Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=C(C=CC=1F)[O:5][C:6]1[C:7](=[O:23])[O:8][C:9]([CH3:22])([CH3:21])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(OCC(Cl)=O)(=O)C.C1CCN2C(=NCCC2)CC1.Cl>CC#N.N1C=CC=CC=1>[CH3:21][C:9]1([CH3:22])[O:8][C:7](=[O:23])[C:6]([OH:5])=[C:10]1[C:11]1[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: CC1(C)OC(=O)C(Oc2ccc(F)c(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Agent: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OC(=O)C(O)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 61.6 %

Procedure:
To a 0° C. solution of the alcohol of Example 1, Step 3 (29.5 g, 122 mmol) in CH3CN (350 mL) were added pyridine (25 mL) and acetoxyacetyl chloride (25 g, 183 mmol). After a period of 7 h at r.t., DBU (31 mL) was added to the reaction mixture. After a period of 1 h at 80° C., a second portion of DBU (35 mL) was added. The reaction mixture was kept at 80° C. for 18 h. The reaction mixture was allowed to cool to r.t. The mixture was poured onto ice-water (2.5 L) containing 100 mL of concentrated HCl. The brown solid was collected and dissolved in hot acetonitrile and was filtered through a plug of silica. The solvent was evaporated and the resultant solid was swished in EtOAc to give the title compound (21.2 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:8]=[C:9]2[O:13][CH:12]([CH3:14])[CH2:11][C:10]=12)=[O:4].[CH3:26]OC(C1C=C(O)C=C2OC(C)(C)CC=12)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:8]=[C:9]2[O:13][C:12]([CH3:26])([CH3:14])[CH2:11][C:10]=12)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Reactant: COC(=O)c1cc(O)cc2c1CC(C)(C)O2
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)(C)O2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 6-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-4-carboxylic acid methyl ester (197e). 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J=9.09 Hz, 2 H) 7.17 (d, J=2.27 Hz, 1 H) 7.10 (d, J=8.84 Hz, 2 H) 6.64 (d, J=2.02 Hz, 1 H) 3.89 (s, 3 H) 3.35 (s, 2 H) 3.06 (s, 3 H) 1.52 (s, 6 H); LCMS for C19H20O5S m/z 377.20 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:16][C:17]([F:31])([F:30])[C:18]1[N:23]=[CH:22][C:21]([C:24](=[CH2:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=1.[OH-].[K+]>CN1C(=O)CCC1>[F:30][C:17]([F:16])([F:31])[C:18]1[N:23]=[CH:22][C:21]([CH:24]([CH2:29][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[C:25]([O:27][CH3:28])=[O:26])=[CH:20][CH:19]=1
Reactant: C=C(C(=O)OC)c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: COC(=O)C(Cn1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccc(C(F)(F)F)nc1

Procedure:
The title compound is prepared from a mixture of 2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, methyl 2-(6-(trifluoromethyl)pyridin-3-yl)acrylate and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][N:11]=2)[N:8]=[C:7]([C:20]([F:23])([F:22])[F:21])[CH:6]=1)([CH3:3])[CH3:2].[Cl:24]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[CH:1]([O:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:12][N:11]=2)[N:8]=[C:7]([C:20]([F:23])([F:21])[F:22])[C:6]=1[Cl:24])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Oc1cc(C(F)(F)F)nn1-c1ccc(S(C)(=O)=O)cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1c(Cl)c(C(F)(F)F)nn1-c1ccc(S(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 60 h
Yield: 11.3 %

