Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])(=O)[CH3:2].Cl.[NH2:24][OH:25].C([O-])(=O)C.[Na+]>C(O)C.C(OCC)(=O)C>[OH:25][N:24]=[C:1]([C:4]1[CH:5]=[C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: NO
Reactant: COC(=O)Cc1cccc(-c2ccc(OC)c(C(C)=O)c2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(-c2ccc(OC)c(C(C)=NO)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
175 mg of Methyl (3′-acetyl-4′-methoxybiphenyl-3-yl)acetate was dissolved in 3 m of ethanol, then 55 mg of hydroxylamine hydrochloride and 65 mg of sodium acetate were added thereto, and the mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated to give methyl [3′-(1-hydroxyiminoethyl)-4′-methoxybiphenyl-3-yl]acetate. This product was dissolved in 4 ml of ethanol, then 0.5 ml of 5N sodium hydroxide was added thereto, and the mixture was left at room temperature for 6 hours. The reaction mixture was neutralized with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then filtered, and the filtrate was concentrated to give 166 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH:13]2[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14]2)=O)=[CH:7][CH:6]=1)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+].Cl.[OH-].[Na+]>CO>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH2:26])[CH:13]2[CH2:16][C:15]([CH3:18])([CH3:17])[CH2:14]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)c1ccc(C(=O)C2CC(C)(C)C2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)c1ccc(C(N)C2CC(C)(C)C2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 58 %

Procedure:
4-(3,3-dimethyl-cyclobutanecarbonyl)-benzoic acid ethyl ester (Intermediate 23) (235 mg, 0.903 mmol) was dissolved in methanol (5 mL). Ammonium acetate (710 mg, 9.03 mmol) was added followed by sodium cyanoborohydride (89.6 mg, 1.36 mmol). This was heated to 60° C. for 17 h before cooling and adding 1 N HCl (3 mL). This was stirred for 15 min and then 1N NaOH (10 mL) was added. The material was extracted into two portions of ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (methanol/ethyl acetate) gave (+/−)-4-[amino-(3,3-dimethyl-cyclobutyl)-methyl]-benzoic acid ethyl ester (137 mg) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J=8.4 Hz, 2H) 7.37 (d, J=8.2 Hz, 2H) 4.38 (q, J=7.0 Hz, 2H) 3.82 (d, J=9.2 Hz, 1H) 2.39 (sxt, J=8.7 Hz, 1H) 1.90-2.02 (m, 1H) 1.60-1.70 (m, 1H) 1.46-1.57 (m, 2H) 1.40 (t, J=7.1 Hz, 3H) 1.11 (s, 3H) 1.06 (s, 3H); GCMS (M): 261.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[C:13]([C:15]([NH:17][NH2:18])=O)[O:12][N:11]=2)=[CH:6][CH:5]=1.Cl.[C:22](=N)([NH2:24])[CH3:23].[OH-].[Na+]>C1COCC1>[CH3:23][C:22]1[NH:18][N:17]=[C:15]([C:13]2[O:12][N:11]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:20])([F:19])[F:1])=[CH:5][CH:6]=3)[CH:14]=2)[N:24]=1
Reactant: NNC(=O)c1cc(-c2ccc(OC(F)(F)F)cc2)no1
Reactant: CC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a mixture of 3-(4-(trifluoromethoxy)phenyl)isoxazole-5-carbohydrazide (2.4 g, 8.5 mmol) and acetimidamide hydrochloride (1.2 g, 12.8 mmol) in dry THF (60 mL), was added NaOH (512 mg, 12.8 mmol). The mixture was then refluxed for 16 h, then cooled to RT and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford the title compound as a white solid (1.9 g, 71%). 1H NMR (500 MHz, DMSO-d6) δ 8.12 (d, J=7.2 Hz, 2H), 7.58 (s, 1H). 7.54 (d, J=6.4 Hz, 2H), 2.46 (s, 3H). MS (ES+) C13H9F3N4O2 requires: 310. found: 311 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[C:5]([C:7]([O:9]C)=[O:8])[N:6]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[N:3]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: COCCCCc1c(C(=O)OC)nc(Cl)n1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCCCCc1c(C(=O)O)nc(Cl)n1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
