Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C:3]([C:5]1[N:6]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:7]2[C:12]([C:13](=[O:26])[C:14]=1[CH2:15][NH:16][C:17]([C:19]1[CH:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1)=[O:18])=[CH:11][CH:10]=[C:9]([Cl:27])[CH:8]=2)=[O:4].[NH:35]1[CH2:40][CH2:39][CH:38]([CH2:41][CH2:42][OH:43])[CH2:37][CH2:36]1>>[Cl:27][C:9]1[CH:8]=[C:7]2[C:12]([C:13](=[O:26])[C:14]([CH2:15][NH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([N:35]4[CH2:40][CH2:39][CH:38]([CH2:41][CH2:42][OH:43])[CH2:37][CH2:36]4)=[N:21][CH:20]=3)=[O:18])=[C:5]([C:3](=[O:4])[N:2]([CH3:34])[CH3:1])[N:6]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:11][CH:10]=1
Reactant: CN(C)C(=O)c1c(CNC(=O)c2ccc(Cl)nc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1
Reactant: OCCC1CCNCC1
Product: CN(C)C(=O)c1c(CNC(=O)c2ccc(N3CCC(CCO)CC3)nc2)c(=O)c2ccc(Cl)cc2n1-c1ccccc1

Procedure:
4-(2-Hydroxy-ethyl)-3,4,5,6-tetrahydro-2H-[1,2]bipyridinyl-5′-carboxylic acid (7-chloro 2-dimethylcarbamoyl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared according to the procedure described for example 3-11, starting from the intermediate 7-chloro-3-{[(6-chloro-pyridine-3-carbonyl)-amino]-methyl}-4-oxo-1-phenyl-1,4-dihydro-quinoline-2-carboxylic acid dimethylamide and 2-(piperidin-4-yl)ethanol. MS calcd. for C32H34ClN5O4 [(M+H)+] 588.2, obsd. 588.3.
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([CH3:15])[CH:8]=1)=[O:5].CS(O)(=O)=[O:18]>>[CH3:14][O:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][C:9]=1[CH3:15])[NH:6][C:4](=[O:5])[C:3]2=[O:18]
Reactant: COc1ccc(NC(=O)C=NO)cc1C
Reactant: CS(=O)(=O)O
Product: COc1cc2c(cc1C)NC(=O)C2=O
Reaction time: 0.17 h
Yield: 77 %

Procedure:
2-Hydroxyimino-N-(4-methoxy-3-methylphenyl)acetamide (0.5 g, 2.4 mmol) was added portionwise to concentrated methanesulfonic acid (1.5 mL). The 2-hydroxyimino-N-(4-methoxy-3-methylphenyl)acetamide was added over a period of 45 min in order to keep the reaction temperature between 65 to 70° C. After addition, the mixture was stirred for 10 min and then poured onto ice (10 g). The resulting aqueous solution was extracted with ethyl acetate (3×50 mL). Combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel with petroleum ether:ethyl acetate (20:1, v/v) as eluent to afford 5-methoxy-6-methyl-1H-indole-2,3-dione (350 mg, 1.8 mmol, 77%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[C:12]1([CH:18]([CH2:22][CH:23]=[CH:24][C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)[C:19](=[O:21])[CH3:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:20][C:19](=[O:21])[CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:22][CH:23]=[CH:24][C:25]2[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)C(CC=Cc1ccc(C)cc1)c1ccccc1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C=CCC(C(=O)C=Cc2ccc(Cl)cc2)c2ccccc2)cc1

Procedure:
A sodium hydroxide solution (8 ml., 20%) is added to a solution of p-chlorobenzaldehyde (20.4 g., 0.14 mole) and crude 3-phenyl-6-(p-methylphenyl)-5-hexen-2-one (Step A, above) in ethanol (350 ml.) with stirring. The off-white solid that separates on continued stirring is filtered, washed with cold ethanol and air-dried, yield 44 g., m.p. 114°-118°C. Recrystallization from ethanol gives material with m.p. 134°-136.5°C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO>[C:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC=C(C(=O)O)CC1
Reaction time: 2 h
Yield: 77.5 %

