Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([CH3:26])[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.[C:27]1([C:33]2[CH2:37][C:36]3([CH2:42][CH2:41][CH2:40][NH:39][CH2:38]3)[O:35][N:34]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.O>[CH3:25][N:22]1[CH2:23][CH2:24][C:19]([C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:4]3[N:3]=[C:2]([N:39]4[CH2:40][CH2:41][CH2:42][C:36]5([O:35][N:34]=[C:33]([C:27]6[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=6)[CH2:37]5)[CH2:38]4)[C:10]([F:11])=[CH:9][C:5]=3[C:6]([NH2:8])=[O:7])=[CH:14][CH:15]=2)([CH3:26])[CH2:20][CH2:21]1
Reactant: c1ccc(C2=NOC3(CCCNC3)C2)cc1
Reactant: CN1CCC(C)(c2ccc(Nc3nc(Cl)c(F)cc3C(N)=O)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCC(C)(c2ccc(Nc3nc(N4CCCC5(CC(c6ccccc6)=NO5)C4)c(F)cc3C(N)=O)cc2)CC1
Yield: 20.3 %

Procedure:
A solution of 6-chloro-2-(4-(1,4-dimethylpiperidin-4-yl)phenylamino)-5-fluoronicotinamide (40 mg, 0.106 mmol), 3-phenyl-1-oxa-2,7-diazaspiro[4.5]dec-2-ene (42.1 mg, 0.127 mmol), and DIEA (0.074 mL, 0.425 mmol) in NMP (1 mL) was heated at 120° C. for 3 h and at 130° C. for 2 h. The reaction mixture was cooled, diluted with water. The resulting brown solid precipitate was filtered and purified by prep-HPLC. The product containing fractions were collected, basified with 1N NaOH, and extracted with methylene chloride twice. The combined organic factions were washed with water and concentrated to give 12 mg yellow solid. LC-MS: 3.04 min (RT). (M+H)+=557.28. 1H NMR (400 MHz, chloroform-d) δ ppm 10.66 (1H, s), 7.67 (2H, dd, J=6.81, 2.86 Hz), 7.50 (2H, d, J=8.79 Hz), 7.36-7.44 (3H, m), 7.22-7.25 (1H, m), 7.13 (2H, d, J=8.79 Hz), 5.43 (2H, br. s.), 3.79-3.90 (2H, m), 3.69-3.75 (1H, m), 3.57-3.67 (1H, m), 3.32 (1H, d, J=16.70 Hz), 3.05 (1H, d, J=16.70 Hz), 2.27-2.45 (4H, m), 2.22 (3H, s), 1.92-2.13 (4H, m), 1.57-1.79 (4H, m), 1.12 (3 H, s).
Reaction SMILES: [Na].[NH2:2][OH:3].O.CO[C:7](=[O:37])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:15]2[CH:20]([C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:19][CH2:18][CH2:17][CH:16]2[C:28]2[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[C:10]([CH2:35][OH:36])[CH:9]=1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:27][C:26]1[C:21]([CH:20]2[CH2:19][CH2:18][CH2:17][CH:16]([C:28]3[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=3)[N:15]2[CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:2][OH:3])=[O:37])=[CH:9][C:10]=2[CH2:35][OH:36])=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(CN2C(c3ncccc3C)CCCC2c2ncccc2C)c(CO)c1
Reactant: NO
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cccnc1C1CCCC(c2ncccc2C)N1Cc1ccc(C(=O)NO)cc1CO
Reaction time: 2 h
Yield: 90.6 %

