Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:12][O:11][C:3]([CH3:10])([CH2:4][CH2:5][CH2:6][C:7]([CH3:9])=[CH2:8])[O:2]1.C([OH:15])C.[OH-].[Na+].OO>CCCCCC>[CH2:12]1[CH2:1][O:2][C:3]([CH3:10])([CH2:4][CH2:5][CH2:6][CH:7]([CH3:9])[CH2:8][OH:15])[O:11]1
Reactant: C=C(C)CCCC1(C)OCCO1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Product: CC(CO)CCCC1(C)OCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
To a solution of 6,6-ethylenedioxy-2-methyl-hept-1-ene (33.95 g) in hexane (132 ml) under a nitrogen atmosphere is added borane-methyl sulfide complex (7.05 ml) at 0° C. over a half hour period. The reaction is allowed to stir for 3 hours at room temperature and is treated with 95% ethanol (68 ml) and 3N sodium hydroxide (21.8 ml), cooled to 0° C., followed by the dropwise addition of 30% hydrogen peroxide (24.5 ml) to maintain a temperature of 25°-35° C. The reaction mixture is heated at reflux for one half hour, poured into ice water (500 ml) and partitioned between ether and water. The aqueous phase is extracted with ether and the combined extracts are washed with brine and dried (Na2SO4). The solvent is removed in vacuo to give 6,6-ethylenedioxy-2-methylheptanol (33.35 g, 89%), nmr (CDCl3,δ), 0.93 (d, 3H, ##STR55## 1.32 (s, 3H, ##STR56## 3.45 (bd, 2H, CHCH2O), 3.93 (s, 5H, ##STR57##
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C@@H:27]([OH:33])[C@H:26]([O:34][C:35](=[O:37])[CH3:36])[C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=[O:3])[CH3:2].N1C=CC=CC=1>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([O:4][C@H:5]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:28]2[C:27](=[O:33])[C@H:26]([O:34][C:35](=[O:37])[CH3:36])[C@@:25]2([CH3:38])[C@H:11]3[CH2:12][C@@H:13]3[O:18][C@@:17]4([O:24][CH2:23][C@H:21]([CH3:22])[CH2:20][CH2:19]4)[C@@H:15]([CH3:16])[C@@H:14]32)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2[C@@H](O)[C@H](OC(C)=O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)[C@H](OC(C)=O)[C@]2(C)[C@@H]4[C@H](C[C@@H]32)O[C@]2(CC[C@@H](C)CO2)[C@H]4C)C1