Procedure:
2-(5-Isopropoxy-3-trifluoromethyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine (105 mg) and NCS (N-chlorosuccinimide) (200 mg) were dissolved in DMF under nitrogen, and the reaction mixture was stirred at room temperature for 2.5 days. The reaction mixture was then diluted with 2:1 ethyl acetate:benzene solution (100 ml), and washed with 0.5 N sodium hydroxide solution (100 ml), water (100 ml), and brine (100 ml). The organic layer was dried with sodium sulfate, and the solvent was evaporated in vacuo to give the crude product which was purified by recrystallization from 2:1 of isooctane:methylene chloride to afford the title compound (13 mg, 11%, MS: 384.1).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:16]([NH:23][C:24]([NH2:26])=[NH:25])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].O>CN(C=O)C>[NH2:26][C:24]1[N:23]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:25]=1
Reactant: O=C(CBr)CCCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC(=N)N
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)n1cc(CCCCCc2ccccc2)nc1N
Reaction time: 48 h
Yield: 63 %

Procedure:
1-bromo-7-phenylheptan-2-one (1.00 g, 3.71 mmol) was placed in a 50 mL round bottomed flask with a stir bar and dissolved in 10 mL of DMF. Boc guanidine (1.77 g, 11.13 mmol) was then added to the reaction mixture and it was allowed to stir for 48 hours. Water was then added to the reaction mixture and it was placed in a separatory funnel. The mixture was then extracted twice with ethyl acetate, washed twice with water, washed twice with brine, concentrated de vacuo and then purified via column chromatography (5% methanol/95% dichloromethane) to provide tert-butyl 2-amino-4-(5-phenylpentyl)-1H-imidazole-1-carboxylate as a hygroscopic light yellow solid (0.77 g, 63% yield), 1H NMR (300 MHz, CDCl3) δ 7.31 (m, 2H), δ 7.26 (m, 3H), δ 6.66 (s, 2H), δ 6.51 (s, 1H), δ 2.63 (t, J=7.5 Hz, 2H), δ 2.39 (t, J=7.5 Hz, 2H), δ 1.67 (m, 4H), δ 1.53 (s, 9H), δ 1.40 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 151.1, 149.8, 143.0, 130.3, 128.7, 128.5, 125.8, 106.2, 84.5, 36.1, 31.6, 29.2, 28.5, 28.4, 28.2 ppm; IR νmax (cm−1) 3433, 2098, 1639, 1454, 1204; HRMS (ESI) calcd for C19H27N3O2 (M+) 329.2103, found 329.2109. Then, tert-butyl 2-amino-4-(5-phenylpentyl)-1H-imidazole-1-carboxylate was dissolved in a 1:4 mixture of trifluoroacetic acid/dichloromethane and allowed to stir for five hours and then concentrated de vacuo. The sample was then dissolved with a dilute HCl/methanol (5 drops HCl/50 mL of methanol) and then concentrated de vacuo to provide 4-(5phenylpentyl)-1H)-imidazol-2-amine hydrochloride as a hygroscopic light yellow solid (0.62 g, 63% overall yield). 1H NMR (300 MHz, CD3OD) δ 7.20 (t, J=7.2 Hz, 2H), δ 7.12 (d, J=7.2 Hz, 3H), δ 6.37 (s, 1H), δ 2.56 (t, J=7.5 Hz, 2H), δ 2.41 (t, J=7.5 Hz, 2H), δ 1.57 (m, 4H), δ 1.34 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3) δ 147.3, 142.5, 128.3, 128.1, 127.7, 125.6, 108.2, 35.5, 31.1, 28.3, 27.0, 24.2 ppm; IR νmax (cm−1) 3385, 2933, 2857, 1679, 1536, 1495, 1453, 1335, 1172, 748, 700; HRMS (ESI) calcd for C14H19N3(M+) 229.1578, found 229.1571.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].Cl[C:10]1[N:15]=[CH:14][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[N+:1]([C:4]1[CH:8]=[CH:7][N:6]([C:10]2[N:15]=[CH:14][C:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:12][CH:11]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(-n2ccc([N+](=O)[O-])n2)nc1
Temperature: 100 °C
Yield: 74.3 %

