Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.C(OC(NCCCCCCCCCCCC(O)=O)=O)C=C.[CH:47]1([N:53]=[C:54]=[N:55][CH:56]2[CH2:61][CH2:60][CH2:59]CC2)CCCCC1>CN1CCCC1=O>[CH3:1][N:53]([C:54]1[CH:59]=[CH:60][CH:61]=[CH:56][N:55]=1)[CH3:47]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C=CCOC(=O)NCCCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: CN1CCCC1=O
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 547 mg of radicicol, 3.75 g of 12-allyloxycarbonylaminododecanoic acid, 15 ml of dry 1-methyl-2-pyrrolidinone, 1.6 g of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 418 mg of the title compound were obtained.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][CH:2]=1.CO.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH:13]=[CH:12]1>O1CCCC1>[CH3:14][OH:15].[NH2:7][C:4]1[CH:5]=[CH:6][C:1]([NH:8][C:11](=[O:17])/[CH:12]=[CH:13]\[C:14]([OH:16])=[O:15])=[CH:2][CH:3]=1
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1ccc(N)cc1
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(NC(=O)/C=C\C(=O)O)cc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 172.1 %

Procedure:
Under a nitrogen atmosphere, into a reaction vessel were charged 10.00 g (92.5 mmol) of 1,4-phenylenediamine and 80 ml of methanol. A solution prepared by dissolving 6.05 g (61.6 mmol) of maleic anhydride in 20 ml of tetrahydrofuran was dropped into this under cooling with ice over a period of 1 hour, then, the mixture was stirred at 0 to 10° C. for 3 hours. After completion of the reaction, the temperature thereof was raised to room temperature, the deposited solid was isolated by filtration, and washed with 50 ml of methanol. The resultant solid was dried under reduced pressure at 40° C., to obtain 12.63 g of (2Z)-4-[(4-aminophenyl)amino]-4-oxo-2-butenoic acid methanol solvate as a pale yellow powder. Yield: 86.0%. H1-NMR (270 MHz, DMSO-d6) δp p m: 10.6 (1H, s), 7.3 (2H, d, J=8.9 Hz), 6.5 (2H, d, J=8.9 Hz), 6.5 (1H, d, J=12.5 Hz), 6.3 (1H, d, J=12.2 Hz), 3.2 (3H, s).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]([C:28]1[NH:32][C:31]([C:33]([OH:35])=O)=[C:30]([Cl:36])[CH:29]=1)=[O:27].[NH2:37][CH2:38][C:39]1[C:40]([F:56])=[C:41]([O:46][C:47]2[CH:48]=[C:49]([CH:52]=[C:53]([Cl:55])[CH:54]=2)[C:50]#[N:51])[C:42]([Cl:45])=[CH:43][CH:44]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:36][C:30]1[CH:29]=[C:28]([C:26]([NH2:25])=[O:27])[NH:32][C:31]=1[C:33]([NH:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([O:46][C:47]2[CH:48]=[C:49]([C:50]#[N:51])[CH:52]=[C:53]([Cl:55])[CH:54]=2)[C:40]=1[F:56])=[O:35]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: NC(=O)c1cc(Cl)c(C(=O)O)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(C(N)=O)cc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
HATU (0.061 g, 0.161 mmol) was added to a solution of 5-(aminocarbonyl)-3-chloro-1H-pyrrole-2-carboxylic acid (0.030 g, 0.161 mmol), 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.161 mmol), and DIPEA (0.028 mL, 0.161 mmol) in DMF (2 mL). This solution was stirred overnight at RT. The reaction mixture was partitioned between water and EtOAc. The organic layer was washed with a 15% solution of Na2CO3, dried over MgSO4, filtered and evaporated. Purification was accomplished by silica gel column chromatography (EtOAc/hexanes) to afford the title compound (0.023 g, 28%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.08 (br. s., 1H), 8.48-8.74 (m, 1H), 7.72-7.98 (m, 2H), 7.27-7.62 (m, 5H), 6.83 (d, 1H), 4.48 (d, 2H). LCMS: m/z 481.0 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:8][C:7]=2B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.Br[C:27]1[C:28]2[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[S:35][C:29]=2[C:30](=[O:34])[N:31]([CH3:33])[CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])=[CH:8][C:7]=2[C:27]2[C:28]3[CH:37]=[C:36]([C:38]([NH2:40])=[O:39])[S:35][C:29]=3[C:30](=[O:34])[N:31]([CH3:33])[CH:32]=2)[CH2:2][CH2:3]1
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cn1cc(Br)c2cc(C(N)=O)sc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cn(C)c(=O)c3sc(C(N)=O)cc23)c1
Temperature: 65 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
A mixture of 2-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (77 mg, 0.22 mmol), 4-bromo-6-methyl-7-oxothieno[2,3-c]pyridine-2-carboxamide (50 mg, 0.18 mmol), K3PO4 (93 mg, 0.44 mmol), Pd(dppf)Cl2 (13 mg, 10%) in dioxane/H2O (1.6 mL/160 uL) was bubbled with nitrogen for 5 min. The sealed vial was stirred at 65° C. for 3 h. The reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc (15 mL). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford a tan residue. The resulting residue was purified by prep-HPLC to afford the title compound (20 mg, 26%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.20 (m, 2H) 0.36 (m, 2H) 0.98 (m, 1H) 1.14 (m, 3H) 3.21-3.31 (m, 2H) 3.61 (s, 3H) 3.98 (m, 2H) 7.38 (d, J=8.6 Hz, 1H) 7.65-7.75 (m, 3H) 7.78 (d, J=2.0 Hz, 1H) 7.91 (dd, J=8.6, 2.0 Hz, 1H) 8.24 (s, 1H). LCMS (M+H)+=447.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15]C(C)(C)[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=2)=[CH:31][CH:30]=1)=O)(C)(C)C.CO.Cl>C1COCC1>[NH2:8][C@@H:9]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:10][C@H:11]([OH:15])[C@@H:12]([NH:13][C:18](=[O:19])[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][N:36]=2)=[CH:33][CH:34]=1
Reactant: Cc1ccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)nc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2ccc(C[C@H](NC(=O)OCc3ccccc3)[C@@H](O)C[C@@H](N)Cc3ccccc3)cc2)nc1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A solution containing the product from Example 74B (0.044 g, 0.068 mmol) in a mixture of THF (0.3 mL), methanol (0.2 mL), and aqueous HCl (0.4 mL, 1 N) was stirred at 50° C. for 16 hours. The solvent was removed under reduced pressure to give the title compound as the hydrochloride salt, which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:9]([NH:11][N:12]([CH2:28][C@@H:29]([OH:33])[C:30]([OH:32])=[O:31])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=3[F:27])=[CH:16][CH:15]=2)=[O:10])[NH:7][N:8]=1)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(Cl)Cl.[F:51][C:52]([F:56])([CH3:55])[CH2:53]O>>[F:51][C:52]([F:56])([CH3:55])[CH2:53][O:31][C:30](=[O:32])[C@H:29]([OH:33])[CH2:28][N:12]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[F:27])=[CH:16][CH:15]=1)[NH:11][C:9]([C:6]1[NH:7][N:8]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=1)=[O:10]
Reactant: CC(F)(F)CO
Reactant: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)[nH]n1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)c1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)OCC(C)(F)F)[nH]n1
Reaction time: 0.17 h
Yield: 78 %

