Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[Cl:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][N:30]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:29][CH2:28]5)=[N:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(Cl)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(Cl)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Yield: 92.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-chlorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (130 mg. 0.197 mmol) was alkylated using (S)-2-methyloxirane (34 mg, 0.59 mmol), DIPEA (73 mg, 0.59 mmol) and ethanol (5 mL) to get 124 mg (92.3% yield) of the titled compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:13]([CH3:16])=[CH:14][CH:15]=1)[NH:9][C:10](=[O:12])[CH3:11])(=[O:3])[CH3:2].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C(O[N:35]=O)CC(C)C.C1OCCOCCOCCOCCOCCOC1>C(Cl)(Cl)Cl.C(Cl)Cl>[C:10]([N:9]1[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:7]=2)[CH:16]=[N:35]1)(=[O:12])[CH3:11]
Reactant: CC(=O)Nc1cc(COC(C)=O)ccc1C
Reactant: CC(C)CCON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCc1ccc2cnn(C(C)=O)c2c1
Yield: 95.8 %

Procedure:
To a suspension of 3-(acetoxymethyl)-6-methyl-N-(acetyl)aniline (10.0 g, 45 mmol) (3) and potassium acetate (8.6 g, 88 mmol) in chloroform (300 mL), was added acetic anhydride (8.3 mL, 88 mmol), isoamylnitrite (35 mL, 300 mmol) and 18-crown-6 (1.5 g, 0.6 mmol) at room temperature. The reaction mixture was heated at reflux for 28 hours. The reaction mixture was diluted with methylene chloride (600 mL) and washed with saturated NaHCO3 aqueous solution (300 mL), water (300 mL) and brine (50 mL). After drying (Na2SO4), the organic solvent was removed under vacuum to give a yellow oil which was purified by a flash chromatography on silica gel (85:15 hexane-ethyl acetate) to yield the title compound (4) (10.01 g, 95%). TLC Rf 0.47 (70:30 of hexane-ethyl acetate); MS (electrospray) 233 (M+1); 1H N MR (CDCl3) δ2.10 (s, 3H), 2.78 (s, 3H), 5.27 (s, 2H), 7.36 (d, 1H, J=8.0 Hz), 7.73 (d, 1H, J=8.0 Hz), 8.12 (s, 1H), 8.47 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:15][C@@H:14]2[C@@H:9]([CH2:10][CH2:11][C@H:12]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]=[CH:18]3)[CH2:13]2)[CH2:8][N:7]1C(OC)=O)=[O:5])[CH3:2].C[Si](I)(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:15][C@@H:14]2[C@@H:9]([CH2:10][CH2:11][C@H:12]([CH2:16][N:17]3[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:19]=[CH:18]3)[CH2:13]2)[CH2:8][NH:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C[C@H]2CC[C@H]3CN(C(=O)OC)[C@H](C(=O)OCC)C[C@H]3C2)cn1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: CCOC(=O)c1cn(C[C@H]2CC[C@H]3CN[C@H](C(=O)OCC)C[C@H]3C2)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 0.90 g of [3S,4aR,6S,8aR]-ethyl-6-((4-ethoxycarbonyl-1H-imidazol-1-yl)methyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate in 20 ml of methylene chloride was added 1.5 ml trimethylsilyl iodide. The reaction was stirred at room temperature for six hours, quenched with excess absolute ethanol and evaporated to dryness. The residue was purified by strong cation exchange chromatography eluting with 10-50% methanol in chloroform followed by 50% 2M ammonia/methanol in chloroform to provide the final title compound, [3S,4aR,6S,8aR]-ethyl-6-((4-ethoxycarbonyl-1H-imidazol-1-yl)methyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[B:10]([O:19]C(C)C)([O:15]C(C)C)[O:11]C(C)C>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([O:11][B:10]([OH:19])[OH:15])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Product: COc1ccc(OB(O)O)cc1
Yield: 69 %

