Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1)=[C:2]=[S:3].[CH3:16][O:17][C:18](=[O:31])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:29]#N)([CH3:28])[CH3:27])=[CH:21][CH:20]=1.C[OH:33].Cl>CN(C=O)C.O>[CH3:16][O:17][C:18](=[O:31])[C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:26]([CH3:27])([CH3:28])[C:29](=[O:33])[N:1]([C:4]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([C:12]([F:13])([F:15])[F:14])[CH:5]=3)[C:2]2=[S:3])=[CH:21][CH:20]=1
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: CO
Reactant: COC(=O)c1ccc(NC(C)(C)C#N)cc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1
Temperature: 60 °C
Yield: 63 %

Procedure:
A mixture of 4-isothiocyanato-2-trifluoromethylbenzonitrile (1a) (0.228 g, 1 mmol) and 4-[(cyanodimethylmethyl)-amino]-benzoic acid methyl ester (49b) (0.14 g, 0.64 mmol) in DMF (2 ml) was heated under microwave irradiation at 60° C. for 12 hours. To this mixture were added methanol (6 ml) and aq. 2N HCl (2 ml). The second mixture was refluxed for 4 h. After being cooled to room temperature, the reaction mixture was poured into cold water (10 ml) and extracted with ethyl acetate (3×30 ml). The organic layer was dried over MgSO4, concentrated and chromatographed (dichloromethane; dichloromethane:acetone, 75:25) to yield 4-[3-(4-cyano-3-trifluoromethylphenyl)-5,5-dimethyl-4-oxo-2-thioxo-imidazolidin-1-yl]benzoic acid methyl ester (49c) [RD152] (0.18 g, 0.4 mmol, 63%), the structure of which is illustrated in Formula 19, as a white powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=4)[C:27]=3[CH3:28])=[O:22])=[CH:16][C:15]=2[CH3:39])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:28][C:27]1[N:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][N:30]=2)[N:25]=[CH:24][C:23]=1[C:21]([NH:20][C:17]1[CH:18]=[N:19][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[C:15]([CH3:39])[CH:16]=1)=[O:22]
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.8 %

Procedure:
To N-[6-(1-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)-5-methylpyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (3.4 g) were added dichloromethane (63 ml) and trifluoroacetic acid (13 ml), stirred at room temperature for 2 hours, and then to the reaction solution was added 4 N aqueous solution of sodium hydroxide under ice-cooling. The precipitated solid was washed with ethanol and water to give the titled compound (2.6 g) as a white solid.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)[C:10]([OH:25])=[C:9]([C:26](OCC)=[O:27])[C:8]2=[O:31])[CH2:3][CH2:2]1.[CH3:33][O:34][CH2:35][CH2:36][NH2:37]>>[CH:1]1([NH:4][C:5](=[O:32])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)[C:10]([OH:25])=[C:9]([C:26]([NH:37][CH2:36][CH2:35][O:34][CH3:33])=[O:27])[C:8]2=[O:31])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CC2)c1=O
Reactant: COCCN
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CC2)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(cyclopropylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine by methods similar to those described in Example 245. The crude material was triturated with a mixture of MeOH and 1N HCl to afford the product as a white solid: 1H NMR (d6-DMSO) δ 10.22 (1H, br), 8.54 (1H, br s), 8.24 (1H, br s), 7.74 (1H, br s), 7.32 (2H, m), 7.11 (2H, m), 4.80 (2H, s), 4.11 (2H, s), 3.51 (4H, m), 3.27 (3H, s), 2.56 (1H, m), 0.59 (2H, m), 0.34 (2H, m); HRMS calcd for C24H25FN4O5+H+: 469.1887. Found: 469.1882.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:37][CH3:38])=[CH:5][C:6]2[CH2:12][CH2:11][CH2:10][C:9]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)[CH2:17][CH:16]3[CH2:34][OH:35])=[O:14])=[CH:8][C:7]=2[CH:36]=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:39]([O:35][CH2:34][CH:16]1[CH2:17][N:18]([CH2:21][C:22]2[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=2)[CH2:19][CH2:20][N:15]1[C:13]([C:9]1[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([O:37][CH3:38])[C:3]([O:2][CH3:1])=[CH:36][C:7]=2[CH:8]=1)=[O:14])(=[O:41])[CH3:40]
Reactant: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1CO)=C2
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)CCCC(C(=O)N1CCN(Cc3cc(OC)c(OC)c(OC)c3)CC1COC(C)=O)=C2
Temperature: 25 °C
Reaction time: 20 h
Yield: 77.8 %

