Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[O:7]=[C:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15].S(=O)(=O)(O)O>>[C:1]([O:5][O:6][C:8]1([O:7][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: CC(C)(C)OO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCCCC1(OOC(C)(C)C)OOC(C)(C)C
Temperature: -10 °C

Procedure:
Ethyl 2,2-di(tertiary-butylperoxy)-1-cyclohexanecarboxylate was prepared by the addition of 92.28% TBHP (tertiary butyl hydroperoxide) (24.41 g, 0.2500 moles) to 95% ethyl 2-oxo-1-cyclohexanecarboxylate (17.92 g, 0.1000 moles) at room temperature in a three necked 250-mL round bottomed flask equipped with a thermometer and mechanical stirrer. The solution was then cooled to −10° C. via a dry ice-acetone bath and 78% sulfuric acid (15.09 g, 0.1200 moles) added dropwise to the solution with temperature at −10° C. Upon completion of the addition of sulfuric acid, the solution was allowed to reach 5° C. where it was maintained by an ice-water bath for three hours with mechanical stirring. The reaction was transferred to a separatory funnel and the lower acidic aqueous layer separated and discarded. The organic layer was then washed with saturated NaCl solution until the aqueous washings had a pH of 4.5 or greater. The organic layer was then dried over MgSO4 and filtered through a Buchner funnel to give a resulting peroxide (24.92 g, 74.92%). The resulting peroxide crystallized and was subsequently re-crystallized with hexanes, analyzed for purity by Gas Chromatography, as presented in Example 1, (95% by area) and it's 10 hr half life temperature was determined to be 93.31° C. by G.C.: m.p. 36-38°; 13C NMR (75 MHz, CDCl3) δ 171.8 (C═O), 106.1 (O—C—O, cyclic), 79.0 (C(CH3)3), 78.9 (C(CH3)3, 59.5 (CH2CH3), 44.3 (CH, Cyclic), 27.6 (CH2, cyclic), 26.3 ((CH3)3), 26.2 ((CH3)3), 2.17 (CH2, cyclic), 21.4 (CH2, cyclic), 13.8 (CH3CH2—O); IR (NaCl, CHCl3) ν 1735, 1370, 1200, 880 Cm−1; Analysis calculated for C17H32O6: C, 61.42; H, 9.70; O, 28.88; found: C, 61.05; H, 9.82: O, 28.22.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([N+:18]([O-])=O)=[CH:13][C:3]=1[O:4][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]1>[Fe].C(O)(=O)C.O>[Cl:1][C:2]1[CH:16]=[C:15]([F:17])[C:14]([NH2:18])=[CH:13][C:3]=1[O:4][C:5]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:7][CH2:6]1
Reactant: CCOC(=O)C1(Oc2cc([N+](=O)[O-])c(F)cc2Cl)CC1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1(Oc2cc(N)c(F)cc2Cl)CC1
Temperature: 25 °C

Procedure:
The obtained ethyl 1-(2-chloro-4-fluoro-5-nitro-phenoxy)cyclopropanecarboxylate (1 equivalent) is added dropwise to a mixture of acetic acid/ water (1/1) containing iron powders (3 equivalents) at 6° C. After completion of addition, the mixture is allowed to cool to room temperature and extracted with ethyl acetate. After concentrating the organic layer, the residue is subjected to chromatography to give ethyl 1-(2-chloro-4-fluoro-5-aminophenoxy)cyclopropanecarboxylate.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C@@H:11]1[OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH2:1]([O:8][CH2:9][C@@H:10]1[C@@H:14]([CH2:15][C:16]([O:18][CH3:20])=[O:17])[CH:13]=[CH:12][C@@H:11]1[OH:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C[C@H]1C=C[C@H](O)[C@@H]1COCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)C[C@H]1C=C[C@H](O)[C@@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 100.2 %