Procedure:
Using the procedure described in Org. Syn., 1976, 55, 84, (3β,5α,11β,12α,25R)-3,12-di(acetoxy)-spirostan-11-ol was oxidized with chromium trioxide and pyridine in methylene chloride to give the title compound.
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][CH:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]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:35]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[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: CC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](NC4CCOCC4C)C3)CC2)n1
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-methyltetrahydro-4H-pyran-4-one (100 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 four isomers. LCMS calculated for C26H39F3N4O2: (M+1) 497.3; found 497.2 for four isomers.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27](O)=[O:28])[N:22]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:27]([C:23]3[N:22]=[N:21][CH:26]=[CH:25][CH:24]=3)=[O:28])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccnn1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: O=C(Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1)c1cccnn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 3-pyridazinecarboxylic acid as starting materials, MS (LC/MS): 409.0 (M+H).
Reaction SMILES: [C:1](O)(=O)/C=C/C(O)=O.[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C@H:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][CH2:25][C@@H:26]2[O:40][C:30]3=[C:31]4[C:36](=[CH:37][CH:38]=[C:29]3[O:28][CH2:27]2)[N:35]=[C:34]([CH3:39])[CH:33]=[CH:32]4)[CH2:20]1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.CO>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C@H:19]1[CH2:23][CH2:22][C@@H:21]([N:24]([CH3:1])[CH2:25][C@@H:26]2[O:40][C:30]3=[C:31]4[C:36](=[CH:37][CH:38]=[C:29]3[O:28][CH2:27]2)[N:35]=[C:34]([CH3:39])[CH:33]=[CH:32]4)[CH2:20]1
Reactant: O=C(O)/C=C/C(=O)O
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CN[C@@H]1CC[C@H](c2c[nH]c4ccc(F)cc24)C1)O3
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN(C)[C@@H]1CC[C@H](c2c[nH]c4ccc(F)cc24)C1)O3
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a mixture of N-[(1R*,3S*)-3-(5-fluoro-1H-indol-3-yl)cyclopentyl]-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine fumarate (200 mg, 0.365 mmol) and formaldehyde (37%, 50 μL, 0.67 mmol) in 2:1 tetrahydrofuran/methanol (3 mL) was added sodium triacetoxyborohydride (155 mg, 0.73 mmol). The reaction was allowed to stir at ambient temperature overnight, then was quenched with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (2×20 cm silica gel, 3% methanol/methylene chloride) afforded 115 mg (70%) of the title compound as a semi-solid, which was converted to its fumarate salt as a white powder: mp 198-199° C. (dec); MS (ES) m/z 446 [M+H]+.[α]D5.3°(c 1.0, DMSO)
Reaction SMILES: Cl[C:2]1[C:3]([F:20])=[N:4][C:5]([F:19])=[C:6]([F:18])[C:7]=1[CH2:8][O:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>[Pd].C(O)C>[F:19][C:5]1[C:6]([F:18])=[C:7]([CH2:8][O:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:2]=[C:3]([F:20])[N:4]=1
Reactant: O=C(OCc1c(F)c(F)nc(F)c1Cl)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(OCc1cc(F)nc(F)c1F)c1ccccc1
Yield: 85.6 %

Procedure:
Benzoic acid 3-chloro-2,5,6-trifluoro-pyridin-4-ylmethyl ester (4.52 g, 15 mmol), anhydrous ethanol (50 ml), 10% palladium on carbon (500 mg), and triethylamine (2.5 ml, 18 mmol) were placed into a 500 ml bottle. The mixture was hydrogenated under hydrogen atmosphere (50 psi) for 1.5 hr. The reaction mixture was filtered through celite pad and the pad was washed with ethanol. The combined filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, ether:hexane (1:15)) to afford 3.43 g (85%) of benzoic acid 2,3,6-trifluoro-pyridin-4-ylmethyl ester as a white solid. m.p. 73-76° C.; 1H NMR (200 MHz, CDCl3) δ 5.52 (2H, s), 6.95 (1H, m), 7.30-7.70 (3H, m), 8.09-8.15 (2H, m).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]([CH3:27])[C:5]1[C:10]([N+:11]([O-])=O)=[C:9]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[NH:25][CH:24]=[N:23][N:22]=3)[CH:18]=[CH:17][C:16]=2[CH3:26])[N:8]=[CH:7][N:6]=1>CO.[Pd]>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][N:4]([CH3:27])[C:5]1[C:10]([NH2:11])=[C:9]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[NH:25][CH:24]=[N:23][N:22]=3)[CH:18]=[CH:17][C:16]=2[CH3:26])[N:8]=[CH:7][N:6]=1
Reactant: Cc1ccc(-c2nnc[nH]2)cc1Nc1ncnc(N(C)CC(C)(C)C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(-c2nnc[nH]2)cc1Nc1ncnc(N(C)CC(C)(C)C)c1N
Reaction time: 1 h
Yield: 25.1 %

