)(C)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2ncccc2c(Br)c1C(COC(=O)C(C)(C)C)OC(C)(C)C(F)(F)F
Temperature: 25 °C

Procedure:
To a stirred solution of trimethylacetyl chloride (19 μL, 0.15 mmol) in pyridine (0.4 mL, 4.95 mmol) was added 2-(5-bromo-7-methylquinolin-6-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethanol (29.8 mg, 0.08 mmol) in CH2Cl2 (0.4 mL) at 0° C. The reaction mixture was allowed to warm to room temperature overnight. The mixture was quenched with water and concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 2-(5-bromo-7-methylquinolin-6-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethyl pivalate. LCMS-ESI+ (m/z): [M+H]+ calc'd for C21H26BrF3NO3: 476.11; Found: 476.2.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[CH2:11]([C:15]1[CH:20]=[C:19](Cl)[N:18]2[N:22]=[CH:23][CH:24]=[C:17]2[N:16]=1)[CH2:12][CH:13]=[CH2:14].O>CN(C=O)C>[CH2:11]([C:15]1[CH:20]=[C:19]([O:3][CH2:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=2)[N:18]2[N:22]=[CH:23][CH:24]=[C:17]2[N:16]=1)[CH2:12][CH:13]=[CH2:14]
Reactant: C=CCCc1cc(Cl)n2nccc2n1
Reactant: OCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCCc1cc(OCc2ccncc2)n2nccc2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.7 %

Procedure:
60% sodium hydride, 0.55 g, was added to a 10 ml-solution of 1.6 g of 4-(hydroxymethyl)pyridine in DMF while being ice-cooled. After the mixture was stirred at 0° C. for 30 minutes, a DMF solution (2.5 ml) containing 2.6 g of 5-(3-butenyl)-7-chloropyrazolo[1,5-a]pyrimidine was added dropwise while being ice-cooled. The mixture was stirred at the same temperature for another 1 hour. After completion of the reaction, water was added to the reaction mixture. The crystals precipitated were collected by filtration and washed with water and then with diethyl ether. The crude crystals obtained were recrystallized from ethyl acetate-n-hexane to provide 1.5 g of the title compound as colorless crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8](Cl)(=[O:17])[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:17])=[CH:10][CH:11]=1
Reactant: Nc1ccncc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2ccncc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.8 %

Procedure:
4-Aminopyridine (1.94 g, 20.6 mmol) was added to a solution of p-anisoyl chloride (3.5 g, 20.6 mmol) and triethylamine (8.6 mL, 62 mmol) in dichloromethane (100 mL) at 0° C. The mixture was stirred 3 h at RT, and then extracted successively with 1N NaOH, water and brine, dried over sodium sulfate, and concentrated. Chromatography on silica (gradient of 30% to 100% ethyl acetate-hexanes) gave 3.8 g (81%) of a colorless solid. 1H NMR (CDCl3, 400 mHz) δ 8.49 (m, 2H), 8.19 (br, 1H), 7.85 (m, 2H), 7.59 (m, 2H), 6.95 (m, 2H), 3.85 (s, 3H), MS (AP+) 229 (MH+).
Reaction SMILES: C(=O)([O:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[CH:22][C:21](Cl)=[N:20]3)=[O:16])[C:9]=1[F:28])OC(C)(C)C.Cl.[O:31]1CCOC[CH2:32]1>CO>[F:28][C:9]1[C:8]([OH:7])=[CH:13][CH:12]=[C:11]([F:14])[C:10]=1[C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][C:21]([O:31][CH3:32])=[N:20]2)=[O:16]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)Oc1ccc(F)c(C(=O)c2ccc3ncc(Cl)nc3c2)c1F
Agent: Cl
Solvent: CO
Product: COc1cnc2ccc(C(=O)c3c(F)ccc(O)c3F)cc2n1
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of tert-butyl (3-(3-chloroquinoxaline-6-carbonyl)-2,4-difluorophenyl) carbonate (55 mg, 0.13 mmol, 1 eq.) in MeOH (5 mL) was added HCl/dioxane (3 N, 5 mL). The resulting mixture was stirred overnight, then concentrated. The residue was purified via flash column chromatography (PE/EA=1/1, v/v) to afford (2,6-difluoro-3-hydroxyphenyl)(3-methoxyquinoxalin-6-yl)methanone (20.3 mg, 49%). LCMS (M−H+) m/z calculated 315.1, found 315.0. 1H NMR (CD3OD, 400 MHz) δ 8.49 (s, 1 H), 8.01-8.06 (m, 3 H), 7.01-7.07 (m, 1 H), 6.86-6.91 (m, 1 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:20]=[CH:19][C:18]2[C:17]3[C:12](=[CH:13][C:14]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]Cl)=[CH:15][CH:16]=3)[CH2:11][C:10]=2[CH:9]=1)=[O:7].[CH2:28]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([CH:35]1[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:20]=[CH:19][C:18]3[C:17]4[C:12](=[CH:13][C:14]([C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][N:38]5[CH2:39][CH2:40][CH:35]([CH2:28][C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH2:36][CH2:37]5)=[CH:15][CH:16]=4)[CH2:11][C:10]=3[CH:9]=2)=[O:7])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(CCCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCCl)ccc1-2
Reactant: c1ccc(CC2CCNCC2)cc1
Product: O=C(CCCCN1CCC(Cc2ccccc2)CC1)c1ccc2c(c1)Cc1cc(C(=O)CCCCN3CCC(Cc4ccccc4)CC3)ccc1-2