Methyl 2-chloro-5-(4-methoxybutyl)-1-phenyl-1H-imidazole-4-carboxylate (450 mg) was dissolved in methanol (5 ml), 1M aqueous sodium hydroxide solution (4.2 ml) was added and the mixture was stirred at 80° C. for 2 hr. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was acidified with 1M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the object product (372 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@@H:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[NH2:27])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.N1C=CC=CC=1.[C:36]([C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1)([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:29])[CH:4]([NH:18][C:19](=[O:28])[C:20]1[CH:25]=[C:24]([Br:26])[CH:23]=[CH:22][C:21]=1[NH:27][S:46]([C:43]1[CH:44]=[CH:45][C:40]([C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:41][CH:42]=1)(=[O:48])=[O:47])[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1N
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(Br)ccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.2 %

Procedure:
To a stirring solution of (2S)-(2-amino-5-bromo-benzoyl-amino)-3-biphenyl-4-yl-propionic acid methyl ester (1.0 g, 2 mmol) prepared above dissolved in DCM containing pyridine (1.58 g, 4 mmol), was added 4-tert-butylbenzenesulfonyl chloride (1.20 g, 2.5 mmol) at 0° C. The reaction mixture was stirred at rt for 3 h, extracted with DCM, washed with 1M HCl and brine, and was concentrated in vacuo, followed by column chromatography purification (silica, CH2Cl2) giving 3-biphenyl-4-yl-2-[5-bromo-2-(4-tert-butyl-benzenesulfonylamino)-benzoylamino]-propionic acid methyl ester (1.25 g) as a white solid which was hydrolyzed according to Procedure C yielding the title compound (1.23 g) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@@:5]12[CH2:10][C@@H:9]1[C@@H:8]([N:11]1[CH:19]=[N:18][C:17]3[C:12]1=[N:13][C:14]([Cl:48])=[N:15][C:16]=3[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][C:33]3[N:34]=[N:35][N:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[C:40]([N+:45]([O-])=O)[CH:39]=4)[CH:37]=3)[CH:23]=1)[C@H:7]([OH:49])[C@@H:6]2[OH:50])=[O:4].C(O)(=O)C>C(#N)C.[Zn]>[CH3:1][NH:2][C:3]([C@@:5]12[CH2:10][C@@H:9]1[C@@H:8]([N:11]1[CH:19]=[N:18][C:17]3[C:12]1=[N:13][C:14]([Cl:48])=[N:15][C:16]=3[NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[C:29][CH2:30][CH2:31][CH2:32][C:33]3[N:34]=[N:35][N:36]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[C:40]([NH2:45])[CH:39]=4)[CH:37]=3)[CH:23]=1)[C@H:7]([OH:49])[C@@H:6]2[OH:50])=[O:4]
Reactant: CNC(=O)[C@@]12C[C@@H]1[C@@H](n1cnc3c(NCc4cccc(C#CCCCc5cn(-c6ccc(F)c([N+](=O)[O-])c6)nn5)c4)nc(Cl)nc31)[C@H](O)[C@@H]2O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CC#N
Product: CNC(=O)[C@@]12C[C@@H]1[C@@H](n1cnc3c(NCc4cccc(C#CCCCc5cn(-c6ccc(F)c(N)c6)nn5)c4)nc(Cl)nc31)[C@H](O)[C@@H]2O
Reaction time: 2 h
Yield: 63.9 %

Procedure:
Zinc dust (3 mg, 0.045 mmol) was added to a solution of compound 203 (5 mg, 0.007 mmol) in acetonitrile (0.5 mL)-acetic acid (0.5 mL) at 0° C. After addition, the reaction mixture was brought to room temperature and stirred for 2 h under the same conditions. The reaction mixture was filtered on a Celite bed, and the filtrate was evaporated under vacuum. The residue was purified on flash silica gel column chromatography (CH2Cl2: MeOH=20:1) to give compound 207 (3 mg, 62%). 1H NMR (CD3OD, 400 MHz) δ 8.65-8.58 (m, 1H),
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:8](Cl)(=[O:11])[CH2:9][CH3:10].C([O-])([O-])=O.[K+].[K+]>CCOCC>[C:8]([NH:2][CH2:3][C:4]([O:6][CH3:7])=[O:5])(=[O:11])[CH2:9][CH3:10]