Procedure:
To a solution of N-(2,2-dimethyl-propyl)-N-methyl-N′-[2-methyl-5-(4H-[1,2,4]triazol-3-yl)phenyl]-5-nitro-pyrimidine-4,6-diamine (20 mg, 0.05 mmol) in 5 mL of methanol was added a catalytic amount of 10% Pd/C. The vessel was placed under a hydrogen atmosphere of 20 psi for 1 h at room temperature. The solution was filtered, and the filtrate was evaporated under vacuum to afford 4.6 mg of the product (Yield: 25%). MS (m/z) calcd for C19H26N8 (MH+), 367.2, found, 367.4.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:15]=[CH:14][C:8]([O:9][CH2:10][CH:11]2[O:13][CH2:12]2)=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH:16]([NH2:19])([CH3:18])[CH3:17]>CO>[CH3:17][CH:16]([NH:19][CH2:12][C@H:11]([OH:13])[CH2:10][O:9][C:8]1[CH:14]=[CH:15][C:5]([CH2:4][C:1]([NH2:2])=[O:3])=[CH:6][CH:7]=1)[CH3:18]
Reactant: CC(C)N
Reactant: NC(=O)Cc1ccc(OCC2CO2)cc1
Solvent: CO
Product: CC(C)NC[C@H](O)COc1ccc(CC(N)=O)cc1
Temperature: 10 °C
Reaction time: 7 h
Yield: 70.2 %

Procedure:
P-Hydroxyphenylacetamide (1 g) and (S)-glycidyl p-toluenesulfonate (1.51 g, 99.3% e.e.) were dissolved in acetone (30 ml). Potassium carbonate (1.19 g) was added to the solution and stirred for 30 hours under refluxing. After the reaction, inorganic materials were filtered off and acetone was removed to give 1.43 g of crude (S)-1-[p-(carbamoylmethyl)phenoxy-2,3-epoxypropane. Then, crude (S)-1-[p-(carbamoylmethyl)phenoxy-2,3-epoxypropane (1.43 g) was dissolved in methanol (8 ml). The solution was dropped in isopropylamine (6.8 g) under cooling to 10° C. over a period of 1 hour and the reaction temperature was raised to room temperature and stirred for 7 hours. After the reaction, the mixture was condensed in vacuo until crystals beginning to separate, cooled, filtrated by suction and dried in vacuo to give crude (S)-atenolol (1.29 g). The optical purity of it was 62.8% e.e. by measurement of Chiral column OD (Daisel Chemical industries Ltd.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[N:11]1([CH2:17][CH2:18][O:19][C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=O)=[CH:22][CH:21]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>O=P(Cl)(Cl)Cl>[Cl:10][C:5]1[C:6]([Cl:9])=[C:7]2[N:8]=[C:24]([C:23]3[CH:27]=[CH:28][C:20]([O:19][CH2:18][CH2:17][N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[CH:21][CH:22]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=C(O)c1ccc(OCCN2CCOCC2)cc1
Reactant: Nc1ncc(Cl)c(Cl)c1N
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Temperature: 100 °C

Procedure:
2,3-Diamino-4,5-dichloropyridine (Example 206a) (0.50 g, 2.5 mmol) and 4-(2-morpholin-4-ylethoxy)benzoic acid (Example 206c) (0.80 g, 2.5 mmol) were dissolved in POCl3 (10 ml) and heated to 100° C. for 10 h. The excess of POCl3 was evaporated off and the residue was dissolved in EtOAc and aqueous NaHCO3. The aqueous phase was basified with 10M NaOH and extracted three times with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4) and evaporated in vacuo to afford the title product as a slightly yellow powder (0.74 g, 75%).
Reaction SMILES: [C:1]([C:9]1[CH:21]=[C:20]2[N:11]([C:12](=[O:22])[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=32)[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>C(O)C.O>[OH:8][CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:21]=[C:20]2[N:11]([C:12](=[O:22])[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=32)[N:10]=1
Reactant: O=C(c1ccccc1)c1cc2c3ccccc3[nH]c(=O)n2n1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c2ccccc2c2cc(C(O)c3ccccc3)nn12
Reaction time: 0.5 h

