Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:4][N:3]=1.[CH3:17][C:18](=O)[CH2:19][C:20](=O)[CH3:21]>CC(O)=O>[CH2:10]([S:9][C:5]1[C:6]([C:7]#[N:8])=[C:2]2[N:1]=[C:18]([CH3:17])[CH:19]=[C:20]([CH3:21])[N:3]2[N:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)CC(C)=O
Reactant: N#Cc1c(N)n[nH]c1SCc1ccccc1
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(SCc3ccccc3)c(C#N)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.7 %

Procedure:
A slurry of 0.5 g (2.2 mmole) of 3-amino-5-benzylthio-4-cyanopyrazole in 15 ml glacial HOAc was stirred at room temperature as 0.44 g (4.4 mmole) of 2,4-pentanedione was added. The mixture was stirred at room temperature for 3 hours. The white solid was collected by filtration, washed with HOAc, and dried to give 0.62 g (95.4 percent) of product as a white powder, m.p. 140° C. The analytical sample was recrystallized from 2-propanol. 1H NMR (DMSO-d-6): 7.5 (m, 2H, benzene), 7.3 (m, 3H, benzene), 7.1 (s, 1H, pyrazolopyrimidinyl H-6), 4.5 (s, 2H, CH2), 2.7 (s, 3H, CH3), 2.5 (s obscured by DMSO, 3H, CH3). 13C NMR (DMSO-d-6): 163.3, 155.3, 150.5, 146.7, 137.0, 129.1, 128.3, 127.3 112.8, 111.1, 79.0, 34.5, 24.1, 16.3. IR (KBr): 2220, 1615, 1550 cm -1.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Cc1cccc(Cl)c1N
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(Nc2c(C)cccc2Cl)cc1
Yield: 89.3 %

Procedure:
1.02 g (7.2 mmol) of 2-chloro-6-methylaniline, 1.23 g (7.2 mmol) 4-bromotoluene, 1.15 g (12 mmol) sodium tert-butoxide, 160 mg (0.7 mmol) tri-tert-butyhphosphine and 130 mg (0.23 mmol) bis-dibenzylideneacetone-palladium(0) are reacted in 50 ml toluene under nitrogen at 90° C. for 20 minutes and at 60° C. over night. Aqueous workup (3N HCl, with hyflo, washing the organic phase with water) and flash-chromatography on silica using heptan/toluene (4:1) as the eluent affords 1.49 g of N-(2′-chloro-6′-methylphenyl)-4-methylaniline.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][C:7]2([CH3:13])[CH3:12].I[CH2:18][CH2:19][CH3:20]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]([CH3:16])[CH3:15])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:18][CH2:19][CH3:20])[CH2:9][CH2:8][C:7]2([CH3:12])[CH3:13]
Reactant: CCCI
Reactant: CC(C)c1cc(Br)c2c(c1)C(C)(C)CCN2
Product: CCCN1CCC(C)(C)c2cc(C(C)C)cc(Br)c21

Procedure:
Following General Procedure A, 8-bromo-6-isopropyl-4,4-dimethyl-1-alkyl-1,2,3,4-tetrahydro-quinoline (Intermediate 4, 3.0 g, 9.1 mmol) and 1-iodopropane (5.2 g, 46 mmol) were reacted to produce the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OCC)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:14][C:10]1[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:3]([O:2][CH3:1])[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1c(C)cccc1OC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)c1c(CBr)cccc1OC
Temperature: 25 °C
Yield: 59.4 %