Procedure:
Following the procedure of Example 7, 20.2g (0.05 mole) of 2,7-bis(5-chlorovaleryl)fluorene, prepared in Example 2, and 70.0g (0.4 mole) of 4-benzylpiperidine were reacted to give the desired product which was recrystallized three times from chloroform-acetone. M.P. 147°-149° C, λmaxEtOH 329, E1cm1% 577.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][C:7]2([C:10]#N)[CH2:9][CH2:8]2)=[C:4](I)[CH:3]=1.[Li]CCCC.C1C[O:23]CC1>>[Br:1][C:2]1[CH:13]=[C:12]2[C:5]([CH2:6][C:7]3([CH2:9][CH2:8]3)[C:10]2=[O:23])=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: N#CC1(Cc2ccc(Br)cc2I)CC1
Agent: [Li]CCCC
Product: O=C1c2cc(Br)ccc2CC12CC2
Temperature: -78 °C
Yield: 51 %

Procedure:
A dried flask was charged with 1-(4-bromo-2-iodobenzyl)cyclopropanecarbonitrile (Intermediate 51, 3.29 g, 9.09 mmol) and dry THF (30 mL) was added under argon atmosphere. The resulting mixture was cooled to −78° C. and n-BuLi (2.5 M in hexanes, 7.27 mL, 18.2 mmol) was added dropwise. The solution was allowed to reach r.t. The reaction was quenched with MeOH (2 mL) and HCl (1M, 5 mL). The mixture was extracted with EtOAc. The water phase was basified with sat NaHCO3 and extracted with EtOAc twice. The organic phases were combined, dried over MgSO4, filtered and concentrated in vacuo. HCl (1 M, 4 mL) and DCM (5 mL) were added and the organic phase was collected. This was repeated twice. The water phase was basified with sat NaHCO3 and extracted with DCM. The combined organic phases were dried through a phase separator and evaporated to dryness to give the title compound (1.1 g, 51% yield): MS (CI) m/z 237 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH2:9][CH2:10][OH:11].C(Cl)Cl.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH3:22][S:23]([O:1][CH2:2][CH2:3][C:4]1[O:5][CH:6]=[CH:7][C:8]=1[CH2:9][CH2:10][O:11][S:23]([CH3:22])(=[O:25])=[O:24])(=[O:25])=[O:24]
Reactant: OCCc1ccoc1CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccoc1CCOS(C)(=O)=O
Reaction time: 1 h