Procedure:
1.65 g 80.0057 mole) of 2-benzoylpyrazolo[1,5-c]-quinazolin-5(6H)-one prepared as in part B above is stirred with 880 mg (4 equiv) of sodium borohydride in absolute ethanol (125 ml) at room temperature for 3 hours. The reaction mixture is stripped to dryness and the resulting solid is suspended in water (40 ml), cooled down to 0° and treated dropwise with 1 N HCl 25 ml). The mixture is stirred for 30 minutes, diluted with water (40 ml) and stirred for another 10 minutes. The white precipitates are filtered off, washed well with water and dried overnight in a vacuum oven at 70° C to give 1.6 g of product.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([NH2:23])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26]>COCCOC.[O-2].[O-2].[Mn+4]>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[C:16]1[NH:28][C:24]([CH:25]([CH3:27])[CH3:26])=[N:23][C:15]1=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)CN
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(N)cc3c12
Agent: [Mn+4]
Agent: [O-2]
Solvent: COCCOC
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc4nc(C(C)C)[nH]c4c3c12

Procedure:
627 mg of 6-amino-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester is stirred in 10 ml of ethylene glycol dimethyl ether with 1.6 g of manganese dioxide and 0.98 ml of isobutylamine for 16 hours at room temperature. The reaction mixture is filtered on Celite, the filtrate is concentrated by evaporation and chromatographed on silica gel with methylene chloride and ethanol=10+1. 499 mg of 2-isopropyl-10-methoxymethyl-1H-imidazo[4,5-g]-β-carboline-9-carboxylic acid isopropyl ester (oily) is obtained from the desired fractions.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:13][C:14]1[C:21]([F:22])=[C:20]([C:23]([F:26])([F:25])[F:24])[C:19]([F:27])=[C:18]([F:28])[C:15]=1[CH2:16]Br>CN(C=O)C>[CH3:12][O:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:16][C:15]2[C:18]([F:28])=[C:19]([F:27])[C:20]([C:23]([F:24])([F:26])[F:25])=[C:21]([F:22])[C:14]=2[F:13])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Reactant: COc1ccc(N)cc1C(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)cc1C(=O)O
Yield: 29.7 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-methoxy-benzoic acid (2.10 g, 12.7 mmole), DMF (50 ml), TEA (6 ml), and 2,3,5,6-tetrafluoro-4-trifluoromethylbenzyl bromide (2.00 ml, 14.0 mmole), 1.50 g (31.5% yield) of 2-methoxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid was obtained as a yellow solid:
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[S:5][CH:6]=[C:7]([CH3:12])[C:8]=1[C:9]([OH:11])=[O:10].O>C(O)(=O)C>[Br:1][C:6]1[S:5][C:4]([CH3:3])=[C:8]([C:9]([OH:11])=[O:10])[C:7]=1[CH3:12]
Reactant: BrBr
Reactant: Cc1csc(C)c1C(=O)O
Solvent: CC(=O)O
Solvent: O
Product: Cc1sc(Br)c(C)c1C(=O)O
Temperature: 10 °C
Yield: 88.3 %