Procedure:
A mixture of 3-Nitro-1H-pyrazole (0.265 gm, 2.34 mmol), tert-butyl 6-chloropyridine-3-carboxylate (0.500 gm, 2.34 mmol) was dissolved in anhydrous DMF (10 mL). Cesium carbonate (1.90 gm, 5.86 mmol) was added and reaction mixture was heated at 100° C. for 6 h. The reaction mixture was cooled to room temperature and poured into ice water, a white precipitate formed was filtered and dried under vacuum to give tert-butyl 6-(3-nitropyrazol-1-yl)pyridine-3-carboxylate (0.505 gm).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[O:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O.CCCCC>C(Cl)Cl.[Zn]>[Br:2][C:1]([Br:5])=[CH:34][C:33]1[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=1[O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=1
Reactant: O=Cc1ccccc1Oc1ccccn1
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: ClCCl
Product: BrC(Br)=Cc1ccccc1Oc1ccccn1
Reaction time: 18 h
Yield: 100.3 %

Procedure:
To a solution of carbon tetrabromide (54.09 g, 162.9 mmol), and zinc (10.97 g, 162.9 mmol) in CH2Cl2 (800 mls) was added triphenylphosphine (42.68 g, 162.9 mmol) and the mixture was allowed to stir for 18 hrs. 2-(2-Pyridyloxy)benzaldehyde (16.21 g, 81.5 mmol) was then added as a solution in CH2Cl2 (50 mls) and the reaction was stirred for 2 hrs. It was then poured into pentane (1.6 liters) with good stirring, then allowed to stand for 1 hr. The solution was decanted and concentrated. The residue left after decantation was taken up in 1N NaOH (500 mls) and filtered through Celite. It was then washed with CH2Cl2 (500 mls). This organic was dried with MgSO4, concentrated and combined with the material obtained from the decanted solution to afford 29.01 g of 1,1-dibromo-2-(2-(2-pyridyloxy)phenyl)ethene as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([S:23][CH3:24])[N:3]=1.[F:25][C:26]([F:35])([F:34])[C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>CCCCO>[CH3:24][S:23][C:4]1[N:3]=[C:2]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([C:26]([F:25])([F:34])[F:35])=[CH:28][CH:29]=2)[C:12]2[CH2:11][CH2:10][N:9]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[N:5]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CSc1nc(Cl)c2c(n1)CCN(c1ncccc1C(F)(F)F)CC2
Solvent: CCCCO
Product: CSc1nc2c(c(Nc3ccc(C(F)(F)F)cc3)n1)CCN(c1ncccc1C(F)(F)F)CC2
Temperature: 160 °C
Yield: 85.7 %

Procedure:
To a solution of 4-chloro-2-methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine (830 mg, 2.22 mmol) in n-BuOH (5 mL) was added 4-trifluoromethylaniline (0.4 mL, 3.30 mmol). The mixture was heated in the microwave at 160° C. for 30 min, then was cooled to rt, quenched with satd. aq. NaHCO3, and extracted with EtOAc. The combined organic layers were dried (MgSO4) and concentrated. The residue was purified (FCC) to give the title compound (950 mg, 86%). MS (ESI): mass calcd. for C22H19F6N5S, 499.13; m/z found, 500.1 [M+H]+. 1H NMR (CDCl3): 8.40-8.37 (m, 1H), 7.89-7.86 (m, 1H), 7.69 (d, J=8.6 Hz, 2H), 7.58 (d, J=9.1 Hz, 2H), 6.99-6.94 (m, 1H), 6.65 (s, 1H), 3.66-3.62 (m, 2H), 3.60-3.56 (m, 2H), 3.21-3.16 (m, 2H), 2.99-2.94 (m, 2H), 2.53 (s, 3H).
Reaction SMILES: [CH2:1]([NH:19][CH2:20][C:21]([NH:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=1[O:34][CH3:35])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][N:44]=[C:45]=[O:46])=[CH:38][CH:37]=1>C(OCC)(=O)C>[CH2:1]([N:19]([C:45]([NH:44][CH2:43][CH2:42][C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1)=[O:46])[CH2:20][C:21]([NH:23][C:24]1[C:29]([O:30][CH3:31])=[CH:28][C:27]([O:32][CH3:33])=[CH:26][C:25]=1[O:34][CH3:35])=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCC/C=C\CCCCCCCCNCC(=O)Nc1c(OC)cc(OC)cc1OC
Reactant: O=C=NCCc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCCN(CC(=O)Nc1c(OC)cc(OC)cc1OC)C(=O)NCCc1ccccc1
Reaction time: 72 h