Procedure:
A solution of 2,3-di(2-hydroxyethyl)furan (23 mmol) in methylene chloride (114 mmol) is cooled to 0° C. and treated with triethylamine (69 mmol) followed by dropwise addition of methanesulfonyl chloride (50.4 mmol) over 10 minutes. After 1 hour the reaction mixture is transferred to a reparatory funnel and extracted with cold water, 10% citric acid, saturated aqueous NaHCO3, and brine. The organic layer is dried and concentrated twice with the aid of dioxane to produce 2,3-di(2-methanesulfonyloxy-ethyl)furan, which is used crude without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:5]2[C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1.Br[CH2:33][C:34]#[N:35].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:34]([CH2:33][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:6]([CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[C:5]2[C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)#[N:35]
Reactant: N#CCBr
Reactant: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(O)cc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2c(CNC(=O)OC(C)(C)C)c(CC(C)C)nc3ccc(OCC#N)cc23)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.6 %

Procedure:
A mixture of tert-butyl {[6-hydroxy-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (2.5 g, 5.9 mmol), bromoacetonitrile (0.5 ml, 7.2 mmol), potassium carbonate (1.0 g, 7.2 mmol) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 12 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl {[6-(cyanomethoxy)-2-isobutyl-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (1.4 g, yield 52%) as pale-yellow crystals.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([O:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[CH:5]=[C:4]([CH3:17])[N:3]=1.[CH3:18][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[OH:27].CC(C)([O-])C.[K+]>C1COCC1>[CH2:13]([CH:12]([O:11][C:6]1[CH:5]=[C:4]([CH3:17])[N:3]=[C:2]([O:27][C:20]2[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=2[CH3:18])[C:7]=1[N+:8]([O-:10])=[O:9])[CH2:15][CH3:16])[CH3:14]
Reactant: Cc1cc(C)c(O)c(C)c1
Reactant: CCC(CC)Oc1cc(C)nc(Cl)c1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
To a mixture of 2-chloro-4-(1-ethyl-propoxy)-6-methyl-3-nitro-pyridine (500 mg, 1.93 mmol) and 2,4,6-trimethylphenol (289 mg, 2.13 mmol) in dry THF was added potassium t-butoxide. The resulting mixture was stirred at rt. overnight. The mixture was quenched with water, brine and extracted 3 times with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness. After silica gel column chromatography purification, the title compound was obtained as a light yellow crystal, mp 106–109° C. Anal. For C20H26N2O4 calc. C, 67.02; H, 7.31; N, 7.82; found, C, 67.34; H, 7.40; N, 7.42.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[N:20]1([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[CH:27][CH:26]=2)[CH:24]=[N:23][N:22]=[N:21]1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:1]=[C:2]1[CH2:7][N:6]([C:32](=[O:33])[CH2:31][C:28]2[CH:27]=[CH:26][C:25]([N:20]3[CH:24]=[N:23][N:22]=[N:21]3)=[CH:30][CH:29]=2)[CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC(N1CCN(C(=O)Cc3ccc(-n4cnnn4)cc3)CC1=O)C2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile (40 mg, 0.16 mmol) and [4-(1H-tetrazol-1-yl)phenyl]acetic acid (38 mg, 0.19 mmol) in DCM (3 ml) was added DMAP (25 mg, 0.20 mmol) and EDC (39 mg, 0.20 mmol). The mixture was allowed to stir at RT for 4 hours. LC showed formation of the desired product. The solvent was removed under vacuum, and the residue was redissolved in methanol, and purified by reverse phase HPLC to give the title product. LC-MS (IE, m/z): 442 [M+1]+.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Cl[C:14]1[N:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:12][C:11]1[C:6]([CH:4]2[CH2:5][N:2]([C:14]3[N:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:3]2)=[N:7][CH:8]=[CH:9][N:10]=1
Reactant: Clc1ncc2ccccc2n1
Reactant: Clc1nccnc1C1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1nccnc1C1CN(c2ncc3ccccc3n2)C1
Temperature: 110 °C
Reaction time: 17 h
Yield: 47.1 %