Reactant: COC(=O)CN
Reactant: CCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CCC(=O)NCC(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
In a round bottomed flask, at 0° C., to a stirred suspension of methyl glycinate hydrochloride (0.68 g, 5.4 mmol) in Et2O (2.0 mL), propanoyl chloride (1.0 g, 10.8 mmol) and saturated K2CO3 solution (3.8 mL) were added. The reaction mixture was stirred at 0° C. for 3 h, then extracted with Et2O (3×10 mL) and the resulting organic layer washed with saturated NaHCO3 solution, H2O, and brine. The aqueous phase was saturated with NaCl and further extracted with AcOEt (50 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude title compound (0.55 g, 71%) as colorless oil, which was used in the next reaction. MS (ESI) m/z: 168 [M−Na]+, 146 [M−H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].Cl.[N:7]1([CH2:13][CH:14]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][N:29](COCC[Si](C)(C)C)[C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:15][C:16]#[N:17])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(N(CC)CC)C.FC(F)(F)C(O)=O.CO.C(N)CN>C(#N)C.C(Cl)Cl>[CH3:1][S:2]([N:10]1[CH2:9][CH2:8][N:7]([CH2:13][CH:14]([N:18]2[CH:22]=[C:21]([C:23]3[C:24]4[CH:31]=[CH:30][NH:29][C:25]=4[N:26]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:15][C:16]#[N:17])[CH2:12][CH2:11]1)(=[O:4])=[O:3]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C(CC#N)CN4CCNCC4)c3)ncnc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(CC(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.7 %

Procedure:
Methanesulfonyl chloride (137 mg, 0.00119 mol), 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (0.5 g, 0.994 mmol) and triethylamine (416 μL, 0.00298 mol) were mixed in acetonitrile (5 mL). The mixture was stirred at RT for 1 h. The completion of the reaction was checked with LC/MS. Solvents were evaporated. The crude product was treated with DCM (1 mL) and trifluoroacetic acid (1 mL, 0.01 mol) for 30 min. The reaction mixture was evaporated under reduced pressure. To the resultant residue was added methanol (3 mL, 0.07 mol) and ethylenediamine (0.3 mL, 0.004 mol) and stirred at RT for 30 min, and concentrated to dryness under reduced pressure. The residue was purified on RP-HPLC (XBridge C-18 Column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH, at flow rate 60 mL/min) to give 110 mg (27%) of the desired product. LCMS calculated for C18H23N8O2S(M+H)+: m/z=415.2; Found: 415.0. 1H NMR (400 MHz, CD3OD): δ 8.66 (1H, s), 8.63 (1H, s), 8.37 (1H, s), 7.51 (1H, d, J=3.6 Hz), 6.95 (1H, d, J=4.0 Hz), 4.95 (1H, m), 3.19-3.14 (6H, m), 2.95 (2H, m), 2.77 (3H, s), 2.67 (2H, m), 2.65 (2H, m) ppm.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][S:41]([CH3:44])(=[O:43])=[O:42])=[CH:36][CH:35]=1)[C:4]([O:6][C@H:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[CH2:8][C:9]1[C:14]([Cl:15])=[CH:13][N+:12]([O-:16])=[CH:11][C:10]=1[Cl:17])=[O:5].[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl.N1C=CC=CC=1>[Cl:15][C:14]1[CH:13]=[N+:12]([O-:16])[CH:11]=[C:10]([Cl:17])[C:9]=1[CH2:8][C@@H:7]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH:25]([F:27])[F:26])=[C:20]([O:28][CH2:29][CH:30]2[CH2:32][CH2:31]2)[CH:19]=1)[O:6][C:4](=[O:5])[C@@H:3]([NH:2][S:46]([CH3:45])(=[O:48])=[O:47])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([O:40][S:41]([CH3:44])(=[O:42])=[O:43])=[CH:38][CH:39]=1
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)Oc1ccc(C[C@H](N)C(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)N[C@@H](Cc1ccc(OS(C)(=O)=O)cc1)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