Procedure:
A mixture of 0.50 g of the product of Example 7, 0.2 g 2-phenethyl isocyanate, and a few mL ethyl acetate were briefly heated on the steambath and then allowed to sit 3 days at room temperature. The reaction mixture was then washed with dilute H3PO4, NaHCO3, and HaCl solutions, dried over MgSO4, filtered, and concentrated to an oil. The oil was chromatographed on SiO2 (70-230 mesh) using EtoAc as eluant. The product was obtained as an oil which crystallized on standing. 0.28 g (44%). NMR (CDCl3) δ 0.88 (3H, t), δ 1.25 (24H, m), δ 1.96 (4H, m) δ 2.84 (2H, t), δ 3.23 (2H, t), δ 3.51 (2H, q), δ 3.69 (6H, s), δ 3.77 (3H, s), δ 4.03 (2H, s), δ 4.70 (1H, t), δ 5.35 (2H, t), δ 6.13 (2H, s), δ 7.16-7.31 (5H, m), δ 7.46 (1H, s). IR (KBr) 3251, 2925, 1662, 1621, 1533, 1465, 1156, 1128, 810 cm-1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[NH:29])[NH:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH:17]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]1)[CH2:12][CH2:11]2.Cl>CO>[NH:19]1[CH2:20][CH2:21][CH:17]([N:13]2[C:14]3[C:10](=[CH:9][C:8]([NH:7][C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)=[NH:29])=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCc3cc(NC(=N)c4cccs4)ccc32)C1
Agent: Cl
Solvent: CO
Product: N=C(Nc1ccc2c(c1)CCN2C1CCNC1)c1cccs1
Yield: 113.2 %

Procedure:
A solution of compound 6 (0.35 g, 0.848 mmol) in methanol (10 mL) was treated with 1 N HCl (10 mL) and the resulting mixture was refluxed for 30 minutes. The reaction was brought to room temperature and solvent was evaporated. The crude product was dissolved into water (10 mL), filtered and washed. Water was evaporated to obtain compound 49 (0.3 g, 92%) as a solid. 1H NMR (DMSO-d6) δ11.25 (s, 1H), 9.82-9.60 (m, 3H), 8.63 (s, 1H), 8.15-8.13 (m, 2H), 7.36 (t, 1H, J=4.5 Hz), 7.12-7.06 (m, 2H), 6.68 (d, 1H, J=8.4 Hz), 4.39-4.35 (m, 1H), 3.56-3.06 (m, 6H), 2.96 (t, 2H, J=8.1 Hz), 2.18-2.00 (m, 2H); ESI-MS (m/z, %): 313 (MH+, free base, 100), 244 (61); ESI-HRMS calculated for C17H21N4S (MH+, free base), calculated: 313.1481; observed: 313.1473; HPLC-purity: 94.05% by area.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH:8]2[CH2:10][CH2:9]2)[C:6](=[O:11])[NH:5][C:4](=[O:12])[C:3]=1[N:13]=O>CN(C=O)C.O=[Pt]=O>[CH:8]1([N:7]2[C:2]([NH2:1])=[C:3]([NH2:13])[C:4](=[O:12])[NH:5][C:6]2=[O:11])[CH2:10][CH2:9]1
Reactant: Nc1c(N=O)c(=O)[nH]c(=O)n1C1CC1
Agent: O=[Pt]=O
Solvent: CN(C)C=O
Product: Nc1c(N)n(C2CC2)c(=O)[nH]c1=O

