Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(OC(=O)[NH:21][C@@H:22]([CH3:25])[CH2:23]O)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.Cl>C(Cl)Cl.O.CCOC(C)=O>[NH2:21][C@@H:22]([CH3:25])[CH2:23][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:11]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(-c2cc[nH]n2)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 64.9 %

Procedure:
2-Chloro-4-(1H-pyrazol-3-yl)benzonitrile (30 g, 145 mmol), (S)-tert-butyl-1-hydroxypropan-2-ylcarbamate (51.4 g, 291 mmol), triphenylphosphine (77 g, 291 mmol) and 210 ml of EtOAc were place in to the reaction vessel under nitrogen atmosphere and stirred for 15 min. DIAD (57.8 ml, 291 mmol) was added slowly in 1.5 h at RT keeping the temperature stable and the reaction was stirred overnight at RT. Concentrated HCl (134 ml, 1453 mmol) was added and the mixture was stirred at RT overnight. Water (165 ml) and DCM (240 ml) were added, the mixture was stirred for 30 min and layers were separated. Organic phase was washed with 2×270 ml of acidic water (pH˜1). Water phases were combined and washed with 2×120 ml of dichloromethane. Dichloromethane (150 ml) was added, pH set to 11.5 by 50% NaOH and the mixture was stirred for 75 min. The solution was filtered through the celite, layers were separated and organic phase was washed with 171 ml of water. DCM was distilled out at 33° C. under reduced pressure and 60 ml of heptanes was added. Precipitation was started, 60 ml of heptane added and the mixture was stirred overnight. Some DCM was evaporated, 60 ml heptanes was added and the mixture was cooled to 10° C. The precipitate was filtered, washed with 20 ml of IPA:heptane (10:90) and dried under vacuum to obtain 24.55 g of the title compound. 1H-NMR (400 MHz, DMSO-d6): δ 1.03 (d, 3H), 3.34-3.43 (d, 2H), 4.14 (d, 2H), 6.99 (d, 1H), 7.89 (d, 1H), 7.96 (dd, 1H), 7.99 (dd, 1H), 8.12-8.14 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@H:30]([NH2:32])[CH3:31]>CC#N>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][C@@H:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=4)[CH3:31])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: C[C@@H](N)c1ccccn1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Solvent: CC#N
Product: COc1cc2c(N[C@H](C)c3ccccn3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 60 °C

Procedure:
A mixture of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitroquinoline (for a preparation see Intermediate 18, 0.4 g, 1.2 mmol) and (1R)-1-(2-pyridinyl)ethanamine (2 eq, 0.293 g) in CH3CN (20 ml) was heated at 60° C. for 2 h. The mixture was extracted with DCM. The organic phase washed with saturated aqueous Sodium hydrogen carbonate and dried over Na2SO4. The solvent was evaporated under reduced pressure and the residue taken up in diethyl ether. The precipitate was filtered off and dried in vacuo to give 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-3-nitro-N-[(1R)-1-(2-pyridinyl)ethyl]-4-quinolinamine (0.4 g) which was used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[O:6][N:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.S(Cl)([Cl:12])=O>C(Cl)(Cl)Cl.C1C=CC=CC=1>[Cl:1][C:2]1[O:6][N:5]=[C:4]([C:7]([Cl:12])=[O:9])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(Cl)on1
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1cc(Cl)on1

Procedure:
A solution of 5-chloroisoxazole-3-carboxylic acid (0.750 g, 4.32 mmol, 1 equiv) and thionyl chloride (9.0 mL, 120 mmol, 28 equiv) in CHCl3 (21 mL) was heated to reflux for 28 h. The volatiles were evaporated to provide a residue which was dissolved in benzene (40 mL), which was subsequently evaporated to give the title intermediate as a yellow oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([O:18][CH2:19][CH3:20])([CH3:17])[CH3:16])[C:5]([NH2:21])=[CH:4][CH:3]=1.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>>[Br:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([O:18][CH2:19][CH3:20])([CH3:17])[CH3:16])[C:5]([NH:21][C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:26][CH:27]=2)=[O:33])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(C)(C)c1ccccc1Oc1nc(Br)ccc1N
Product: CCOC(C)(C)c1ccccc1Oc1nc(Br)ccc1NC(=O)Nc1ccc(OC(F)(F)F)cc1