Procedure:
To a stirred solution of methyl 1-Boc-1,2,3,6-tetrahydro-4-pyridinecarboxylate (2.22 g, 9.2 mmol) in methanol (10 mL) was added 1.0 N aqueous sodium hydroxide (25 mL). After stirring for 2 h, the solvent was removed in vacuo. The residue was partitioned between diethyl ether and water, and the layers were separated. The aqueous phase was acidified to pH 2.5 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with saturated aqueous sodium chloride, dried (magnesium sulfate), filtered, and concentrated in vacuo to give 1.62 g (78%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]([NH2:50])[C:14]3[N:15]=[CH:16][N:17]([C:48]=3[N:49]=2)[C@@H:18]2[O:47][C@H:37]([CH2:38][O:39][Si](C(C)(C)C)(C)C)[C@@H:28]([O:29][Si](C(C)(C)C)(C)C)[C@H:19]2[O:20][Si](C(C)(C)C)(C)C)=[CH:4][CH:3]=1.F.F.F.C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]([NH2:50])[C:14]3[N:15]=[CH:16][N:17]([C:48]=3[N:49]=2)[C@@H:18]2[O:47][C@H:37]([CH2:38][OH:39])[C@@H:28]([OH:29])[C@H:19]2[OH:20])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(OCCc4ccc(Cl)cc4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: F
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1nc(OCCc2ccc(Cl)cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 50 °C
Yield: 62 %

Procedure:
To a solution of 2-[2-(4-chlorophenyl)ethoxy]-2′,3′,5′-tri-O-(TERT-butyldimethylsilyl)-adenosine (Example 1, 500 mg, 0.654 mmol) in 7 mL of anhydrous methanol flushed with nitrogen was added 532 μL (3.3 mmol, 5 eq.) of triethylamine trihydrofluoride. The reaction was heated to 50° C. for 18 hours. On disappearance of the starting material as indicated by LC analysis, the reaction was allowed to cool which resulted in precipitation of a white solid. This was collected by filtration, rinsed with 3 mL of methanol and dried to provide 171 mg (62%) of the desired product as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]2)=[CH:9][C:8]=1[C:19]([F:22])([F:21])[F:20])[CH3:2]>CCOC(C)=O.[Pd]>[O:18]=[C:15]1[CH2:16][CH2:17][C@@H:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])=[C:8]([C:19]([F:20])([F:21])[F:22])[CH:9]=2)[CH2:14]1
Reactant: CCOC(=O)C=Cc1ccc([C@@H]2CCC(=O)C2)cc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc([C@@H]2CCC(=O)C2)cc1C(F)(F)F
Reaction time: 8 h

