Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C.[NH:4]1[CH:8]=[CH:7][N:6]=[C:5]1[CH:9]=[O:10].[CH3:11][N:12]([CH3:17])[S:13](Cl)(=[O:15])=[O:14]>C(N(CC)CC)C>[CH:9]([C:5]1[N:4]([S:13]([N:12]([CH3:17])[CH3:11])(=[O:15])=[O:14])[CH:8]=[CH:7][N:6]=1)=[O:10]
Reactant: O=Cc1ncc[nH]1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1ccnc1C=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 65.3 %

Procedure:
To an acetonitrile (500 mL) solution of 1H-imidazole-2-carboaldehyde (64 g) and triethylamine (140 mL), dimethylsulfamoyl chloride (100 g) was added at room temperature. The reaction solution was stirred at 50° C. for 16 hours. After the reaction solution was cooled to room temperature, the precipitated crystal was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was washed with ethyl acetate to obtain the crude title compound. The washing was washed with saturated brine and then dried over anhydrous sodium sulfate. After removing the anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by silica gel chromatography (ethyl acetate) to obtain the crude title compound. The obtained compound was combined with the crystal obtained previously and then washed with ether to obtain the title compound (88.32 g) having the following physical properties.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:20]([NH:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[F:12])=[O:21])[CH:10]=1
Reactant: O=C=Nc1ccccc1F
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1F)Nc1cc(Cl)ccc1C(=O)O

Procedure:
2-Amino-4-chlorobenzoic acid (0.3 g), 2-fluorophenylisocyanate (0.2 ml) and triethylamine (0.24 ml) were stirred in toluene (20 ml) for a week. More 2-fluorophenylisocyanate (0.1 ml) was added and stirring continued for another week. The mixture was concentrated to almost dry, water was added and the pH was adjusted to 1 with diluted HCl. Water was decanted and the residue was dissolved in warm 96% EtOH. The pH was adjusted to 1 again with 4N HCl resulting in the precipitation of a solid, which was filtered and dried to give 4-chloro-2-[3-(2-fluoro-phenyl)-ureido]-benzoic acid (0.25 mg). Mp.=195-197° C. 4-Chloro-2-[3-(3-trifluromethyl-phenyl)-ureido]-benzenesulfonamide (Compound 10):
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](F)=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1.[CH3:22][S-:23].[Na+].C[S-].O>CS(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([S:23][CH3:22])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1
Reactant: C[S-]
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N)n1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc(-c2cc(C(C)C)nc(N)n2)c2ccccc12
Reaction time: 2 h
Yield: 98 %

Procedure:
2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropyl-pyrimidine (0.281 g) was dissolved in dimethyl sulphoxide (DMSO) (10 mL) and sodium thiomethoxide (0.070 g) was added. The reaction mixture was stirred at room temperature for 2 hours at which time another equivalent of thiomethoxide was added and the reaction stirred for another 2 hours. The mixture was poured into water (100 mL) and the product was extracted into ethyl acetate/hexane (3×50 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The reaction product was purified by column chromatography on silica gel, eluting with hexane/ethyl acetate to give 2-amino-4-(4-methylthionaphth-1-yl)-6-isopropylpyrimidine (0.303 g), m.p. 139-140° C.
Reaction SMILES: [N:1]1[N:9]2[C:4]([N:5]=[C:6]3[CH2:21][CH2:20][CH2:19]CC[C:7]3=[C:8]2[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:3][CH:2]=1.C(OC1C=CC(C2N3C(=CC=N3)N=C3C=2CCC3)=CC=1)C1C=CC=CC=1.[H][H]>[Pd]>[N:1]1[N:9]2[C:4]([N:5]=[C:6]3[C:7](=[C:8]2[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:19][CH2:20][CH2:21]3)=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: Oc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Agent: [Pd]
Agent: c1ccc(COc2ccc(-c3c4c(nc5ccnn35)CCC4)cc2)cc1
Product: Oc1ccc(-c2c3c(nc4ccnn24)CCC3)cc1

