Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1CCCCC1=O.[C:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([Cl:19])[C:14]1=[O:20])(C)(C)C>>[Cl:19][CH:15]1[CH2:16][CH2:17][CH2:18][CH:13]([CH3:9])[C:14]1=[O:20]
Reactant: CC(C)(C)C1CCCC(Cl)C1=O
Solvent: CC1CCCCC1=O
Product: CC1CCCC(Cl)C1=O

Procedure:
The chlorination of 2-methylcyclohexanone takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: C1(C([O:14][C:15](=[O:36])[C:16]([OH:35])=[CH:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[N:22]([C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:21]=2)=[O:19])C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH3:33][N:31]([CH3:32])[C:30]([N:22]1[C:23]2[C:28](=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:20]([C:18](=[O:19])[CH:17]=[C:16]([OH:35])[C:15]([OH:36])=[O:14])=[CH:21]1)=[O:34]
Reactant: CN(C)C(=O)n1cc(C(=O)C=C(O)C(=O)OC(c2ccccc2)c2ccccc2)c2cc(Cl)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)n1cc(C(=O)C=C(O)C(=O)O)c2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 356 mg (0.7 mmol) of the ester derivative obtained in above (1) in dichloromethane (3.6 ml) was added under ice-cooling, 0.5 ml of trifluoroacetic acid. The mixture was stirred for 30 minutes under ice-cooling. The reaction solution was concentrated under reduced pressure. The residues was dissolved in ethyl acetate. The ethyl acetate was washed successively with water and brine, and then dried. The obtained residue was crystallized from ether and recrystallized from 95% ethanol to give 0.16 g of the titled compound. Yield: 67%.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:5]=1[CH2:6]O)([CH3:3])[CH3:2].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:5]=1[CH2:6][Cl:17])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1CO
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C(C)C)c1CCl
Yield: 99.3 %

Procedure:
To a solution of 1.37 g (7.12 mmol) of 2, 6-diisopropylbenzyl alcohol in 20 ml of toluene was added 0.78 ml (10.7 mmol) of thionyl chloride, and the resultant mixture was stirred at room temperature for 3.5 hours. The reaction mixture was washed with water, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo to give 1.49 g of 2, 6-diisopropylbenzyl chloride as an oil.
Reaction SMILES: [OH:1][CH:2]([C@@H:14]([NH:28][C:29](=[O:43])[O:30][CH2:31][C:32]1([CH2:36][C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH2:35][CH2:34][CH2:33]1)[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6].OC([C@@H](NC(=O)OCC1(CC2C=CC=CC=2)CCCCC1)CCCCNC(N1CCOCC1)=O)C(=O)N[C@@H](C1C=CC=CC=1)C>>[N:22]1([C:20]([NH:19][CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]([NH:28][C:29](=[O:43])[O:30][CH2:31][C:32]2([CH2:36][C:37]3[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=3)[CH2:35][CH2:34][CH2:33]2)[C:2](=[O:1])[C:3](=[O:13])[NH:4][C@@H:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:6])=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OCC1(Cc2cccnc2)CCC1)c1ccccc1
Agent: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OCC1(Cc2ccccc2)CCCCC1)c1ccccc1
Product: C[C@@H](NC(=O)C(=O)[C@H](CCCCNC(=O)N1CCOCC1)NC(=O)OCC1(Cc2cccnc2)CCC1)c1ccccc1