Procedure:
A solution of (R)-3-[4-(3-oxo-cyclopentyl)-2-trifluoromethyl-phenyl]-acrylic acid ethyl ester (preparation 7, 1.55 g) in EtOAc (40 mL) containing Pd/C (300 mg) was hydrogenated overnight at rt. The catalyst was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure, affording the title compound as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.54-7.48 (m, 1H), 7.39-7.24 (m, 2H), 4.14 (q, 2H), 3.51-3.35 (m, 1H), 3.12 (t, 2H), 2.75-2.23 (m, 7H), 2.05-1.90 (m, 1H), 1.25 (t, 3H).
Reaction SMILES: OC1CCC(C)(C)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2.[CH3:27][C:28]1([CH3:52])[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][CH2:47][CH3:48])=[O:45])=[CH:42][N:41]=3)=[CH:33][C:32]=2[C:31](=[O:51])[CH2:30][CH2:29]1>>[OH:51][CH:31]1[CH2:30][CH2:29][C:28]([CH3:52])([CH3:27])[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][CH2:47][CH3:48])=[O:45])=[CH:42][N:41]=3)=[CH:33][C:32]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=O)CCC3(C)C)nc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3O)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(O)CCC3(C)C)nc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-5-hydroxy-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 9), 700 mg (2 mmol) of ethyl 6-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-3-yl)ethynyl]nicotinate (Compound 4) was converted into the title compound using 60 mg (1.6 mmol) of sodium borohydride.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[O:10][C:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[CH:12][C:13]=2[CH3:14])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:28])=O.C(N(CC)CC)C.O>ClCCl>[Cl:28][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[O:10][C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:12][C:13]=1[CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)oc1C(O)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)oc1C(Cl)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl{3-methyl-5-[4-(trifluoromethyl)phenyl]furan-2-yl}methanol (0.7 g) in dichloromethane (5 mL) were added oxalyl chloride (0.3 mL) and triethylamine (0.5 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.8 g, 100%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:8]2[CH2:9][CH2:10][O:11][C:7]=2[CH:6]=1.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.Cl>N1C=CC=CC=1>[S:28]([C:25]1[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=1)([OH:1])(=[O:30])=[O:29].[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[C:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][C:8]2[CH2:9][CH2:10][O:11][C:7]=2[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: OCCCc1cc2c(cc1OCc1ccccc1)CCO2
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of 7 (1.16 g, 4.07 mmol) in dry pyridine (3 mL) was added p-toluenesulfonyl chloride (0.707 g, 2.72 mmol) and the mixture allowed to warm to room temperature and stir for 1 hour. The reaction mixture was poured into ice water (25 mL) and acidified with 2N HCl. The resulting precipitate was collected by filtration, washed with water (2×5 ML), and vacuum dried to give 8a. 2,3-Dihydro-4-(3-hydroxypropyl)-5-benzyloxybenzofuran tosylate (8b) can be produced in similar fashion
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]2[N:8]([C@H:22]3[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]3)[C:9](=[O:21])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=3)[C:6]=2[CH:5]=1)([OH:3])=O.[OH-].[NH4+].Cl.C[N:35](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]([C:4]1[CH:30]=[CH:29][C:7]2[N:8]([C@H:22]3[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24][CH2:23]3)[C:9](=[O:21])[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([Cl:20])[CH:13]=3)[C:6]=2[CH:5]=1)(=[O:3])[NH2:35]
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ccc(C(=O)O)cc32)cc1Cl
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](O)CC3)c3ccc(C(N)=O)cc32)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 5-carboxy-3-(3-chloro-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H-benzimidazol-2-one (72 mg), ammonium hydroxide (0.1 mL, 28% NH3 in water), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (35.2 mg) and 1-hydroxybenzotriazole (27.1 mg) in anhydrous dimethylformamide (1 mL) was stirred at ambient temperature for 4 hours. The mixture was partitioned between water and ethyl acetate. The separated organic layer was washed successively with an aqueous saturated sodium bicarbonate solution, water, 1N-hydrochloric acid and brine. The organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was subjected to a preparative silica gel column chromatography eluting with 5% methanol in chloroform. The obtained solid was washed with acetonitrile to give 5-carbamoyl-3-(3-chloro-4-methoxybenzyl)-1-(trans-4-hydroxycyclohexyl)-2,3-dihydro-1H-benzimidazol-2-one (217.9 mg) as a colorless solid.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:12]1[O:16][CH:13]1[CH2:14][CH3:15].C(C1CCCCC1O)(C)(C)C.C1OC1C>>[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[CH2:6]1)([CH3:4])([CH3:2])[CH3:3].[C:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([O:11][CH2:12][CH:13]([OH:16])[CH2:14][CH3:15])[CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCC1CO1
Agent: CC(C)(C)C1CCCC(O)C1
Agent: CC(C)(C)C1CCCCC1O
Agent: CC1CO1
Product: CCC(O)COC1CCCC(C(C)(C)C)C1

Procedure:
The synthesis was carried out in the same manner as described in Example 1, except that 30.0 g (0.192 mol) of 3-tert-butylcyclohexanol (cis:trans=2:8) and 13.8 g (0.192 mol) of 1,2-butyleneoxide were used instead of 30.0 g (0.192 mol) of 2-tert-butylcyclohexanol (cis:trans=8:2) and 11.1 g (0.192 mol) of propyleneoxide. 11.3 g of 3-tert-butylcyclohexanol and 9.3 g of 1-(3-tert-butylcyclohexyloxy)-2-butanol (cis:trans=2:8) (bp. 145° to 148° C./10 mm Hg) were obtained in a 32% yield. Then, the cis-trans isomers of 1-(3-tert-butylcyclohexyloxy)-2-butanol were separated from each other in the same manner as described in Example 1.
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[N:14]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:26]([N:14]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@@H:9]1[CH2:10][CH2:11][CH2:12][CH2:13][C@H:8]1[C:6]([OH:7])=[O:5])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@@H]2CCCC[C@H]2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@@H]2CCCC[C@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
To a solution of 1.364 g (2.97 mmol) of the product from Example 5 in 10 mL of dichloromethane was added 10 mL of trifluoroacetic acid and the mixture was stirred for 4 h at room temperature. The solvent was then concentrated in vacuo and the residue was chromatographed on silica gel eluting with 10-100% ethyl acetate/hexane to provide 1.092 g (73%) of the desired product as a white solid. Electrospray Mass Spec 404.2 (M+H)
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH2:10][OH:11])[CH3:8])[CH3:3].[H][H]>>[CH3:8][C@H:7]1[CH2:9][C:10](=[O:11])[C@H:4]([CH:2]([CH3:3])[CH3:1])[CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: CC(C)=CCCC(C)CCO
Product: CC(C)[C@@H]1CC[C@@H](C)CC1=O

