Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(O)=O.[Na+].[C:9]1(/[CH:15]=[CH:16]/[S:17]([NH:20][C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][C:29](Cl)=[O:30])[CH:24]=[CH:25][CH:26]=2)(=[O:19])=[O:18])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCCC1>[OH:3][NH:2][C:29](=[O:30])[CH:28]=[CH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([NH:20][S:17](/[CH:16]=[CH:15]/[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:19])=[O:18])[CH:22]=1
Reactant: O=C(Cl)C=Cc1cccc(NS(=O)(=O)/C=C/c2ccccc2)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(C=Cc1cccc(NS(=O)(=O)/C=C/c2ccccc2)c1)NO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of hydroxylamine hydrochloride (0.27 g, 3.88 mmol) in tetrahydrofuran (5 ml) a saturated NaHCO3 solution (3 ml) was added and the resultant mixture was stirred at ambient temperature for 10 min. To the reaction mixture a solution of crude 3-{3-[(E)-2-phenylethenesulfonylamino]phenyl}acryloyl chloride (27a) (0.27 g, 0.77 mmol) in tetrahydrofuran (3.5 ml) was added and the mixture was stirred at ambient temperature for one hour. The reaction mixture was partitioned between ethyl acetate and 2N HCl. The organic layer was washed successively with water and saturated NaCl, then the solvent was removed. The residue was crystallised from ethyl acetate and washed with diethyl ether affording the title compound (0.115 g, 42%) as white crystals. M.p. 171° C. 1H NMR (DMSO-d6, HMDSO) δ: 6.38 (d, J=16.0 Hz, 1H); 7.07-7.80 (m, 12H); 9.03 (br s, 1H); 10.16 (s, 1H); 10.76 (br s, 1H). HPLC analysis on Symmetry C18 column: impurities 1% (column size 3.9×150 mm; mobile phase acetonitrile-0.1M phosphate buffer (pH 2.5), 35:65; sample concentration 0.4 mg/ml; flow rate 1.2 ml/min; detector UV 254 nm). Anal. Calcd for C17H16N2O4S, %: C, 59.29; H, 4.68; N, 8.13. Found %: C, 59.13; H, 4.70; N, 7.92.
Reaction SMILES: [CH3:1][CH:2]1[S:7][CH2:6][CH2:5][CH2:4][S:3]1.C([Li])CCC.[F:13][C:14]([F:21])([F:20])[C:15]([O:17]CC)=O.[Cl-].[NH4+]>C1COCC1>[F:21][C:14]([F:13])([F:20])[C:15]([C:2]1([CH3:1])[S:7][CH2:6][CH2:5][CH2:4][S:3]1)=[O:17]
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC1SCCCS1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C(=O)C(F)(F)F)SCCCS1
Temperature: -20 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
2-Methyl-1,3-dithiane (1.50 g, 11.2 mmol) was dissolved in THF (50 mL), followed by cooling to −20° C. Then, n-butyllithium (1.58 M solution in hexane, 7 mL, 11.1 mmol) was added dropwise and the mixture was stirred for two hours. Ethyl trifluoroacetate (1.4 mL, 11.8 mmol) was added, and the mixture was heated to room temperature and stirred for 20 hours. Aqueous ammonium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=100/0, 95/5, 85/15) to obtain 1.09 g of the title compound as a pale yellow solid (42%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=O)[CH:5]=[C:4]([NH:12][CH3:13])[N:3]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].C([Mg]Cl)(C)C.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([N:16]([O:17][CH3:18])[CH3:15])=[O:10])[CH:5]=[C:4]([NH:12][CH3:13])[N:3]=1
Reactant: CNc1cc(C(=O)OC)nc(Cl)n1
Reactant: CNOC
Agent: CC(C)[Mg]Cl
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1cc(C(=O)N(C)OC)nc(Cl)n1
Temperature: -10 °C
Reaction time: 0.67 h
Yield: 35.2 %

Procedure:
To a suspension of methyl 2-chloro-6-(methylamino)pyrimidine-4-carboxylate (1.95 g) and N,O-dimethylhydroxylamine hydrochloride (1.887 g, 19.34 mmol) in THF at −20° C. was added isopropylmagnesium chloride (23.60 mL, 47.2 mmol) dropwise through a dropping funnel over a period of 30 min, and the reaction mixture was stirred at −10° C. for 40 min. The reaction was worked up with sat. NH4Cl and EtOAc, and the crude product was purified by Biotage eluting with 40-90% EtOAc/Hexanes to give the title compound as a colorless oil (786 mg). LC-MS (M+H)+=231.01.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[Br:14]CC(C1C=C(CC)C=CN=1)=O>>[Br:14][CH2:2][C:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CC(=O)c1cc(C(C)(C)C)ccn1
Reactant: CCc1ccnc(C(=O)CBr)c1
Product: CC(C)(C)c1ccnc(C(=O)CBr)c1