Procedure:
A mixture of 1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine-2-methanol (500 mg), acetic anhydride (153 mg), triethylamine (150 mg), 4dimethylaminopyridine (10 mg) and methylene chloride (5 ml) is stirred for 20 hours at room temperature. To the reaction mixture is added methylene chloride, and the organic layer is washed with an aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate, then concentrated under reduced pressure. The concentrate is purified by means of a silica gel column chromatography (eluent:ethyl acetate) to give 2-acetoxymethyl-1-(2,3-dimethoxy-6,7-dihydro-5H-benzocyclohepten-8-ylcarbonyl) -4-(3,4,5-trimethoxybenzyl)piperazine (420 mg). This product is converted to its hydrochloride, followed by recrystallization from ethanol to give colorless prisms, m.p. 135-139° C.
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[CH:8]1.C(N(CC)CC)C.[C:28](Cl)(=[O:30])[CH3:29].O>N1C=CC=CC=1>[NH2:20][C:11]1[C:10]2[N:9]=[CH:8][N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][NH:1][C:28](=[O:30])[CH3:29])[C:19]=2[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[N:12]=1
Reactant: CC(=O)Cl
Reactant: NOCCCCn1cnc2c(N)nc3c(c21)CCCC3
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)NOCCCCn1cnc2c(N)nc3c(c21)CCCC3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the 1-[4-(aminooxy)butyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine from Part C (200 mg, 0.73 mmol) and triethylamine (512 μL, 3.56 mmol) in pyridine (25 mL) was added acetyl chloride (57 μL, 0.80 mmol). The solution was stirred for 30 minutes at ambient temperature, and additional acetyl chloride (1 equivalent) was added. After 1 hour, water was added and the mixture was extracted with dichloromethane (2×). The aqueous layer was concentrated under reduced pressure to yield a white solid that was purified by chromatography (silica gel, gradient elution with 0-10% methanol in dichloromethane with a small amount of concentrated ammonium hydroxide added) to provide 30 mg of N-[4-(4-amino-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl)butoxy]acetamide as a white solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1([C:16](OC)=[O:17])[CH2:15][CH:14]=[CH:13][CH2:12]1)=O>O1CCCC1.C1(C)C=CC=CC=1>[OH:8][CH2:9][C:11]1([CH2:16][OH:17])[CH2:15][CH:14]=[CH:13][CH2:12]1
Reactant: COC(=O)C1(C(=O)OC)CC=CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCC1(CO)CC=CC1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
The desired diol 2 was prepared via LAH reduction of the corresponding diester 1. To a flame dried round-bottomed flask was placed lithium aluminum hydride (LAH, Aldrich 95%, 6.99 g, 175 mmol) and anhydrous tetrahydrofuran (THF, 235 mL). The resulting suspension was cooled to 0° C. and then a solution of the dimethyl diester 1 in 58 mL of anhydrous THF was added dropwise via an additional funnel. The resulting mixture was allowed to stir at ° C. for 4 hours while monitored by TLC. The reaction mixture was then carefully quenched by sequential addition of 6 mL of water, 6 mL of 3 N aqueous solution of NaOH and 17.5 mL of water. The resulting mixture was allowed to slowly come to room temperature and then filtered through a bed of Celite. The resultant solid cake was washed repeatedly with refluxing THF (total of 250 mL). The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford a light yellow oil which was dissolved in 150 mL of refluxing toluene and the water was azeotropically removed. Removal of the remaining toluene gave an off-white solid, which was recrystallized from refluxing toluene. The desired diol 2 was obtained as white needles in 86.2% yield. Mp (DSC) 81.21° C., 1H-NMR (CDCl3, 300 MHz) δ5.59 (s, 2H), 3.73 (s, 2H), 3.63 (s, 4H), 2.16 (S, 4H); 13C-NMR (CDCl3, 300 MHz) δ128.69, 69.19, 47.53, 38.61; FT-IR (CH2Cl2) (cm−1) 3323, 3055, 2918, 2846, 1619, 1442, 1419, 1357, 1266 1114, 1093, 1025, 955, 909, 896.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[CH:13][C:12]([CH2:23][N:24]([CH3:34])[C:25](=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:35]1[CH2:39][C:38](=[O:40])[NH:37][C:36]1=[O:41]>>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH:21]=[C:39]3[S:35][C:36](=[O:41])[NH:37][C:38]3=[O:40])=[CH:19][CH:20]=2)=[CH:13][C:12]([CH2:23][N:24]([CH3:34])[C:25](=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CSC(=O)N1
Reactant: CCCCCCCC(=O)N(C)Cc1ccc(OCc2ccccc2)c(-c2ccc(C=O)cc2)c1
Product: CCCCCCCC(=O)N(C)Cc1ccc(OCc2ccccc2)c(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1