Procedure:
A process for producing menthol which comprises dehydrogenating citronellol in a reaction system containing a Raney-type catalyst or a metal oxide catalyst at a temperature of about 150° to about 260° C in an atmosphere of hydrogen under a pressure of 0 to about 5 kg/cm2.G to produce menthone as claimed in claim 1, and then, in the same reaction system without separating the catalyst or adding additional catalyst, hydrogenating the menthone produced by decreasing the temperature to about 110° to about 130° C and increasing the hydrogen pressure to about 10 to about 50 kg/cm2 to produce menthol.
Reaction SMILES: CC[O:3][C:4]([CH:6]1[C:12](=O)[CH2:11][CH:10]([C:14]([O:16]CC)=O)[C:8](=O)[CH2:7]1)=O.C(=O)(O)O.[NH2:23][NH:24][C:25]([NH2:27])=[NH:26].[NH2:28][NH:29][C:30]([NH2:32])=[NH:31]>C(O)CCC>[NH2:26][C:25]1[N:24]([NH2:23])[C:14](=[O:16])[C:10]2[CH2:11][C:12]3[N:31]=[C:30]([NH2:32])[N:29]([NH2:28])[C:4](=[O:3])[C:6]=3[CH2:7][C:8]=2[N:27]=1
Reactant: CCOC(=O)C1CC(=O)C(C(=O)OCC)CC1=O
Reactant: N=C(N)NN
Agent: O=C(O)O
Solvent: CCCCO
Product: Nc1nc2c(c(=O)n1N)Cc1nc(N)n(N)c(=O)c1C2
Yield: 123.2 %