Procedure:
Using the method described for the preparation of 4-(6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-yl)-phenol, the reaction of 8-(4-benzyloxy-phenyl)-6,7-dihydro-5H-1,4,8a-triaza-s-indacene and hydrogen in the presence of 10% Pd/C provided the title compound.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]2[N:23]=[CH:24][NH:25][C:21]=2[CH:20]=1>>[NH:23]1[C:22]2[CH:26]=[CH:27][C:19]([NH:18][C:12]([C:8]3[CH:7]=[C:6]([N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:15][CH2:16][CH3:17])[N:11]=[CH:10][N:9]=3)=[O:14])=[CH:20][C:21]=2[N:25]=[CH:24]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1ccc2nc[nH]c2c1
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc3[nH]cnc3c2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclopropylmethyl-propyl-amino)-pyrimidine-4-carboxylic acid (Intermediate 21) and 5-aminobenzimidazole (ABCR), the title compound was obtained as a white solid after purification by preparative HPLC.
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])([OH:10])=[O:9].[C:12]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19](O)[CH2:18][CH2:17]1)(=[O:14])[CH3:13].C(=O)([O-])O.[Na+]>C(#N)C>[C:12]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([O:9][N+:8]([O-:11])=[O:10])[CH2:18][CH2:17]1)(=[O:14])[CH3:13]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N[C@H]1CC[C@H](O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: CC(=O)N[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
28.3 ml (0.3 mol) acetic acid anhydride are mixed with 375 ml acetonitrile, cooled in an ice-bath to 0°-5° C. and 12.6 ml (0.3 mol) 100% nitric acid added dropwise. After 30 minutes, 15.7 g (0.1 mol) solid trans-N-acetyl-4-hydroxycyclohexylamine are added thereto with stirring and cooling at 0°-5° C. The reaction mixture is further stirred for 3 h at 0°-5° C. and subsequently allowed to flow carefully into a solution of 150 g (18 mol) sodium hydrogen carbonate in 500 ml ice water. After extraction with ethyl acetate, drying of the organic phase with sodium sulphate and distilling off in a vacuum, there remain 17.8 g of crude product. After recrystallisation from ethyl acetate, there are obtained 10.3 g of the title compound of the m.p. 146°-148° C., i.e. 50% of theory.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:28]=[CH:27][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([C@:20]2([CH3:26])[CH2:24][O:23]C(=O)[NH:21]2)[CH:14]=[CH:13]3)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(O)C.[OH-].[Li+].O>>[NH2:21][C@@:20]([C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([O:9][C:8]3[CH:27]=[CH:28][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[CH:11]=2)[CH:16]=1)([CH3:26])[CH2:24][OH:23]
Reactant: CC(C)Oc1ccc(Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc(Oc2ccc3cc([C@@](C)(N)CO)ccc3c2)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
(R)-4-[6-(4-Isopropoxy-phenoxy)-naphthalen-2-yl]-4-methyl-oxazolidin-2-one (1.092 g, 0.002894 mol) was dissolved in ethanol (60 mL, 1 mol), followed by 4 M lithium hydroxide in water (30 mL, 0.1 mol). The reaction mixture was then heated at 80° C. for 5 hours. LCMS indicates no SM remains with mostly DP RT=1.26 min, M+1=352. All solvent was removed under reduced pressure. The solid was triturated with DCM, and the solvent was then washed with water. Organic was dried over MgSO4, filtered and concentrated to dryness. Residue was then placed on the high vac for 5 hours. 1H NMR and LCMS were consistent with structure. ESI-MS: 360 (M-16)+ 1H NMR (400 MHz, CHLOROFORM-d) δ=7.88-7.67 (m, 3 H), 7.50-7.21 (m, 5 H), 7.00 (m, 2 H), 6.45-6.13 (m, 1 H), 4.82-4.67 (m, 1 H), 4.43 (s, 2 H), 2.17 (s, 3 H), 1.46-1.28 (d, J=9.0 Hz, 6 H)
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[CH2:24][CH:23]([CH2:25][CH:26]3[CH2:31][CH2:30][N:29]([CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH2:28][CH2:27]3)[C:21](=[O:22])[C:16]2=[CH:17][C:18]=1[O:19][CH3:20]>C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[CH2:24][CH:23]([CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:30][CH2:31]3)[C:21](=[O:22])[C:16]2=[CH:17][C:18]=1[O:19][CH3:20].[C:1]([O-:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(O)c1ccccc1O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: O=C([O-])c1ccccc1O
Temperature: 25 °C

