Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[C:24]=1[S:30](Cl)(=[O:32])=[O:31]>>[Cl:22][C:23]1[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[C:24]=1[S:30]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)(=[O:31])=[O:32]
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)N1CCC2(CC1)CSC1=C(O2)c2ccccc2C(=O)C1=O

Procedure:
Compound 81 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride and conditions outlined in procedure P. M.p.=247-249° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.89-7.86 (m, 1H), 7.66-7.61 (m, 1H), 7.57-7.52 (m, 1H), 7.41-7.38 (m, 1H), 3.80 (s, 3H), 3.56-3.51 (m, 2H), 3.11 (s, 2H), 2.88-2.81 (m, 2H), 2.29 (s, 3H), 2.13-2.06 (m, 2H), 1.93-1.84 (m, 2H); LCMS: 494 [M+H].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:23][N:22]=[C:21]([OH:24])[CH:20]=3)=[CH:15][CH:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:25](Cl)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]>C(Cl)(Cl)Cl.C(N(CC)CC)C.C(OCC)(=O)C>[C:25]([O:24][C:21]1[CH:20]=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][CH2:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)=[CH:18][CH:17]=2)[O:23][N:22]=1)(=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=[N+]([O-])c1cccc(CCOc2ccc(-c3cc(O)no3)cc2)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Oc1cc(-c2ccc(OCCc3cccc([N+](=O)[O-])c3)cc2)on1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(4-(2-(3-nitrophenyl)ethoxy)phenyl)isoxazol-3-ol (117 mg) obtained in Example 37 in chloroform (5 ml), 0.15 ml of triethylamine and 0.052 ml of pivaloyl chloride were added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate, washed with a saturated saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/hexane (0:1-1:3)) to afford the title compound as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:33])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[CH:34]1([CH:40]=O)[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.C([BH3-])#N.[Na+].O>C(O)C.C(O)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:33])[CH2:10][C@@:11]1([C:20]2[S:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([CH2:40][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:13][CH2:12]1
Reactant: CCc1ccc(-c2ccc([C@@]3(CC(=O)NOC4CCCCO4)CCNCCS3(=O)=O)s2)cc1
Reactant: O=CC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CCc1ccc(-c2ccc([C@@]3(CC(=O)NOC4CCCCO4)CCN(CC4CCCCC4)CCS3(=O)=O)s2)cc1
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a solution of N-(2-tetrahydropyranyloxy)-2-[(S)-7-(5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (100 mg) and cyclohexanecarbaldehyde (46 mg) in ethanol were added sodium cyanoborohydride (26 mg) and acetic acid (1 drop) in an ice-water bath. After 1 hour stirring, to the reaction mixture was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with water twice and brine, dried over magnesium sulfate and evaporated. The residue was purified by flash silica gel chromatography eluting with hexane-ethyl acetate=5-1, 2-1, 1-2 to give N-(2-tetrahydropyranyloxy)-2-[(S)-4-(cyclohexylmethyl)-7-(5-(4-ethylphenyl)-2-thienyl)-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (91 mg) as colorless amorphous.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=1.[NH2:10][C:11]1[CH:12]=[N:13][N:14]([C:16]([CH3:23])([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:15]=1.O>COCCOCCOC>[CH3:23][C:16]([N:14]1[CH:15]=[C:11]([NH:10][C:3]2[NH:8][C:7](=[O:9])[CH:6]=[CH:5][N:4]=2)[CH:12]=[N:13]1)([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CSc1nccc(=O)[nH]1
Reactant: CCOC(=O)C(C)(C)n1cc(N)cn1
Solvent: COCCOCCOC
Solvent: O
Product: CCOC(=O)C(C)(C)n1cc(Nc2nccc(=O)[nH]2)cn1
Temperature: 140 °C
Reaction time: 7 h
Yield: 91.2 %

Procedure:
To a solution of 2-(methylsulfanyl)pyrimidin-4(3H)-one (9.1 g) obtained in Step A of Example 347 in diglyme (60 mL) was added ethyl 2-(4-amino-1H-pyrazol-1-yl)-2-methylpropanoate (13 g) obtained in Step B of Example 347, and the mixture was stirred at 140° C. for 7 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (17 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][C:10]([C:17]([F:20])([F:19])[F:18])=[N:9]2)=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.C(Cl)Cl>[F:18][C:17]([F:20])([F:19])[C:10]1[CH:11]=[C:12]([C:13]([F:14])([F:15])[F:16])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH2:27][C:24]3[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=3)=[CH:7][CH:6]=2)[N:9]=1
Reactant: O=Cc1ccncc1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(C(F)(F)F)n(-c2ccc(NCc3ccncc3)cc2)n1
Reaction time: 8 h
Yield: 77.7 %