Procedure:
* 2-Bromoacetyl-4-tert-butylpyridine was prepared from 2-acetyl-4-tert-butylpyridine (E. C. Constable et al., J. Am. Chem. Soc., 1997, 119, 5606) according to the procedure for preparing 2-bromoacetyl-4-ethylpyridine described in Example 57.
Reaction SMILES: COCCCN.[CH2:7]1[O:9][CH2:8]1.C[O:11][CH2:12][CH2:13][N:14]([CH2:18][CH2:19]O)[CH2:15][CH2:16][OH:17]>>[CH3:7][O:9][CH2:8][CH2:19][CH2:18][N:14]([CH2:15][CH2:16][OH:17])[CH2:13][CH2:12][OH:11]
Reactant: C1CO1
Reactant: COCCN(CCO)CCO
Agent: COCCCN
Product: COCCCN(CCO)CCO

Procedure:
3-Methoxypropylamine (665.5 g, 7.466 mole) and ethylene oxide (624 g, 14.18 mole) were reacted as described above in the procedure for making methoxyethyldiethanolamine (Example 5 (i)). The material was analyzed and the neutralization equivalent was determined 177.13.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[C:13]([Cl:15])=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[C:3]([C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([CH3:17])[CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[C:12]([Cl:16])[C:13]([Cl:15])=[CH:14][C:8]2=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2cc(Cl)c(Cl)cc2n1
Product: CC(C#N)(Cn1nc2cc(Cl)c(Cl)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5,6-dichloro-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 13, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (90 mg, 34%). MS (ES): M/Z [M+H]=474. 1H NMR: (400 MHz, DMSO-d6): 1.74 (s, 3H), 5.41-5.51 (m, 2H), 7.82-7.91 (m, 4H), 8.41 (br s, 2H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.94 (s, 3F).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8]O)[CH:5]=[CH:4][CH:3]=1.[Br:10]N1C(=O)CCC1=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][Br:10])[N:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCc1cccc(Br)n1
Solvent: ClCCl
Product: BrCc1cccc(Br)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of (6-bromopyridin-2-yl)methanol (25 g, 133 mmol) in dichloromethane (200 ml) was charged with triphenylphosphene (41.8 g, 160 mmol). The reaction was cooled to 0° C. and N-bromosuccinimide (26 g, 146 mmol) was added over one minute. After 1 hour, the reaction was concentrated in vacuo and directly purified via silica gel chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[F:12].C([O-])=O.[NH4+]>CO.O.[Zn]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:11])[C:3]=1[F:12]
Reactant: O=[N+]([O-])c1cc(Cl)c(F)c(Cl)c1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: Nc1cc(Cl)c(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of 1,3-dichloro-2-fluoro-5-nitro-benzene (71.4 g, 340 mmol) in methanol (1.5 L) was added a solution of ammonium formate (180.2 g, 2.86 mol) in water (300 mL). Zinc dust (93.4 g, 1.43 mol) was then added in four equal portions over 20 min. The reaction was stirred for 1 h and then allowed to cool to room temperature. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. Ethyl acetate (300 mL) and water (300 mL) were added and the mixture was again filtered through diatomaceous earth. The layers were separated, and the aqueous layer was further extracted with ethyl acetate (350 mL). The combined organics were washed with 500 mL of brine, dried over Na2SO4, filtered, and concentrated to afford 56.4 g of the title compound as a brown solid, m/z 180.2 [M+H]+. This material was used without any further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)#[N:2].Cl.[CH3:13][C:14]1[C:18]([CH2:19][N:20]2[CH:24]=[C:23]([NH2:25])[CH:22]=[N:21]2)=[C:17]([CH3:26])[O:16][N:15]=1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:25][C:23]1[CH:22]=[N:21][N:20]([CH2:19][C:18]2[C:14]([CH3:13])=[N:15][O:16][C:17]=2[CH3:26])[CH:24]=1)=[O:8])#[N:2]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)c2cccc(C#N)c2)cn1
Yield: 15 %