Procedure:
Salicylic acid (1.38 g, dissolved in 35 ml of acetone) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 175.8° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])[C:5]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:6]([CH2:8][C:9]#[N:10])[CH:7]=1.[H-].[Na+].[C:23](N1C=CN=C1)(=[O:25])[CH3:24]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([O:16][CH2:17][CH2:18][O:19][CH3:20])[C:5]([O:11][CH2:12][CH2:13][O:14][CH3:15])=[C:6]([CH:8]([C:23](=[O:25])[CH3:24])[C:9]#[N:10])[CH:7]=1
Reactant: CC(=O)n1ccnc1
Reactant: COCCOc1cc(F)cc(CC#N)c1OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1cc(F)cc(C(C#N)C(C)=O)c1OCCOC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 90.9 %

Procedure:
A solution of (5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile (250 mg, 0.88 mmol) in tetrahydrofuran (2 mL) was added to a suspension of sodium hydride (40% oil dispersion, 70 mg, 1.8 mmol) in tetrahydrofuran (5 mL), followed by the addition of 1-acetylimidazole (145 mg, 1.3 mmol). After five minutes at room temperature, stirring was continued at 60° C. for 20 minutes. After cooling to room temperature, the reaction mixture was quenched with hydrochloric acid (1M, 20 mL) and extracted with ethyl acetate (3×20 mL). The combined extract was washed with water and brine (20 mL each), dried over sodium sulfate, filtered and concentrated to give the crude 2-(5-fluoro-2,3-bis{[2-(methyloxy)ethyl]oxy}phenyl)-3-oxobutanenitrile (0.26 g, 0.80 mmol, 91% yield). 1H NMR (400 MHz, CDCl3): 6.73-6.69 (m, 2H), 4.29-4.21 (m, 2H), 4.15-4.13 (m, 2H), 3.79-3.76 (m 2H), 3.62-3.57 (m, 2H), 3.44 (s, 3H), 3.41 (s, 3H), 2.26 (s, 3H); MS (EI) for C16H20FNO5: 326 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22](O)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].CN(C(ON1N=[N:58][C:53]2[CH:54]=[CH:55][CH:56]=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C1(CN)CC1>CN(C=O)C>[CH:54]1([CH2:53][NH:58][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:27]([CH3:28])=[C:19]([C:18]3[C:13]4[CH:12]=[CH:11][C:10](=[O:42])[N:9]([C:3]5[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=5[F:8])[C:14]=4[N:15]=[C:16]([N:29]4[CH2:34][CH2:33][CH:32]([N:35]5[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]5)[CH2:31][CH2:30]4)[N:17]=3)[CH:20]=2)[CH2:56][CH2:55]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 18 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and 1-cyclopropylmethanamine (7.15 uL, 0.0825 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (6.2 mg, 18%). LC-MS m/z 627 (M+H)+.
Reaction SMILES: [Na].[NH2:2][C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[C:4]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.[C:21](OCC)(=[O:28])[CH2:22][C:23](OCC)=[O:24].Cl>C(O)C.O>[OH:24][C:23]1[CH:22]=[C:21]([OH:28])[N:7]2[N:6]=[C:5]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[C:4]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:3]2[N:2]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Nc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Oc1cc(O)n2nc(-c3ccc(F)cc3)c(-c3ccncc3)c2n1
Yield: 65.2 %

Procedure:
To a solution of sodium (51 mg) in dry ethanol (3 ml) was added 5-amino-3-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole (254 mg) and diethyl malonate (176 mg). The mixture was refluxed for 5 hours and cooled. To the reaction mixture were added 1N-hydrochloric acid (4 ml) and water (6 ml). The separated solid was collected, washed with water and dried to give 5,7-dihydroxy-2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine (210 mg).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:23]([SH:25])[CH3:24].[H-].[Na+].Cl>CN(C)C=O>[CH2:23]([S:25][C:2]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])[CH3:24]
Reactant: CCS
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1I
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCSc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1C(=O)O