Procedure:
A mixture of 1-(4′-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole (0.059 g, 0.2 mmol) and pyridine-4-carboxaldehyde (20 μL, 0.2 mmol) in methanol (0.8 mL) and acetic acid (0.2 mL) was stirred at room temperature for 15 minutes Sodium cyanoborohydride (0.032 g, 0.5 mmol) was added, and the reaction mixture stirred overnight. The reaction mixture was diluted with CH2Cl2 (50 mL), washed with brine (2×20 mL), dried over anhydrous Na2SO4 and evaporated. The residue was purified by flash column chromatography over silica gel (2% acetone in CH2Cl2) to give the above-named compound (0.060 g, 78%): mp 92-94° C. NMR (DMSO-d6) δ 4.40 (2H, d), 6.65 (2H, d), 6.97 (1H, t), 7.23 (2H, d), 7.35 (2H, d), 6.65 (2H, d), 7.7 (1H, s), 8.51 (2H, d).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][C:26]#[N:27]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][C:26]#[N:27])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: N#CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 31.5 %

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (11 g, 50 mmol), K2CO3 (8.5 g, 74 mmol) and 3-bromopropionitrile (8.2 g, 1.2 eq) in acetonitrile (300 ml) was heated at reflux for 24 hours. The mixture was cooled and the insolubles were filtered. The solvent was removed on a rotary evaporator and the crude product was purified by flash chromatography over a silica gel column (SiO2, 120 g). The product thus purified weighed 8.94 g. Recrystallization from ethanol yielded the nitrile as white crystals 4.3 g, m.p. 100°-101 ° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.[CH2:10]([O:12][C:13](=[O:19])[CH2:14][C:15](=[O:18])[CH2:16][CH3:17])[CH3:11]>>[CH2:10]([O:12][C:13](=[O:19])[CH:14]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)[C:15](=[O:18])[CH2:16][CH3:17])[CH3:11]
Reactant: Fc1ccc(CBr)cc1
Reactant: CCOC(=O)CC(=O)CC
Product: CCOC(=O)C(Cc1ccc(F)cc1)C(=O)CC

Procedure:
The title compound was prepared by the method of Preparation 34a using 1-bromomethyl-4-fluorobenzene and 3-oxopentanoic acid ethyl ester.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]=[C:6]=[O:7].CO[C:10]([C:12]1([CH3:34])[CH2:24][C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:25][CH3:26])[CH:21]=3)[NH:16][C:15]=2[CH:14]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=2)[NH:13]1)=[O:11]>>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[C:6](=[O:7])[N:13]2[CH:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=3)[C:15]3[NH:16][C:17]4[C:22]([C:23]=3[CH2:24][C:12]2([CH3:34])[C:10]1=[O:11])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][CH:18]=4
Reactant: COC(=O)C1(C)Cc2c([nH]c3ccc(OC)cc23)C(c2cccc(O)c2)N1
Reactant: O=C=NCCCCl
Product: COc1ccc2[nH]c3c(c2c1)CC1(C)C(=O)N(CCCCl)C(=O)N1C3c1cccc(O)c1

Procedure:
The title compound is prepared analogously to the procedure described for example 22, using chloro propyl isocyanate and (1RS,3SR)-1-(3-hydroxy-phenyl)-6-methoxy-3-methyl-2,3,4,9-tetrahydro-1H-betacarboline-3-carboxylic acid methyl ester. MS: m/z (MH+)=454.0
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:17])=[O:16])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][NH:25]1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1>C(Cl)Cl>[ClH:17].[N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([N:25]3[CH2:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24]3)=[O:16])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)CNC2
Reactant: O=C(Cl)c1ccc(OCCCN2CCCCC2)cc1C(F)(F)F
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: Cl
Product: O=C(c1ccc(OCCCN2CCCCC2)cc1C(F)(F)F)N1Cc2ccccc2C1
Reaction time: 16 h