Procedure:
2-(Azetidin-3-yl)-3-chloropyrazine hydrochloride (1.50 g, 7.28 mmol), 2-chloroquinazoline (1.20 g, 7.28 mmol, Parkway Scientific), and cesium carbonate (5.22 g, 16.0 mmol, Fluka) were mixed in DMF (30 mL) in a round bottom flask under a nitrogen atmosphere. The mixture was stirred at 110° C. for 17 h. The reaction mixture was cooled to room temperature, diluted with water, and extracted with EtOAc (2×). The combined organic extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude mixture was purified via silica gel flash column chromatography eluting with 0% to 100% EtOAc in hexanes to give 1.02 g (47%) of a yellow amorphous solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.41-4.50 (m, 1H) 4.58-4.63 (m, 2H) 4.65-4.72 (m, 2H) 7.22-7.28 (m, 1H) 7.61-7.72 (m, 3H) 8.28 (d, J=2.35 Hz, 1H) 8.51 (d, J=2.35 Hz, 1H) 9.04 (s, 1H). m/z=298 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([OH:21])=O)=[N:4][C:5]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])[CH2:12][CH:13]=2)=[CH:6][N:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(N(CC)CC)C.[CH3:41][C:42]1[CH:47]=[C:46]([NH2:48])[CH:45]=[CH:44][N:43]=1>CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[C:3]([C:19]([NH:48][C:46]2[CH:45]=[CH:44][N:43]=[C:42]([CH3:41])[CH:47]=2)=[O:21])=[N:4][C:5]([C:8]2[CH2:9][CH2:10][N:11]([S:14]([CH2:17][CH3:18])(=[O:15])=[O:16])[CH2:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: Cc1cc(N)ccn1
Reactant: CCS(=O)(=O)N1CC=C(c2cnc(N)c(C(=O)O)n2)CC1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(C(=O)Nc3ccnc(C)c3)n2)CC1
Temperature: 100 °C
Reaction time: 16 h
Yield: 29.6 %

Procedure:
A solution of 3-amino-6-(1-ethylsulfonyl-3,6-dihydro-2H-pyridin-4-yl)pyrazine-2-carboxylic acid (79.87 mg, 0.255 mmol), CDI (82.92 mg, 0.511 mmoles), triethylamine (107 uL, 0.767 mmoles), and DMAP (1.56 mg, 0.012 mmol) was treated with 2-methylpyridin-4-amine (55.30 mg, 0.511 mmol). The reaction was allowed to stir at 100° C. for 16 hours, filtered and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried to give the title compound (30.4 mg, 21% Yield). 1H NMR (400.0 MHz, DMSO) d 11.10 (s, 1H), 8.69-8.67 (m, 2H), 8.25-8.22 (m, 2H), 7.72 (s, 2H), 6.77 (d, J=3.3 Hz, 1H), 3.99 (d, J=2.9 Hz, 2H), 3.48 (t, J=5.7 Hz, 2H), 3.16 (q, J=7.4 Hz, 2H), 2.79 (s, 2H), 2.68 (s, 3H) and 1.25 (t, J=7.3 Hz, 3H) ppm; MS (ES+) 403.0
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:9][C:10]([O:12][CH3:13])=[O:11].CCN(CC)CC>CC#N>[CH3:13][O:12][C:10](=[O:11])[CH2:9][S:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Sc1ccccn1
Reactant: COC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CSc1ccccn1
Yield: 94.3 %

Procedure:
A solution of 2-mercaptopyridine (484 mg, 4.35 mmol), methyl bromoacetate (0.45 ml, 4.8 mmol), and Et3N (0.79 ml, 5.7 mmol) in CH3CN (22 ml) was stirred at room temperature for 20 h to give (pyridin-2-ylsulfanyl)-acetic acid methyl ester as a colorless oil (752 mg, 94%) after aqueous work-up and purification.
Reaction SMILES: [C:1]1([S:7]([CH:10]=[CH:11][C:12]2[CH:13]=[C:14]([CH:22]=[C:23]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:24]=2)[CH:15]=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC1C=CC(S(NN)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:1]1([S:7]([CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:22]=[C:23]([CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH:24]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C=Cc1cc(C=CS(=O)(=O)c2ccccc2)cc(Cc2cccnc2)c1
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1cc(CCS(=O)(=O)c2ccccc2)cc(Cc2cccnc2)c1
Yield: 78.4 %