Procedure:
15.9 g of 6-amino-1-cyclopropyl-5-nitroso-2,4-(1H,3H)-pyrimidinedione (III) was catalytically hydrogenated in 1 liter of DMF and in the presence of 0.1 g PtO2 for 4 hours and at room temperature and at a pressure of 200 kPa. The catalyst and the crystals were filtered off and washed with ethanol. Yield 12.9 g (87%) (IV).
Reaction SMILES: Br[C:2]1[C:3]([Cl:27])=[C:4]([N:10]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[NH2:28][CH:29]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([O:12][C:11]([N:10]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)[C:4]1[C:3]([Cl:27])=[C:2]([NH:28][CH:29]2[CH2:30][CH2:31][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:33][CH2:34]2)[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C#N)cc(Br)c2Cl)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2cc(C#N)cc(NC3CCN(C(=O)OC(C)(C)C)CC3)c2Cl)cc1
Temperature: 95 °C
Yield: 59.2 %

Procedure:
A mixture of tert-butyl (3-bromo-2-chloro-5-cyanophenyl)(4-methoxybenzyl)carbamate (Example 357A) (300 mg, 0.624 mmol), tert-butyl 4-aminopiperidine-1-carboxylate (162 mg, 0.811 mmol), Pd2(dba)3 (28.6 mg, 0.031 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (36.1 mg, 0.062 mmol), and Cs2CO3 (610 mg, 1.872 mmol) in a dried microwave vial was flushed with nitrogen. Dioxane (6 mL) was added and the vial was sealed and heated at 95° C. overnight. The reaction was diluted with EtOAc and filtered through celite. Removed solvent from the filtrate followed by radial silica gel chromatography eluting with hexane containing 0 to 40% EtOAc to give tert-butyl 4-((3-((tert-butoxycarbonyl)(4-methoxybenzyl)amino)-2-chloro-5-cyanophenyl)amino)piperidine-1-carboxylate (211 mg, 56% yield) as a foam. This was dissolved in DCM (3 mL) and anisole (0.202 ml, 1.847 mmol) and TFA (2 ml) were added. After 4 hr, the solvents were removed and the residue was taken up in MeOH and applied onto an SCX column. This was washed with MeOH, and then eluted with 2N NH3 in MeOH. Removal of the solvents followed by silica gel radial chromatography with DCM containing 0 to 12% 2 N NH3 in MeOH gave 3-amino-4-chloro-5-(piperidin-4-ylamino)benzonitrile (84 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:16][C:15]=2[CH:28]2[CH2:33][C:32]([CH3:35])([CH3:34])[CH2:31][C:30]([CH3:37])([CH3:36])[CH2:29]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:21][O:20][C:18]1[C:17]([N:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)=[CH:16][C:15]([CH:28]2[CH2:29][C:30]([CH3:36])([CH3:37])[CH2:31][C:32]([CH3:35])([CH3:34])[CH2:33]2)=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=1
Reactant: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c(C2CC(C)(C)CC(C)(C)C2)cc1N1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCNCC2)c(C2CC(C)(C)CC(C)(C)C2)cc1N1CCCCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.6 %

Procedure:
A mixture of the 4-[5-methoxy-4-piperidin-1-yl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (88 mg, 0.17 mmol) produced in Example (72a), trifluoroacetic acid (0.25 mL, 3.2 mmol) and dichloromethane (0.5 mL) was stirred for 1 hour and 10 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 56 mg of the title compound as a red solid.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[C:6]([Cl:9])=[N:5][S:4][N:3]=1.[OH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(N(CC)CC)C>O1CCCC1>[Cl:9][C:6]1[C:7](=[O:8])[C:2]([O:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[N:3][S:4][N:5]=1
Reactant: Oc1cccnc1
Reactant: O=c1c(Cl)nsnc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1c(Cl)nsnc1Oc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41.4 %