Procedure:
4-Methoxyphenylboric acid was prepared in the same manner as described in Example 33B from 4-bromoanisole and triisopropyl borate in 69% yield. This was used in the next step without any further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:18](=[O:19])[CH:17]([NH:20][C:21](=[O:40])[C@@H:22]([C@H:25]2[C@@H:30]([OH:31])[C@@H:29](/[CH:32]=[CH:33]/[C:34]([CH3:37])([CH3:36])[CH3:35])[O:28]C(C)(C)[O:26]2)[O:23][CH3:24])[CH2:16][S:15][CH2:14][CH2:13]1.Cl.[OH-].[Na+]>C1COCC1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[C:18](=[O:19])[CH:17]([NH:20][C:21](=[O:40])[C@H:22]([O:23][CH3:24])[C@H:25]([OH:26])[C@@H:30]([OH:31])[C@H:29]([OH:28])/[CH:32]=[CH:33]/[C:34]([CH3:37])([CH3:35])[CH3:36])[CH2:16][S:15][CH2:14][CH2:13]1
Reactant: CO[C@@H](C(=O)NC1CSCCN(Cc2ccc3ccccc3c2)C1=O)[C@@H]1OC(C)(C)O[C@H](/C=C/C(C)(C)C)[C@@H]1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CO[C@@H](C(=O)NC1CSCCN(Cc2ccc3ccccc3c2)C1=O)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C
Reaction time: 5 h
Yield: 67.3 %

Procedure:
40 mg of 44 (70 μmol) are mixed with 0.38 ml of THF and 0.75 ml of 1N hydrochloric acid, with stirring and under argon. Stirring is continued for 5 hours at room temperature. The solution is then cooled to 0° C. and neutralized to pH 7.0 with 1N sodium hydroxide. The mixture is extracted twice with 2 ml of EtOAc. The organic phases are combined, dried over magnesium sulfate and filtered and then evaporated to dryness. 25 mg of expected product Example 16 are obtained (yield=67%).
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18](Cl)=O.O>CC(C)=O>[C:2]1([C:1]2[N:8]=[C:18]([C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccccc1
Reactant: O=C(Cl)c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: c1ccc(-c2noc(-c3cccs3)n2)cc1
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
Benzamide oxime (5.00 g, 36.7 mmol) was dissolved in acetone (50 mL) at 0° C. The solution was stirred and 50% aqueous sodium hydroxide (4.5 mL) added. An exotherm was noted and a precipitate formed in the reaction mixture. The exotherm lasted for about 15 minutes and the slurry became thick. The solution was warmed to 20° C. and external cooling was added. The 2-thiophenecarbonyl chloride (5.36, 36.7 mmol) was added over 15 minutes maintaining the reaction mixture below 30° C. The reaction was maintained at 30° C. for 15 minutes and the slurry became thinner. The reaction mixture was cooled to room temperature and stirred for 20 additional minutes. Water (50 mL) was added and the resulting solids were stirred for 1 hour. The solids were collected by vacuum filtration, washed with water (2×50 mL) and dried on a Buchner funnel with air flow from vacuum overnight. 3-Phenyl-5-(2-thienyl)-1,2,4-oxadiazole (6.94 g, 30.4 mmol) was obtained as a white solid (83% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[ClH:18]>C(O)(=O)C>[ClH:18].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(C)ccc1-c1ccncc1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccc(-c2ccncc2)c(C(=O)O)c1

Procedure:
A mixture of methyl 5-methyl-2-(pyridin-4-yl)benzoate (8.8 g), 6 N hydrochloric acid (65 mL) and acetic acid (100 mL) was heated under reflux overnight. The solvent was evaporated under reduced pressure, and the obtained solid was washed with ethyl acetate to give the title compound (6.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]([CH2:25][N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[C:13]([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl>>[ClH:1].[C:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:13](=[O:14])[CH:12]([NH:11][S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])[CH2:25][N:26]1[CH:30]=[CH:29][N:28]=[CH:27]1)([OH:23])=[O:22]
Reactant: COC(=O)CCCCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(O)CCCCCNC(=O)C(Cn1ccnc1)NS(=O)(=O)c1ccc(Cl)cc1
Yield: 197.8 %

Procedure:
The procedure described in Example 92 was repeated, except that (RS)-2-(4-chlorobenzenesulfonylamino)-N-(5-methoxycarbonylpentyl)-3-(1H-imidazol-1-yl)propanamide (23.9 mg) was hydrolyzed, and then reacted with HCl to obtain (RS)-N-(5-carboxypentyl)-2-(4-chlorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide hydrochloride (24.8 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].N1C(C)=CC=CC=1C.Cl/[C:24](=[CH:27]/[C:28]#[N:29])/[C:25]#[N:26].Cl/C(=C\C#N)/C#N>CO>[NH2:29][C:28]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:24]([C:25]#[N:26])[CH:27]=1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: N#C/C=C(/Cl)C#N
Agent: N#C/C=C(\Cl)C#N
Solvent: Cc1cccc(C)n1
Solvent: CO
Product: N#Cc1cc(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n1
Reaction time: 16 h
Yield: 71 %