Procedure:
A solution of 4-(3-piperidin-1-yl-propoxy)-2-trifluoromethyl-benzoyl chloride (D6) (150 mg) in DCM (10 ml) was added to isoindoline (0.046 ml) and diethylaminomethyl polystyrene (0.60 g; 3.2 mmol/g). The mixture was stirred for 16 h, then loaded directly onto a silica column and eluted with 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM. The isolated free base was dissolved in DCM (5 ml) and treated with 4N HCl/dioxane solution (1 ml) with stirring for 10 min. The mixture was concentrated, and the residue co-evaporated with toluene (3×10 ml) and then dried at 50° C. under high vacuum for 16 h to yield the title compound (E16) as a beige solid (0.094 g). MS electrospray (+ion) 433 (MH+). 1H NMR δ (DMSO-d6): 9.96 (1H, s), 7.63 (1H, d, J=8.36 Hz), 7.46-7.23 (6H, m), 4.82 (2H, s), 4.47 (2H, s), 4.20 (2H, t, J=5.88 Hz), 3.47 (2H, m), 3.19 (2H, m), 2.87 (2H, m), 2.20 (2H, m), 1.80-1.38 (6H, m).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([NH:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][CH:9]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)Nc1cccc(OCCCN)c1
Reactant: Fc1ccc(-c2csc3ncnc(Cl)c23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1cccc(OCCCNc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Temperature: 120 °C
Yield: 75.8 %

Procedure:
A mixture of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (100 mg, 0.378 mmol), N-[3-(3-amino-propoxy)-phenyl]-acetamide (94 mg, 0.45 mmol), diisopropylethylamine (147 mg, 1.14 mmol) and N,N-dimethylformamide (3.0 mL) was warmed to 120° C. for 20 minutes by microwave irradiation. The solvent was then concentrated in vacuo and the residue was dissolved in ethyl acetate (50 mL) and washed with of aqueous sodium bicarbonate (2×30 mL). The organic layer was concentrated in vacuo and purified by column chromatography over silica gel using 1% methanol in dichloromethane as eluant to give 125 mg (73%) of N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy)phenyl]acetamide as a white solid. MS [M+H] 437.1, 1H NMR (CDCl3) 6 (ppm) 8.50 (s, 1H), 7.41-7.36 (m, 2H), 7.25 (s, 1H), 7.21 (t, J=8.1 Hz, 1H), 7.07-6.95 (m, 3H), 6.94 (d, J=8.1 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 5.01 (b, 1H), 3.89 (t, J=6.0 Hz, 2H), 3.64 (m, 2H), 2.19 (s, 3H), 1.98 (m, 2H).
Reaction SMILES: C(C1N(C[C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][C:14]=2Cl)C(C=O)=CN=1)CCC.C(C1C=CC(C2NC(C=O)=CN=2)=CC=1)(OCC)=O.[CH2:43]([C:47]1[N:48](CC2C=CC=CC=2Cl)[C:49](/[CH:52]=[C:53](\[CH2:57][C:58]2[S:59][CH:60]=[CH:61][CH:62]=2)/[C:54]([OH:56])=[O:55])=[CH:50][N:51]=1)[CH2:44][CH2:45][CH3:46]>>[CH2:43]([C:47]1[N:48]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)[C:49](/[CH:52]=[C:53](\[CH2:57][C:58]2[S:59][CH:60]=[CH:61][CH:62]=2)/[C:54]([OH:56])=[O:55])=[CH:50][N:51]=1)[CH2:44][CH2:45][CH3:46]
Reactant: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1Cc1ccccc1Cl
Reactant: CCCCc1ncc(C=O)n1Cc1ccc(C(=O)OCC)cc1Cl
Agent: CCOC(=O)c1ccc(-c2ncc(C=O)[nH]2)cc1
Product: CCCCc1ncc(/C=C(\Cc2cccs2)C(=O)O)n1-c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared following the procedure of Example 42 replacing 2-n-butyl-1-[(4-carboethoxy-2-chlorophenyl)methy]imidazole-5-aldehyde with 2-n-butyl-[(4-carboethoxyphenyl]imidazole-5-aldehyde; mp 260°-265° C.(d).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][S:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:23][CH:24]([CH3:26])[CH3:25].O>CN(C)C(=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:23][CH:24]([CH3:26])[CH3:25])[S:10]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1ccccc1)NCc1ccc(Br)cc1
Reactant: CC(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)CN(Cc1ccc(Br)cc1)S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a solution of N-[(4-bromophenyl)methyl]-1-phenyl-methanesulfonamide (Example 5, Step 1) (2 g, 5.82 mmol) in N,N-dimethylacetamide (20 mL) was added sodium hydride (60% in mineral oil) (353 mg, 8.8 mmol) and the reaction was stirred at ambient temperature for 30 minutes. 1-Bromo-2-methyl-propane (0.96 mL, 8.81 mmol) was then added and the reaction was stirred for 16 hours. Water was added and the reaction was diluted with EtOAc. The reaction was then washed with water (3×) and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-50% EtOAc in heptane) to give N-[(4-bromophenyl)methyl]-N-isobutyl-1-phenyl-methanesulfonamide (1.20 g, 52% yield). LCMS (m/z) ES+ 418.1 [M+Na]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].O=S(Cl)Cl.[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=[S:21]>>[OH:1][CH2:2][C:3]1([NH2:4])[CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]1[S:21][CH2:2][C:3]2([CH2:12][CH2:11][CH2:10][CH2:9]2)[NH:4]1
Reactant: NCCO
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Solvent: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NC2(CCCC2)CS1
Product: NC1(CO)CCCC1