Procedure:
To a stirred solution of 12.8 grams (0.07 mole) of 3,5-dichloro-4H-1,2,6-thiadiazin-4-one and 6.7 grams (0.07 mole) of 3-hydroxypyridine in 300 ml of tetrahydrofuran was added dropwise 7.1 grams (0.07 mole) of triethylamine. During the addition the exothermic reaction caused the reaction mixture temperature to rise to 34° C. Upon complete addition, the reaction mixture was stirred for 16 hours during which time it cooled to ambient temperature. The reaction mixture was filtered to remove triethylamine hydrochloride. The filter cake was washed with tetrahydrofuran. The filtrate and wash were combined and evaporated under reduced pressure to a residual solid. The residue was triturated with 300 ml of distilled water and the insolubles collected by filtration. The filter cake was washed with water and recrystallized twice from ethanol. A sample of the recrystallized solid was dissolved in chloroform and subjected to analysis by thin layer chromatography. This analysis indicated that the solid contained impurities. The filtrates from the recrystallizations were combined and evaporated under reduced pressure to a residue. The residue was combined with the twice-recrystallized solid and dissolved in chloroform. The solution was slurried with silica gel in an effort to remove the impurities. The mixture was filtered and the filtrate was evaporated under reduced pressure to a residual solid. The solid was recrystallized from ethanol to give 7.0 grams (42%) of 3-chloro-5-(3-pyridyloxy)-4H-1,2,6-thiadiazin-4-one; m.p. 134.5°-135.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][N:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10](Br)[CH:11]=2)[CH:6]=1.[CH3:29][N:30](C)C(=O)C>O.[C-]#N.[Zn+2].[C-]#N.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>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])=[CH:18][N:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:29]#[N:30])[CH:11]=2)[CH:6]=1
Reactant: CC(=O)N(C)C
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(Br)cc23)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(C#N)cc23)nc1
Temperature: 150 °C
Reaction time: 24 h

Procedure:
A mixture of [6-bromo-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (29 mg, 0.07 mmol, methyl ester of example 12-1), zinc cyanide (10 mg, 0.084 mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.014 mmol) and N,N-dimethylacetamide (0.2 mL) was stirred at 150° C. for 24 hours under an argon atmosphere. The reaction mixture was diluted with water (5 mL), and extracted with ethyl acetate (20 mL×2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative TLC (30% ethyl acetate in petroleum ether) to give [6-cyano-4-(5-ethanesulfonyl-pyridin-2-yloxy)-naphthalen-2-yl]-acetic acid methyl ester (17 mg) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)(=[O:10])=[O:9])[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[O:30]([CH2:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[O:30]([CH2:37][C:38]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][S:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)(=[O:10])=[O:9])[CH2:5][CH2:6]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: O=S(=O)(NC1CCNCC1)c1ccc2ccccc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COc1ccccc1)N1CCC(NS(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-(Piperidin-4-yl)naphthalene-2-sulfonamide (50 mg, 0.17 moles) was dissolved in 10 mL DCM and to that di-isopropyl ethyl amine (0.1 mL, 0.34 moles) was added under nitrogen at 0° C. The reaction was allowed to stir for 10 min and phenoxy acetyl chloride (33 mg, 0.19 moles) was added at 0° C. and warmed room temperature and stirred for 3 h. After completion of the reaction as monitored by TLC, reaction was quenched with cold water and extracted with ethyl acetate (2×25 mL). The combined organic phase was washed with bicarbonate solution and brine and dried over sodium sulphate. The solvent was filtered and evaporated on rotavap to obtain a crude compound which was washed further with hexane to yield the title compound as a white solid.