4-((S)-2-((S)-2-amino-3-(4-(methylsulfonyloxy)phenyl)propanoyloxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide hydrochloride (30 mg, 0.05 mmol) was dissolved in DCM (2 ml) and pyridine (100 μl), then methanesulfonyl chloride (7 mg, 0.06 mmol) was added. The mixture was stirred at RT for 2 h, then was washed with HCl 1N (2×). The crude was purified by semi-preparative HPLC to give 29 mg of the final compound (Yield: 80%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@@H:11]3[CH2:15][CH2:14][CH2:13][C:12]3([CH3:17])[CH3:16])=[C:8]([C:18]([NH2:20])=[O:19])[CH:7]=[N:6][N:5]2[CH:21]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]>>[CH3:16][C:12]1([CH3:17])[CH2:13][CH2:14][CH2:15][C@H:11]1[NH:10][C:9]1[C:4]2[N:5]([CH:21]=[C:2]([N:22]3[CH2:26][CH2:25][CH2:24][C:23]3=[O:27])[CH:3]=2)[N:6]=[CH:7][C:8]=1[C:18]([NH2:20])=[O:19]
Reactant: CC1(C)CCC[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Reactant: O=C1CCCN1
Product: CC1(C)CCC[C@H]1Nc1c(C(N)=O)cnn2cc(N3CCCC3=O)cc12

Procedure:
4-(((1R)-2,2-dimethylcyclopentyl)amino)-6-(2-oxo-1-pyrrolidinyl) pyrrolo[1,2-b]pyridazine-3-carboxamide was prepared from Intermediate 50 and pyrrolidin-2-one using a similar procedure as described for the preparation of Example 312 LCMS: 356.18 (M+H)+; HPLC (condition L): retention time=7.44 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[C:18]1(O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O>[O:17]([CH2:16][CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[CH:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1nc2ccccc2c2c1ncn2CCO
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2c2c1ncn2CCOc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)ethanol (25 mg, 0.108 mmol) and N,N-dimethylformamide (1 mL) were combined. Phenol (12 mg, 0.130 mmol) and triphenylphosphine (34 mg, 0.130 mmol) were added and the resulting slurry was sonicated for about 1 minute. Diethyl azodicarboxylate (23 mg, 0.130 mmol) was added and the reaction mixture was shaken at ambient temperature for 24 hours. Analysis by LC-MS showed that a major amount of starting material remained. An additional equivalent each of phenol, triphenylphosphine and diethyl azodicarboxylate were added. The reaction mixture was sonicated for 30 minutes. After 1 hour analysis by LC-MS showed product. The solvent was removed and the residue was purified by semi-preparative HPLC using Method A. Mass Measurement: TM=304, NM[M+H]+1=305.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])(C)(C)C.[Br:13][C:14]1[CH:15]=[C:16]([C:21]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=2[C:36]#[N:37])=[N:22]S(C(C)(C)C)=O)[CH:17]=[CH:18][C:19]=1[F:20].Cl>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]([C:21]2([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)[C:29]3[C:30](=[C:31]([F:35])[CH:32]=[CH:33][CH:34]=3)[C:36]([NH2:37])=[N:22]2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: Ic1ccncc1
Reactant: CC(C)(C)S(=O)N=C(c1ccc(F)c(Br)c1)c1cccc(F)c1C#N
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: NC1=NC(c2ccncc2)(c2ccc(F)c(Br)c2)c2cccc(F)c21
Temperature: -100 °C
Reaction time: 0.5 h
Yield: 9.4 %

Procedure:
A solution of 4-iodopyridine (0.530 g, 2.59 mmol) in THF (5 mL) was added dropwise to a is mixture of tert-butyllithium (1.6 M in pentane, 2.94 mL, 4.70 mmol) in THF (20.00 mL) at −100° C. under an argon atmosphere. N-((3-Bromo-4-fluorophenyl)(2-cyano-3-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (1.00 g, 2.35 mmol) in THF (7.50 mL) was added and the resulting reaction mixture was stirred at −100° C. for 30 min. The cooling bath was removed and the mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with EtOAc (×3). The combined organic layers were dried over Na2SO4 and