Procedure:
To a solution of 23.6 g of (1S,2S,3S)-2-benzyloxymethyl-3-carboxymethyl-4-cyclopenten-1-ol [the compound described in J. Am. Chem. Soc., 93, 1492 (1971)] in 200 ml of acetone, 27.6 g of potassium carbonate and 11.36 g of methyl iodide were added. The mixture was stirred for 50 min at room temperature, and then refluxed for 2 hrs. After reacting, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 24.9 g of the title compound having the following physical characteristics, in a 99% yield.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:11][C:12]([NH:14][C@H:15]1[CH2:18][C@H:17]([C:19]([O:21]C)=O)[CH2:16]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO>[NH:2]([C:19]([C@H:17]1[CH2:18][C@H:15]([NH:14][C:12](=[O:13])[O:11][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:16]1)=[O:21])[NH2:3]
Reactant: NN
Reactant: COC(=O)[C@H]1C[C@H](NC(=O)OCc2ccccc2)C1
Solvent: O
Solvent: CO
Product: NNC(=O)[C@H]1C[C@H](NC(=O)OCc2ccccc2)C1
Reaction time: 24 h

Procedure:
Hydrazine monohydrate (10 ml) was added to a methanol (50 ml) solution of methyl trans-3-{[(benzyloxy)carbonyl]amino}cyclobutanecarboxylate (Neurochemical Research, 1980, 5, 393-400) (995 mg, 3.78 mmol) at room temperature and the resulting mixture was stirred for 24 hours. The precipitated solid was collected by filtration, washed with water and then dried to give 760 mg (76%) of the title compound as a colorless solid.
Reaction SMILES: C([O-])(=O)C.[Na+].[N+:6]([C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[N:12][NH:13]2)([O-:8])=[O:7].C(Cl)(Cl)Cl.[Br:22]Br>C(O)(=O)C>[Br:22][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[CH:17][C:9]=2[N+:6]([O-:8])=[O:7])[NH:13][N:12]=1
Reactant: BrBr
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2[nH]nc(Br)c12
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Sodium acetate (52.8 g, 644 mmol) and 4-nitro-1H-indazole (100 g, 613 mmol) were mixed with acetic acid (1000 mL) and chloroform (1000 mL) in a 5 L 4-neck flask with mechanical stirring. A solution of bromine (103 g, 644 mmol) in acetic acid (120 mL) was added over approximately 3.5 hours, while keeping the temperature below 21° C. After the addition was completed, the reaction mixture was stirred for an additional 2 hours. The reaction mixture was concentrated under reduced pressure. Water (2000 mL) was added to the residue. The yellow solids were collected by filtration and washed with water (3×1000 mL). The solids were air-dried on the filter and then under vacuum at 40° C. to give the desired product (129 g) as a yellow solid.
Reaction SMILES: C(C1OC1)Cl.B(F)(F)F.[CH3:10][CH2:11][O:12][CH2:13][CH3:14].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21].[CH3:27][N:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=CC1=O>CCOCC.C(Cl)Cl>[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:20]([O+:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH3:21].[F:15][B-:16]([F:19])([F:18])[F:17].[CH2:11]([O:12][C:13]1[CH:14]=[CH:31][C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[N+:28]=1[CH3:27])[CH3:10]
Reactant: Cn1c(=O)ccc2ccccc21
Reactant: CCOCC
Agent: CC[O+](CC)CC
Agent: FB(F)F
Agent: F[B-](F)(F)F
Solvent: ClCC1CO1
Solvent: ClCCl
Product: CCOc1ccc2ccccc2[n+]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
Triethyloxonium fluoroborate is prepared from 3.70 g (0.040 mole) of epichlorohydrin in 14 ml of ether and 7.58 g (0.054 mole) of boron trifluoride etherate in 6 ml of ether. The resulting solid triethyloxonium fluoroborate is dissolved in 20 ml of dry methylene chloride and treated under nitrogen with 6.47 g (0.040 mole) of N-methyl-2-quinolone in 15 ml of methylene chloride. The reaction mixture is stirred under nitrogen at room temperature overnight. The solid is filtered to give 9.2 g (83.5%) of 2-ethoxy-1-methylquinolinium fluoroborate.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[O:1]([C:8]1[CH:13]=[CH:12][N+:11]([O-:22])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(Oc2ccncc2)cc1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: [O-][n+]1ccc(Oc2ccccc2)cc1
Reaction time: 22 h