Procedure:
To a stirred solution of sodium (320 mg, 14 mmol) in anhydrous MeOH (15 mL) was added NH2OH.H2O (550 mg, 7.9 mmol) followed by a solution of 4-(3,3″-dimethyl-3′,4′,5′,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-3-hydroxymethyl-benzoic acid methyl ester (700 mg, 1.6 mmol) in anhydrous MeOH (7 mL). The mixture was stirred for 2 h, at which time TLC indicated that the reaction had stalled. A solution of sodium (320 mg, 14 mmol) and NH2OH.H2O (550 mg, 7.9 mmol) in anhydrous MeOH (8 mL) was added to the reaction mixture and stirring was continued for 2 hours. The reaction mixture was diluted with CHCl3 (100 mL) and poured into a saturated NaHCO3 solution (100 mL). The aqueous layer was extracted with CHCl3 (5×100 mL). The combined organic portions were concentrated to 100 mL, washed once with saturated NaHCO3 solution (20 mL), dried over Na2SO4, concentrated, and dried under high vacuum to give COMPOUND 45 (647 mg, 92%) as an off-white solid. 1H NMR (DMSO-d6) δ 1.46 (d, 2H, J=12.0 Hz), 1.69-1.84 (m, 1H), 2.01-2.11 (m, 1H), 2.48 (s, 6H), 3.59 (s, 2H), 4.13 (d, 2H, J=3.8 Hz), 4.40 (d, 2H, J=10.8 Hz), 4.79-4.85 (m, 1H), 5.74 (s, 1H), 6.84-6.91 (m, 3H), 7.06 (d, 1H, J=7.5 Hz), 7.18-7.28 (m, 3H), 8.14 (d, 2H, J=3.3 Hz), 8.75 (s br, 1H), 10.82 (s br, 1H); 13C NMR (D2O) δ 18.38(2), 24.40, 25.32(2), 55.27, 60.85(2), 64.75, 122.31(2), 123.64, 124.88, 126.82, 132.62, 137.64(2), 138.08, 143.18, 145.86(2), 158.58, 164.49; ES-MS m/z 447 (M+H). Anal. Calcd. For C26H30N4O3.1.1H2O: C, 66.96; H, 6.96; N, 12.01. Found: C, 66.95; H, 6.71; N, 11.66.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH2:24][C:25]#N)[CH2:4][CH3:5])[CH3:2].P(=O)(O)(O)[OH:28].[OH-].[Na+]>O>[CH2:1]([CH:3]([N:6]1[C:7]2[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:8]=2[CH2:24][C:25]1=[O:28])[CH2:4][CH3:5])[CH3:2]
Reactant: O=P(O)(O)O
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCC(CC)N1C(=O)Cc2c1cc(C)nc2Oc1c(C)cc(C)cc1C
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A mixture of [4-(1-ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-3-yl]-acetonitrile (800 mg, 2.27 mmol), 6 ml of 85% phosphoric acid and 2 ml of water was heated at reflux for 2 hours and cooled to room temperature. The reaction mixture was neutralized with 2N NaOH and extracted twice with chloroform. The chloroform layer was dried and concentrated to give a yellow solid. The solid was purified through silica gel column chromatography using hexane to 6% ethyl acetate in hexane as eluent to give 730 mg (92.2%) of a white solid. 1H NMR (CDCl3) δ 6.87(s,2H), 6.5(s,1H), 4.1(m,1H), 3.12(s,2H), 2.38(s,3H), 2.30(s,3H), 2.10(s,3H), 1.7–2.0(m,4H), 0.8(t,6H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:26])=[CH:4][C:5]([O:15][CH2:16][CH2:17][O:18][Si](C(C)(C)C)(C)C)=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]2)[CH:7]=1.Cl[C:28]1[N:33]=[C:32]([NH:34][C@@H:35]2[CH2:43][C@H:42]3[N:38]([CH2:39][CH2:40][CH2:41]3)[C:37]([CH3:45])([CH3:44])[CH2:36]2)[C:31]([C:46]#[N:47])=[CH:30][N:29]=1.[C:48]1([S:54]([OH:57])(=[O:56])=[O:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CC(O)C>[CH3:44][C:37]1([CH3:45])[CH2:36][C@H:35]([NH:34][C:32]2[C:31]([C:46]#[N:47])=[CH:30][N:29]=[C:28]([NH:1][C:2]3[CH:7]=[C:6]([N:8]4[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[N:9]4)[C:5]([O:15][CH2:16][CH2:17][OH:18])=[CH:4][C:3]=3[F:26])[N:33]=2)[CH2:43][C@H:42]2[N:38]1[CH2:39][CH2:40][CH2:41]2.[C:48]1([S:54]([OH:57])(=[O:56])=[O:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2C#N)C[C@@H]2CCCN21
Reactant: Cn1nnn(-c2cc(N)c(F)cc2OCCO[Si](C)(C)C(C)(C)C)c1=O
Agent: O=S(=O)(O)c1ccccc1
Solvent: CC(C)O
Product: Cn1nnn(-c2cc(Nc3ncc(C#N)c(N[C@@H]4C[C@@H]5CCCN5C(C)(C)C4)n3)c(F)cc2OCCO)c1=O
Temperature: 80 °C