Procedure:
[1-(3-Pyridinylmethyl)cyclobutyl]methyl(1S)-5-[(4-morpholinylcarbonyl)amino]-1-(oxo{[(1R)-1-phenylethyl]amino}acetyl)pentylcarbamate was prepared as in example 9j except that [1-(3-pyridinylmethyl)cyclobutyl]methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-[(4-morpholinylcarbonyl)amino]pentylcarbamate was substituted for (1-benzylcyclohexyl)methyl(1S)-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)-5-[(4-morpholinylcarbonyl)amino]pentylcarbamate. ES-LCMS m/z 616 (M+Na). Retention time=2.94 min. LC-MS results obtained using a Phenomenex max RP 50×2 MM column with 4 u packing eluted at 0.8 mL/min with a 5 minute gradient from 85% water: 15% methanol to 100% methanol. The mobile phase contained a 0.1% formic acid modifier. HRMS C32H43N5O6 m/z 594.3292 (M+Na)Cal; 594.3279 (M+Na)Obs.
Reaction SMILES: CC1(C)C2C=CC(C#CC3C=CC(C(O)=O)=CC=3)=CC=2C(SCC)=CC1.[CH3:27][C:28]1([CH3:59])[C:37]2[CH:36]=[CH:35][C:34]([C:38]#[C:39][C:40]3[CH:50]=[CH:49][C:43]([C:44]([O:46]CC)=[O:45])=[CH:42][CH:41]=3)=[CH:33][C:32]=2[C:31]([S:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:30][CH2:29]1>>[CH3:27][C:28]1([CH3:59])[C:37]2[CH:36]=[CH:35][C:34]([C:38]#[C:39][C:40]3[CH:50]=[CH:49][C:43]([C:44]([OH:46])=[O:45])=[CH:42][CH:41]=3)=[CH:33][C:32]=2[C:31]([S:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[CH:30][CH2:29]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(SCc2ccccc2)=CCC3(C)C)cc1
Agent: CCSC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)O)cc3)cc21
Product: CC1(C)CC=C(SCc2ccccc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(7,8-dihydro-8,8-dimethyl-5-ethylthionaphth-3-yl)ethynyl]benzoic acid (Compound 152), 100 mg (0.38 mmol) of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-benzylthionaphth-3-yl)ethynyl]benzoate (Compound 161) was converted into the title compound (white needles, recrystallized from a 50% solution of acetonitrile and ethyl acetate) using 2 ml of KOH (2N aqueous solution).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:30][C:31]1[C:32]([C:44]([NH:46][CH3:47])=[O:45])=[N:33][C:34]([C@H:37]2[CH2:42][CH2:41][C@H:40]([OH:43])[CH2:39][CH2:38]2)=[CH:35][CH:36]=1>O>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:30][C:31]3[C:32]([C:44](=[O:45])[NH:46][CH3:47])=[N:33][C:34]([C@H:37]4[CH2:38][CH2:39][C@H:40]([OH:43])[CH2:41][CH2:42]4)=[CH:35][CH:36]=3)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CNC(=O)c1nc([C@H]2CC[C@H](O)CC2)ccc1N
Solvent: O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)nc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 231 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (44.9 mg, 0.0989 mmol) and 3-amino-6-(trans-4-hydroxycyclohexyl)-N-methylpyridine-2-carboxamide (Example 232A, 37 mg, 0.15 mmol). The reaction mixture was poured into water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, concentrated and purified on an ISCO CombiFlash system (eluting with 0-4% MeOH/DCM) to isolate, after concentrating the relevant fractions and drying in vacuo, the desired product as 44.5 mg of a white solid. 1H NMR (400 MHz, DMSO-d6) d 1.20 (t, J=7.07 Hz, 6H), 1.23-1.33 (m, 2H), 1.59-1.72 (m, 2H), 1.77-1.86 (m, 2H), 1.94 (dd, J=13.01, 3.66 Hz, 2H), 2.56-2.67 (m, 1H), 2.83 (d, J=4.80 Hz, 3H), 3.28 (d, J=17.94 Hz, 2H), 3.45-3.55 (m, 1H), 3.74 (s, 3H), 3.94-4.04 (m, 4H), 4.57 (d, J=4.29 Hz, 1H), 6.89 (ddd, J=8.02, 2.27, 2.08 Hz, 1H), 7.05 (s, 1H), 7.35 (d, J=8.84 Hz, 1H), 7.41 (br. s., 1H), 8.38 (s, 1H), 8.88-8.95 (m, 1H), 9.01 (br. s., 1H), 12.33 (s, 1H). HRMS (ES+): m/z=667.2100 (100) [M+1]. HPLC: tR=1.50 min (ZQ2, polar—3 min).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6]O.C(N(CC)CC)C.CS(Cl)(=O)=O.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>C(Cl)Cl.CCOCC>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[C:8]1([C:5]2([CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:6]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN(C)CCC(CO)(c1ccccc1)c1ccccc1O
Agent: CS(=O)(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN(C)CCC1(c2ccccc2)COc2ccccc21
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of 14.8 g (52 mmole) 4-dimethylamino-2-(2-hydroxyphenyl)-2-phenylbutanol in 300 ml CH2Cl2 and 21.5 ml (156 mmole) triethylamine which had been cooled in an ice bath for 20 minutes was added a solution of 6 ml (78 mmole) methanesulfonyl chloride in 50 ml CH2Cl2. After the mixture was stirred 3 hours at ice bath temperature, it was diluted with 800 ml CH2Cl2, washed with 10% NaOH solution (2×125 ml) and saturated NaCl solution (125 ml), and dried over MgSO4. Filtration and evaporation gave 14.0 g of a crude oil. A solution of 5 g of this material in 15 ml CH2Cl2 was added to excess oxalic acid in Et2O. The precipitated solid was recrystallized from ethanol to give 4.2 g (63%) of crystals, m.p. 158°-160°.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=O)[C:13]2[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=2[N:15]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:25].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:1][CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:11][C:12](=[S:25])[C:13]2[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=2[N:15]=1
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3ccccc3OCC)nc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCc1nn(C)c2c(=S)[nH]c(-c3ccccc3OCC)nc12
Reaction time: 0.5 h
Yield: 144.6 %