Procedure:
A mixture of 12.8 g of diethyl 1,4-cyclohexanedione-2,5-dicarboxylate and 13.6 g of aminoguanidine aminoguanidine bicarbonate in 100 ml of n-butanol was heated at reflux for 9 hours. Cooling produced 17 g of the desired intermediate, mdesired intermediate, mp>300° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1.[CH2:42]([N:44]=[C:45]=[O:46])[CH3:43].CCN(C(C)C)C(C)C.[N-]=C=O.C(O)C(N)(CO)CO>C(Cl)Cl>[CH2:42]([NH:44][C:45](=[O:46])[NH:1][C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH:11][C:12]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])=[O:13])=[CH:10][C:5]=2[N:4]([C:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:3]=1)[CH3:43]
Reactant: CCN=C=O
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)c(N)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1
Agent: NC(CO)(CO)CO
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To an 8 mL vial charged with (R)-1-(3-amino-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (25 mg, 0.046 mmol) in DCM (1 ml) was added ethyl isocyanate (5.51 μl, 0.070 mmol) and DIEA (0.024 ml, 0.139 mmol). The vial was capped and the contents stirred at room temperature for 16 h. The course of reaction was followed by LCMS analysis. Only minor product formation was observed. Excess isocyanate (1.5 eq) was added and the reaction mixture heated to 40° C. for a further 16 h. Unreacted isocyanate was quenched by adding MP-Trisamine (229 mg, 0.464 mmol) and tumbling the vial for 3 h. The resin was filtered and the volatiles removed in vacuo to afford crude (R)-1-(3-(3-ethylureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea which was taken forward without purification. MS ESI calc'd. For C37H36N7O2 [M+H]+ 610. found 610.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:32])([CH2:26][N:27]1[CH:31]=[N:30][N:29]=[N:28]1)[C:10]([C:13]1[N:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1)([F:12])[F:11]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:32])([CH2:26][N:27]1[CH:31]=[N:30][N:29]=[N:28]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=1)([F:11])[F:12]
Reactant: CCOC(=O)/C=C/c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of 4 (20 mg, 0.04 mmol) in ethyl alcohol (EtOH; 5 mL) was added 10% palladium on carbon (Pd/C; 2 mg) under N2 atmosphere, and the reaction mixture was stirred under hydrogen atmosphere (balloon pressure) at RT for 3 h. The reaction mixture was filtered through a pad of Celite®, the Celite® bed was washed thoroughly with EtOH (2×5 mL), and the obtained filtrate was concentrated under vacuum. The crude material was purified by column chromatography (eluting with EtOAc/hexane) to afford 5 (10 mg, 0.02 mmol, 50%) as an off-white solid. 1H NMR (500 MHz, CDCl3): δ 8.75 (s, 1H), 8.40 (s, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.36-7.31 (m, 1H), 6.77 (app t, 1H), 6.65 (app t, 1H), 5.56 (d, J=14.5 Hz, 1H), 5.10 (d, J=14.5 Hz, 1H), 4.12 (q, J=7.5 Hz, 2H), 2.98 (t, J=7.0 Hz, 2H), 2.64 (t, J=7.0 Hz, 2H), 1.23 (t, J=7.4 Hz, 3H). MS (ESI): m/z 454 [M++1]. HPLC: 97.4%.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([CH3:10])[N:7]=[C:6]([Br:11])[CH:5]=1.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[Br:11][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[C:8]([CH3:10])[N:7]=1
Reactant: COC(=O)c1cc(C)nc(Br)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: Cc1cc(CO)cc(Br)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a chilled (−78° C.) solution of 2-bromo-6-methyl-isonicotinic acid methyl ester (1.90 g, 8.26 mmol) in CH2Cl2 (200 mL) was added a 1 M solution of DIBAH (24.8 mL, 24.8 mmol) in CH2Cl2. The mixture was allowed to warm to room temperature. After 12 hours, the reaction was quenched with saturated aqueous sodium bicarbonate (100 mL). After 5 hours, phases were separated and the aqueous layer was extracted with CH2Cl2 (3×100 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography eluting with a gradient of 0-100% ethyl acetate in heptane to afford (2-bromo-6-methyl-pyridin-4-yl)-methanol as white solid. MS m/z 202.45 (M+), 204.44 (M+2).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[S:20][C:19]([NH:21]C(=O)OC(C)(C)C)=[N:18][CH:17]=2)=[CH:4][CH:3]=1>C(OCC)(=O)C.ClCCl>[N:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]2[S:20][C:19]([NH2:21])=[N:18][CH:17]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2ccccc2COc2ccncc2)s1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2ccccc2COc2ccncc2)s1
Reaction time: 4 h
Yield: 78.5 %

Procedure:
20 ml of a 4M gaseous hydrochloric acid solution in ethyl acetate are added to 1 g of tert-butyl 5-{2-[(4-pyridinyloxy)methyl]phenyl}-1,3-thiazol-2-ylcarbamate, obtained in step 7.3, in 20 ml of dichloromethane. The mixture is left for 4 hours at room temperature. The reaction medium is concentrated and it is brought to a basic pH with a 5% sodium hydrogen sulfate solution. The precipitate formed is filtered and chromatographed on a silica gel column, eluting with a dichloromethane/methanol 95/5 (V/V) mixture to give 0.58 g of a beige foam.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)=[C:15]3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][CH2:40][C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:40](=[O:39])[CH2:41][OH:42])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:35])[NH:14][C:15]=23)[CH2:33][CH2:34]1
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f27) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].C(OC([NH:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:34][CH:35]([O:39][CH:40]([CH3:42])[CH3:41])[C:36]([O-:38])=[O:37])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])=O)(C)(C)C>>[CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([NH:24][CH2:25][C:26]1[CH:27]=[C:28]([CH2:34][CH:35]([O:39][CH:40]([CH3:42])[CH3:41])[C:36]([OH:38])=[O:37])[CH:29]=[CH:30][C:31]=1[O:32][CH3:33])=[O:8])[CH3:2]
Reactant: COc1ccc(CC(OC(C)C)C(=O)[O-])cc1CNC(=O)OC(C)(C)C
Reactant: CCOc1cc(C(F)(F)F)ccc1C(=O)O
Product: CCOc1cc(C(F)(F)F)ccc1C(=O)NCc1cc(CC(OC(C)C)C(=O)O)ccc1OC

Procedure:
Using 2-ethoxy-4-(trifluoromethyl)benzoic acid and 3-[3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 3-(3-[(2-ethoxy-4-(trifluoromethyl)benzoyl]aminomethyl)-4-methoxyphenyl]-2-isopropoxypropanoic acid was obtained in the same method as in Example 38).