Procedure:
A 50 mL round-bottom flask was charged with (2,6-dichloro-4-trifluoromethyl-phenyl)-hydrazine (1.2 g, 4.84 mmol), 2,6-lutidine (0.57 g, 5.32 mmol, 1.1 equiv.) and methanol (10 mL). A mixture of chloromaleonitrile and chlorofumaronitrile (0.82 g, 7.29 mmol) was slowly added at 20-25° C. Stirring was continued for about 16 hours at that temperature. The solution was then concentrated at a pressure of 50 mbar. The residue was purified by flash column chromatography (silica, hexanes/EtOAc 100:0→70:30) to give the product as a off-white solid (1.1 g, 3.43 mmol, 71%), melting point: 117-118° C., 1H-NMR (360 MHz, CDCl3): δ [ppm]=7.78 (d, 2H, J=0.4 Hz); 6.04 (s, 1H); 3.83 (bs, 2H), 13C-NMR (125 MHz, DMSO-d6): δ [ppm]=150.0; 136.0; 135.9; 132.7 (q, J=34 Hz); 126.43; 126.42; 122.4 (q, J=273 Hz); 114.6; 90.8.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[O:32])[NH:15][C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].F[C:35]1[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14](=[O:32])[NH:15][C:16]2[CH:21]=[C:20]([O:22][C:35]3[CH:42]=[CH:41][C:38]([CH:39]=[O:40])=[CH:37][CH:36]=3)[CH:19]=[C:18]([O:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=3)[CH:17]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2cc(O)cc(Oc3ccc(C#N)cc3)c2)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)Nc2cc(Oc3ccc(C#N)cc3)cc(Oc3ccc(C=O)cc3)c2)CC1

Procedure:
Following the procedure of Example 42(b) {trans-4-[3-(4-cyano-phenoxy)-5-hydroxy-phenylcarbamoyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.0 g, 2.21 mmol) and 4-fluorobenzaldehyde (0.475 ml, 4.43 mmol) were used to afford 0.4 g of the required product. 1H NMR (DMSO-d6): δ 1.11 (4H, m), 1.29 (9H, s), 1.8 (4H, m), 2.11 (1H, m), 3.15 (1H, m), 6.82 (1H, d), 7.34 (6H, m), 7.86 (2H, d), 7.92 (2H, d), 10.11 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]#[N:9])[CH2:4][CH2:3]1.[CH3:10][O-:11].[Na+]>CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](=[NH:9])[O:11][CH3:10])[CH2:4][CH2:3]1
Reactant: CN1CCN(C#N)CC1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)N1CCN(C)CC1

Procedure:
In the manner given in Example 2, 4-methyl-1-piperazinecarbonitrile is treated with sodium methoxide in methanol to give methyl 4-methyl-1-piperazinecarboximidate.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([CH3:22])=[C:7]([CH3:21])[CH:8]=2)[N:3]=1.[I-:23].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>CC(=O)CC.C(OCC)(=O)C>[CH2:16]([O:15][P:13]([CH2:12][C:11]1[C:2]([I:23])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([CH3:21])=[C:6]([CH3:22])[CH:5]=2)([O:18][CH2:19][CH3:20])=[O:14])[CH3:17]
Reactant: CCOP(=O)(Cc1cc2cc(C)c(C)cc2nc1Cl)OCC
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1cc2cc(C)c(C)cc2nc1I)OCC
Yield: 55.2 %

Procedure:
2-Chloro-3-diethylphosphonomethyl-6,7-dimethylquinoline (0.40 g, 1.17 mmol), prepared as described in Example 4 was dissolved in 2-butanone (20 ml) and treated with sodium iodide (0.39 g, 2.6 mmol) and p-toluenesulfonic acid (0.11 g, 0.58 mmol). The mixture was refluxed for 10 hours. Ethyl acetate and saturated sodium hydrogen carbonate were added. The organic phase was separated and filtered through a pad of silica gel. Evaporation of solvents gave 0.28 g of 3-diethylphosphonomethyl-6,7-dimethyl-2-iodoquinoline.
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[S:8]([O-])([O-:11])(=[O:10])=[O:9].[Na+:13].[Na+].S(=O)(=O)(O)O>C(O)(=O)C>[S:8]([O-:11])([O:4][C:1](=[O:3])[CH3:2])(=[O:10])=[O:9].[Na+:13]
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OS(=O)(=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A sulfating mixture comprising sodium acetyl sulfate was prepared as follows: 162.9 grams acetic anhydride and 52.5 grams glacial acetic acid were added to a 1 liter jacketed resin flask. 30.8 grams of sodium sulfate were added and the contents stirred for 5 minutes. 20.15 grams of concentrated sulfuric acid (98% by weight) were added dropwise at such a rate that the temperature of the reactor contents did not exceed 55° C. The rate of addition of sulfuric acid may be increased, if desired, if cooling is applied by circulating ice water through the jacket of the reactor. The reactor was stirred for 30 minutes after the addition of the sulfuric acid was completed.
Reaction SMILES: [NH2:1][C@@H:2]([C@H:8]([OH:12])[CH:9]([CH3:11])[CH3:10])[C:3]([O:5]CC)=[O:4]>Cl>[NH2:1][C@@H:2]([C@H:8]([OH:12])[CH:9]([CH3:11])[CH3:10])[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)[C@@H](N)[C@H](O)C(C)C
Agent: Cl
Product: CC(C)[C@@H](O)[C@H](N)C(=O)O
Temperature: 130 °C
Reaction time: 1 h
Yield: 117.5 %