Procedure:
2-(2-ethoxy)-phenyl-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidine-7-one (50 g (0.16 mol)), phosphorus pentasulfide (17.8 g (0.08 mol)), pyridine (250 ml) were added into a 500 ml three-neck flask with a mechanical stirrer, stirred, heated and refluxed for 6 hours, TLC tracing was performed until the reactants were totally disappeared. The solvent pyridine was removed by distilling under reduced pressure, concentrated ammonia water ((25-28%) 75 ml) and ethanol 300 ml were added, heated and refluxed for 30 min. It was cooled, filtered, dried, and crude product (45 g) was obtained. The crude product was heated and solved into chloroform (150 ml), activated carbon (5 g) was added, stirring and reflux was performed for 30 min, it was filtered and the filtrate was washed with saturated brine and water consequently and dried with magnesium sulfate anhydrous, chloroform was removed by distilling, the obtained solid was re-crystallized with ethanol and dried, solid (38 g) was obtained with a yield of 72%.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[CH:37]=O>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:37][C:28]3[CH:29]=[CH:30][C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:27]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: O=Cc1ccc2ccccc2c1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc3ccccc3c2)CC1
Yield: 73 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (1.98 g) as starting compound and 2-naphthaldehyde (0.74 g) were reacted and treated in the same manner as in Example 121 to give 1.81 g of 4-amino-5-chloro-2-methoxy-N-((1-(5-(2-naphthylmethylamino)pentyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: CO[C:3](=[O:10])[C@@H:4]1[CH2:8][C@H:7]([OH:9])[CH2:6][NH:5]1.C([O-])([O-])=O.[K+].[K+].[Cl:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=[O:27])[CH:21]=[C:22]([Cl:24])[CH:23]=1>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]([N:25]2[C:3](=[O:10])[C@@H:4]3[CH2:8][C@H:7]([OH:9])[CH2:6][N:5]3[C:26]2=[O:27])[CH:21]=[C:22]([Cl:24])[CH:23]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1[C@@H]2C[C@H](O)CN2C(=O)N1c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.1 %

Procedure:
To a solution of cis-4-hydroxy-L-proline methyl ester (0.53 g) (0.0036 mol) in 10 mL of DMF cooled at 0° C. was added K2CO3 (0.52 g) (1.1 eq.), then 3,5-dichlorophenyl isocyanate (0.75 g) (1.1 eq.). The reaction was stirred overnight at RT and the insoluble material removed by filtration. The solution was concentrated under vacuum and the residue dissolved in DCM. The organic layer was washed with water, dried over MgSO4, and evaporated under reduced pressure. The resulting residue was purified on a SiO2 column (eluent: DCM/acetone-95/5) to afford the titled compound as a white solid (0.25 g). NMR (CDCl3, 200 MHz): 7.35 (3H, s), 4.45 (1H, m), 4.30 (1H, dd), 4.0 (1H, d), 3.1 (1H, dd), 2.35-2.2 (2H, m), 1.95 (1H, bs, OH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]#[CH:12].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][SH:19])=[CH:16][CH:15]=1.[Na]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1/[CH:11]=[CH:12]\[CH:18]([S:19][CH:18](/[CH:12]=[CH:11]\[C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1)[C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1
Reactant: C#Cc1ccc(OC)cc1OC
Reactant: Fc1ccc(CS)cc1
Agent: [Na]
Product: COc1ccc(/C=C\C(SC(/C=C\c2ccc(OC)cc2OC)c2ccc(F)cc2)c2ccc(F)cc2)c(OC)c1

Procedure:
A solution of 2,4-dimethoxyphenylacetylene (0.02 mol), 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-dimethoxystyryl-4-fluorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][O:7][C:8](F)(F)[C:9]([F:18])=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]>CCCCC>[F:18]/[C:9](=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])/[C:8]([O:7][CH3:6])=[O:2]
Reactant: CCCCCCCC=C(F)C(F)(F)OC
Reactant: O=S(=O)(O)O
Solvent: CCCCC
Product: CCCCCCC/C=C(\F)C(=O)OC
Temperature: 20 °C
Reaction time: 40 h
Yield: 54.5 %