Procedure:
2-Iodo-5-(2-chloro-4-trifluoromethylphenoxy) benzoic acid (0.1 mole) in dimethylformamide (500 ml) was cooled to 0°. Cuprous oxide (0.11 mole) was added, followed by ethyl mercaptan (0.1 mole). The mixture was stirred while sodium hydride (0.25 mole) was added in portions. After 15 minutes the temperature was raised to 80° for 6 hours. The mixture was cooled and poured into hydrochloric acid (2 molar). The mixture was twice extracted with ether. The ether extract was washed with water, dried (Na2SO4) and evaporated. The residue was recrystallised from ether to give 2-ethylthio-5-(2-chloro-4-trifluoromethylphenoxy)benzoic acid, with a melting point of 153°-155°.
Reaction SMILES: [C:1]1([C:7]([C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]1>>[C:1]1([C:7](=[N:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]2)[C:9]2[NH:17][C:12]3=[CH:13][N:14]=[CH:15][CH:16]=[C:11]3[CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(ON)C1
Reactant: O=C(c1ccccc1)c1cc2ccncc2[nH]1
Product: CC(C)(C)OC(=O)N1CCCC(ON=C(c2ccccc2)c2cc3ccncc3[nH]2)C1

Procedure:
tert-Butyl 3-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]piperidine-1-carboxylate was prepared from phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone (Example 35) and tert-butyl 3-(aminooxy)piperidine-1-carboxylate (Reference Example 11) following the procedure described for Example 104 (geometry of the oxime double bond undefined).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][C:12]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].O.[OH-].[Li+]>CS(C)=O>[CH3:20][C:18]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:19]=1
Reactant: Cc1ccc(C#N)c(N)c1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(C#N)c(Nc2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 1-fluoro-2-nitro-benzene (5.34 g, 37.83 mmol), 2-amino-4-methyl-benzonitrile (5.00 g, 37.83 mmol), lithium hydroxide monohydrate (3.17 g, 75.66 mmol) and DMSO (70.0 ml) and stir at 55° C. Afer 16 hours; cool to ambient temperature, pour the mixture onto ice chips and stir. After 1 hour, remove the resulting yellow precipitate by vacuum filtration. Dry the precipitate under vacuum, recrystallize in ethanol to give 5.15 g (54%) of fine, amber colored needles: mp 162-164° C.; mass spectrum (ion spray): m/z 254.0 (M+1).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:28]=[C:29]([O:33][CH3:34])[CH:30]=[CH:31][CH:32]=1>>[CH3:34][O:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: COc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Product: COc1cccc(C(=O)c2cn(-c3cccc(-c4ccccc4C#N)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12d and 3-bromoanisole.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[C:5]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)=[N:4][N:3]=1.[NH:25]1[CH2:37][CH2:36][CH:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:26]1.O>CN1CCCC1=O>[C:32]([O:31][C:29]([CH:28]1[CH2:36][CH2:37][N:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=3)[C:5]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=3)=[N:4][N:3]=2)[CH2:26][CH2:27]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: COc1ccc(CNc2nnc(Cl)c3ccc(C#N)cc23)cc1Cl
Reactant: CC(C)(C)OC(=O)C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(CNc2nnc(N3CCC(C(=O)OC(C)(C)C)CC3)c3ccc(C#N)cc23)cc1Cl
Temperature: 170 °C
Yield: 56.6 %