Procedure:
A mixture of 1-(5-amino-2-(2-(tert-butyldimethylsilyl)oxyethoxy)-4-fluorophenyl)-4-methyl-1H-tetrazol-5(4H)-one (200 mg), (7R,8aS)—N-(2-chloro-5-cyanopyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine (120 mg), and benzenesulfonic acid (120 mg) in IPA (2 mL) was heated to 80° C. overnight. After cooling to ambient temperature, the crude mixture was concentrated to dryness. The crude product was absorbed onto silica gel and purified by CombiFlash chromatography (2N NH3 in MeOH/CH2Cl2=0-20%) to give desired product with benzenesulfonic acid. The methanol solution of the salt was passed through an ion-exchange resin column to remove acid to give the free base of compound 78 (120 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:36])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=2[NH:20][CH:21]([CH:23]2[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]2)[CH3:22])=[N:6][CH:7]=1.[B-][N+](C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:36])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=2[NH:20][CH:21]([CH:23]2[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]2)[CH3:22])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(C)C2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [B-][N+](C)(C)C
Product: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(C)C2CCNCC2)c1
Yield: 24.7 %

Procedure:
Using a similar procedure to that described in Example 47-D, N-(5-chloropyridin-2-yl)-2-[[1-(1-Boc-piperidin-4-yl)-ethyl]amino]-4-methoxycarbonylbenzamide (0.35 g, 0.68 mmol) and borane trimethylamine complex (0.15 g, 2.0 mmol) afforded 70 mg of the title compound. IS-MS, m/e 417 (m+1) Analysis for C21H25ClN4O3.2 HCl:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3([C:27](=[O:30])[NH:28][CH3:29])[CH2:26][CH2:25]3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:31][N:32](C)[C:33](=O)OC(C)(C)C)[CH:9]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3([C:27]([NH:28][CH3:29])=[O:30])[CH2:25][CH2:26]3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:31][NH:32][CH3:33])[CH:9]=1
Reactant: CNC(=O)C1(COc2ccc(S(=O)(=O)n3cc(CN(C)C(=O)OC(C)(C)C)cc3-c3ccccc3F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2ccc(OCC3(C(=O)NC)CC3)cc2)c1
Reaction time: 1 h

Procedure:
tert-Butyl ((5-(2-fluorophenyl)-1-((4-((1-(methylcarbamoyl)cyclopropyl)methoxy)phenyl)sulfonyl)-1H-pyrrol-3-yl)methyl)(methyl)carbamate 6a (100 mg, 0.18 mmol) was dissolved in 3 mL of dichloromethane, followed by addition of 1 mL of trifluoracetic acid and then the reaction solution was stirred for 1 h. 10 mL of saturated sodium bicarbonate solution were added, and the reaction solution was extracted with dichloromethane (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by thin layer chromatography with elution system A to obtain the title product 1-((4-((2-(2-fluorophenyl)-4-((methylamino)methyl)-1H-pyrrol-1-yl)sulfonyl)phenoxy)methyl)-N-methylcyclopropylcarboxamide 6 (30 mg, a yellow oil) in 37% yield.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][N:11]=[C:10]2[NH:15][C@@H:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:17][N:18]=[N+:19]=[N-:20])=[O:4].[OH-].[NH4+:28]>C(O)(C)C.C1COCC1.O>[N:18]([CH2:17][C@@H:16]([NH:15][C:10]1[C:9]2[C:14](=[C:5]([C:3]([NH2:28])=[O:4])[CH:6]=[CH:7][CH:8]=2)[N:13]=[CH:12][N:11]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[N+:19]=[N-:20]
Reactant: COC(=O)c1cccc2c(N[C@H](CN=[N+]=[N-])c3ccccc3)ncnc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: [N-]=[N+]=NC[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1ccccc1
Reaction time: 24 h