Procedure:
A mixture of ethyl 3-(2-phenylsulphonylethenyl)-5-(3-pyridylmethyl)cinnamate (preparation 20; 0.485 g) and 4-methylphenylsulphonyl hydrazine (2.08 g) in toluene (25 ml) was heated under reflux for 3 hours and then evaporated under vacuum. The residue was chromatographed on silica gel using an ethyl acetate in hexane elution gradient (50 to 100% ethyl acetate) initially followed by an ethyl acetate:diethylamine (95:5) mixture as eluent. The product fractions were combined and evaporated under vacuum to give the title compound as a gum (0.384 g); Rf 0.50 (SS 4); δ (CDCl3): 1.23(3H,t), 2.57(2H,t), 2.86(2H,t), 2.99(2H,m), 3.33(2H,m), 3.91(2H,s), 4.13(2H,q), 6.82(1H,s), 6.87(1H,s), 6.91(1H,s), 7.22-7.25(1H,m), 7.43-7.47(1H,m), 7.57-7.72(3H,m), 7.94-7.98(2H,m), 8.48-8.51(2H,m).
Reaction SMILES: [C@:1]12([CH2:11][S:12]([OH:15])(=[O:14])=[O:13])[C:8]([CH3:10])([CH3:9])[CH:5]([CH2:6][CH2:7]1)[CH2:4][C:2]2=[O:3].N#N>C1(C)C=CC=CC=1.C1COCC1>[CH3:9][C:8]1([CH3:10])[C:1]2([CH2:11][S:12]([OH:15])(=[O:14])=[O:13])[C:2]([CH2:4][CH:5]1[CH2:6][CH2:7]2)=[O:3]
Reactant: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: N#N
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Yield: 99 %

Procedure:
Thirty (30) g of the compound of Formula II and 0.386 g (2 mole %) of (1S)-(+)-10-camphorsulfonic acid (CSA) was charged in a 500 mL 3 necked round bottom flask equipped with a thermometer, N2 inlet and addition funnel. 111 mL of dry THF was charged to dissolve the 30 g of the compound Formula II, and the (1S)-(+)-10-camphorsulfonic acid at about 20 to 25° C. 2.2 mL of pre formed (R)-MCBS catalyst in toluene (3 mole %) was charged. 39.9 mL of 1M borane THF complex in THF solution was slowly charged over 1.5 hours at a temperature range between about 23 and 28° C. The batch was sampled for HPLC to monitor the progress of the reaction. After the reaction was judged complete, using the same subsequent procedure as described in Example 1 (i.e. quenching with MeOH, vacuum concentration of the batch, etc., but in appropriate ratios of reagents for this example), the compound of Formula I was obtained. Results varied, but in general, ˜99% yield and ˜94% de were obtained.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([CH:20]=[CH:21][C:22]2[C:30]3[C:25](=[CH:26][C:27]([NH:31][C:32]4[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=4[C:34]([OH:36])=O)=[CH:28][CH:29]=3)[NH:24][N:23]=2)[CH:14]=1.[NH2:41][CH2:42][C:43]#[C:44][CH2:45][O:46][C:47](=[O:49])[CH3:48]>>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15](/[CH:20]=[CH:21]/[C:22]2[C:30]3[C:25](=[CH:26][C:27]([NH:31][C:32]4[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=4[C:34]([NH:41][CH2:42][C:43]#[C:44][CH2:45][O:46][C:47](=[O:49])[CH3:48])=[O:36])=[CH:28][CH:29]=3)[NH:24][N:23]=2)[CH:14]=1
Reactant: Cc1cc(C)nc(C=Cc2n[nH]c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Reactant: CC(=O)OCC#CCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)OCC#CCNC(=O)c1ccccc1Nc1ccc2c(/C=C/c3cc(C)cc(C)n3)n[nH]c2c1