Procedure:
To a solution of ethyl 2-methoxy-6-methylbenzoate (0.813 g, 4.19 mmol) in CCl4 (8 mL) was added recrystallized N-bromosuccinimide (0.751 g, 4.22 mmol) followed by benzoyl peroxide (52 mg, 0.22 mmol). The resultant mixture was heated to reflux for 90 minutes then cooled to room temperature. The mixture was diluted with diethyl ether (50 mL), filtered through filter paper, and the filtrate was concentrated. Purification of the crude material by column chromatography (8:1 hexanes-EtOAc) provided 0.68 g (60%) of ethyl 6-(bromomethyl)-2-methoxybenzoate as a colorless oil. 1H NMR (CDCl3) δ 1.42 (t, 3H, J=7.2 Hz), 3.84 (s, 3H), 4.45 (q, 2H, J=7.2 Hz), 4.50 (s, 2H), 6.89 (d, 1H, J=8.4 Hz), 7.01 (d, 1H, J=7.2 Hz), 7.34 (dd, 1H, J=7.2, 8.4 Hz).
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1.CN(C1C=CC=CN=1)C.C(N(C(C)C)CC)(C)C.C(N=C=NCCCN(C)C)C>ClCCl>[O:14]=[C:10]1[CH2:11][CH2:12][CH2:13][C:8]([NH:7][C:1](=[O:6])[CH2:2][CH2:3][CH3:4])=[CH:9]1
Reactant: CCCC(=O)O
Reactant: NC1=CC(=O)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCC(=O)NC1=CC(=O)CCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 10 %

Procedure:
Butyric acid (465 mg, 5.28 mmol) and 3-amino-2-cyclohexene-1-one (645 mg, 5.81 mmol) were dissolved in dichloromethane (50 mL). Dimethylaminopyridine (750 mg, 5.81 mmol), diisopropylethylamine (774 mg, 6.34 mmol) and 1-ethyl-3-dimethylaminopropyl carbodiimide (1.13 g, 5.81 mmol) were added to the resulting mixture, followed by stirring at room temperature for about 14 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (developing solvent: n-hexane/ethyl acetate=6/4) to obtain the N-(3-oxo-cyclohexen-1-yl)butyramide (1a-1) shown by the formula below.
Reaction SMILES: [CH:1]([CH:3]([O:6][CH:7]([N:10]1[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]1=[O:17])[CH:8]=[O:9])[CH2:4][OH:5])=[O:2].[NH2:18][C:19]1[S:20][CH2:21][CH2:22][N:23]=1>O>[OH:9][CH:8]1[C@H:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:6][C@H:3]([CH2:4][OH:5])[CH:1]([OH:2])[N:18]1[C:19]1[S:20][CH2:21][CH2:22][N:23]=1
Reactant: O=CC(CO)OC(C=O)n1ccc(=O)[nH]c1=O
Reactant: NC1=NCCS1
Solvent: O
Product: O=c1ccn([C@@H]2O[C@H](CO)C(O)N(C3=NCCS3)C2O)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
[R-(R*, R*)]-α-(1-Formyl-2-hydroxyethoxy)-3,4dihydro-2,4-dioxo-1(2H)-pyrimidineacetaldehyde, (uridinedialdehyde), (2.4 g) was dissolved in water (10 ml). To the solution was added 2-amino-2-thiazoline (1.2 g). The mixture was stirred at ambient temperature overnight. An insoluble material was filtered off. The filtrate was evaporated in vacuo. The residue was triturated with acetone to give 1-[(2R, 6R)-3,5-dihydroxy-6-hydroxymethyl-4-(2-thiazolin-2-yl)morpholin-2-yl]uracil (0.98 g).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([F:10])([F:9])[F:8].C[N+]([O-:15])(C)C>>[F:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[O:15]
Reactant: FC(F)(F)CCCCCBr
Reactant: C[N+](C)(C)[O-]
Product: O=CCCCCC(F)(F)F