Procedure:
To a solution of 4-((S)-2-Azido-1-phenyl-ethylamino)-quinazoline-8-carboxylic acid methyl ester (0.5 g, 1.48 mmol) in isopropanol (0.5 mL) and THF (0.5 mL) was added ammonium hydroxide (28-30% solution, 7.5 mL). The reaction was stirred for 24 hours then diluted with water. Solid formed collected by filtration and dried under vacuum (0.28 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.72-3.81 (m, 1 H) 3.91 (dd, J=12.57, 9.98 Hz, 1 H) 5.73-5.85 (m, 1 H) 7.25-7.32 (m, 1 H) 7.36 (t, J=7.47 Hz, 2 H) 7.52 (d, J=7.27 Hz, 2 H) 7.71 (t, J=7.86 Hz, 1 H) 7.77-7.88 (m, 1 H) 8.60 (dd, J=7.47, 1.32 Hz, 1 H) 8.58 (s, 1 H) 8.66 (dd, J=8.32, 1.39 Hz, 1 H) 8.95 (d, J=8.30 Hz, 1 H) 10.26 (br. s., 1 H).
Reaction SMILES: [CH:1]1([N:7]([C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27][O:28][CH3:29])[CH2:23][CH2:22]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16]C(O)=O)=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:30]1(N[C@H]2CC[C@H](COCC)CC2)CCCCC1.C([O:49][C:50](=[O:60])[CH:51](SC1SC(N)=NC=1)C)C>>[CH:1]1([N:7]([C@H:21]2[CH2:22][CH2:23][C@H:24]([CH2:27][O:28][CH2:29][CH3:30])[CH2:25][CH2:26]2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][CH2:51][C:50]([OH:60])=[O:49])=[CH:13][N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCCCC2)CC1
Reactant: CCOC(=O)C(C)Sc1cnc(N)s1
Reactant: CCOC[C@H]1CC[C@H](NC2CCCCC2)CC1
Product: CCOC[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCCC2)CC1

Procedure:
Prepared in a similar manner to {2-[3-cyclohexyl-3-(trans-4-methoxymethyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid via cyclohexyl-(trans-4-ethoxymethyl-cyclohexyl)-amine and (2-amino-thiazol-5-ylsulfanyl)-propionic acid ethyl ester to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)[CH:3]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:8]([C:5]1[N:6]=[N:7][C:2]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]2[NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[CH:3][C:4]=1[NH:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1)(=[O:9])[NH2:10]
Reactant: Cc1cc(C)cc(Nc2cc(Cl)nnc2C(N)=O)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)cc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)c1
Temperature: 140 °C
Reaction time: 7 h
Yield: 41.5 %

Procedure:
To a solution of 6-chloro-4-(3,5-dimethylphenylamino)pyridazine-3-carboxamide (44 mg, 159 μmol) in NMP (530 μL) was added tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (68.2 mg, 318 μmol) and the mixture heated to 140° C. for 20 h. Additional tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (68.2 mg, 318 μmol) was then added and heating continued for a further 7 h. Finally, another portion of tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (34.1 mg, 159 μmol) was added and the mixture heated for 16 h. The reaction mixture was cooled, and then diluted with ethyl acetate. The phases were separated and the organic phase then washed with water and brine. The organic phase was collected, concentrated in vacuo, and the residue obtained was purified by chromatography (silica, 30 to 70% ethyl acetate in hexanes) to give tert-butyl (1S,2R)-2-(6-carbamoyl-5-(3,5-dimethylphenylamino)pyridazin-3-ylamino)cyclohexylcarbamate (30 mg, 66.0 μmol, 42%) as a brown oil. MS (EI/CI) m/z: 455.2 [M+H].
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][C:12](=[O:20])OC1C=CC=CC=1.[CH:21]1([S:27][C:28]2[C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=[C:30]([C:36]([F:39])([F:38])[F:37])[N:29]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>CS(C)=O.O>[CH:21]1([S:27][C:28]2[C:33]([CH2:34][NH:35][C:12]([NH:11][C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)=[O:20])=[CH:32][CH:31]=[C:30]([C:36]([F:38])([F:39])[F:37])[N:29]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(Nc1ccc2ccccc2n1)Oc1ccccc1
Reactant: NCc1ccc(C(F)(F)F)nc1SC1CCCCC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCc1ccc(C(F)(F)F)nc1SC1CCCCC1)Nc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.9 %