concentrated. The residue was dissolved in MeOH (15.00 mL), and then hydrogen chloride (2 M in diethyl ether, 2.351 mL, 4.70 mmol) was added and the mixture was stirred at room temperature for 1.5 h. The solvents were removed in vacuo, and the residue was partitioned between aqueous sodium bicarbonate (saturated) and chloroform. The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. Purification by silica gel chromatography using a gradient of 0 to 10% (3.5 M ammonia in methanol) in dichloromethane afforded 0.088 g (9% yield) of the title compound. MS (ES+) m/z 400 [M+1]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13]>N1C=CC=CC=1>[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: Clc1cnccn1
Reactant: NCCCCN
Solvent: c1ccncc1
Product: NCCCCNc1cnccn1

Procedure:
(4-aminobutyl)pyrazin-2-ylamine was prepared by refluxing 2-chloropyrazine and 1,4-diaminobutane in pyridine (50 mL) for 18 hrs. The solution was then concentrated in vacuo and the residue was partitioned between ethyl acetate and 10% sodium carbonate. The phases were separated, and the organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The desired product was isolated by flash chromatography using 10:1:1 Ethanol/Ammonium Hydroxide/water. EI-MS m/z 167 (M+H)+.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:13][CH:14]=2)[OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C>ClCCl.CS(C)=O>[CH:1]1([C:7]([C:9]2[CH:14]=[N:13][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=3)=[N:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OC(c1cnc(-c2ccc(C(F)(F)F)cc2)nc1)C1CCCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(c1cnc(-c2ccc(C(F)(F)F)cc2)nc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of (+/−)-cyclohexyl{2-[4-(trifluoromethyl)phenyl]pyrimidin-5-yl}methanol (0.440 g, 1.31 mmol) in dichloromethane (4.8 ml), dimethyl sulfoxide (3.7 ml) and triethylamine (0.911 ml, 6.54 mmol) was cooled to 0° C. Sulfur trioxide pyridine complex (0.625 g, 3.92 mmol) was added in portions and the mixture stirred at 0° C. for 1 hour then slowly raised to ambient temperature over 12 hours. The reaction was quenched with water and diluted with diethylether. The aqueous layer was extracted with diethylether and the combined organic layers were washed with brine. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated in vacuo, affording a crude solid. This material was used without further purification.
Reaction SMILES: [Na].[CH:2]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[O:7][C:5]1=O)=[O:3].[BH4-].[Na+]>CO>[F:16][C:13]1[CH:12]=[CH:11][C:10]([CH:8]2[CH2:9][CH:4]([CH2:2][OH:3])[CH2:5][O:7]2)=[CH:15][CH:14]=1
Reactant: O=CC1CC(c2ccc(F)cc2)OC1=O
Agent: [BH4-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: OCC1COC(c2ccc(F)cc2)C1

Procedure:
To a suspension of 200 g of sodium salt of α-formyl-γ-(4-fluorophenyl)-γ-butyrolactone in 1.5 liters of methanol is added slowly 70 g of sodium borohydride with stirring. The mixture is stirred at room temperature for 18 hours, and the methanol is then distilled off under reduced pressure. The residue is dissolved in 1 liter of water, and the solution is adjusted to pH 1 with concentrated sulfuric acid and heated under reflux for 1 hour. After cooling, the solution is adjusted to pH 11-12 with 40% aqueous sodium hydroxide solution, and stirred at 50° C. for 2 hours and then cooled. The reaction mixture is extracted twice with ethyl acetate. The combined extracts are washed with water and dried over magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is distilled to give 71 g of 2-(4-fluorophenyl)-4-(hydroxymethyl)tetrahydrofuran as colorless oil, boiling at 120°-126° C. (0.06 mmHg).