Procedure:
To a solution of 4-phenoxypyridine (3.0 g, 17.5 mmol) in dichloromethane (500 mL) was added 3-chloro-perbenzoic acid (5.18 g, 21.0 mmol) on an ice bath, and the solution was stirred for 22 hours. An aqueous solution of saturated sodium thiosulfate and an aqueous solution of saturated sodium bicarbonate were added to the reaction solution, the solution was stirred at room temperature for 10 minutes, then, the organic layer was separated, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and 4-phenoxy-pyridine N-oxide (3.3 g, quantitatively) was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:19][C:20]1([CH3:36])[C:24]([CH3:26])([CH3:25])[O:23][B:22]([C:27]2[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=2)[O:21]1>C1COCC1.ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([B:22]3[O:23][C:24]([CH3:25])([CH3:26])[C:20]([CH3:36])([CH3:19])[O:21]3)=[CH:35][CH:34]=2)[CH:3]=1
Reactant: Cc1ccnc(N)c1
Reactant: CC1(C)OB(c2ccc(C(=O)Cl)cc2)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccnc(NC(=O)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 41.4 %

Procedure:
To a stirred solution of 4-methylpyridin-2-amine (7.86 mmol, 850 mg) in THF (50 mL) was added dropwise a solution of 1M LiHMDS in THF (8.0 mmol, 8 mL) at room temperature. After the reaction mixture turned dark green, a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl chloride (9.6 mmol, 2.56 g) in dichloromethane (55 mL) was added dropwise. The mixture was stirred at room temperature for 2.5 h and was then concentrated. 3% aq. Citric acid solution (18 mL) was added and the mixture was extracted with dichloromethane (2×15 mL). The combined organic layer was washed with 3% aq. citric acid solution, dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in THF (15 mL) and 6M NaOH solution (15 mL) was added. The mixture was stirred for 4 h. at room temperature. Ethyl acetate was added and the layers were separated. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by chromatography on silica (eluent: DCM/MeOH=98/2 to DCM/MeOH=95/5) to yield 1.1 g of N-(4-methylpyridin-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (40.7%).
Reaction SMILES: [C:1]([CH2:3][N:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])#[N:2].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[CH3:22][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:5]=1[N:4]([CH2:3][C:1]#[N:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(N(CC#N)c2ccccc2)c(C(=O)O)c1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: COC(=O)c1cc(OC)ccc1N(CC#N)c1ccccc1
Yield: 68.8 %

Procedure:
A mixture of 7.1 g (0.025 mole) of 2-[(cyanomethyl)phenylamino]-5-methoxybenzoic acid [P. C. Unangst and M. E. Carethers, J. Heterocyclic Chem., 21, 709 (1974)], 4.0 g (0.029 mole) of anhydrous potassium carbonate, and 3.0 ml (4.0 g; 0.032 mole) of dimethyl sulfate in 200 ml of acetonitrile was stirred at reflux for 24 hours. The mixture was cooled and filtered, and the filter cake was washed several times with fresh acetonitrile. The combined filtrates were evaporated to an oil, which crystallized upon standing at room temperature. Recrystallization from aqueous methanol yielded 5.1 g (68% yield) of the ester product. A sample recrystallized again as above was analytically pure, mp 107°-109° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH2:17]([OH:19])C.[C:20]1([CH3:26])C=CC=CC=1.Cl>>[C:2]1([NH:1][C:17](=[O:19])[O:9][CH2:20][CH3:26])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: Cc1ccccc1
Reactant: CCO
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Solvent: Nc1ccccc1
Product: CCOC(=O)Nc1ccccc1
Temperature: 25 °C

Procedure:
Into a 100 ml capacity SUS 316 stainless autoclave were fed the above catalyst (61.9 mg) (0.020 mmol in terms of Pd), aniline (0.931 g, 0.010 mol), nitrobenzene (1.23 g, 0.010 mol), ethanol (4.61 g, 0.10 mol), toluene (10.6 g, 0.11 mol) and 35% hydrochloric acid aqueous solution (0.071 g, HCl=0.68 mmol, H2O=0.067 mmol), followed by introducing CO gas up to 28 Kg/cm2 at room temperature without purging the air inside the system, reacting them at a reaction temperature of 190° C. for 3 hours, cooling the reaction mixture down to room temperature after the reaction, returning the pressure inside the system to the atmospheric pressure and analyzing the reaction product according to gas chromatography. As a result, ethyl N-phenylcarbamate (NPU) (2.97 g) was formed (NPU yield: 90%), and aniline (0.093 g, 0.001 mol) and nitrobenzene (0.123 g, 0.001 mol) remained unreacted.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>>[CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:27][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: Nc1ccccn1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccccn3)nc2n1C1CCCC1
Yield: 293.8 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.34 mmol) and pyridine-2-ylamine (64 mg, 0.68 mmol) gave 7-cyclopentyl-2-(pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (350 mg, 84%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:12]2[O:13][CH2:14][C:15]3[S:19][C:18]([SH:20])=[N:17][C:16]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)C.Br[CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[S:20][C:18]2[S:19][C:15]3[CH2:14][O:13][C:12]4[C:7]([O:6][CH2:5][C:4]([OH:3])=[O:21])=[CH:8][CH:9]=[CH:10][C:11]=4[C:16]=3[N:17]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)COc1cccc2c1OCc1sc(S)nc1-2
Product: O=C(O)COc1cccc2c1OCc1sc(SC(c3ccccc3)c3ccccc3)nc1-2
Yield: 17 %