Procedure:
In a 35 ml microwave vial, ethyl (2S*,3R*)-2-amino-3-hydroxy-4-methyl-pentanoate (0.232 g, 1.33 mmol) was dissolved in a 6.0 M HCl aqueous solution (25 mL) and stirred at 130° C. for 1 h. The reaction mixture was extracted with Et2O (3×15 mL), the aqueous phase was concentrated under reduced pressure resulting in a white solid (0.23 g, 81%), which was used without further purification in the following step. MS (ESI) m/z: 148 [M−H]+; (ESI) m/z: 146 [M−H]−. 1H NMR (DMSO-d6) δ 0.87 (d, J=6.64 Hz, 3H), 0.93 (d, J=6.50 Hz, 3H), 1.74 (tq, J=5.79, 6.46, 11.64 Hz, 1H), 3.51-3.60 (m, 1H), 3.92 (s, 1H), 5.76 (s, 1H), 8.12 (s, 3H), 13.72 (s, 1H) [see also Tetrahedron 2001, 57, 8267-8276].
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)(=O)=O)=CC=1.[N:28]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32][CH2:31][CH:30]2[CH2:34][NH:35][CH2:36][CH:29]12.C(N(CC)CC)C>C(#N)C>[NH2:18][C:16]1[N:17]=[C:12]([N:35]2[CH2:34][CH:30]3[CH:29]([N:28]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32][CH2:31]3)[CH2:36]2)[C:13]2[CH2:23][CH2:22][CH2:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[C:14]=2[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2CNCC21
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2ccccc2-3)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCCc3ccccc3-4)CC21

Procedure:
A solution of the product from Example 59C (76 mg, 0.2 mmol), t-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (CAS #159877-36-8) (59 mg, 0.22 mmol) and triethylamine (0.1 mL) in acetonitrile (1 mL) was heated in a microwave reactor at 160° C. for 1 hour. The mixture was concentrated and chromatographed on silica gel eluting with EtOAc:hexane (1:1) mixture to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([CH:10]([O:13][CH3:14])[O:11][CH3:12])[N:3]=1.[CH:15](=O)[CH3:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[C:8]([C:7]1[C:2]([NH:1][CH2:15][CH3:16])=[N:3][C:4]([CH:10]([O:13][CH3:14])[O:11][CH3:12])=[CH:5][CH:6]=1)#[N:9]
Reactant: COC(OC)c1ccc(C#N)c(N)n1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCNc1nc(C(OC)OC)ccc1C#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76.6 %

Procedure:
2-Amino-3-cyano-6-dimethoxymethylpyridine (39.6 g, 0.2 mol) and 12 ml (0.2 mol) of acetaldehyde were dissolved in 400 ml of acetic acid, and the resulting solution was mixed with 45.5 g (0.2 mol) of sodium triacetoxyborohydride and stirred for 2.5 hours at room temperature. The reaction solution was concentrated under a reduced pressure, diluted with chloroform and then washed with 1 N sodium hydroxide aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and then the filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 33.9 g of 3-cyano-2-ethylamino-6-dimethoxymethylpyridine as an oily material. The yield was 77%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7]1)=[O:5])[CH3:2].[BH4-].[Na+].O>C1COCC1.CCOCC>[OH:11][CH:8]1[CH2:9][CH2:10][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]1
Reactant: CCOC(=O)C1CCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCC(O)C1
Temperature: 0 °C