Procedure:
In a manner similar to that of Example 1(f), by reacting 11.5 g (22 mmol) of N-(6-benzyloxy-4′-formylbiphenyl-3-ylmethyl)-N-methyloctanamide and 2.5 g (22 mmol) of 2,4-thiazolidine dione, the expected product is obtained in the form of a pale yellow powder with a melting point of 162° C.
Reaction SMILES: C1(C(=[N:14][C:15]([CH3:22])([CH2:18][CH2:19][CH2:20][F:21])[C:16]#[N:17])C2C=CC=CC=2)C=CC=CC=1.[ClH:23]>O1CCCC1.O>[ClH:23].[NH2:14][C:15]([CH3:22])([CH2:18][CH2:19][CH2:20][F:21])[C:16]#[N:17]
Reactant: CC(C#N)(CCCF)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(N)(C#N)CCCF
Temperature: 25 °C
Reaction time: 8 h

Procedure:
18.94 g (56.62 mmol; 88% purity) of rac-2-[(diphenylmethylene)amino]-5-fluoro-2-methylpentanonitrile from Example 71A were dissolved in 264.6 ml of tetrahydrofuran and 10.2 ml of water, 124.6 ml (62.28 mmol) of hydrogen chloride solution (0.5 N in diethyl ether) were added and the mixture was stirred at room temperature overnight. The reaction solution was admixed with 28.3 ml (56.62 mmol) of hydrogen chloride solution (2 N in diethyl ether) and concentrated by rotary evaporation. The isolated crude product was reacted further directly without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14](Cl)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(O)(C)C>[CH2:1]([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:13][CH:12]=[N:11][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncnc2c1CCN(Cc1ccccc1)C2
Reactant: C1COCCN1
Solvent: CC(C)O
Product: c1ccc(CN2CCc3c(ncnc3N3CCOCC3)C2)cc1
Yield: 100.1 %

Procedure:
To a solution of 7-benzyl-4-chloro-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine 4a (0.46 g, 1.77 mmol) in isopropanol (20 mL) was added morpholine (0.38 g, 4.42 mmol), and the reaction mixture was heated to reflux for 18 h. The solvent was removed in vacuo, and the residue was suspended in a saturated solution of NaHCO3, and the product was extracted with dichloromethane. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to provide a residue, which was purified by chromatography to give 0.55 g of 7-benzyl-4-morpholin-4-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine 5a as a pale yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:22])([CH2:16][O:17]C(=O)CC)[CH2:10][O:11][C:12](=[O:15])[CH2:13][CH3:14].C([O-])(=O)C>C1CCCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:22])([CH2:10][O:11][C:12](=[O:15])[CH2:13][CH3:14])[CH2:16][OH:17]
Reactant: CCC(=O)OCC(O)(COC(=O)CC)c1ccc(F)cc1F
Agent: CC(=O)[O-]
Solvent: C1CCCCC1
Product: CCC(=O)OC[C@](O)(CO)c1ccc(F)cc1F
Temperature: 30 °C
Yield: 62.8 %

Procedure:
A 200 ml reaction vessel was charged with 3 g of 2-(2,4-difluorophenyl)-1,3-dipropionyloxy-2-propanol, 200 mg of Lipase D made by Amano Pharmaceutical Co., Ltd. (derived from Rhizpus delemer, Enzyme No. 6), 100 ml of 50 mM acetate buffer (pH 5) and 10 ml of cyclohexane. The resulting mixture was stirred at 30° C. to react for 18 hours. After the reaction liquid was extracted three times with 50 ml of ethylacetate, the organic layers were combined and the combined organic layer was washed with saturated aqueous solution with sodium bicarbonate and with saturated aqueous solution with sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give 1.55 g of oily (R)-2-(2,4-difluorophenyl)-3-propionyloxy-1,2-propanediol. An optical purity thereof was determined in the same manner as in Example 35. (Elution time: 16.7 minutes ((R)-form) and 13.5 minutes ((S)-form)).
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][CH2:4][N:3]=1.[CH3:7][C:8]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=1[NH2:10]>C(#N)C>[CH3:7][C:8]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:9]=1[NH:10][C:2]1[CH2:6][CH2:5][CH2:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Reactant: ClC1=NCCC1
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])ccc1NC1=NCCC1
Yield: 51.5 %