Procedure:
Prepared as in Example 4-8 from 3-cyanobenzoic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 15%. MS M+H calculated 322.6, found 322.3.
Reaction SMILES: C(O[C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=[O:5])C.[N:24]([C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=1)=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:5])[N:24]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=3)[C:25]2=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1ccc(N=C=O)cc1C
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccc(C)c(C)c3)c(=O)n(C3CCCC3)c12
Yield: 79.7 %

Procedure:
1-Cyclopentyl-3-(3,4-dimethyl-phenyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (106 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.32 mmol) and 1-isocyanato-3,4-dimethyl-benzene (0.48 mmol) following general procedure C. LCMS: m/z 416 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:16][C:17]([OH:19])=O)[CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=1.[NH2:20][C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[C:33]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:17](=[O:19])[CH2:16][C:5]3[CH:6]=[CH:7][C:8]([C:9]4[CH:14]=[CH:13][N:12]=[C:11]([CH3:15])[CH:10]=4)=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:26][CH:25]=2)[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: COc1cc(CC(=O)O)ccc1-c1ccnc(C)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)Nc2ccc(N3CCN(C(C)=O)CC3)cn2)ccc1-c1ccnc(C)c1
Temperature: 25 °C

Procedure:
To a mixture of 2-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)acetic acid 182-3 (26 mg, 0.1 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (22 mg, 0.1 mmol) and HATU (38 mg, 0.1 mmol) in DMF (0.6 mL) was added DIEA (52 uL, 0.3 mmol) and the mixture was stirred at room temperature over night. The reaction mixture was diluted into DMSO and purified by reverse phase HPLC to give N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(3-methoxy-4-(2-methylpyridin-4-yl)phenyl)acetamide 182. MS m/z 460.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ10.52 (s, 1H), 8.43 (d, 1H), 8.03 (s, 1H), 7.94 (d, 1H), 7.43-7.30 (m, 3H), 7.15 (s, 1H), 7.04 (d, 1H), 3.79 (s, 2H), 3.72 (b, 2H), 3.57 (b, 2H), 3.14 (b, 2H), 3.07 (b, 2H), 2.49 (s, 3H), 2.04 (s, 3H), 1.23 (s, 3H).
Reaction SMILES: B(F)(F)F.S(C)C.C[O:9][C:10](=[O:29])[CH2:11][C:12]1[CH:17]=[C:16]([Br:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)=[C:14]([Br:28])[CH:13]=1>ClCCl>[Br:18][C:16]1[CH:17]=[C:12]([CH2:11][C:10]([OH:29])=[O:9])[CH:13]=[C:14]([Br:28])[C:15]=1[O:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(OC)cc2)c(Br)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: O=C(O)Cc1cc(Br)c(Oc2ccc(O)cc2)c(Br)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
BF3—SMe2 (24 mL, 228 mmol) was added to a stirred solution of methyl[3,5-dibromo-4-(4-methoxyphenoxy)phenyl]acetate (2.5 g, 5.8 mmol) and dichloromethane (50 mL) at 0° C. The reaction mixture was stirred for 20 hours at room temperature and subsequently quenched with ice water (50 mL). The two layers were separated with a phase separator and the remaining water phase was extracted with ethyl acetate. Filtration through a silica pad gave the crude 3,5-dibromo-4-(4-hydroxyphenoxy)phenylacetic acid. The residue was dissolved in methanol (40 mL) and thionyl chloride (4 mL) was added carefully to the reaction. After 1.5 hours of heating at reflux, the organic phase was removed in vacuo and the residue was dissolved in chloroform. The organic phase was washed with water and concentrated to give methyl[3,5-dibromo-4-(4-hydroxyphenoxy)phenyl]acetate as beige solid (1.8 g, 75%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH:14]([OH:16])[CH3:15]>C(OCC)(=O)C.CCCCCC>[I:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15]
Reactant: COc1cc(I)c(C(C)O)cc1OC(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(I)c(C(C)=O)cc1OC(C)C