Procedure:
Example 582 was prepared from 6-bromo-2-(2-(2-ethoxypropan-2-yl)phenoxy)pyridin-3-amine and p-trifluoromethoxyphenyl isocyanate according to the procedure described for Example 2. (M−EtO)=508, 510. 1H NMR (400 MHz, DMSO-d6) δppm 0.82 (t, J=7.0 Hz, 3H), 1.53 (s, 6H), 3.21 (q, J=7.0 Hz, 2H), 7.21 (dd, J=8.1, 1.3 Hz, 1H), 7.30 (m, 6H), 7.56 (m, 4H), 8.49 (d, J=8.4 Hz, 1H), 8.73 (s, 1H), 9.61 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][NH:7][C:8]2[N:43]=[CH:42][CH:41]=[CH:40][C:9]=2[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[C:15]([O:26][CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][N:29]3C(OC(C)(C)C)=O)[CH:14]=2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]2[N:43]=[CH:42][CH:41]=[CH:40][C:9]=2[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:24])([F:25])[C:20]([F:21])([F:22])[F:23])=[C:15]([O:26][CH2:27][CH:28]3[CH2:32][CH2:31][CH2:30][NH:29]3)[CH:14]=2)=[O:11])=[CH:44][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1cc(NC(=O)c2cccnc2NCc2ccc(F)cc2)ccc1C(F)(F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)c(OCC2CCCN2)c1)c1cccnc1NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.17 h

Procedure:
2-(4-Fluoro-benzylamino)-N-[3-(1-Boc-pyrrolidin-2-ylmethoxy)-4-pentafluoroethyl-phenyl]-nicotinamide (Example 43) was dissolved in CH2Cl2 (8 mL) and TFA (8 mL) was added. After stirring at RT for 70 min, the mixture was concentrated in vacuo, diluted with 2N NaOH and CH2Cl2. The layers were separated and the aqueous layer was back extracted with CH2Cl2. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide an light pink-orange solid. M+H 539.5. Calc'd for C26H24F6N4O2: 538.2.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][CH:11]1[C:12]([O:54][CH:55]([O:57][CH2:58][CH3:59])[CH3:56])([CH3:53])[CH2:13][CH2:14][CH:15]([O:47][CH:48]([O:50][CH2:51][CH3:52])[CH3:49])[CH2:16][C:17]([O:19][CH:20](/[C:25](/[CH3:46])=[CH:26]/[CH:27]=[CH:28]/[CH:29]([CH3:45])[CH2:30][CH:31]2[O:44][CH:32]2[CH:33]([CH3:43])[CH:34]([O:37][CH:38]([O:40][CH2:41][CH3:42])[CH3:39])[CH2:35][CH3:36])[CH:21]([CH3:24])[CH:22]=[CH:23]1)=[O:18])(=O)C.C(O)(=O)C.C(OCC)(=O)C>CO.O>[CH2:51]([O:50][CH:48]([O:47][CH:15]1[CH2:14][CH2:13][C:12]([O:54][CH:55]([O:57][CH2:58][CH3:59])[CH3:56])([CH3:53])[CH:11]([OH:10])[CH:23]=[CH:22][CH:21]([CH3:24])[CH:20](/[C:25](/[CH3:46])=[CH:26]/[CH:27]=[CH:28]/[CH:29]([CH3:45])[CH2:30][CH:31]2[O:44][CH:32]2[CH:33]([CH3:43])[CH:34]([O:37][CH:38]([O:40][CH2:41][CH3:42])[CH3:39])[CH2:35][CH3:36])[O:19][C:17](=[O:18])[CH2:16]1)[CH3:49])[CH3:52]
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(C)=O)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(C)=O)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCOC(C)OC1CCC(C)(OC(C)OCC)C(O)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Reaction time: 2 h

Procedure:
Potassium carbonate (138 mg, 0,996 mmol) was added to a solution of (8E,12E,14E)-7-acetoxy-3,6,21-tri(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (250 mg, 0.332 mmol) in methanol (5 mL) at room temperature, followed by stirring at the same temperature for 2 hours. Acetic acid (60 mg, 1 mmol), ethyl acetate and water were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, spherical, neutral, 40 to 50 μm, ethyl acetate-hexane=1:2 and 1:1, successively) to obtain the title compound (242 mg, 100%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1.CN(P(N(C)C)(N(C)C)=O)C.C1OC1C>CCN(CC)CC>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([N+:14]([O-:16])=[O:15])=[C:8]2[C:3]=1[C:4]([CH3:17])=[CH:5][CH:6]=[N:7]2
Reactant: BrCCCCCc1ccco1
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Agent: CC1CO1
Solvent: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCc1ccco1