Procedure:
A mixture of 2-chloro-1-pyrroline (1.2 mole), prepared as in Example 1, and 91.3 g (0.6 mole) of 2-methyl-4-nitroaniline were heated at reflux in 900 ml of acetonitrile for two hours. The solid obtained by cooling and filtering was combined with that obtained by concentrating the filtrate to dryness, then dissolved in hot water and filtered. The solution was cooled and washed with ethyl acetate, and the aqueous phase was made basic with 4 N sodium hydroxide. The crude product was extracted into dichloromethane, which was then removed in vacuo. The resultant solid was washed repeatedly with diethyl ether to give 67.7 g of pure title compound. Structure assignment was supported by the nmr spectrum and by elemental analysis.
Reaction SMILES: [C:1]1([C:6]2[CH:7]=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([CH:12]=2)[NH2:11])[CH2:5][CH2:4][CH2:3][CH:2]=1.C(N(CC)CC)C.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH3:35][NH:36][CH2:37][CH2:38][CH3:39]>ClCCl>[C:1]1([C:6]2[CH:7]=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[C:10]([NH:11][C:27](=[O:33])[N:36]([CH3:35])[CH2:37][CH2:38][CH3:39])[CH:12]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCCNC
Reactant: Nc1cc(C2=CCCC2)ccc1[N+](=O)[O-]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(C)C(=O)Nc1cc(C2=CCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.7 %

Procedure:
To a solution of 5-(cyclopent-1-en-1-yl)-2-nitroaniline (0.13 g, 0.61 mmol, 1.0 equiv.) in dichloromethane were added triethylamine (0.68 mL, 4.90 mmol, 8.0 equiv.) and triphosgene (0.18 g, 0.61 mmol, 1.0 equiv.) at 0° C. The mixture was warmed to room temperature and stirred for 3 h at room temperature. Triethylamine (0.17 mL, 1.22 mmol, 2.0 equiv.) and N-methylpropan-1-amine (0.07 g, 0.92 mmol, 1.5 equiv.) were added slowly to the reaction mixture. The reaction mixture was slowly warmed to 50° C. and stirred for 2 h. The mixture was diluted with dichloromethane, washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give crude 3-(5-(cyclopent-1-en-1-yl)-2-nitrophenyl)-1-methyl-1-propylurea (0.14 g, 76% crude yield) which was used in the next step without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([OH:15])[CH:9]=1)(C)(C)C.[CH3:17][N:18]1[CH2:22][CH2:21][C@H:20](O)[CH2:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([NH2:7])=[CH:9][C:10]=1[O:15][C@@H:20]1[CH2:21][CH2:22][N:18]([CH3:17])[CH2:19]1
Reactant: CN1CC[C@H](O)C1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)c(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN1CC[C@@H](Oc2cc(N)ccc2Cl)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.7 %

Procedure:
To a cooled (0° C.) solution of 4-chloro-3-hydroxyphenylcarbamic acid tert-butyl ester (55 g, 0.23 mol), (S)-1-methyl-pyrrolidin-3-ol (24 g, 0.24 mol), and triphenylphosphine (89 g, 0.34 mol) in THF (1.1 L) was added dropwise via addition funnel a solution of DIAD (67 mL, 0.34 mol) in THF (100 mL) over 1 h. The resultant solution was allowed to slowly warm to ambient temperature and maintained for 16 h. The THF was removed in vacuo and the residue treated with 6 N HCl (650 mL). The resultant mixture was stirred at room temperature for 4 h, at which time it was diluted with water (500 mL) and the filtered to remove the triphenylphosphine oxide. The filtrate was washed with EtOAc (3×1 L) and chloroform (5×1 L) to remove additional reaction by-products. The aqueous layer was then basified with solid NaOH pellets and extracted with ether (2×1 L) and EtOAc (2×1 L). The combined organic layers were washed with saturated NaHCO3 (2×1 L) and brine (1 L), dried (MgSO4), and concentrated to give 40 g (80%) of the title compound: MS (ES+) m/e [M+H]+227.
Reaction SMILES: C([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])C.[OH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[CH2:23]CC#N>>[OH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[CH2:23][CH2:14][C:13]1[NH:3][C:4](=[O:12])[C:5]2[C:6]([CH:11]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: CCN(CC)C(=O)c1ccccc1C
Reactant: N#CCCN1CCCCC1CO
Product: O=c1[nH]c(CCN2CCCCC2CO)cc2ccccc12
Yield: 15.3 %