Procedure:
Phenyl quinolin-2-ylcarbamate (A) (60 mg, 0.23 mmol) and (2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yl)methanamine (69 mg, 0.24 mmol) was dissolved in dimethyl sulfoxide. Then triethylamine (0.06 mL, 0.45 mmol) was added. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give 1-((2-(cyclohexylthio)-6-(trifluoromethyl)pyridin-3-yl)methyl)-3-(quinolin-2-yl)urea (example compound II) (55 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:6]([N+:16]([O-])=O)=[CH:5][CH:4]=1.C1CCCCC=1>[Pd].C(O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[C:6]([NH2:16])=[CH:5][CH:4]=1
Reactant: COc1ccc([N+](=O)[O-])c(N2CCN(C)CC2)n1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: COc1ccc(N)c(N2CCN(C)CC2)n1

Procedure:
1.30 g (0.0052 mol) of the product 1-(6-methoxy-3-nitropyrid-2-yl)-4-methylpiperazine synthesized according to the above procedure, 25 ml of ethanol, 5 ml of cyclohexene and 0.6 g of palladium-on-charcoal were placed in a fully equipped round-bottomed flask.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].N1C=CC=CC=1.O[C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:34])[CH:28]=[C:29]([CH3:33])[O:30]2)=[CH:25][CH:24]=1>O>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:23]1[CH:32]=[C:31]2[C:26]([C:27](=[O:34])[CH:28]=[C:29]([CH3:33])[O:30]2)=[CH:25][CH:24]=1)(=[O:5])=[O:4]
Reactant: Cc1cc(=O)c2ccc(O)cc2o1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: O
Product: Cc1cc(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, 0.2 ml of trifluoromethansulfonic anhydride was added at 0° C. to 3 ml solution of pyridine with 10 mg of 7-hydroxy-2-methyl-4H-chromen-4-one, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, extracted with ethyl acetate. Ethyl acetate layer was washed with saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were separated and purified by silicagel chromatography (hexane/ethyl acetate=10/1) to obtain 112 mg of the above compound as a white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[C:16]1([C:22](=O)[CH:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:24][C:25](=O)[CH3:26])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C.C(Cl)Cl>[CH3:26][C:25]1[N:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=1
Reactant: CCOC(=O)CN
Reactant: CC(=O)CC(C(=O)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1c(C)cc(-c2ccccc2)c1-c1ccccc1
Temperature: 100 °C
Yield: 68.4 %

Procedure:
Ethyl 2-aminoacetate hydrochloride (0.548 g, 3.92 mmol) was diluted with Ethanol (10 ml) then charged with triethylamine (0.746 ml, 5.35 mmol) and 1,2-diphenylpentane-1,4-dione (0.900 g, 3.57 mmol), added as a solution in DCM. The reaction was heated at 100° C. overnight, after which TLC showed a new spot (less polar, Rf˜0.9 in 20% EtOAc/hexanes). The reaction was diluted with 10 mL DCM and washed with water (10 mL). The aqueous layer was back-extracted with DCM (10 mL×2). The organics were combined, dried, filtered, and concentrated to yield a crude orange oil. This oil was loaded on a SiO2 column and purified using a 0-20% gradient of EtOAc in hexanes, affording ethyl 2-(5-methyl-2,3-diphenyl-1H-pyrrol-1-yl)acetate (0.780 g, 2.442 mmol, 68.5% yield). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.37-7.33 (m, 3H), 7.27-7.24 (m, 2H), 7.16-7.11 (m, 4H), 7.07-7.04 (m, 1H), 6.24 (b, 1H), 4.42 (s, 2H), 4.21 (q, 2H), 2.27 (s, 3H), 1.25 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.O.[NH2:15][NH2:16].ClCCl>O1CCOCC1>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:15][NH2:16])=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Clc1cc(N2CCCC2)c(Cl)nn1
Reactant: NN
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: NNc1cc(N2CCCC2)c(Cl)nn1
Yield: 27.3 %