Procedure:
1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was sequentially reacted with SOCl2 and 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclohexyl bromide according to Method D2e to give 2-(2-methyl-4-nitrophenylimino)-1-cyclohexyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:32])[C:18]=1[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1)=[O:21]>>[Cl:32][C:17]1[CH:16]=[N:15][CH:14]=[C:13]([Cl:12])[C:18]=1/[CH:19]=[C:20](\[O:21][C:3](=[O:4])[N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)/[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: COc1ccc(C(=O)Cc2c(Cl)cncc2Cl)cc1OC
Product: COc1ccc(/C(=C/c2c(Cl)cncc2Cl)OC(=O)N(C)c2ccccc2)cc1OC

Procedure:
The compound was obtained starting from methyl-phenyl-carbamoyl chloride and 2-(3,5-dichloro-pyridin-4-yl)-1-(3,4-dimethoxy-phenyl)-ethanone, following the procedure of Example 28.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16](=[O:18])[CH3:17])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:19][C:20]([OH:22])=O.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH:32]([C:36]([NH2:38])=[O:37])[CH2:31]1.C(Cl)CCl.C(N(CC)CC)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:11][CH2:12][N:13]([C:16](=[O:18])[CH3:17])[CH2:14][CH2:15]2)[CH:6]=[CH:5][C:4]=1[CH2:19][C:20]([N:33]1[CH2:34][CH2:35][N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH3:23])[CH2:31][CH:32]1[C:36]([NH2:38])=[O:37])=[O:22]
Reactant: COc1cc(OC2CCN(C(C)=O)CC2)ccc1CC(=O)O
Reactant: Cc1ccccc1N1CCNC(C(N)=O)C1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cc(OC2CCN(C(C)=O)CC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Methoxy-4-(1-acetyl-4-piperidyloxy)phenylacetic acid (35 mg, 0.11 mmol), 4-(2-methylphenyl)piperazine-2-carboxamide (25 mg, 0.11 mmol), EDC (28 mg, 0.15 mmol), and HBT (17 mg, 0.13 mmol) were combined in DMF (4 ml) under nitrogen. The mixture was rendered basic by addition of triethylamine (0.043 ml) and stirred at ambient temperature for 18 hours. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel eluted with 2% methanol in methylene chloride. The combined product fractions were evaporated to dryness in vacuo and the residue was rechromatographed on silica gel eluted with 96:4:0.4 methylene chloride:methanol:concentrated ammonia. The combined product fractions were evaporated to dryness in vacuo and the residue was concentrated from methanol and ether to give 1-(2-methoxy-4-(1-acetyl-4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl)-piperazine-2-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[C:4]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[N:16][CH:17]=2)[CH:3]=1.[F:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[F:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:8](=[O:10])[C:6]2[CH:5]=[C:4]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[N:16][CH:17]=3)[CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:23][CH:24]=1
Reactant: Cc1cc(Oc2cncnc2)cc(C(=O)O)n1
Reactant: Nc1ccc(F)cn1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Oc2cncnc2)cc(C(=O)Nc2ccc(F)cn2)n1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 36.1 %