Procedure:
Concentration of fraction B (Rf 0.6 in 1:1 v/v ethyl acetate/hexane) afforded the starting alcohol 6 (200 mg, 19% recovery) as a pale-yellow oil that was identical, as judged by 1H NMR spectroscopic analysis, with authentic material.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]1.Cl>CO>[OH:1][CH2:2][C:3]1([C:16]([O:18][CH3:19])=[O:17])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1
Reactant: COC(=O)C1(CO)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: COC(=O)C1(CO)CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-(hydroxymethyl)piperidine-1,4-dicarboxylate (470 mg, 1.72 mmol, 1.0 equiv.) in MeOH (1 mL) was added HCl (4 M in dioxane, 1 mL). The mixture was stirred at rt for about 1 h and concentrated to dryness to give methyl 4-(hydroxymethyl)piperidine-4-carboxylate, which was used without further purification. LRMS (M+H+) m/z 174.0.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@H:17]([C@:22]2([CH3:28])[CH2:26][O:25]C(=O)[NH:23]2)[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].C(O)C.O>>[NH2:23][C@@:22]([C@@H:17]1[CH2:16][CH2:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([O:11][C@H:8]3[CH2:7][CH2:6][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:10][CH2:9]3)[CH:13]=2)[CH2:18]1)([CH3:28])[CH2:26][OH:25]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@@H]([C@]2(C)COC(=O)N2)C3)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@@H]([C@@](C)(N)CO)C3)CC1

Procedure:
The mixture of (R)-4-((R)-6-(trans-4-tert-butylcyclohexyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one (46.6 mg, 0.000121 mol) (from isomer 3) and lithium hydroxide (31.8 mg, 0.00133 mol) in ethanol (0.77 mL, 0.013 mol) and water (0.26 mL, 0.014 mol) was heated to reflux for overnight. LCMS showed SM was consumed and peak Rf=1.65 left. The solvent was removed under vacuum and the residue was partitioned between water and dichloromethane. The aqueous was extensively extracted with dichloromethane and the combined organic phase was dried over Na2SO4. The concentrated residue was taken up into dichloromethane and subjected to chromatography purification with dichloromethane/MeOH (10:90 to 80:20) to give the product (21.2 mg, 49% yield). LCMS 360.42 ([M+1], 100%). 1H NMR (400 MHz, CD3OD) δ ppm 0.89 (s, 9H), 1.06 (s, 3H), 1.04-1.40 (m, 6H), 1.77-1.88 (m, 3H), 1.97 (m, 1H), 2.15 (m, 2H), 2.56 (dd, J=15.8, 12.1 Hz, 1H), 2.71-2.84 (m, 3H), 3.47 (d, J=10.9 Hz, 1H), 3.51 (d, J=10.9 Hz, 1H), 4.07 (m, 1H), 6.58 (d, J=2.5 Hz, 1H), 6.63 (dd, J=8.2, 2.5 Hz, 1H), 6.96 (d, J=8.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C@@H:10]([C@@H:12]([NH:17][C:18](=[O:41])[O:19][C@H:20]([CH2:25][N:26]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)=[N:27]2)[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13][CH2:14][CH2:15][CH3:16])[OH:11])[CH:5]=[CH:4][CH:3]=1.FC1N=C(NC[C@H]([C@@H](NC(=O)O[C@H](CN2C=CC(C3C=CC(C(F)(F)F)=CC=3)=N2)C(C)(C)C)CCCC)O)C=CC=1.O[C@H]([C@@H](NC(=O)O[C@H](CN1C=CC(C2C=CC(C(F)(F)F)=CC=2)=N1)C(C)(C)C)CCCC)CNS(C1C=CC=CN=1)(=O)=O.O[C@@H]([C@@H](NC(=O)O[C@H](CN1C=CC(C2C=CC(C(F)(F)F)=CC=2)=N1)C(C)(C)C)CCCC)CNS(C1C=CC=CN=1)(=O)=O>>[F:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([C@@H:12]([NH:17][C:18](=[O:41])[O:19][C@H:20]([CH2:25][N:26]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:39])([F:38])[F:40])=[CH:33][CH:32]=3)=[N:27]2)[C:21]([CH3:22])([CH3:24])[CH3:23])[CH2:13][CH2:14][CH2:15][CH3:16])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@@H](O)CNc1cccc(F)n1
Agent: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@H](O)CNc1cccc(F)n1
Product: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)C(=O)CNc1cccc(F)n1

Procedure:
(1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{[(6-fluoro-2-pyridinyl)amino]acetyl}pentylcarbamate was prepared as in example 3g (15% yield) except that (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1S)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate & (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1R)-2-[(6-fluoro-2-pyridinyl)amino]-1-hydroxyethyl}pentylcarbamate were substituted for (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate & (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate. ES-LCMS m/z 600 (M+Na); HRMS C29H35N5O3F4 m/z 578.2754 (M+H)+Cal; 578.2745 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.Cl>C1(C)C=CC=CC=1>[ClH:5].[Cl:5][CH2:4][CH2:3][CH2:2][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: C1COCCN1
Reactant: ClCCCBr
Agent: Cl
Solvent: Cc1ccccc1
Product: ClCCCN1CCOCC1
Temperature: 84 °C
Reaction time: 3 h