Procedure:
A solution of bromine (0.73 mL, 2.25 g, 14 mmol) in glacial acetic acid (8 mL) was added to a solution of 2,4-dimethylthiophene-3-carboxylic acid (2.1 g, 13 mmol) in glacial acetic acid (24 mL) at 6° C. Upon completion, the reaction was stirred at 10° C. for an hour, diluted with glacial acetic acid (30 mL), stirred for 14 hours at room temperature, poured into water (400 mL) and extracted with ether (3×40 mL). The combined ethereal extracts were extracted with dilute sodium hydroxide (0.2 N, 3×30 mL). The combined basic extracts were cooled in an ice bath and then acidified to pH 3 using concentrated hydrochloric acid. Precipitated solids were extracted with ether (3×40 mL). Pooled organic extracts were washed with water (50 mL) and brine (50 mL), dried over magnesium sulphate and concentrated under reduced pressure. The residue was recrystallised from ethyl acetate/hexane to give product as an amorphous white solid (2.7 g, 85%): mp 183–184° C.; 1H NMR (CDCl3) δ 2.67 (s, 3H), 2.38 (s, 3H); EI/MS 235 m/e (M+); IR (liq film) 1674 cm−1; Calcd. for C7H7BrO2S: C, 35.8; H, 3.00; S, 13.6; Found: C, 35.8; H, 2.99; N, 13.5.
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][N:5]1[CH2:13][C:12]2[CH:11]=[C:10]3[NH:14][C:15]([C:17]4[C:18](=[O:35])[NH:19][CH:20]=[CH:21][C:22]=4[NH:23][CH:24]([CH3:34])[CH2:25][C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=4[CH3:33])=[N:16][C:9]3=[C:8]([CH3:36])[C:7]=2[C:6]1=O.C(O)(=[O:41])C>[Zn]>[CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][N:5]1[CH2:6][C:7]2[C:8]([CH3:36])=[C:9]3[N:16]=[C:15]([C:17]4[C:18](=[O:35])[NH:19][CH:20]=[CH:21][C:22]=4[NH:23][CH:24]([CH3:34])[CH2:25][C:26]4[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=4[CH3:33])[NH:14][C:10]3=[CH:11][C:12]=2[C:13]1=[O:41]
Reactant: CC(=O)O
Reactant: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)CN(CCN(C)C)C3=O
Agent: [Zn]
Product: Cc1ccc(F)cc1CC(C)Nc1cc[nH]c(=O)c1-c1nc2c(C)c3c(cc2[nH]1)C(=O)N(CCN(C)C)C3

Procedure:
A mixture of 6-(2-(dimethylamino)ethyl)-2-(4-(1-(5-fluoro-2-methylphenyl)propan-2-ylamino)-2-oxo-1,2-dihydropyridin-3-yl)-4-methyl-6,7-dihydroimidazo[4,5-f]isoindol-5(1H)-one (0.27 g, 0.51 mmol), zinc dust (0.33 g, 5.09 mmol), and 8.5 mL of acetic acid was heated at reflux for 13-14 h under an argon atmosphere. Product was separated by a silica gel column using methylene chloride and methanol (85:15 v/v) as eluent to afford 30 mg of the designed compound as yellowish solid. 1H NMR (500 MHz, DMSO-d6) δ; Mass (ESI, positive) m/z 517.2 [M+H]+, 539.2 [M+Na]+.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)=[N:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O1CCCC1>[OH:3][CH:1]([C:4]1[C:5]([C:17]2[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=2)=[N:6][C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[N:8][C:9]=1[CH3:10])[CH3:2]
Reactant: CC(=O)c1c(C)nc(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccccc2)nc(-c2ccc([N+](=O)[O-])cc2)c1C(C)O
Reaction time: 2 h
Yield: 19.9 %

Procedure:
The mixture of 5-acetyl-6-methyl-4-(4-nitrophenyl)-2-phenyl-pyrimidine (1.5 g) and sodium borohydride (170 mg) in methanol (15 ml) and tetrahydrofuran (20 ml) was stirred for 2 hours at 5°-7° C. with ice cooling. The mixture was extracted with chloroform (100 ml) and 10% aqueous hydrochloric acid (50 ml). The separated organic layer was washed successively with saturated sodium hydrogen carbonate, saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The residue is recrystallized from ether to give 5-(1-hydroxyethyl)-6-methyl-4-(4-nitrophenyl)-2-phenylpyrimidine (0.3 g).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([N:12]([CH2:34][CH3:35])[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]=2)=[CH:18][CH:17]=1)[CH3:11]>O1CCCC1>[CH2:34]([N:12]([CH2:10][CH3:11])[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([N:22]([C:23]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]=2)[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:20][CH:21]=1)[CH3:35]
Reactant: O=C=Nc1ccccc1
Reactant: CCN(CC)CCOc1ccc(NC2=NN(c3ccccc3)CC2)cc1
Solvent: C1CCOC1
Product: CCN(CC)CCOc1ccc(N(C(=O)Nc2ccccc2)C2=NN(c3ccccc3)CC2)cc1