Procedure:
By the reaction in the same manner as in Example 1a, using N,N-diethyl-2-methylbenzamide (3.42 g) and 3-(2-hydroxymethylpiperidin-1-yl)propionitrile (1.51 g), 3-[2-(2-hydroxymethylpiperidin-1-yl)ethyl]-2H-isoquinolin-1-one (392 mg) was obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([CH2:8]Cl)[N:5]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[N:4]=1.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K]>CN(C=O)C>[C:27]1(=[O:37])[N:31]([CH2:2][C:3]2[CH:7]=[C:6]([CH2:8][N:31]3[C:30](=[O:32])[C:29]4=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]4[C:27]3=[O:37])[N:5]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=3[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])[N:4]=2)[C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12
Reactant: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1nc(CCl)cc1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1cc([N+](=O)[O-])ccc1-n1nc(CN2C(=O)c3ccccc3C2=O)cc1CN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 12.8 g. (32.8 mmol) of the end product of Example 24, 18.5 g. (100 mmol) of potassium phthalimide, and 250 ml. of DMF was stirred and heated at 65° for 18 hours. After cooling, the mixture was poured over ice, washed with dil. brine, dried (MgSO4) and concentrated in vacuo. The residue was filtered through silica gel using EtOAc as an eluent. Removal of the solvent left the end product as a pale yellow solid, mp. 220°-224°. The analytical sample was prepared by recrystallization from acetone-hexane: pale yellow needles, mp 225°-226.5°.
Reaction SMILES: [O:1]=[O+][O-].[C:4]1([CH3:21])[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=CC)[C:12]=1[OH:20]>C(OCC)(=O)C.C(O)(=O)C>[OH:20][C:12]1[C:11]([S:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH3:21])=[CH:16][CH:15]=[CH:14][C:13]=1[CH:17]=[O:1]
Reactant: O=[O+][O-]
Reactant: CC=Cc1cccc(Sc2ccccc2C)c1O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccccc1Sc1cccc(C=O)c1O

Procedure:
Ozone gas was introduced into a solution of 2-(o-tolylthio)-6-(1-propenyl)phenol (24.3 g) in a mixture of ethyl acetate (200 ml) and acetic acid (5 ml) at 3° C. for 1.5 hours. The excess of ozone was removed by air-bubbling and further decomposed with aqueous sodium hydrogen sulfite. The resultant organic layer was separated, washed with aqueous sodium hydrogen sulfite and water in turn, dried and then evaporated under reduced pressure. The oily residue was crystallized with ethanol to give yellow needles of 2-hydroxy-3-(o-tolylthio)benzaldehyde (12.2 g), mp. 42°-43° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:23][CH2:22]3)[CH:16]=2)[N:11]=1)([N+:7]([O-])=O)[CH3:6])[CH3:2]>C(O)(=O)C.C(#N)C.[Zn]>[CH2:1]([O:3][C:4](=[O:31])[C:5]([NH2:7])([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:25][CH2:26]3)[CH:16]=2)[N:11]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(N)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
2-[6-(trans-4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-2-nitro-propionic acid ethyl ester (76 mg, 0.00018 mol) was dissolved in acetic acid (1.0 mL, Fisher), and cooled in a 20° C. water bath, followed by addition of zinc (115 mg, 0.00176 mol, Aldrich) in small portions. After 2 h, the reaction was diluted with acetic acid and acetonitrile and filtered through a PTFE filter. The excess of solvents were removed under vacuum, and the residue was purified via preparative HPLC (10-90% acetonitrile with 0.1% TFA) to give a pure product (18 mg, 20%) as TFA salt.