Procedure:
To a solution of 1-bromo-3-chloropropane (45 g, 0.29 mol) in toluene (100 mL) was added morpholine (38 g, 0.44 mol). The solution was stirred at 84° C. for 3 h, during which time a precipitate formed. After cooling to rt, the precipitate was isolated by vacuum filtration, washed with ether, and the solid was discarded. The mother liquor was acidified with HCl (4 M in dioxane, 72 mL, 0.29 mol), which caused the desired product to precipitate as an HCl salt. Solvent was removed under reduced pressure, and the resultant solid was dried to afford the title compound (53 g, 90%): 1H NMR (DMSO-d6) δ: 11.45 (1H, br s), 3.94-3.77 (4H, m), 3.74 (2H, t), 3.39 (2H, m), 3.15 (2H, m), 3.03 (2H, m), 2.21 (2H, m).
Reaction SMILES: [N:1]1([CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[NH2:7])[CH2:4][CH2:3][CH2:2]1.O[C:17]1[C:18]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH2:29])=[O:28])[C:19]=2[N:20]=[N:21][N:22]=1>>[N:1]1([CH2:5][C@@H:6]([NH:7][C:17]2[C:18]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH2:29])=[O:28])[C:19]=3[N:20]=[N:21][N:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H](CN1CCC1)c1ccc(Cl)c(Cl)c1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: NC(=O)c1cccc2c(N[C@H](CN3CCC3)c3ccc(Cl)c(Cl)c3)nnnc12

Procedure:
Compound 16 was prepared following general synthetic scheme 7 wherein (S)-2-(Azetidin-1-yl)-1-(3,4-dichlorophenyl)ethanamine was reacted with 4-hydroxybenzo[d][1,2,3]triazine-8-carboxamide to give the title compound. LC-MS [417 (M+1)].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([OH:22])=O)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[NH:24]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]1>>[O:30]=[S:27]1(=[O:31])[CH2:28][CH2:29][N:24]([C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=3)=[C:9]([F:23])[CH:10]=2)=[O:22])[CH2:25][CH2:26]1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Reactant: O=S1(=O)CCNCC1
Product: Nc1cnc(-c2ccc(-c3ccccc3C(=O)N3CCS(=O)(=O)CC3)cc2F)cn1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and thiomorpholine 1,1-dioxide. MS (ESI): mass calcd. for C21H19FN4O3S, 426.12; m/z found, 427.0 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.11 (s, 1H), 8.11-8.02 (m, 1H), 7.58-7.47 (m, 3H), 7.43 (d, J=7.5, 1H), 7.37 (dd, J=8.1, 1.8, 1H), 7.32 (dd, J=12.1, 1.7, 1H), 4.74 (s, 2H), 4.23 (s, 1H), 4.05 (s, 1H), 3.57-3.48 (m, 1H), 3.38 (s, 1H), 3.01 (s, 1H), 2.85 (s, 1H), 2.62 (s, 1H), 2.05 (s, 1H).
Reaction SMILES: N[C:2]1[N:6]=[CH:5][NH:4][N:3]=1.N([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>S(=O)(=O)(O)O.O>[C:16]1([S:22][C:2]2[N:6]=[CH:5][NH:4][N:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1ccccc1
Reactant: Nc1nc[nH]n1
Agent: CC(=O)[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: c1ccc(Sc2nc[nH]n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Amino-1,2,4-triazole (12 g) is dissolved in 40% sulfuric acid (26 ml), and with temperature held at 5° C. or below, a solution consisting of sodium nitrite (11.9 g) dissolved in water (36 ml) is added dropwise. Subsequently, a saturated aqueous solution of sodium acetate is added to adjust the pH of the mixture to 4-5. The resulting solution is added over 1.5 h under cooling with ice to a solution composed of thiophenol (11.6 ml), sodium hydroxide (4.72 g) and water (30 ml). The reaction is stirred at room temperature for 0.5 h, then at 40°-50° C. for 1.5 h. After the reaction, the resulting product is extracted with ethyl acetate, washed with water, and dried with magnesium sulfate. When the solvent is distilled off, an oil remains. When this is purified by silica gel chromatography (solvent: chloroform-2% methanol), an oil is produced in an amount of 12.88 g; yield, 64.9%.