Procedure:
Prepared in a similar manner to that described for Example 6 above, except using 2-[3-[2-(4,6-dimethyl-pyridin-2-yl)-vinyl] 1H-indazol-6-ylamino]-benzoic acid p-toluene sulfonate and Acetic acid 4-amino-but-2-ynyl ester. 1H NMR (CD3CN): δ 11.00 (1H, bs), 9.59 (1H, s), 7.99 (1H, d, J=8.6 Hz), 7.86 (1H, d, J=16.4 Hz), 7.58 (1H, d, J=7.8 Hz), 7.49–7.37 (4H, m), 7.32 (1H,s ), 7.21 (1H, s), 7.06 (1H, dd, J=8.8, 1.8 Hz), 6.96 (1H, s), 6.90 (1H, t, J=7.8 Hz), 4.63 (2H, s), 4.16 (2H, d, J=5.6 Hz), 2.49 (3H, s), 2.32 (3H, s), 2.01 (3H, s).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[N:4][CH:5]=[C:6]([CH2:8]Br)[CH:7]=1.[CH3:19][S-:20].[Na+]>CN(C)C=O>[Br:1][C:2]1[C:3]([O:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[N:4][CH:5]=[C:6]([CH2:8][S:20][CH3:19])[CH:7]=1
Reactant: C[S-]
Reactant: Fc1ccc(Oc2ncc(CBr)cc2Br)c(F)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCc1cnc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
The product from Example 311c (0.75 g, 1.979 mmol) and sodium thiomethoxide (0.139 g, 1.979 mmol) were combined in dimethylformamide (3.96 mL), stirred for 4 hours at ambient temperature, and partitioned into ethyl acetate and cold water. The organic layer was washed with saturated aqueous sodium chloride, dried (Na2SO4), filtered, and concentrated to afford the title compound (0.66 g, 96%).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19]#[N:20])=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[SH2:28]>N1C=CC=CC=1>[C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19](=[S:28])[NH2:20])=[C:13]([C:15]([F:17])([F:18])[F:16])[N:14]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: S
Reactant: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C#N)s1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C(N)=S)s1
Reaction time: 48 h

Procedure:
2-(N-BOC-Aminomethyl)-5-cyano-4-trifluoromethylthiazole [sic] (4.6 g, 14.97 mmol) was dissolved in pyridine (20 ml), triethylamine (24 ml) was added, and the solution was saturated with hydrogen sulfide. After two days at room temperature, the solvent was removed on a rotary evaporator. The crude product was taken up in ethyl acetate and washed in succession with 20% strength sodium hydrogen sulfate solution and water. After drying (MgSO4), the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography. Yield: 2.5 g (7.32 mmol, 49%).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:22])[N:5]([CH2:19][C:20]#[CH:21])[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](C=O)[CH:12]=2)=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2].Cl.[NH2:24][OH:25]>C(O)C>[CH2:1]([C:3]1[C:4](=[O:22])[N:5]([CH2:19][C:20]#[CH:21])[C:6]([C:11]2[CH2:12][C:13](=[N:24][OH:25])[CH:14]=[CH:15][CH:16]=2)=[N:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: NO
Reactant: C#CCn1c(-c2cccc(C=O)c2)nc(CC)c(CC)c1=O
Agent: Cl
Solvent: CCO
Product: C#CCn1c(C2=CC=CC(=NO)C2)nc(CC)c(CC)c1=O
Yield: 60.9 %

Procedure:
To a 100 mL RBF were charged 1.1 g (3.7 mmol) of 5,6-diethyl-2-(3-formyl-phenyl)-3-propargyl-4(3H)-pyrimidinone, 0.52 g (7.5 mmol) of hydroxylamine hydrochloride and 50 mL of ethanol. The reaction mixture was refluxed for 17 hours. The ethanol was removed in vacuo and ether and ethyl acetate were added to the residue. The organics were washed 3 times with water. The organic layer was gravity filtered to remove 0.22 g of 5,6-diethyl-2-(3-hydroxyiminophenyl)-3-propargyl-4(3H)-pyrimidinone (compound 139). The organic layer was dried over MgSO4 and concentrated to yield a further 0.67 g of 5,6-diethyl-2-(3-hydroxyiminophenyl)-3 -propargyl-4(3H)-pyrimidinone (compound 139) as a white solid. A combined yield of 77.6% was obtained. 1H-NMR (CDCl3) 1.25(6H,m); 2.35(1H,t); 2.65(4H,m); 4.6(2H,d); 7.49-8.15(4H,m); 8.7(1H,s)