Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][CH2:3][C:4]1[CH:5]=[C:6]([OH:11])[C:7]([CH3:10])=[N:8][CH:9]=1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>N1C=CC=CC=1>[CH2:12]([NH:14][C:15]([O:11][C:6]1[C:7]([CH3:10])=[N:8][CH:9]=[C:4]([CH2:3][O:2][C:15](=[O:16])[NH:14][CH2:12][CH3:13])[CH:5]=1)=[O:16])[CH3:13]
Reactant: Cc1ncc(CO)cc1O
Reactant: CCN=C=O
Agent: Cl
Solvent: c1ccncc1
Product: CCNC(=O)OCc1cnc(C)c(OC(=O)NCC)c1
Temperature: 0 °C

Procedure:
To a solution of 0.9 g. of 5-hydroxymethyl-2-methyl-3-pyridinol hydrochloride in 10 ml. of pyridine was added 0.8 g. of ethyl isocyanate and the mixture was stirred at 100°C for 2 hours. After cooling, the mixture was poured into ice water and extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and the solvent was distilled off to give a crystalline product, which was recrystallized from ethyl acetate-n-hexane to give 0.95 g. of the desired product as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH2:6][CH2:7][OH:8].C(O[CH:15](OCC)[CH2:16][Cl:17])C.Cl>O>[Cl:17][CH2:16][CH:15]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7][O:8]1
Reactant: CCOC(CCl)OCC
Reactant: COc1cccc(CCO)c1
Agent: Cl
Solvent: O
Product: COc1ccc2c(c1)CCOC2CCl
Yield: 9.6 %

Procedure:
A mixture of 30 g of 3-methoxyphenethyl alcohol, 30 g of chloroacetaldehyde diethyl acetal and 50 ml of concentrated hydrochloric acid was heated at 60°-80° C for 30 minutes, and, after cooling, water was added to the reaction mixture. The resultant oil was extracted into ethyl acetate, rinsed with water and dried. By this procedure was obtained 4.0 g of 1-chloromethyl-6-methoxyisochroman as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:5]([CH:19]=[N:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:4]=1.[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:5]([CH2:19][NH:20][CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:4]=1
Reactant: COc1ccc(OCCCN2CCOCC2)c(C=NCCc2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(OCCCN2CCOCC2)c(CNCCc2ccccc2)c1
Temperature: 35 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
A stirred solution of 4-[3-[4-methoxy-2-[[(2-phenylethyl)imino]methyl]phenoxy]propyl]morpholine (41.7 g) in 190 ml of methanol is reduced with 12.4 g of sodium borohydride (added portionwise). A cold water bath is used to maintain the temperature of the reaction mixture at 35° C. After 3 hours, the solvent is treated with water and the product is extracted two times with ether. The ether fractions are combined, treated with water, dried and concentrated to give 33.3 g of the title compound, boiling point 249°-254° C. at 0.3-0.4 mm of Hg.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=O.[K+].S(Cl)(Cl)=O.C(N(C(C)C)CC)(C)C.[NH2:25][C:26]1[C:27]([Br:34])=[N:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1>C(Cl)(Cl)Cl>[Br:34][C:27]1[C:26]([NH:25][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[N:10][C:2]=2[CH3:1])=[CH:31][CH:30]=[C:29]([O:32][CH3:33])[N:28]=1
Reactant: COc1ccc(N)c(Br)n1
Reactant: Cc1ncccc1C(=O)[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COc1ccc(NC(=O)c2cccnc2C)c(Br)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.4 %

Procedure:
To a suspension of potassium 2-methylnicotinate (1.96 g) in chloroform (30 mL) was added thionyl chloride (2.5 mL). The mixture was stirred overnight at room temperature under a drying tube. Diisopropylethylamine (5 mL) was added followed by 3-amino-2-bromo-6-methoxypyridine (2.25 g). After 10 minutes additional diisopropylethylamine (5 mL) was added. After 2 hours the mixture was diluted with chloroform, washed with water, dried (Na2SO4,) filtered, and evaporated. Chromatography of the residue over silica gel (chloroform/methanol) gave N-(2-bromo-6-methoxy-3-pyridinyl)-2-methylnicotinamide (2.80 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:20][CH2:19]3)=[CH:14][CH:13]=2)[C:5]([Cl:10])=[C:6]([OH:9])[C:7]=1[OH:8].Br[CH2:22]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[C:7]2[O:8][CH2:22][O:9][C:6]=2[C:5]([Cl:10])=[C:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:19][CH2:20]3)=[CH:14][CH:13]=2)[CH:3]=1
Reactant: Oc1c(Br)cc(Cc2ccc(C3CC3)cc2)c(Cl)c1O
Reactant: BrCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1c(Cc2ccc(C3CC3)cc2)cc(Br)c2c1OCO2
Temperature: 90 °C
Reaction time: 12 h
Yield: 64.6 %