Procedure:
(R)-3-[N′-(5-Acetyl-2H-pyrazole-3-carbonyl)-N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)hydrazino]-2-hydroxypropionic acid (15.0 mg, 32 μmol), HOBt (12.8 mg, 95 μmol) and EDC (16.8 μL, 95 μmol) were combined in DCM (121 μL, 1.9 mmol) and stirred for 10 minutes. 2,2-Difluoropropanol (24.3 mg, 253 μmol) was added and the resulting mixture was stirred at room temperature until the reaction was complete (≈48 hours). The mixture was evaporated under reduced pressure and the product was purified (reverse phase column) to yield the title compound (13.8 mg, purity 96%) as a TFA salt. MS m/z [M+H]+ calc'd for C25H24ClF3N4O5, 553.14. found 553.1.
Reaction SMILES: [F:1][C:2]([F:35])([CH2:23]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[CH:6]=[C:5]1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[N-:36]=[N+:37]=[N-:38].[Na+].O>CN(C=O)C>[N:36]([CH2:23][C:2]([F:35])([F:1])[CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)[CH:6]=[C:5]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N+:37]=[N-:38]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(F)(F)COS(=O)(=O)c3ccc(C)cc3)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC(F)(F)CN=[N+]=[N-])c2c1
Temperature: 95 °C
Yield: 119.5 %