Procedure:
Commercially available 6-bromo-1,1,1-trifluorohexane (Oakwood) and trimethylamine oxide were processed using the method described in example 137A to afford the title compound. MS (ESI+) m/z 154 (M+NH4—H2O)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.Br[CH2:36][CH2:37][F:38]>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH2:36][CH2:37][F:38])[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Reactant: FCCBr
Product: FCCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 87.5 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 1-bromo-2-fluoroethane, 153 was obtained as a yellow solid (60 mg, 87.5%) over two steps. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.12 (s, 1H), 8.63 (s, 1H), 8.51 (s, 1H), 8.28 (s, 1H), 7.95 (s, 1H), 7.49-7.66 (m, 1H), 7.13-7.15 (d, J=7.5 Hz, 1H), 6.55-6.57 (d, J=8.5 Hz, 1H), 4.88-4.90 (m, 1H), 4.73-4.80 (m, 1H), 4.54-4.58 (m, 1H), 4.49-4.52 (m, 1H), 3.77-3.83 (m, 4H), 2.97-2.99 (m, 2H), 2.70-2.72 (m, 2H), 1.87-1.89 (m, 2H); MS (ESI) m/z: 407 [M+H]+.
Reaction SMILES: [ClH:1].Cl.C([N:10]1[CH2:15][C:14](=O)[N:13](CC2C=CC=CC=2)[CH:12]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:11]1=O)C1C=CC=CC=1.Cl>CO.C(OCC)(=O)C.[C].[Pd]>[ClH:1].[ClH:1].[CH:24]([CH:12]1[CH2:11][NH:10][CH2:15][CH2:14][NH:13]1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C1C(C(c2ccccc2)c2ccccc2)N(Cc2ccccc2)C(=O)CN1Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: c1ccc(C(c2ccccc2)C2CNCCN2)cc1
Yield: 205 %

Procedure:
A solution of 1,4-dibenzyl-3-benzhydryl-2,5-piperazinedione dihydrochloride (840 mg) in methanol (10 ml) was hydrogenated over 10% palladium-carbon (50% wet, 84 mg) at room temperature under atmospheric pressure for 5 hours. After removal of the catalyst by filtration, the filtrate was evaporated under reduced pressure to give an oil, which was treated with 4N hydrogen chloride in ethyl acetate solution to give 2-benzhydrylpiperazine dihydrochloride (525 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14](Cl)=[O:15])=[CH:4][CH:3]=1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]1.C(N(CC)CC)C>ClCCl>[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[C:14]([C:9]1[N:10]=[C:11]([CH3:13])[S:12][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:15]
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Reactant: c1ccc2oc(CC3CCCCN3)cc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3ccccc3o2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
5-(4-Fluorophenyl)-2-methyl-thiazole-4-carbonyl chloride (136 mg, 0.53 mmol) in dichloromethane (1 ml) was added to a solution of (RS)-2-(2-benzofuranylmethyl)piperidine (104 mg, 0.48 mmol) and triethylamine (0.20 ml, 1.45 mmol) in dichloromethane (4 ml) and the mixture shaken at ambient temperature for 30 min. The resultant was washed with saturated aqueous sodium hydrogen carbonate (8 ml). The organic layer was applied directly onto a pre-packed silica gel column and chromatographed eluting with ethyl acetate hexane mixtures to give the title compound (50 mg, 24%) as an off-white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[C:11]([O-])([O-])=O.[K+].[K+].IC>CC(C)=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1cccc(O)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1cccc(C(C)C)c1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of 3-isopropyl-phenol (5.00 g, 36.2 mmols) in 50 mL of acetone was added K2CO3(7.50 g, 54.3 mmols) and iodomethane (10.3 g, 72.5 mmols). The resulting solution was heated to 50° C. and stirred for 18 hours, cooled to room temperature, and concentrated under reduced pressure. The residual oil was dissolved in Et2O and washed with H2O, saturated aqueous NaHCO3, and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The crude methyl ether was used without further purification.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[O:10][CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1)=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[C:33]([O:39][CH3:40])(=[O:38])[CH2:34][C:35]([CH3:37])=O>CS(C)=O.C(OCC)(=O)C>[Cl:19][C:14]1[CH:13]=[C:12]([C@@H:11]2[O:10][CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C@H:5]2[CH2:4][N:1]2[C:35]([CH3:37])=[C:34]([C:33]([O:39][CH3:40])=[O:38])[N:3]=[N:2]2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN=[N+]=[N-])C1
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nnn(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO[C@H]2c2ccc(Cl)c(Cl)c2)c1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6S,7R)-6-(azidomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (200 mg) in DMSO (2 mL) were added potassium carbonate (276 mg) and methyl acetoacetate (0.08 mL) at room temperature, and the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (149 mg).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]1[C:12]#[N:13])=[O:4].[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>C(#N)C>[CH:14]1([NH:20][CH2:2][C:3]([N:5]2[C@@H:9]([C:10]#[CH:11])[CH2:8][CH2:7][C@H:6]2[C:12]#[N:13])=[O:4])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CCl
Reactant: NC1CCCCC1
Solvent: CC#N
Product: C#C[C@H]1CC[C@@H](C#N)N1C(=O)CNC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of (2S,5R)-1-(chloroacetyl)-5-ethynylpyrrolidine-2-carbonitrile (0.035 g, 0.178 mmol, Example 8D) in acetonitrile (3 mL ) at room temperature under nitrogen was added cyclohexylamine (0.041 mL, 0.356 mmol ), The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was flash chromatographed with 2-3% MeOH/CH2Cl2 to provide the desired compound as a pale yellow oil. MS (DCI) m/z 260 (M+H)+; 1H NMR (300 MHz, DMSO) δ 1.5-2 (10H, m), 2.13-2.31 (2H, m), 2.41-2.48 (2H, m), 3.76 (1H, d), 3.8-4.5 (2H, m), 4.53-4.55 (1H, t), 4.9 (1H, m), 5.05 (1H, m).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH2:9][C:10]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([N:21]2[CH2:25][CH2:24][C@H:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)[C:15](Br)=[C:14]([CH3:30])[C:11]=1[C:12]#[N:13].[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[NH2:9][C:10]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([N:21]2[CH2:25][CH2:24][C@H:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)[C:15]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:14]([CH3:30])[C:11]=1[C:12]#[N:13]
Reactant: Cc1c(Br)c(N2CC[C@H](N(C)C)C2)c([N+](=O)[O-])c(N)c1C#N
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1c(C#N)c(N)c([N+](=O)[O-])c(N2CC[C@H](N(C)C)C2)c1-c1ccccc1
Yield: 90.2 %