Procedure:
To a mechanically stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (WRAIR, 4.00 g, 0.017 mol), 1-bromo-5-(2-furyl) pentane (3.65 g, 0.017 mol) and HMPA (25 ml), at 105°-110° C., was added dropwise, during 60 min, a solution of Et3N(3.5 ml) and propylene oxide (6.5 ml). The mixture was heated at 105°-110° C. for 2 hr, allowed to cool and extracted with a solution of pet. ether (20°-40° C.) and Et2O (1:1 v/v, 200 ml), leaving behind a black residue. The organic layer was washed with 10% NaOH solution (3×50 ml). The combined basic wash solutions were re-extracted with a pet. ether (20°-40° C.)-Et2O solution (1:1 v/v, 2×75 ml) and the combined organic layers were washed with H2O (2×50 ml), dried (Na2SO4), treated with Darco, filtered and concentrated to give 5-[5-(2-furyl) pentoxy]-6-methoxy-4-methyl-8-nitroquinoline as a yellow solid, 2.5 g (40%) mp. 47°-49° C. This material was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[Cl:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20]>C(OCC)C>[Cl:15][CH2:16][CH2:17][NH:18][C:19](=[O:20])[NH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)Cc1ccccc1-2
Reactant: O=C=NCCCl
Solvent: CCOCC
Product: O=C(NCCCl)Nc1ccc2c(c1)Cc1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 40 %

Procedure:
To a solution of 2 g of 2-aminofluorene in 125 mL of anhydrous ethyl ether is added dropwise 1.25 g of 2-chloroethyl isocyanate. This solution is stirred for 16 h at room temperature, cooled at -20° C., and filtered. A white solid separated and was recrystallized from ethanol (white flakes), yield 40%, mp 206°-208° C., IR (KBr pellet): 3300 (NH), 1730 (C=O, ester), and 1640 cm-1 (C=O, ureido); 1H NMR (DMSO-d6 : CDCl3): 8.08 ppm, 7.44 ppm, 7.35 ppm, 7.3 ppm, 7.27 ppm, 7.25 ppm, 7.16 ppm, 7.13 ppm, 7.02 ppm, 6.97 ppm, 6.96 ppm, 6.94 ppm, 6.93 ppm, 6.9 ppm, 6.87 ppm, 6.8 ppm, 3.5 ppm, 3.36 ppm, 3.33 ppm, 3.3 ppm, 3.25 ppm, 3.23 ppm, 3.2 ppm, 2.85 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12](C(OCC)=O)=[C:11]([CH3:20])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([CH3:20])[N:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C)ncn(-c2ccc(Cl)cc2)c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2ccc(Cl)cc2)cn1
Yield: 40 %

Procedure:
Treatment of 2.93 g (10 mmole) of ethyl 1-(4-chlorophenyl)-1,6-dihydro-4-methyl-6-oxopyrimidine-5-carboxylate prepared as in Example 1 with either 20 ml of concentrated hydrochloric acid or a mixture of 10 ml of concentrated hydrochloric acid and 10 ml of acetic acid at reflux for 5 hours gives, after methylene chloride extraction and ethanol recrystallization, a 40-45% yield of 1-(4-chlorophenyl)-1,6-dihydro-4-methyl-6-oxopyrimidine, m.p. 177°-9° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C>[C:16]1([S:22][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Sc1ccccc1
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1Sc1ccccc1
Temperature: 80 °C
Yield: 71.3 %

Procedure:
2-fluoro-benzaldehyde (2.00 g, 16.1 mmol), potassium carbonate (2.45 g, 17.7 mmol) and thiophenol (17.1 mmol) were dissolved in 10.0 mL DMF in a 50 mL round-bottomed flask under dry nitrogen, topped with a reflux condenser. The reaction mixture was heated to 80° C. for 24 hrs. After cooling, the mixture was added to 50 mL of saturated potassium carbonate solution and extracted with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using 9:1 petroleum ether 60-80 and dichloromethane as eluent to give a yellow oil (2.46 g, 71%). 1H NMR (200 MHz, CDCl3): δ 7.07 (dd, J1=7.8, J2=1.2, 1H), 7.27-7.45 (m, 7H), 7.87 (dd, J1=7.3, J2=2.0, 1H), 10.37 (s, 1H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][OH:9])=[NH:7])=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:22]=[C:21]([C:29](O)=O)[N:20]=2)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[N:22]=[C:21]([C:29]3[O:9][N:8]=[C:6]([C:5]4[CH:10]=[CH:11][C:2]([NH2:1])=[N:3][CH:4]=4)[N:7]=3)[N:20]=2)=[CH:17][CH:18]=1
Reactant: N=C(NO)c1ccc(N)nc1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)cc(C(F)(F)F)n1
Product: Nc1ccc(-c2noc(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)n2)cn1