Procedure:
To a 0° C. solution of ethyl-3-oxo-cyclopentane-1-carboxylate (2.0 g) in THF (50 mL) was added NaBH4 (970 mg). The reaction mixture was maintained at 0° C. for 30 min, and then overnight at ambient temperature. The reaction was then treated with H2O and diluted with Et2O. The resulting layers were separated, and the aqueous layer was further extracted with Et2O. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting crude product (a mixture of cis/trans isomers) was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:44])([CH3:43])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:27]/[CH:28]=[CH:29]/[C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:32]([CH3:42])[CH:31]=1)[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5]>C(O)C.[Pd]>[CH3:43][C:2]([CH3:1])([CH3:44])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:32]([CH3:42])[CH:31]=1)[CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8])=[O:5]
Reactant: Cc1cc(/C=C/C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c2ccccc2)C(C)(C)C)ccc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(CCC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c2ccccc2)C(C)(C)C)ccc1-c1ccccc1
Yield: 108 %

Procedure:
A solution of tert-butyl (3R,5E)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hex-5-enoate (1.91 gm, 3.2 mmol) in ethanol (80 mL) was hydrogenated over 10% palladium on charcoal (120 mg) at 3 bar and 20° C. for 16 h. The mixture was filtered through Arbocel filter aid and concentrated under reduced pressure to give tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hexanoate (2.07 gm, 108%), as a colourless foam, which was taken onto the next step without purification (see Example 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([OH:13])[CH:7]=[CH:6]2.C1(=O)O[CH2:17][CH2:16][O:15]1>CO.C(Cl)(Cl)Cl.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([O:13][CH2:17][CH2:16][OH:15])[CH:7]=[CH:6]2
Reactant: O=C1OCCO1
Reactant: COc1ccc2cc(O)ccc2c1
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CO
Product: COc1ccc2cc(OCCO)ccc2c1

Procedure:
*Prepared from 6-methoxy-2-naphthol and ethylene carbonat according to the procedure of Example 134, step 1, in WO 00/76984. The reaction mixture was refluxed for 2 h. Pure 2-(6-methoxy-naphthalen-2-yloxy)ethanol was obtained by recrystallization from MeOH/CHCl3/n-hexane.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([CH3:19])[C:10]([CH3:18])=[C:11]([O:16][CH3:17])[CH:12]=3)[C:7]2=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:21]C(C)([O-])C.[K+].CI>C(O)(C)(C)C>[CH:1]1([C:6]2([CH3:21])[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([CH3:19])[C:10]([CH3:18])=[C:11]([O:16][CH3:17])[CH:12]=3)[C:7]2=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)[O-]
Reactant: COc1cc2c(c(C)c1C)C(=O)C(C1CCCC1)CC2
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CI
Product: COc1cc2c(c(C)c1C)C(=O)C(C)(C1CCCC1)CC2
Temperature: 20 °C

Procedure:
2-Cyclopentyl-6-methoxy-7,8-dimethyl-1-tetralone (Example V, Step 4) (12.5 g., 0.046 mole) is dissolved in t-butyl alcohol (250 ml.) under a stream of nitrogen. The mixture is heated to reflux and then a solution of potassium t-butoxide (7.5 g., 0.067 mole) dissolved in t-butyl alcohol (175 ml.) is added. The dark solution is refluxed for 1 hour, cooled to 20° C. and methyl iodide (14.2 g., 0.1 mole) is added. The mixture is refluxed for 10 minutes. Potassium iodide precipitates and the color of the mixture becomes lighter. The mixture is cooled, water (25 ml.) is added and the mixture is evaporated to dryness. The crude product is collected, washed with water and air dried to obtain 2-cyclopentyl-2,7,8-trimethyl-6-methoxy-1-tetralone.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8]([C:12]([O-:14])=O)=[C:7]2O.[NH:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[NH2:17]>S(Cl)(Cl)=O.C(O)C>[F:1][C:2]1[C:11]2[N:10]=[N:9][C:8]3[C:12](=[O:14])[N:16]([C:18]4[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:25][CH:26]=4)[NH:17][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: O=C([O-])c1nnc2c(F)cccc2c1O
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: O=C(O)c1ccc(-n2[nH]c3c(nnc4c(F)cccc43)c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude 8-Fluoro-4-hydroxycinnoline-3-carboxylate from the previous stage (1.00 g, 4.95 mmol) was dissolved in thionyl chloride (50 ml). The solution was heated to reflux for 2-3 h until no further gas evolution was observed. The reaction mixture was cooled to room temperature and excess thionyl chloride was removed under vacuum. The crude intermediate was azeotroped with toluene (3×25 ml). A dark brown solid was obtained, which was taken up in ethanol (25 ml). 4-Hydrazinobenzoic acid (640 mg, 4.21 mmol) was added and the mixture was stirred at room temperature overnight. The solids were collected by filtration, slurried in 1 M HCl (100 ml), filtered, washed with hexane (50 ml) and dried under vacuum. A brown solid was obtained (890 mg of crude product). LCMS: m/z [M+H]+ 325.