Procedure:
Phenylisocyanate (1.05 ml) was added dropwise to a solution of N-[4-(2-diethylaminoethoxy)phenyl]-4,5-dihydro-1-phenyl-1H-pyrazol-3-amine (2.4 g) in tetrahydrofuran (30 ml) and the solution heated to reflux for 4 hours. After cooling the solvent was removed and water added to the residue, which was then extracted with ether. The combined ether layer was washed with water and dried. Solvent was removed to give a solid which was recrystallised from ethyl acetate and petroleum ether to give the title compound (1.3 g) mp 140°-1°.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9]CC)=O.[CH3:12][NH:13][CH3:14]>C(O)C>[CH3:12][N:13]([CH3:14])[C:7]([CH:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[O:1])=[O:9]
Reactant: CNC
Reactant: CCOC(=O)C1CCCC1=O
Solvent: CCO
Product: CN(C)C(=O)C1CCCC1=O

Procedure:
0.337 mol (50 ml) of ethyl 2-oxocyclopentanecarboxylate and 152 ml 33% dimethylamine solution in ethanol were stirred in a pressure reactor for 4 h at 110° C. The reaction mixture was then evaporated to dryness and the crude product was purified over 400 g silica gel with ethyl acetate/hexane 1/1. 17.7 g of the title compound were obtained.
Reaction SMILES: [CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH2:13])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2].[C:20](Cl)(=[O:22])[CH3:21]>>[CH2:1]([C:3]1[N:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:20](=[O:22])[CH3:21])=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CC(=O)Cl
Reactant: CCc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: CCc1noc(-c2sc(NC(C)=O)nc2-c2ccccc2)n1

Procedure:
Prepared from 5-(3-ethyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and acetyl chloride.
Reaction SMILES: Br[C:2]1[C:3]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][CH2:5]2.C(OCC)(=O)C.[CH3:31][N:32](C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[CH:14]1([C:12]([N:8]2[C:9]3[C:4](=[C:3]([O:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:2]([C:31]#[N:32])=[CH:11][CH:10]=3)[CH2:5][CH2:6][C@@H:7]2[CH3:17])=[O:13])[CH2:16][CH2:15]1
Reactant: C[C@H]1CCc2c(ccc(Br)c2Oc2ccccc2)N1C(=O)C1CC1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: C[C@H]1CCc2c(ccc(C#N)c2Oc2ccccc2)N1C(=O)C1CC1
Temperature: 160 °C
Yield: 32 %

Procedure:
A mixture of (S)-(6-bromo-2-methyl-5-phenoxy-3,4-dihydroquinolin-1(2H)-yl)(cyclopropyl)methanone (0.100 g, 0.26 mmol), tetrakis(triphenylphosphine)palladium (O) (0.30 g, 0.03 mmol), and zinc cyanide (0.036 g, 0.31 mmol) in N,N-dimethylformamide (2 mL) was heated with microwave irradiation for 30 min at 160° C. The reaction mixture was cooled to room temperature, poured into ethyl acetate (10 mL), washed with water (3×2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 1:8, ethyl acetate/petroleum ether) to afford (5)-1-(cyclopropanecarbonyl)-2-methyl-5-phenoxy-1,2,3,4-tetrahydroquinoline-6-carbonitrile (0.27 g, 32%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ ppm 0.74-0.82 (m, 1H), 0.90-1.10 (m, 2H), 1.10-1.18 (m, 3H), 1.28-1.39 (m, 1H), 1.49-1.61 (m, 1H), 1.80-1.91 (m, 1H), 2.10-2.22 (m, 1H), 2.39-2.51 (m, 1H), 2.67-2.80 (m, 1H), 4.71-4.89 (m, 1H), 6.85 (d, J=8.10 Hz, 2H), 7.08 (t, J=7.50 Hz, 1H), 7.28-7.38 (m, 2H), 7.40-7.47 (m, 1H), 7.49-7.55 (m, 1H). MS (ESI, pos. ion) m/z 333 [M+H]+.