Procedure:
Potassium phosphate (115 mg, 0.54 mmol) and Pd(PPh3)4 (16 mg, 5 mol %) were added to a dioxane (3 ml) solution of 2-amino-5-bromo-4-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-methyl-3-nitrobenzonitrile (I-267) (100 mg, 0.27 mmol) and phenylboronic acid (40 mg, 0.33 mmol), followed by purging with nitrogen and heating under reflux for 18 hours. After cooling, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure, and the residue was subjected to column chromatography, and eluted with a mixed solvent of chloroform/methanol (2:1, v/v) to obtain the entitled compound (89 mg, 90%) as a dark red solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[C:20]1([NH:19][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Reactant: Nc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
To a solution of 6.0 g (22.5 mmoles) of ethyl 4-chloro-8-methoxy-3-quinolinecarboxylate in 80 ml of tetrahydrofuran was added 2.3 g (24.8 mmoles) of aniline in 60 ml of tetrahydrofuran. The solution was briefly warmed and after standing for 10 minutes, a yellow solid began to precipitate. The mixture was kept at room temperature for 18 hours. The solvent was rotary evaporated. The residue dissolved in 200 ml of methanol and the pH made slightly basic (pH 8) with sodium bicarbonate. Water (700 ml) was added and an oil formed which solidified and after standing, additional solid crystallized. The solid was filtered and air-dried to give 6.9 g (95%) of crude material. The solid was dissolved in 300 ml of hot isooctane and the solution was charcoaled and filtered. The volume of the filtrate was reduced to 150 ml. Upon cooling, pale yellow needles separated; 6.5 g (89%); m.p. 120°-121° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:14][C:13]1[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([F:20])([F:21])[F:22])[C:12]=1[F:11]
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: Clc1nc2ccccc2[nH]1
Product: Fc1c(Nc2nc3ccccc3[nH]2)cccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 2-fluoro-3-(trifluoromethyl)aniline by Procedure A. The product was isolated by filtration and preparative LCMS to give the title compound as the free base (solid, mp 91-92° C.). MS(ES+) m/z 296 ([M+1]+, 100).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:14]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:4].[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1.[H-].[Na+].Cl>O1CCCC1>[CH3:12][O:11][C:10]1[CH:9]=[CH:8][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][C:20]([OH:22])=[O:21])[CH:14]=2)=[CH:6][C:5]=1[C:3](=[N:2][O:1][CH2:29][C:28]1[CH:27]=[CH:26][C:25]([C:24]([F:23])([F:33])[F:34])=[CH:32][CH:31]=1)[CH3:4]
Reactant: COc1ccc(-c2cccc(CC(=O)O)c2)cc1C(C)=NO
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc(CC(=O)O)c2)cc1C(C)=NOCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.9 %