Procedure:
1-Chloro-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine (2 g) prepared in Example 1 and t-butyl isonipecotate (2 g) were dissolved in 20 ml of N-methyl-2-pyrrolidone. The obtained solution was heated at 170° C. for 5 hours and cooled, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The obtained residue was subjected to silica gel column chromatography and eluted with toluene/tetrahydrofuran (10:1) to give 1.6 g of 1-(4-tert-butoxycarbonyl-piperidino)-4-(3-chloro-4-methoxybenzyl)amino-6-cyanophthalazine.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:45]([O:49][C:50]([NH:52][C@H:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58](O)=[O:59])=[O:51])([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl.C(Cl)(Cl)Cl>[C:45]([O:49][C:50](=[O:51])[NH:52][C@@H:53]1[CH2:57][CH2:56][CH2:55][C@@H:54]1[C:58]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:19][CH2:20]1)=[O:59])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(=O)O
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H]1C(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.2 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (0.372 g, 1.1 mmol), HOBt (0.145 g, 1.1 mmol), EDCI (0.246 g, 1.32 mmol) and rac-cis-2-(tert-butoxycarbonylamino)-cyclopentanecarboxylic acid (0.275 g, 1.2 mmol) were dissolved in 5 ml of dry CH2Cl2. The mixture allowed to stir at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of CHCl3 and washed with 10 ml of H2O. The organic layer was dried over MgSO4 and concentrated to dryness. The crude product was purified through a column of silica gel with a gradient of 30% to 70% EtOAc in hexane to afford the rac-((1R,2S)-2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidine-1-carbonyl}-cyclopentyl)-carbamic acid tert-butyl ester (592 mg, 99%).
Reaction SMILES: FC1C=C(CN)C=NC=1.[N:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1.[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33](O)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:20][CH2:19]1>>[CH:18]1([CH2:21][N:22]2[CH2:26][CH2:25][N:24]([C:27]3[S:28][C:29]([C:33]([NH:17][CH2:16][C:13]4[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=4)=[O:34])=[C:30]([CH3:32])[N:31]=3)[C:23]2=[O:36])[CH2:19][CH2:20]1
Reactant: NCc1ccncc1
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1ccncc1
Yield: 43 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with pyridin-4-ylmethanamine to react with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 43% yield: mp>200° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.55-8.53 (m, 2H), 7.23 (d, J=6.0 Hz, 2H), 6.17-6.13 (m, 1H), 4.57 (d, J=6.0 Hz, 2H), 4.14-4.09 (m, 2H), 3.73-3.68 (m, 2H), 3.18 (d, J=7.1 Hz, 2H), 2.62 (s, 3H), 0.99-0.91 (m, 1H), 0.60-0.54 (m, 2H), 0.27-0.22 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.8, 157.5, 155.2, 153.9, 149.9, 147.5, 122.2, 116.4, 48.6, 42.6, 42.2, 42.1, 17.3, 8.9, 3.4; MS (ES+) m/z 372.2 (M+1).
Reaction SMILES: C[C:2]1[NH:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[H-].[Na+].CI>CN(C)C=O>[NH:3]1[C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=[CH:2]1
Reactant: Cc1nc2cnccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: c1cc2[nH]cnc2cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-methyl-1H-imidazo[4,5-c]pyridine in 50 ml of dimethylformamide was added 1.43 g of 50% sodium hydride in oil followed, after 20 minutes, by 1.86 ml of methyl iodide. After stirring at room temperature overnight, the solvent was concentrated in vacuo and the residue treated with chloroform and filtered. Removal of the chloroform gave a brown solid which was chromatographed on 150 g of silica gel using 5% methanol in chloroform as the eluent giving 774 mg of a less polar isomer and 356 mg of the desired 1H-imidazo[4,5-c]pyridine isomer.
Reaction SMILES: [CH2:1]1[C:3]([NH2:7])([C:4]([OH:6])=[O:5])[CH2:2]1.[C:8]([O:16][CH2:17][CH2:18][O:19][C:20](ON1C(=O)CCC1=O)=[O:21])(=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[C:8]([O:16][CH2:17][CH2:18][O:19][C:20]([NH:7][C:3]1([C:4]([OH:6])=[O:5])[CH2:2][CH2:1]1)=[O:21])(=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: NC1(C(=O)O)CC1
Reactant: CCCCCCC(=O)OCCOC(=O)ON1C(=O)CCC1=O
Product: CCCCCCC(=O)OCCOC(=O)NC1(C(=O)O)CC1
Yield: 12.2 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, ACPC (0.530 g, 5.2 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl heptanoate (1 g, 4.03 mmol) were reacted to provide 0.148 g (15.4% yield) of the title compound (13) as a white powder after work-up and mass-guided preparative HPLC purification. M.p.: 112.6-113.2° C. 1H NMR (CDCl3, 400 MHz): δ=6.79 (q, 1H), 5.81 (s, 0.2H), 5.4 (s, 0.8H), 2.3 (m, 2H), 1.64 (m, 4H), 1.51 (d, 3H), 1.32 (m, 8H), 0.98 (t, 3H). MS (ESI) m/z 324.05 (M+Na)+; 300.04 (M−H)−.