Procedure:
To a mixture of 3 g 75% sulfuric acid and 15 mL of n-pentane at 20° C. in a round-bottom 50 mL flask was added the crude 1-methoxy-1,1,2-trifluoro-2-decene (1.2 g). The resulting mixture was stirred for 40 hours at 20° C. The reaction mixture was poured into a large excess of ice-water and the liquid extracted twice with diethyl ether. The ether layers were combined, washed with water and brine, then dried over anhydrous magnesium sulfate. Evaporation of solvent gave a yellow oil which was chromatographed on silica gel (5% ethyl acetate in hexanes) to give 0.59 g (64.5%) of methyl (Z)-2-fluoro-2-decenoate as a clear liquid: 1H-NMR (300 MHz, CDCl3): δ 0.86(3H, t), 1.24(1OH), 2.22(2H, dq,J=2,8 Hz), 3.80(3H, s), 6.10(1H, dt, J=8, 33Hz). Mass spectrum: m/e=202 (M+ ). 19F-NMR (CDCl3): φ 131.8(d, J=33.0).
Reaction SMILES: C[C:2]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10](N)[CH:11]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([OH:19])=[O:18].Cl.N([O-])=[O:22].[Na+].S(=O)(=O)(O)O>O>[OH:22][C:9]1[CH:8]=[C:7]2[C:12]([C:13]3[CH:5]=[CH:4][C:3]([CH2:16][C:17]([OH:19])=[O:18])=[CH:2][C:14]=3[CH2:6]2)=[CH:11][CH:10]=1
Reactant: O=N[O-]
Reactant: Cc1c(CC(=O)O)ccc2c1Cc1cc(N)ccc1-2
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1ccc2c(c1)Cc1cc(O)ccc1-2
Reaction time: 2 h

Procedure:
A solution of 14.5g. of methyl 7-aminofluorene-2-acetic acid in 380ml. of water containing 14ml. of concentrated hydrochloric acid is cooled to 2° and a solution of 3.63g. of sodium nitrite in 15ml. of water added dropwise while stirring. The diazonium solution is added over a 1 hour period while stirring to a refluxing solution of 1.1 liters of water containing 18ml. of sulfuric acid. The mixture is cooled and the solid collected by filtration. The solid is refluxed with 120ml. of 10% aqueous potassium hydroxide solution for 2 hr., and treated with Darco. The suspension is filtered, acidified with hydrochloric acid and the solid collected by filtration, dried, and crystallized from acetonitrile to give 9.4g. of the title compound, 240°-241°d.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:18]([O:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A mixture of ethyl 3-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate (7.76 g), benzyl bromide (3.97 ml), potassium carbonate (6.91 g) and N,N-dimethylformamide (75 ml) was stirred overnight at 50° C. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dilute hydrochloric acid, and then washed successively with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-benzyloxy-1-phenyl-1H-pyrazole-4-carboxylate (8.29 g, yield 77%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 113–114° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[CH2:16]([O:18][C:19]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22])[CH3:17]>O1CCOCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([NH:14][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[C:27]([O:28][CH3:29])[C:19]=2[O:18][CH2:16][CH3:17])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: CCOc1c(OC)cccc1C(=O)Cl
Reactant: COC(=O)c1ccc(N)c(C(=O)OC)c1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCOc1c(OC)cccc1C(=O)Nc1ccc(C(=O)OC)cc1C(=O)OC
Yield: 97.2 %