Procedure:
To a solution of phenol 192 (1.75 g, 4.95 mmol) in DMF (25 mL) were added dibromomethane (0.42 mL, 5.94 mmol) and Cs2CO3 (5.7 g, 17.3 mmol) at r.t. The mixture was stirred at 90° C. for 12 hours. The mixture was cooled to r.t. and filtered off to remove inorganic salts. The filtrate was extracted with EtOAc/aq. 50% NaCl solution (100 mL/500 mL). The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the product 193 (1.17 g, 65%).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH:4]=[CH2:5].CC(C)C(=O)C.[CH:13]12[O:18][CH:14]1[CH2:15][CH2:16][CH2:17]2>>[CH:4]1[CH2:3][CH2:2][CH2:1][CH:5]=1.[C:14]1(=[O:18])[CH2:15][CH2:16][CH2:17][CH2:13]1
Reactant: C1CC2OC2C1
Reactant: C=CCCC=O
Solvent: CC(=O)C(C)C
Product: C1=CCCC1
Product: O=C1CCCC1

Procedure:
According to the invention, it is possible that the mixture which comprises 4-pentenal, 3-methyl-2-butanone and cyclopentene oxide and is obtained as a by-product of the oxidation of cyclopentene to cyclopentanone is used directly in the oxidation in step (a) of the process according to the invention. However, it is also possible in principle that a mixture obtained as a by-product of the oxidation of cyclopentene to cyclopentanone is first treated suitably before use in step (a). For example, this mixture, before step (a), can be concentrated and/or the proportion of other components which disrupt step (a) and/or subsequent steps in the mixture can be reduced.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1)=[O:4].[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].[OH-].[Na+]>CN(C)C=O.C(O)C>[CH2:14]([N:17]([CH2:18][CH2:19][CH3:20])[C:11]([C:8]1[CH:7]=[CH:6][C:5]([C:3]([OH:2])=[O:4])=[CH:10][N:9]=1)=[O:13])[CH2:15][CH3:16]
Reactant: CCCNCCC
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1ccc(C(=O)O)cn1
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
N,N′-carbonyldiimidazole (145 mg, 0.89 mmol) was added to a solution of 5-(methoxycarbonyl)pyridine-2-carboxylic acid (162 mg, 0.89 mmol) in N,N-dimethylformamide (2.5 mL) at 60° C. The reaction mixture was stirred at 60° C. for 10 min. Dipropylamine (90 mg, 0.89 mmol) in N,N-dimethylformamide (1 mL) was added, and the reaction mixture was stirred at ambient temperature over night. The mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. Half the amount of the crude intermediate (83 mg, 0.31 mmol) was dissolved in ethanol (3 mL) and 1 M sodium hydroxide (3 mL, 3 mmol) and heated to 50° C. for 30 min. The solvents were removed in vacuo and the residue was dissolved in water (3 mL) and cooled on ice. A 6 M hydrochloric acid solution was added dropwise and the solvents were removed in vacuo. The residue was added acetonitrile followed by evaporation in vacuo in order to remove trace of water. The procedure was repeated twice. The material was suspended in N,N-dimethylformamide and filtered. The filtrate was concentrated in vacuo to give 80 mg (64% total yield); MS (APPI/APCI) m/z 251[M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].N1C=CC=CC=1.[O:18](S(C(F)(F)F)(=O)=O)[S:19]([C:22]([F:25])([F:24])[F:23])(=O)=[O:20].CCOC(C)=O>C(Cl)Cl>[CH:4]([C:3]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=1[O:1][S:19]([C:22]([F:25])([F:24])[F:23])(=[O:20])=[O:18])=[O:5]
Reactant: COc1ccc(C=O)c(O)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C=O)c(OS(=O)(=O)C(F)(F)F)c1
Temperature: -10 °C
Reaction time: 2.5 h
Yield: 82.2 %