Procedure:
To a solution of diethyl 1-(2,2-difluoro-3-{[(4-methylphenyl)sulfonyl]oxy}propyl)-1H-indole-2,6-dicarboxylate (4.7 g, 59% pure, 5.5 mmol) in DMF (40 mL) is added sodium azide (908 mg, 13.8 mmol). The mixture is heated at 95° C. for 40 h. Water (250 mL) is added and the mixture is extracted with EtOAc (3×250 mL). The organic layers are combined, washed with water (3×250 mL), dried (Na2SO4) and concentrated to afford the title crude compound (2.5 g) which is used in the next step without purification.
Reaction SMILES: [CH3:1][N:2]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1>CO>[CH3:1][N:2]([CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[CH:10][CH:11]=1)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: CN(CCOc1ccc([N+](=O)[O-])cc1)c1ccncc1
Solvent: CO
Product: CN(CCOc1ccc(N)cc1)c1ccncc1

Procedure:
A solution of the product of part (ii) (0.50 g) in methanol (30 ml) was hydrogenated at room temperature and 3.5 bar in the presence of 5% palladium on carbon (50 mg) until the required amount of hydrogen had been absorbed. The catalyst was filtered off and the filtrate was evaporated to give the product, (0.43 g), m.p. 141°-142° (from ethyl acetate/hexane).
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([NH2:8])=[N:5][C:4]=1[CH3:9])[CH3:2].[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1>>[Cl:10][C:11]1[C:12]([CH3:21])=[C:13]([S:17]([NH:8][C:6]2[S:7][C:3]([CH2:1][CH3:2])=[C:4]([CH3:9])[N:5]=2)(=[O:19])=[O:18])[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: CCc1sc(N)nc1C
Product: CCc1sc(NS(=O)(=O)c2cccc(Cl)c2C)nc1C
Yield: 25 %

Procedure:
The title compound was prepared from 5-ethyl-4-methyl-1,3-thiazol-2-ylamine (METHOD I) and 3-chloro-2-methylbenzenesulfonyl chloride according to METHOD A, yellow solid, 42 mg (25% yield): HRMS Calcd (found) for C13H15ClN2O2S2 m/z 330.0263 (330.0250).
Reaction SMILES: [N-:1]=[C:2]=[O:3].[C:4]1(C)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[C:4]1([N:1]=[C:2]=[O:3])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N-:1]=[C:2]=[O:3]
Reactant: Cc1ccccc1
Agent: [N-]=C=O
Product: O=C=Nc1ccccc1

Procedure:
A solution of 1.00 g phenylisocyanate in 50 ml dry toluene was prepared. Several dilutions of the stock isocyanate solution were made and an infrared absorbance versus concentration curve was obtained using the IR absorbance at 2265 cm-1 divided by the IR cell path length (in cm). The slope of this line gave a concentration factor of 0.118 mmole isocyanate/absorbance unit cm-1.
Reaction SMILES: [N:1]1[N:2]([CH2:10][CH2:11][C:12]#[C:13][C:14]2[N:19]=[C:18]([NH2:20])[CH:17]=[CH:16][CH:15]=2)[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:21](O)=[O:22]>>[N:1]1[N:2]([CH2:10][CH2:11][C:12]#[C:13][C:14]2[N:19]=[C:18]([NH:20][CH:21]=[O:22])[CH:17]=[CH:16][CH:15]=2)[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=CO
Reactant: Nc1cccc(C#CCCn2nc3ccccc3n2)n1
Product: O=CNc1cccc(C#CCCn2nc3ccccc3n2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32 %

Procedure:
A solution of anhydride acetic (0.75 mL) and formic acid (0.32 mL) was heated at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, 6-(4-benzotriazol-2-yl-but-1-ynyl)-pyridin-2-ylamine (70 mg, 0.27 mmol, 169(A)) was added over 15 min. and the reaction mixture was stirred at room temperature for 1 day. After evaporation of the solvent, the crude residue was triturated with diisopropyl ether, filtered and dried to yield 25 mg (86 μmol, 32%) of N-(6-(4-(2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-yl)formamide as a brown solid.
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3]O.[CH3:11][S:12](Cl)(=[O:14])=[O:13]>>[C:5]1([C@@H:2]2[CH2:3][CH2:11][S:12](=[O:14])(=[O:13])[NH:1]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: CS(=O)(=O)Cl
Product: O=S1(=O)CC[C@@H](c2ccccc2)N1