Procedure:
6-methyl-4-(pyrimidin-5-yloxy)picolinic acid (610 mg, 2.64 mmol, 1 eq) and 5-fluoro-2-aminopyridine (296 mg, 2.64 mmol, 1 eq) were dissolved in pyridine (40 mL) in a flame-dried round-bottom flask. The reaction was cooled to −15° C. and phosphorus oxychloride (270 μL, 2.90 mmol, 1.1 eq) was added dropwise while keeping the temperature below −15° C. After stirring for 30 minutes at −15° C. and the reaction was quenched with ice-water and neutralized with 10% K2CO3. The mixture was extracted with EtOAc (3×) and the combined organics were dried (MgSO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 310 mg (36%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.48 (s, 1H), 9.18 (s, 1H), 8.88 (s, 2H), 8.40 (d, J=3.0 Hz, 1H), 8.27 (dd, J=9.2 Hz, 4.10 Hz, 1H), 7.86 (td, J=8.6, 3.1 Hz, 1H), 7.55 (d, J=2.3 Hz, 1H), 7.29 (d, J=2.3 Hz, 1H), 2.58 (s, 3H); ES-MS [M+1]+: 326.2.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC1N=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29]N=1.CCN(C(C)C)[CH:46]([CH3:48])[CH3:47]>O1CCOCC1>[N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:46]3[CH:48]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:47]=3)[C@@H:14]([CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]3[CH3:25])[CH2:13]2)(=[O:10])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1
Reactant: CCN(C(C)C)C(C)C
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Solvent: C1COCCO1
Product: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 100 °C
Yield: 72.5 %

Procedure:
A 20-mL vial was charged with (3S)-4-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-piperazinyl)methyl)-3-methylmorpholine (0.797 g, 2.04 mmol, step 4), (2-chloro-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.859 g, 3.06 mmol, Intermediate D), DIPEA (1.10 mL, 6.30 mmol) and 1,4-dioxane (10 mL). The vial was sealed and heated at 100° C. for 12 h. The reaction mixture was allowed to cool to room temperature and then partitioned between water (30 mL) and EtOAc (20 mL). The aqueous phase was extracted with EtOAc (40 mL). The combined organic phases were washed with saturated aqueous NaCl (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 0 to 50% EtOAc in hexanes) to afford 2-(4-((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.936 g) as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([Cl:12])[N:3]=1.[NH2:13][CH2:14][C:15]([NH2:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16].C(N(CC)CC)C.N1C=CC=NC=1>C(O)C>[ClH:12].[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:13][CH2:14][C:15]([NH2:23])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH3:16])[N:3]=1
Reactant: CC(N)(CN)c1ccccc1
Reactant: Nc1nc(O)c([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: c1cncnc1
Product: CC(N)(CNc1nc(N)nc(O)c1[N+](=O)[O-])c1ccccc1
Product: Cl
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
2-Amino-6-chloro-4-hydroxy-5-nitropyrimidine (0.626 g; 3.0 mmole) was dissolved in 130 ml of refluxing absolute ethanol and 0.45 g of 1,2-diamino-2-phenylpropane free-base (3.0 mmole) was added all at once dissolved in 8 ml of absolute ethanol. The mixture was stirred and maintained at reflux as a light yellow precipitate formed. Analysis by HPLC at 30 minutes showed a marked slowing of the condensation after a little over one-half of the reactants had been consumed. (Partisil SCX column (25×0.46 cm) eluted with 0.1M ammonium hydroxide made to pH 3.3 with formic acid/methanol, 3:2 v/v). Completion of the reaction to within 97% utilization of the diamine was accomplished by addition of 3.6 ml of 1M triethylamine in absolute ethanol (3.6 mmole) followed by 0.063 g of the above pyrimidine, the reaction being refluxed an additional hour. After being kept overnight at -15° C. the majority of the somewhat gelatinous product was collected by centrifugation, washed with 10 ml cold ethanol, and finally, twice with 30 ml each of ethyl ether. A second crop of equal purity was collected after allowing the mother liquor supernate to stand for an additional 5 days at -15° C., and similarly washed. These materials dried under vacuum in the presence of P2O5 gave 0.97 g (0.889+0.081) of the monohydrochloride salt for a yield of 95% based upon diamine.