Procedure:
To a solution of 2-hydroxy-4-methoxy-benzaldehyde (30 g, 197 mmol) in DCM (anhydrous, 120 mL) was added pyridine (79 mL, 986 mmol) at room temperature. After the mixture was cooled to −10° C., the Tf2O (50 mL, 296 mmol) was slowly added to the reaction between −10° C. to 0° C. The addition took about 2.5 hours. After the addition, the stirring was kept for 30 minutes. The EtOAc (200 mL) was added. The organic layer was washed with 1 M HCl (3×80 mL), dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified over silica gel, eluting with 5% EtOAc/hexanes to give trifluoro-methanesulfonic acid 2-formyl-5-methoxy-phenyl ester (2) 46 g in 82% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.13 (s, 1 H), 7.95 (d, J=8.99 Hz, 1 H), 7.03 (dd, J=8.60, 2.34 Hz, 1 H), 6.88 (d, J=2.34 Hz, 1 H), 3.93 (s, 3 H)
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([OH:36])=[C:17]([CH2:19][N:20]2[N:24]=[C:23]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[O:22][C:21]2=[O:35])[CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:36][C:16]2[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][C:17]=2[CH2:19][N:20]2[N:24]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=3)[O:22][C:21]2=[O:35])=[O:8])=[CH:5][CH:4]=1
Reactant: O=c1oc(-c2ccc(C(F)(F)F)cc2)nn1Cc1cc(Cl)ccc1O
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Oc1ccc(Cl)cc1Cn1nc(-c2ccc(C(F)(F)F)cc2)oc1=O)c1ccc(CCl)cc1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
A solution of 4-(chloromethyl)benzoyl chloride (2.24 g, 11.9 mmol) in methylene chloride (25 mL) was added to a cold (0° C.) stirred suspension of 3-[(5-chloro-2-hydroxyphenyl)methyl]-5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2(3H)-one (4.0 g, 10.8 mmol) and pyridine (0.96 mL, 11.9 mmol) in methylene chloride (25 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with 1 N HCl and extracted with ethyl acetate (100 mL). The organic layer was separated and washed with sat'd NaHCO3, water, brine and then dried (MgSO4). Evaporation of the solvent gave the crude product which was recrystallized from methylene chloride/hexanes to afford the title compound as white crystals (4.8 g, 85%): mp 142-144° C.; MS m/e: 523 (MH+).
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=[O:4].[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11]>>[CH2:10]([N:12]([CH2:13][CH3:14])[C:1](=[O:7])[CH2:2][C:3](=[O:4])[CH3:5])[CH3:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: CCNCC
Product: CCN(CC)C(=O)CC(C)=O
Yield: 65.7 %

Procedure:
40 g (0.31 mol) of ethyl acetoacetate and 24 g (0.33 mol) of diethylamine were stirred in a Parr apparatus at 150° C. for 10'. The crude mixture was distilled at 115°-120° C./9 mmHg, to give 32 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:15][C@H:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:17][OH:18])=[N:4][C:5]([NH:8][C:9]2[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=2)=[CH:6][CH:7]=1.[C:26](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C@@H:16]([N:15]2[C:3]3=[N:4][C:5]([NH:8][C:9]4[CH:13]=[C:12]([CH3:14])[NH:11][N:10]=4)=[CH:6][CH:7]=[C:2]3[N:1]=[CH:26]2)[CH2:17][OH:18])=[CH:24][CH:23]=1
Reactant: Cc1cc(Nc2ccc(N)c(N[C@@H](CO)c3ccc(F)cc3)n2)n[nH]1
Reactant: CC(=O)O
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(Nc2ccc3ncn([C@@H](CO)c4ccc(F)cc4)c3n2)n[nH]1