Procedure:
Dimethyl- 4-amino-isophthalate (5 g) in 50 ml of dioxane and 10 ml of anhydrous pyridine is treated with 7.5 g of 2-ethoxy-3-methoxybenzoyl chloride at room temperature, overnight. After dilution with water, the precipitate is collected, dissolved in ethyl acetate, and washed with 5% NaHCO3 and then with water. After evaporation to dryness under vacuum, the material is crystallized from isopropyl ether, yielding dimethyl- 4-(2'-ethoxy-3'-methoxy-benzoylamino)-isophthalate (9 g; m.p. 113°-115° C.), which is dissolved in 80 ml of dioxane and treated with 70 ml of 1N NaOH at room temperature for 4 hours. After acidification with diluted HCl, the precipitate is collected under vacuum and washed with water until neutral. The yield is 7.4 g of 4-(2'-ethoxy-3'-methoxy-benzoylamino)-isophthalic acid (m.p.=244°-246° C.), which are treated with 10 ml of acetic anhydride at the reflux temperature for 10'.
Reaction SMILES: Cl.FC1C=CC(CNC2C=NC=CC=2[N+]([O-])=O)=CC=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][N:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[N:29]=[C:28]1[NH:36][CH:37]1[CH2:42][CH2:41][N:40]([CH2:43][C:44]#[N:45])[CH2:39][CH2:38]1.N.[H][H]>[Ni].CO>[NH2:45][CH2:44][CH2:43][N:40]1[CH2:39][CH2:38][CH:37]([NH:36][C:28]2[N:27]([CH2:26][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[C:31]3=[N:32][CH:33]=[CH:34][CH:35]=[C:30]3[N:29]=2)[CH2:42][CH2:41]1
Reactant: [H][H]
Reactant: N#CCN1CCC(Nc2nc3cccnc3n2Cc2ccccn2)CC1
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CO
Product: NCCN1CCC(Nc2nc3cccnc3n2Cc2ccccn2)CC1
Yield: 90 %

Procedure:
A mixture of 17 parts of 4-[[3-(2-pyridinylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidineacetonitrile and 400 parts of methanol, saturated with ammonia, was hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from acetonitrile, yielding 15 parts (90%) of N-[1-(2-aminoethyl)-4-piperidinyl]-3-(2-pyridinylmethyl)-3H-imidazo[4,5-b]pyridin-2-amine; mp. 151.1° C. (intermediate 102).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[OH:12])=[O:5])[CH3:2].N12CCCN=C1CCCCC2.[CH3:24][N:25]([CH3:29])[C:26](Cl)=[S:27]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[O:12][C:26](=[S:27])[N:25]([CH3:29])[CH3:24])=[O:5])[CH3:2]
Reactant: CN(C)C(=S)Cl
Reactant: CCOC(=O)c1sc(C)nc1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(C)nc1OC(=S)N(C)C
Temperature: 60 °C
Reaction time: 3 h
Yield: 55.3 %

Procedure:
To a mixture of 4-hydroxy-2-methyl-thiazole-5-carboxylic acid ethyl ester (7.2 g, 37.4 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (11.2 ml, 74.8 mmol) in DMF (50 ml) is added N,N-dimethyl-carbamothioyl chloride (6.94 g, 56.1 mmol). The mixture is stirred at RT for 14 h and at 60° C. for 3 h, poured onto water (100 ml) and extracted with EtOAc (3×50 ml). The combined organic layers are washed with water (2×50 ml), dried over sodium sulfate and concentrated. The residue is chromatographed (silica gel, 10% EtOAc/hexane) to give 4-(dimethyl-carbamothioyl)oxy-2-methyl-thiazole-5-carboxylic acid ethyl ester (5.7 g, 20.7 mmol, 55%).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:24]([C:23]2[CH:22]=[CH:21][C:20]([N+:17]([O-:19])=[O:18])=[CH:28][CH:27]=2)[OH:25])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc([N+](=O)[O-])cc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-nitrobenzoic acid
Reaction SMILES: [CH:1]1([CH2:9][C:10]2[N:11]=[CH:12][NH:13][CH:14]=2)[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][CH2:2]1.C([O-])(O)=[O:16].[Na+].ClC(OC1C=CC=CC=1)=O>C1COCC1.O>[CH:1]1([CH2:9][C:10]2[NH:11][C:12](=[O:16])[NH:13][CH:14]=2)[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C([O-])O
Reactant: c1nc(CC2CCC3=C2CCC3)c[nH]1
Agent: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]cc(CC2CCC3=C2CCC3)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-(1,2,3,4,5,6-hexahydro-pentalen-1-ylmethyl)-1H-imidazole; fumarate salt (Intermediate A5 as described in Example A, 340 mg, 1.81 mmol) in THF (15 mL) and water (15 mL) was treated with NaHCO3 (1.52 g, 18 mmol) at rt for 30 m. Phenyl chloroformate (600 mL, 4.7 mmol) was added and stirring was continued for 1 h at 65 EC. The mixture was diluted with water (30 mL) and extracted with EtOAc (3×30 mL). The organic portions were combined and freed of solvent. The residue was dissolved in EtOH (15 mL):water (15 mL) and treated with Na2CO3 (500 mg) for 1.5 h at 95 EC. The mixture was cooled to rt and the product was collected on a glass frit to give a white solid (˜50%) 4-(1,2,3,4,5,6-Hexahydro-pentalen-1-ylmethyl)-1,3-dihydro-imidazol-2-one (Compound 41).