Procedure:
Using ethyl[(2-mercapto-4H-[1]benzopyrano[4,3-d]thiazol-6-yl)oxy]acetate and bromodiphenylmethane, the procedure of Example 1 was otherwise repeated to synthesize the title compound. Yield 17%.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=[C:4]([OH:12])[N:3]=1.P(Cl)(Cl)(Cl)=O.[CH3:18][O-].[Na+]>[Cl-].[NH4+]>[CH3:18][O:12][C:4]1[N:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[N:5]=1
Reactant: C[O-]
Reactant: Cc1nc(O)nc(C)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1nc(C)c([N+](=O)[O-])c(C)n1
Temperature: 100 °C
Reaction time: 1.33 h

Procedure:
4,6-Dimethyl-5-nitropyrimidin-2-ol (18.4 g, 108 mmol) wad added portionwise to a stirred phosphoryl chloride (3.0 mL) at 0° C., and the mixture was stirred at 100° C. for 80 min. The mixture was concentrated in vacuo, and methanol (180 mL) was added to the residue carefully at 0° C. Sodium methoxide (28% solution in methanol, 68.8 g, 357 mmol) was added dropwise to a stirred mixture at 0° C., and the mixture was stirred at 0° C. for 10 min. The mixture was diluted with aqueous saturated ammonium chloride and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a yellow wax (13.0 g, 71.0 mmol, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]#[N:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:16](I)[CH3:17]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]#[N:13])=[CH:8][N:9]2[CH2:16][CH3:17])=[CH:5][CH:4]=1
Reactant: CCI
Reactant: COc1ccc2c(C#N)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C#N)c2ccc(OC)cc21
Reaction time: 0.25 h

Procedure:
A solution of 6-methoxyindole (10.0 g, 68.0 mmol) in DMF (120 mL) is cooled to 0° C. and treated with chlorosulfonyl isocyanate (7.72 mL, 88.4 mmol). After the addition, the reaction mixture is stirred at this temperature for 1 h. The dark solution is poured into ice water (600 mL) and the light brown solid is collected by filtration, washed with additional H2O and dried to afford 9.9 g (85%) of 6-methoxy-1H-indole-3-carbonitrile as a light brown solid. Step B: To a solution of 6-methoxy-1H-indole-3-carbonitrile (9.9 g, 57.6 mmol) in DMF (150 mL) is added NaH (60% dispersion in mineral oil, 3.45 g, 86.3 mmol). The reaction mixture is stirred for 15 min and then ethyl iodide (5.53 mL, 69.1 mmol) is added and the mixture is stirred at room temperature overnight. The reaction mixture is then diluted with H2O and extracted with EtOAc (2×). The organic phases are washed with H2O (3×) and saturated NaCl and then dried and concentrated to a semi-solid. The crude product is purified via column chromatography on silica gel (200 g) using CH2Cl2/hexanes (50-100%) as eluent to yield 6-methoxy-1-ethyl-1H-indole-3-carbonitrile as a tan solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([OH:12])[CH:5]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:28]([CH3:30])[CH3:29]>CN(C)C=O>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH:28]([CH3:30])[CH3:29])[CH:5]=1)[CH3:14]
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C=O)c(OC(C)C)c1
Reaction time: 7 h
Yield: 91.3 %