Procedure:
(R)-2-(3-Amino-6-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Method 62, 0.28 g, 0.82 mmol) and formamidine acetate (0.17 g, 1.6 mmol) in EtOH (5 ml) was heated at reflux overnight. Saturated sodium bicarbonate solution (10 ml) and EtOAc (30 ml) was added. The organic layer was separated, washed with brine (10 ml) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by chromatography (EtOAc-MeOH=40:1) to give the title compound as off white solid (0.021 g, 73%). 1H NMR (400 MHz) δ 11.72 (s, 1H), 9.24 (s, 1H), 8.33 (s, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.40 (m, 2H), 7.17 (m, 2H), 6.93 (d, J=8.0 Hz, 1H), 6.27 (s, 1H), 5.71 (br s, 1H), 5.32 (t, J=4.2 Hz, 1H), 4.34 (m, 1H), 4.12 (m, 1H), 4.03 (m, 1H), 2.22 (s, 3H). MS: Calcd.: 352. Found: [M+H]+ 353.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2].B(F)(F)F.[CH3:59][CH2:60]OCC.[N+](=CC)=[N-]>CCOCC>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH2:59][CH3:60])[CH2:45]2)[CH:7]([CH3:53])[CH2:6][CH2:5][C:4]1=[O:54])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: CCOCC
Agent: CC=[N+]=[N-]
Agent: FB(F)F
Product: CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-di-methoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (200 mg, Example 38) in ether (6 ml) is added borontrifluoride etherate (10 μl) followed by freshly prepared diazoethane (100 fold excess). The mixture is stirred at room temperature for 15 min and quenched with sat'd aqueous sodium bicarbonate solution. The organic layer is separated, washed (sat'd aqueous NaCl) and dried over anhydrous magnesium sulfate. Removal of solvent followed by preparative tlc on silica to separate the regioisomers gives the title compound.
Reaction SMILES: C1(=O)C2C(=CC=CC=2)C=CC1.[C:12]1(O)[C:21]2[CH2:20][CH2:19][CH:18]([OH:22])[CH2:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.O1CC1COC1C=CC=C2C=1CCC(O)C2>>[CH:17]1[C:16]2[C:21](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:20]=[CH:19][C:18]=1[OH:22]
Reactant: Oc1cccc2c1CCC(O)C2
Agent: O=C1CC=Cc2ccccc21
Agent: OC1CCc2c(cccc2OCC2CO2)C1
Product: Oc1ccc2ccccc2c1

Procedure:
Employing the procedure of Example 3 (a), but substituting a 6-alkoxy-1-tetralone as shown in the left hand (first) column of Table II for 6-methoxy-1-tetralone, a 6-alkoxy-1-naphthol is produced, which is converted as per Example 3 (b) to the corresponding 5-hydroxy-3,4-dihydro-2(1 H)-naphthalenenone shown in the middle column of Table II; employing the procedure of Example 3 (c) the naphthalenone is converted to the corresponding 5,6,7,8-tetrahydro-1,6-naphthalenediol which is reacted with an epoxide of the structure ##EQU13## in accordance with the procedure of Example 3 d to form the corresponding 1,2,3,4-tetrahydro-5-[2,3-epoxy-propoxy]-2-naphthol which is reacted with an amine of the structure ##EQU14## in accordance with the procedure of Example 3 e to form the corresponding 1,2,3,4-tetrahydro-5-[2-hydroxy-3-(R1, R2 -substituted amino)propoxy]-2-naphthol (formula I) as shown in the right hand (third) column of Table II.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]1[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=[CH:26][C:23]=1[CH:24]=O.C(O)=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([CH2:24][C:23]3[CH:26]=[CH:27][C:28]([O:32][CH3:33])=[C:29]([O:30][CH3:31])[C:22]=3[O:21][CH3:20])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: COc1ccc(C=O)c(OC)c1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=CO
Product: COc1ccc(CN2CCC(c3ccc(Oc4ccccc4)cc3)CC2)c(OC)c1OC
Temperature: 120 °C
Yield: 73 %

Procedure:
A mixture of 1.27 g of the compound (9) synthesized in Example 2 and 0.8 g of 2,3,4-trimethoxybenzaldehyde was stirred at 120° C., then, 0.18 ml of formic acid was added dropwise. This was stirred for one hour at the same temperature, then ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate were added and the results were shaken. The organic layer was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to obtain the above-referenced compound (29) in an amount of 1.46 g (yield 73%).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:27])=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1)=O)(C)(C)C.C([O:32]C(N[C@H]1CCN(S(C2C3C(Br)=CN=CC=3C=CC=2)(=O)=O)C1)=O)(C)(C)C>>[NH2:8][CH:9]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:18]3[C:19]([Cl:27])=[CH:20][N:21]=[C:22]([OH:32])[C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH2:10]1.[ClH:27]
Reactant: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Product: Cl
Product: NC1CCN(S(=O)(=O)c2cccc3c(O)ncc(Cl)c23)C1