Procedure:
Using (R)-2-amino-2-phenylethanol (1.37 g) and methanesulfonyl chloride (1.6 mL) and by the reaction and treatment in the same manner as in Preparation Example 1, the title compound (391 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30](O)=[O:31].[CH3:33][NH:34][CH3:35].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:15][CH2:16][N:17]([C:20]3[N:21]=[CH:22][C:23]([CH2:26][O:27][CH3:28])=[CH:24][N:25]=3)[CH2:18][CH2:19]2)[CH:5]=[CH:4][C:3]=1[CH2:29][C:30]([N:34]([CH3:35])[CH3:33])=[O:31]
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(Cl)c3)CC2)nc1
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)N(C)C)c(Cl)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-chloro-4-{2-[(1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl]ethoxy}phenyl)acetic acid (50 mg, 109 mmol) was dissolved in DMF (1 ml) and dimethylamine (0.163 g, 0.326 mmol), DIEA (0.057 ml, 0.326 mmol), and HATU (62 mg, 0.163 mmol) added. The mixture was stirred at RT overnight. The solution was loaded directly onto a Biotage RP C18 cartridge (30 g) and purified using a gradient eluant of 10-100% water:acetonitrile+0.05% formic acid. The volatiles were removed in vacuo to afford the title compound. LC/MS (m/z): 487 (M+H)+. GPR119 Human EC50: 2.3 nM.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2C(=O)C3C(=CC=CC=3)C2=O)=[N:6][C:5]=1[Cl:21]>N.CO>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][C:5]=1[Cl:21]
Reactant: COC(=O)c1ccc(N2C(=O)c3ccccc3C2=O)nc1Cl
Agent: N
Solvent: CO
Product: COC(=O)c1ccc(N)nc1Cl
Yield: 88.8 %

Procedure:
A solution of 2-chloro-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-nicotinic acid methyl ester (1.0 g, 3.2 mmol) in NH3/MeOH (3M, 50 mL) was stirred at room temperature overnight. The solvent was removed under vacuum and the residue was dissolved in methylene chloride (50 mL), and was washed with saturated aqueous Na2CO3 and water. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (methylene chloride) to give amino-2-chloronicotinic acid methyl ester (0.53 g, 90%). 1H NMR (400 MHz, DMSO) δ 7.86 (d, J=8.8 Hz, 1H), 7.15 (brs, 2H), 6.38 (d, J=8.4 Hz, 1H), 3.72 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22](C(OCC)=[O:26])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[BrH:30]>O>[OH2:26].[BrH:30].[BrH:30].[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccncc3n2Cc2ccc(F)cc2)CC1
Agent: Br
Solvent: O
Product: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccncc32)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
A mixture of 23.8 parts of ethyl 4-[[3-[(4-fluorophenyl)methyl]-3H-imidazo[4,5-c]pyridin-2-yl]amino]-1-piperidine carboxylate and 275 parts of a hydrobromic acid solution 48% in water was stirred overnight at 80° C. The reaction mixture was evaporated and the residue was crystallized from ethanol, yielding 14.7 parts (48%) of 3-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-3H-imidazo[4,5-c]pyridin-2-amine dihydrobromide monohydrate; mp. 291.6° C. (39).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:23]C(=O)C)([CH2:21][OH:22])[CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:10]=2)[CH2:5]1.[Li+].[OH-]>CO>[NH2:23][C:3]([CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:10]=2)[CH2:5]1)([CH2:21][OH:22])[CH2:2][OH:1]
Reactant: CCCCCCCCc1ccc2c(c1)CC(C(CO)(CO)NC(C)=O)C2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCc1ccc2c(c1)CC(C(N)(CO)CO)C2
Yield: 37.4 %