Reaction SMILES: [Cl-].[Ca+2].[Cl-].C(O)(=O)C.O[C:9]([C:12]1[S:13][CH:14]=[C:15]2[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C:16]=12)([CH3:11])[CH3:10]>C(Cl)(Cl)Cl>[CH2:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]2[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C:16]=12)[CH3:11]
Reactant: CC(C)(C)OC(=O)N1Cc2csc(C(C)(C)O)c2C1
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: C=C(C)c1scc2c1CN(C(=O)OC(C)(C)C)C2
Yield: 102.8 %

Procedure:
5 g of calcium chloride and 0.17 ml (3 mmol) of acetic acid are added to a solution of 0.81 g (2.86 mmol) of 1-(2-hydroxy-2-propyl)-5-(1,1-dimethyl-ethoxy) carbonyl-5,6-dihydro-4H-thieno[3,4-c]pyrrole in 60 ml of chloroform. The mixture is heated at reflux for 24 hours, filtered, washed with a 5% sodium bicarbonate solution, then dried over sodium sulphate and evaporated to dryness. 0.78 g of an oily product is obtained.
Reaction SMILES: [CH:1]([C@H:4]1[N:9]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)[CH2:8][CH2:7][NH:6][C:5]1=[O:20])([CH3:3])[CH3:2].CC([O-])(C)C.[K+].C1COCC1.[F:32][C:33]1[CH:42]=[C:41](F)[C:40]([N+:44]([O-:46])=[O:45])=[CH:39][C:34]=1[C:35]([O:37][CH3:38])=[O:36].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[CH3:38][O:37][C:35](=[O:36])[C:34]1[CH:39]=[C:40]([N+:44]([O-:46])=[O:45])[C:41]([N:6]2[CH2:7][CH2:8][N:9]([C:10]3[N:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][N:11]=3)[C@H:4]([CH:1]([CH3:3])[CH3:2])[C:5]2=[O:20])=[CH:42][C:33]=1[F:32]
Reactant: CC(C)[C@@H]1C(=O)NCCN1c1nccc(C(F)(F)F)n1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])c(N2CCN(c3nccc(C(F)(F)F)n3)[C@H](C(C)C)C2=O)cc1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-3-isopropyl-4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-2-one (986 mg, 3.42 mmol) in DMF (5 mL) was added a 2 M solution of KOtBu in THF (2.14 mL, 4.28 mmol) dropwise at 0° C. The reaction stirred for 1 h at 0° C. and was then cooled to −78° C. In a separate flask, a solution of methyl 2,4-difluoro-5-nitrobenzoate (928 mg, 4.28 mmol) in DMF (15 mL) was cooled to −78° C. To this solution was added a solution of the above anion via cannula at −78° C. over a 5 min period. The reaction was allowed to warm to −50° C. and stirred at this temperature for 2 h. Sat. aq. NH4Cl (20 mL) was added to quench the reaction, followed by EtOAc (30 mL). The EtOAc layer was separated and the aqueous layer was extracted with EtOAc (3×15 mL). The EtOAc layers were combined, dried and evaporated to give crude (R)-methyl-2-fluoro-4-(3-isopropyl-2-oxo-4-(4-(trifluoromethyl)pyrimidin-2-yl)piperazin-1-yl)-5-nitrobenzoate which was taken on directly for the next step without further purification.