Procedure:
Intermediate 16 can be used in the method of Example 6-1, Step A instead of Intermediate 1a, then the resultant can be used in the method of Step B in a similar manner, and then the title compound can be obtained as hydrochloride according to the method described in Example 7-1.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([CH3:28])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:29][O:30][CH:31]1[C:36](=O)[CH2:35][CH2:34][O:33][CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[C:20]([CH3:28])[N:19]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:36]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[O:30][CH3:29])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](N)C3)CC2)n1
Reactant: COC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)cc(C)n3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-(4-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine (120 mg, 0.30 mmol), 3-methoxytetrahydro-4H-pyran-4-one (120 mg, 0.90 mmol), and triethylamine (0.12 mL, 0.90 mmol) in methylene chloride (20 mL) was added sodium triacetoxyborohydride (0.19 g, 0.90 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with methylene chloride, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography to provide the desired product as a mixture of cis/trans isomers. LCMS calculated for C26H40F3N4O3: (M+H) 513.3; found 513.2 for both isomers.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][NH:12][C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[CH3:26][Si]([N-][Si](C)(C)C)(C)C.CI>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][CH2:22][C:10]2([C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:13][N:12]([CH3:26])[C:11]2=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NN=C2c1ccccc1
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: CN1N=C(c2ccccc2)C2(CCCN(C(=O)OC(C)(C)C)C2)C1=O
Temperature: 25 °C

Procedure:
To a solution of racemic mixture of 4-Oxo-1-phenyl-2,3,7-triaza-spiro[4.5]dec-1-ene-7-carboxylic acid tert-butyl ester (150 mg, 0.45 mmol) in THF (3 ml) under nitrogen at −78° C. was added 1M LiHMDS solution in THF (0.55 ml, 0.55 mol). The reaction mixture was allowed to warm to RT for 30 mins before cooling back to −78° C. and adding 2M MeI in THF solution (0.45 ml, 0.9 mmol). The reaction mixture was left to warm to RT overnight. The mixture was diluted with EtOAc (10 ml) and washed with brine (20 ml). The aqueous phase was extracted with a further EtOAc (10 ml). The organics portions were combined, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-50% EtOAc in iso-hexane afforded the title compound.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][C:5]([C:14]#[N:15])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.C(N(CC)CC)C.[CH3:26][N:27]([CH3:33])[C@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1.C(=O)([O-])O.[Na+]>CS(C)=O.C(OCC)(=O)C>[CH3:26][N:27]([CH3:33])[C@H:28]1[CH2:32][CH2:31][N:30]([C:2]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][C:5]([C:14]#[N:15])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=2)[CH2:29]1
Reactant: N#Cc1cc(-c2ccccc2)c(F)cc1[N+](=O)[O-]
Reactant: CN(C)[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C)[C@H]1CCN(c2cc([N+](=O)[O-])c(C#N)cc2-c2ccccc2)C1
Reaction time: 19 h
Yield: 94.8 %

Procedure:
6-Fluoro-4-nitrobiphenyl-3-carbonitrile (I-241) (6.0 g, 24.77 mmol) was dissolved in dimethyl sulfoxide (60 ml), and at room temperature, triethylamine (6.9 ml, 49.54 mmol) and (3S)-3-(dimethylamino)pyrrolidine (3.77 ml, 29.73 mmol) were added. After stirring at the same temperature for 19 hours, the reaction liquid was fractionated with ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was subjected to column chromatography with silica gel, and the fraction with chloroform:methanol=95:5 gave the entitled compound (7.90 g, 95%) as an orange powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([O:23][C:24](=[O:26])[CH3:25])=[C:8]2[CH:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:34])C(=O)C1.C(OOC(C1C=CC=CC=1)=O)(C1C=CC=CC=1)=O>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:23][C:24](=[O:26])[CH3:25])=[C:8]2[C:16]([Br:34])=[CH:15][N:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2-c2ccccc2)c1OC(C)=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: CCOC(=O)c1nc(C#N)c2c(c(Br)cn2-c2ccccc2)c1OC(C)=O

Procedure:
Prepared in analogy to a bromination procedure in that of Example 103(a) from 4-Acetoxy-7-cyano-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, NBS and BzOOBz. The title compound, ESI MS (m/z): 428 (M+H)+.