Procedure:
The title compound was prepared from 6-amino-N-hydroxy-nicotinamidine (example C.3) (0.15 g, 1.0 mmol) and 4-(4-chloro-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.1) (0.15 g, 0.5 mmol) according to the general procedure V. Obtained as a light brown solid (0.05 g, 24%). MS (ISP) 419.0 [(M+H)+]; mp 211° C.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[N:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]2=[C:10]([C:17]2[N:22]=[C:21]([NH:23][C@@H:24]3[CH2:29][CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25]3)[CH:20]=[N:19][CH:18]=2)[CH:9]=1>C(Cl)Cl>[NH:26]1[CH2:27][CH2:28][CH2:29][C@@H:24]([NH:23][C:21]2[CH:20]=[N:19][CH:18]=[C:17]([C:10]3[CH:9]=[N:8][N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=34)[N:22]=2)[CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Nc2cncc(-c3cnn4ccccc34)n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccn2ncc(-c3cncc(N[C@@H]4CCCNC4)n3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.9 %

Procedure:
Trifluoroacetic acid (0.35 mL, 4.56 mmol) was added to a solution of (R)-tert-butyl 3-(6-(pyrazolo[1,5-a]pyridin-3-yl)pyrazin-2-ylamino)piperidine-1-carboxylate (Preparation 28a, 0.30 g, 0.76 mmol) in methylene chloride (10 mL) and the resulting solution was stirred at ambient temperature overnight and then at 50° C. for additional 24 h. The solvent was then evaporated and the residue was redissolved in methylene chloride and washed with a 10% aqueous sodium hydroxide solution. The organic phase was dried over magnesium sulphate, filtered and the solvent was evaporated. The crude product was purified by flash chromatography (10-15% MeOH/CH2Cl2/NH3) to yield the title compound (0.125 g, 56%) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[OH-].[Na+].[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].Cl>O1CCOCC1.O.O1CCOCC1>[CH3:19][O:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[O:24]
Reactant: NCCc1ccc(-c2ccc(O)cc2)cc1
Reactant: COc1ccccc1C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1C(=O)NCCc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 9 gm (42 millimols) of 4-[2-aminoethyl]-4'-hydroxy-biphenyl in a solution of 1.72 gm (43 millimols) of sodium hydroxide in 100 ml of a mixture of water/dioxane (1:1) was acylated at 0° C with a solution of 13 gm (76 millimols) of 2-methoxybenzoyl chloride in 50 ml of dioxane, while maintaining the pH at 10 by periodic addition of sodium hydroxide. After all of the acid chloride had been added, the mixture was stirred at room temperature for 2 hours, and then the pH of the resulting suspension was adjusted to between 4 and 5 by addition of 2 N hydrochloric acid. The suspension was now extracted with chloroform. After extraction with a dilute sodium bicarbonate solution, the chloroform phase was dried with sodium sulfate, evaporated, and the residue was recrystallized from ethyl acetate. Yield: 8.7 gm (59% of theory); m.p. 118° C.
Reaction SMILES: Cl.[C:2]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:17]1[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[N:18]=1.C(N(CC)CC)C.O>O1CCCC1>[C:2]([CH:10]1[CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH3:23])[C:21](=[O:24])[CH:20]=[C:19]([C:25]3[CH:26]=[CH:27][N:28]=[CH:29][CH:30]=3)[N:18]=2)[CH2:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1c(N2CCC(C(=O)c3ccccc3)CC2)nc(-c2ccncc2)cc1=O
Yield: 89 %

Procedure:
A solution of 4-benzoylpiperidine hydrochloride (903 mg, 4.00 mmol), 2-chloro-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (666 mg, 3.00 mmol) and triethylamine (2.0 ml, 15 mmol) in tetrahydrofuran (30 ml) was refluxed for several hours. After cooling, water was added to the reaction mixture. The precipitate was filtered, washed with water and dried to give the title compound (1.00 g, 81%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[NH2:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccnc1N
Reactant: Cc1ccccc1C=O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccccc1CNc1cccnc1N
Temperature: 25 °C
Reaction time: 96 h
Yield: 34.4 %