Procedure:
To a suspension of 4-diethylamino-2-hydroxybenzaldehyde (300 mg, 1.55 mmol), potassium carbonate (428 mg, 3.10 mmol), and cesium carbonate (50 mg, 0.15 mmol) in 1.6 mL of dry N,N-dimethylformamide was added 2-iodopropane (0.47 mL, 4.7 mmol) at room temperature. After being stirred at the same temperature for 7 h, the reaction mixture was filtered to remove inorganic salts. The filtrate was diluted with diethyl ether, and the solution was washed with water, saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 75/25) to obtain the title compound as a colorless oil (333 mg, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18]([OH:20])=O)[C:11]([CH3:25])([CH3:24])[CH2:10]2)=[O:4].ON1C2C=CC=CC=2N=N1.[CH3:36][N:37]([CH3:46])[CH2:38][CH2:39][CH2:40][N:41]=C=NCC.Cl.CN1CCOCC1.CN1CCC(N)C1>ClCCl>[CH3:25][C:11]1([CH3:24])[CH2:10][C:9]2[C:14](=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=[CH:7][CH:8]=2)[NH:13][CH:12]1[C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](=[O:20])[NH:41][CH:40]2[CH2:39][CH2:38][N:37]([CH3:36])[CH2:46]2)[CH:16]=1
Reactant: COC(=O)c1cccc2c1NC(c1cccc(C(=O)O)c1)C(C)(C)C2
Reactant: CCN=C=NCCCN(C)C
Agent: CN1CCC(N)C1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)c1cccc2c1NC(c1cccc(C(=O)NC3CCN(C)C3)c1)C(C)(C)C2
Reaction time: 1 h

Procedure:
To a suspension of 3-(8-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (63 mg, 0.19 mmol) in dichloromethane (5.0 mL) was added N-hydroxybenzotriazole (37.6 mg, 0.28 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide.hydrochloric acid (106.7 mg, 0.56 mmol), followed by 4-methylmorpholine (56.3 mg, 0.56 mmol) and the resultant mixture was stirred at room temperature for 1 h., then 1-methylpyrrolidin-3-amine (27.9 mg, 0.28 mmol) was added to the flask and the reaction mixture was stirred for an additional 1 h. LC-MS showed the reaction was complete. The reaction was quenched with water and separated. The aqueous layer was extracted with dichloromethane (twice) and the combined organic layers were washed with 5% sodium hydroxide aqueous solution (twice) and water (3 times), dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 76 mg of methyl 3,3-dimethyl-2-(3-(1-methylpyrrolidin-3-ylcarbamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-8-carboxylate as a white solid, which was used in next step without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]([O:8][C@H:9]1[N:12]([CH:13]([C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])O)[C:11](=[O:31])[C@@H:10]1[NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:7])=[O:5])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:49])=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@H:6]([O:8][C@H:9]1[N:12]([CH:13]([C:15]([O:17][CH:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[Cl:49])[C:11](=[O:31])[C@@H:10]1[NH:32][C:33](=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:7])=[O:5])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)[C@@H](C)O[C@@H]1[C@@H](NC(=O)c2ccccc2)C(=O)N1C(O)C(=O)OC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H](C)O[C@@H]1[C@@H](NC(=O)c2ccccc2)C(=O)N1C(Cl)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
4.58 g of the product from step (2) above was dissolved in 50 ml of methylene chloride, and to the solution after ice-cooling were added 1.38 g of pyridine and 2.08 g of thionyl chloride, followed by agitation for 30 minutes to effect the chlorination.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH:42]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH:42]3[CH2:43][CH2:44][CH2:45][CH2:46]3)[CH:37]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C3CCCC3)c2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C4CCCC4)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (218 mg, 0.75 mmol) and 3-[3-(2-cyclopentyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K61) (274 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (369 mg, 86%).
Reaction SMILES: [C:1]([N:5]([CH:15]([CH3:17])[CH3:16])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)(=[O:4])[CH:2]=[CH2:3].Cl.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH3:21])[CH2:3][CH2:2][C:1]([N:5]([CH:15]([CH3:17])[CH3:16])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)=[O:4]
Reactant: CNC
Reactant: C=CC(=O)N(c1ccc([N+](=O)[O-])cc1)C(C)C
Agent: Cl
Product: CC(C)N(C(=O)CCN(C)C)c1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from N-acryloyl-N-isopropyl-4-nitro-aniline and dimethylamine hydrochloride