Procedure:
To a solution of 6 (8 mg, 0.022 mmol) in MeOH (0.1 mL) was added LiOH (0.01 g, 0.154 mmol). The reaction was refluxed for 2 hours. The resulting solution was concentrated and purified with silica gel chromatography eluding with 75% MeOH and 25% CH2Cl2. The reaction provided 7 (2.6 mg, 0.00822 mmol, 37%).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>O>[C:29]([O:10][CH2:9][C:8]1[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:32])[CH:30]=[CH2:31]
Reactant: C=CC(=O)Cl
Reactant: OCc1ccccc1-c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CC(=O)OCc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
Into a 200 mL three-neck flask equipped with a stirrer, a thermometer, a cooling tube, and a calcium chloride tube, 20.0 g of ortho-phenylbenzyl alcohol, 100.0 g of anhydrous toluene, 13.2 g of triethylamine, and 7.8 mg of methoquinone were charged, and they were cooled to 10° C. or less using an ice bath. Into the flask, 11.8 g of acryloyl chloride was dropped over 30 minutes. The temperature was increased to room temperature and a reaction was caused to proceed for two hours. After the reaction, the reaction solution was poured into water and washed with a 5% NaOH aqueous solution and a saline solution, and the solvent was distilled off to obtain an orange liquid. The orange liquid was purified with a silica gel column to obtain 20.44 g of ortho-phenylbenzyl acrylate. The obtained ortho-phenylbenzyl acrylate was a colorless, transparent liquid at ordinary temperature and had a refractive index of 1.5776 and a viscosity of 27 mPa·s at 25° C. The measurement result of 1H-NMR is shown below.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[N:6][NH:5][C:4](=[O:17])[CH2:3]1.BrBr.Br>C(O)(=O)C>[CH3:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=2)=[N:6][NH:5][C:4](=[O:17])[CH:3]=1
Reactant: CC1CC(=O)NN=C1c1cccc([N+](=O)[O-])c1
Agent: Br
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1cc(=O)[nH]nc1-c1cccc([N+](=O)[O-])c1

Procedure:
A 24.9 g. portion of 4,5-dihydro-5-methyl-6-(m-nitrophenyl)-3(2H)-pyridazinone (prepared as described in Example 9 of U.S. Pat. No. 3,822,260) is dissolved in 200 ml. of warm stirred acetic acid. A 19.2 g. (6.2 ml.) portion of bromine, dissolved in 50 ml. of acetic acid is added dropwise over a 15 minute period. After an additional 20 minutes of warming to expel the HBr, the reaction mixture is poured into crushed ice. The resulting solid is recovered by filtration and washed with large amounts of water. The solid is dried yielding 5-methyl-6-(m-nitrophenyl)-3(2H)-pyridazinone as a cream colored solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1.[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH:17]=[O:18].[Cl-].[NH4+]>O1CCCC1.II>[CH3:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:16]=1[CH:17]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1)[OH:18]
Reactant: Brc1ccc(C2OCCO2)cc1
Reactant: Cc1cccc(C)c1C=O
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Product: Cc1cccc(C)c1C(O)c1ccc(C2OCCO2)cc1
Yield: 85.9 %

Procedure:
Iodine (10 mg) was added to a mixture of magnesium (1.20 g) and tetrahydrofuran (50 mL) with vigorous stirring and 2-(4-bromophenyl)-1,3-dioxolane (10.0 g) was added dropwise at room temperature. After the completion of the dropwise addition, the reaction mixture was stirred at room temperature for 1 hr and a solution of 2,6-dimethylbenzaldehyde (5.0 g) in tetrahydrofuran (20 mL) was added dropwise at 0° C. After the completion of the dropwise addition, the temperature of the reaction mixture was allowed to return to room temperature and the mixture was further stirred for 1 hr. The reaction mixture was poured into saturated aqueous ammonium chloride, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was concentrated and the residue was purified by silica gel column chromatography. The residue was developed with ethyl acetate-hexane (gradient of 1:9 to 7:3 by volume ratio) to give the title compound (9.10 g, yield 73%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>C(OCC)(=O)C>[C:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Oc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(Oc1ccc(Br)cc1)c1ccccc1
Yield: 86.7 %

Procedure:
To a solution of 360 g of 4-bromophenol in 4.3 liters of ethyl acetate, was added 326 ml of triethylamine. To the mixture, while being cooled in ice and stirred, was added dropwise 300 g of benzoyl chloride over a period of 90 minutes. After two hours of stirring, water was added to the reaction mixture to remove the triethylamine hydrochloride. The ethyl acetate layer was washed successively with a dilute aqueous alkali solution, dilute hydrochloric acid, and saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and freed from the solvent by distillation. The residue was washed with ethanol and dried to obtain 500 g of 4-bromophenyl benzoate.