Procedure:
Molecular Sieves (16 g) was added to a solution of 2,3-diaminopyridine (8 g), 2-methylbenzaldehyde (8.81 g), and acetic acid (4.2 ml) in methanol (160 ml) and the mixture was stirred for 96 hours at room temperature. Sodium cyanoborohydride (4.61 g) was added portionwise to the mixture with stirring under ice-cooling over a period of 20 minutes. After being stirred for 3 hours, the mixture was made alkaline with aqueous sodium bicarbonate solution and filtered by suction. The filtrate was evaporated in vacuo, and to the residue was added water and then extracted with methylene chloride. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of ethyl acetate and n-hexane to give 2-amino-3-(2-methylbenzylamino)pyridine (5.38 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:29]([O:30][CH3:31])=[CH:28][C:8]2[N:9]([CH3:27])[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Li+]>>[CH3:31][O:30][C:29]1[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]2[N:11]=[C:10]([NH:12][C:13]3[S:14][C:15]4[CH:21]=[C:20]([O:22][C:23]([F:26])([F:25])[F:24])[CH:19]=[CH:18][C:16]=4[N:17]=3)[N:9]([CH3:27])[C:8]=2[CH:28]=1
Reactant: COC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1OC
Agent: [Li+]
Agent: [OH-]
Product: COc1cc2c(cc1C(=O)O)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 77.4 %

Procedure:
6-Methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (60 mg) was prepared by following General Procedure E starting from 6-methoxy-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester (80 mg) and lithium hydroxide (30 mg). LC/MS: m/z 439.8.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][NH2:10]>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:10][CH3:9])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CN
Solvent: CCO
Product: CNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4,6-dichloro-pyrimidine(3.53 g, 23.7 mmol) and methylamine (33 wt % in ethanol, 10 ml, 80 mmol) in ethanol is kept stirring overnight at room temperature. The reaction mixture is concentrated, triturated with water and filtered. The crude product is washed with water, a small amount of ethanol and ethyl ether sequentially, and air-dried to give (6-Chloro-pyrimidin-4-yl)-methyl-amine as white powder: 1H NMR 400 MHz (d6-DMSO) δ 8.36-8.16 (m, 1H), 7.69 (s, 1H), 6.50 (s, 1H), 2.90-2.68 (m, 3H); MS m/z 144.00 (M+1).
Reaction SMILES: CO.[Cl:3][C:4]1[CH:5]=[C:6]([C:27]2[C:28]([CH3:42])=[CH:29][C:30]([O:33][CH2:34][C:35]([CH3:41])([CH3:40])[C:36]([O:38]C)=[O:37])=[N:31][CH:32]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1.[OH-].[Na+].Cl>C(OCC)(=O)C.O1CCCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:27]2[C:28]([CH3:42])=[CH:29][C:30]([O:33][CH2:34][C:35]([CH3:40])([CH3:41])[C:36]([OH:38])=[O:37])=[N:31][CH:32]=2)[CH:7]=[CH:8][C:9]=1[C:10]1[N:11]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[N:14]=1
Reactant: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)c(Cl)c2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCC(C)(C)C(=O)O)ncc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)c(Cl)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 104.3 %

Procedure:
Methanol (1.5 mL) and tetrahydrofuran (1.5 mL) were added to methyl 3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoate (274 mg), and after adding 2N aqueous sodium hydroxide solution (1.5 mL) to the mixture, the resulting mixture was stirred 50° C. for 2 hours. Ethyl acetate was added to the reaction mixture, and the resulting mixture was neutralized by 1N hydrochloric acid. The organic layer was separated, washed with a saturated brine, and concentrated under reduced pressure to obtain 3-[(5-{3-chloro-4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]phenyl}-4-methylpyridin-2-yl)oxy]-2,2-dimethylpropanoic acid (279 mg).
Reaction SMILES: C(OC([C@H]1[C@H](CC2C=CC=CC=2)CCCC(=O)N1)=O)C.[OH:21][NH:22][C:23]([C@H:25]1[C@@H:31]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[S:39]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)(=[O:41])=[O:40])=[O:24]>>[OH:21][NH:22][C:23]([C@H:25]1[C@H:31]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[S:39]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)(=[O:41])=[O:40])=[O:24]
Reactant: COc1ccc(S(=O)(=O)N2CCCC[C@H](Cc3ccccc3)[C@@H]2C(=O)NO)cc1
Agent: CCOC(=O)[C@@H]1NC(=O)CCC[C@H]1Cc1ccccc1
Product: COc1ccc(S(=O)(=O)N2CCCC[C@@H](Cc3ccccc3)[C@@H]2C(=O)NO)cc1

Procedure:
trans-3-Benzyl-1-(4-methoxybenzenesulfonyl)-azepane-2-carboxylic acid-hydroxyamide was synthesized from trans-3-Benzyl-7-oxo-azepane-2-carboxylic acid ethyl ester using the procedures for the preparation of cis-3-Benzyl-1-(4-methoxybenzenesulfonyl)-azepane-2-carboxylic acid-hydroxyamide.