Procedure:
9 mg of [3′-(1-Hydroxyiminoethyl)-4′-methoxybiphenyl-3-yl]acetic acid was dissolved in 0.2 mg of tetrahydrofuran, then 25 mg of 4-trifluoromethylbenzyl bromide and 10 mg of sodium hydride were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was neutralized with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by reverse-phase high performance liquid chromatography to give 5.21 mg of the title compound.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH:27]1([O:32][C:33]([O:35][CH2:36]I)=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:36][O:35][C:33]([O:32][CH:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:34])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C(OCI)OC1CCCC1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Agent: [Na+]
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCOC(=O)OC3CCCC3)=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Yield: 80.5 %

Procedure:
In the same manner as in Example 81, 167 mg of the title compound was prepared from 160 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 128 mg of cyclopentyloxycarbonyloxymethyl iodide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]2[CH:41]=[C:42]([Sn](CCCC)(CCCC)CCCC)[S:43][C:39]=2[C:38](C)=[N:37]1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:42]3[S:43][C:39]4[CH:38]=[N:37][N:36]([CH3:35])[C:40]=4[CH:41]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2c(s1)c(C)nn2C
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cn1ncc2sc(-c3nc(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)cc21
Temperature: 90 °C

Procedure:
In a 30 mL sealed cap glass vessel, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (119 mg, 0.238 mmol), 1,3-dimethyl-5-(tributylstannyl)-1H-thieno[3,2-c]pyrazole (210 mg, 0.476 mmol) and tetrakis(triphenylphosphine)palladium(0) (137 mg, 0.119 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. The mixture was concentrated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-7-fluoro-4-(1-methyl-1H-thieno[3,2-c]pyrazol-5-yl)-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and the reaction mixture was stirred for 1 hour. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparatory HPLC eluting with a gradient of 15-50% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (65 mg, 68%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79 (d, J=10.86 Hz, 1H), 2.04-2.26 (m, 1H), 3.55-3.68 (m, 2H), 3.80 (d, J=11.62 Hz, 1H), 3.89 (br s, 1H), 3.99 (s, 3H), 4.02-4.06 (m, 1H), 4.33 (td, J=8.27, 4.67 Hz, 1H), 4.45 (s, 2H), 7.40 (d, J=5.05 Hz, 1H), 7.74 (d, J=0.76 Hz, 1H), 7.96 (d, J=4.55 Hz, 2H), 8.65 (s, 1H), 9.28 (d, J=0.76 Hz, 1H). ESI-MS m/z [M+H]+ calc'd for C18H19FN6O2S, 403. found, 403.
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][NH:27][CH2:26][CH2:25][NH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1.C(N(CC)CC)C>CN(C)C=O>[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][N:27]([C:2]3[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][N:13]=[CH:12][N:11]=4)[N:3]=3)[CH2:26][CH2:25][NH:24]2)=[C:19]([O:29][CH3:30])[CH:18]=1
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Reactant: COc1cc(F)ccc1C1CNCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1C1CN(c2nc(-c3ccncn3)cc(=O)n2C)CCN1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
2-Chloro-3-methyl-6-(4-pyrimidyl)-pyrimidin-4-one (223 mg, 1:0 mmol) was added to an ice-cooled solution of 2-(4-fluoro-2-methoxyphenyl)piperazine (210 mg, 1.0 mmol), triethylamine (0.15 ml, 1.1 mmol) in N,N-dimethylformamide (10 ml) and stirred at that temperature for 0.5 hr and then at room temperature for 3 hours. Reaction was quenched by ice-water and the filtrate was washed with water and dried to give 2-(2-(4-fluoro-2-methoxyphenyl)piperazin-4-yl)-3-methyl-6-(4-pyrimidyl)-pyrimidin-4-one (262 mg, 66%).