Procedure:
A solution of 3,6-dichloro-4-(pyrrolidin-1-yl)pyridazine (53 g, 0.24 mol) and hydrazine monohydrate (105 ml, 2.2 mol) in 1,4-dioxane (820 ml) was heated at reflux overnight. The solution was allowed to cool, and dichloromethane was added, precipitating a solid. This was filtered off, affording the title compound as a pale yellow solid (14 g, 27%). The filtrate was concentrated in vacuo, and the residue purified by flash chromatography on silica gel, eluting with 2-5% methanol in dichloromethane containing 0.1% concentrated aqueous ammonia, yielding a further 5 g (4%) of the title compound. 1H NMR (250 MHz, CDCl3) δ1.98 (4H, m), 3.26 (2H, br s), 3.57 (4H, m), 6.11 (1H, s), 6.41 (1H, br s). MS (ES+) m/e 214 [MH]+, 216 [MH]+.
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:20])=[C:10]([CH:19]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].[Cl-].[NH4+].Cl>O1CCCC1.CCOCC>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:20])=[C:10]([C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH:1]=[CH2:2])[OH:12])[CH:19]=1
Reactant: C=C[Mg]Cl
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CC(O)(c1ccccc1)c1cc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
225 ml of a filtered solution of 2.5 M/liter of vinyl magnesium chloride in tetrahydrofuran were added dropwise with stirring at -10° C. to a mixture of 58 g of 5-chloro-2-hydroxy-benzophenone and 900 ml of anhydrous ether and the mixture was stirred at room temperature for 16 hours and was refluxed for 3 hours. The mixture was iced and 600 ml of aqueous 10% ammonium chloride solution and 50 ml of concentrated hydrochloric acid were added thereto dropwise. The decanted organic phase was washed twice with 100 ml of water, was dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The oil residue was chromatographed over silica gel and was eluted with methylene chloride to obtain 34.4 g of 5-chloro-2-hydroxy-α-phenyl-α-ethenyl-benzene-methanol.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].ClC1[C:25](Cl)=[N:26][CH:27]=[C:28](C=1)[C:29]([OH:31])=O.N1CC[C@@H](O)C1.CCN(C(C)C)C(C)C>CC(O)C>[Cl:1][C:2]1[C:3]([N:26]2[CH2:27][CH2:28][C@@H:29]([OH:31])[CH2:25]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Cl)c1
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Agent: O[C@@H]1CCNC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Cl)c1

Procedure:
A mixture of 5,6-dichloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (prepared from 5,6-dichloronicotinic acid in an analogous fashion to that described in Stage 6.2, 1.5 g, 4.27 mmol) and (R)-pyrrolidin-3-ol (447 mg, 5.13 mmol), iPrOH (10 mL) and DIPEA (1.104 g, 8.54 mmol) were subjected to MW irradiation at 140° C. for 60 min. The RM was quenched with water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over MgSO4, filtered and the filtrate was evaporated off under reduced pressure to afford the title compound as a beige powder. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.85-1.97 (m, 2H) 3.59 (d, J=12 Hz, 1H) 3.7-3.8 (m, 1H) 3.8-3.95 (m, 2H) 4.35-4.40 (m, 1H) 5.00 (s, 1H) 7.35 (d, J=2 Hz, 2H) 7.86 (d, J=2 Hz, 2H) 8.17 (s, 1H) 8.66 (s, 1H) 10.22 (s, 1H).
Reaction SMILES: CO[C:3](=[O:20])[C:4]([C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[CH:11]=1)=[CH:5]OCC.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.[C:28]1(OC2C=CC=CC=2)C=CC=CC=1>>[F:18][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH3:17])[C:9]([C:4]1[C:3](=[O:20])[C:23]2[C:22](=[CH:27][CH:26]=[C:25]([CH3:28])[N:24]=2)[NH:21][CH:5]=1)=[O:19]
Reactant: Nc1cccnc1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCOC=C(C(=O)OC)C(=O)c1ccc(OC)c(F)c1
Product: COc1ccc(C(=O)c2c[nH]c3ccc(C)nc3c2=O)cc1F

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1 were used with 0.70 g (2.61 mmol) of 3-Ethoxy-2-(3-fluoro-4-methoxy-benzoyl)acrylic acid methyl ester, 0.25 g (2.61 mmol) of 3-aminopyridine, and 15 mL of diphenyl ether to yield 3-(3-Fluoro-4-methoxy-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one.