Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17](Cl)=[O:18].Cl.[C:21]1([C:27]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH:35]3[CH:31]([CH2:32][NH:33][CH2:34]3)[C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])([OH:36])[CH:29]([OH:45])[CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[C:46]1([C:27]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:35]3[CH:31]([CH2:32][NH:33][CH:34]3[C:17](=[O:18])[CH2:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[O:9][CH3:8])[C:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[O:43][CH3:44])([OH:36])[CH:29]([OH:45])[CH2:28]2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: COc1ccccc1CC(=O)Cl
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1CC(=O)C1NCC2C1C(c1ccccc1)(c1ccccc1)CC(O)C2(O)c1ccccc1OC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 77.5 %

Procedure:
4.2 cm3 of triethylamine and then 2.4 g of (2-methoxyphenyl)acetic acid chloride in 50 cm3 of dichloromethane are added to a solution of 4.5 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindole-4,5-diol hydrochloride in 100 cm3 of dichloromethane, cooled to 0° C. The reaction mixture is stirred at room temperature for 90 minutes; it is washed with twice 10 cm3 of water, and is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid which has crystallized is taken up in. 100 cm3 of diisopropyl ether and then filtered off and washed with 50 cm3 of a saturated solution of sodium bicarbonate and then 50 cm3 of diisopropyl ether. 4.35 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-(2-methoxyphenyl)- acetylperhydroisoindole-4,5-diol are obtained in the form of a light beige solid which melts at 278° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:18][OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:10][CH:9]1[CH2:18][O:19][S:21]([CH3:20])(=[O:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)CC1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)CC1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(Hydroxymethyl)-4-(methanesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (1.715 g) was dissolved in pyridine (20 ml), and methanesulfonylchloride (0.6 ml) was added thereto. The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate, and washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[F:21])[C:6]=2[CH:22]=1.[Cl:23][CH2:24][C:25](=O)[CH2:26][CH2:27][CH2:28][CH2:29][OH:30]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:25]([CH2:26][CH2:27][CH2:28][CH2:29][OH:30])[CH2:24][Cl:23])[CH2:9][N:8]=[C:7]([C:14]3[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=3[F:20])[C:6]=2[CH:22]=1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1
Reactant: O=C(CCl)CCCCO
Solvent: C1CCOC1
Product: OCCCCC(CCl)=NNC1=Nc2ccc(Cl)cc2C(c2c(F)cccc2F)=NC1

Procedure:
In the manner given in Example 1, 7-chloro-2-hydrazino-5-(2,6-difluorophenyl)-3H-1,4-benzodiazepine in tetrahydrofuran can be treated with 1-chloro-6-hydroxy-2-hexanone under nitrogen to give 7-chloro-2-[[2-chloro-1-(4-hydroxybutyl)ethylidene]hydrazino]-5-(2,6-difluoropheny1)-3H-1,4-benzodiazepine.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH:10]3[CH2:12][C:6]([C:13]([OH:15])=[O:14])([CH2:7][CH:8]1[CH2:9]3)[CH2:5]2)(=[O:3])[CH3:2].[C:16](Cl)(=O)C>CO>[C:1]([C:4]12[CH2:11][CH:10]3[CH2:12][C:6]([C:13]([O:15][CH3:16])=[O:14])([CH2:7][CH:8]1[CH2:9]3)[CH2:5]2)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)C12CC3CC1CC(C(=O)O)(C3)C2
Solvent: CO
Product: COC(=O)C12CC3CC(C1)C(C(C)=O)(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To 3-acetyltricyclo[3.3.1.03,7]nonane-1-carboxylic acid (2.4 g, 11.4 mmol) obtained in step I, in MeOH (48 mL) cooled to ice bath temperature, was added acetyl chloride (1.64 mL, 22.8 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 h. The volatiles were removed under reduced pressure and the crude product was purified by column chromatography to obtain methyl 3-acetyltricyclo[3.3.1.03,7]nonane-1-carboxylate (2.4 g) in 93% yield as viscous liquid. m/z (M+1) 223. IR cm−1 2953, 1728, 1698, 1461, 1234, 1078, 755. 1H NMR (CDCl3) 300 MHz δ 3.66 (s, 3H), 2.75-2.70 (m, 1H), 2.53-2.46 (m, 1H), 2.40-2.32 (m, 1H), 2.19 (s, 3H), 2.15-2.05 (m, 1H), 2.03-1.60 (m, 8H). 13C NMR (CDCl3) 75 MHz δ 210.9, 175.3, 61.4, 53.4, 51.6, 50.5, 48.0, 45.9, 45.6, 42.6, 41.9, 36.8, 35.9, 26.4.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([CH:16]([C:22](=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:14][CH3:15]>CCCCCC.C(OCC)(=O)C>[CH2:12]([C:16](=[C:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CCCCC(C(=O)OCC)C(=O)C(=O)OCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCC(C(=O)OCC)=C(Nc1ccc(C(=O)OC)cc1)C(=O)OCC
Temperature: 60 °C
Reaction time: 30 h
Yield: 100.8 %

Procedure:
27.8 g of methyl 4-aminobenzoate and 47 g of diethyl 2-butyl-3-oxo-butanedioate were mixed and 2 g of activated siliporite were added. The mixture was stirred for about 30 hours at 60° C. and after chromatography (eluant: hexane-ethyl acetate 95-5), 70 g of the expected product were obtained.
Reaction SMILES: Br[C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[NH2:13][CH:14]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>CCOCC>[CH2:18]([O:17][C:15]([CH:14]([NH:13][C:2]1([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11])[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)C(N)CCc1ccccc1
Reactant: CC1(Br)C(=O)Nc2ccccc21
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CCc1ccccc1)NC1(C)C(=O)Nc2ccccc21

Procedure:
A solution of 2.5 g 3-bromo-3-methyloxindole, 2 g ethyl 2-amino-4-phenylbutyrate and 1.6 ml triethylamine in 150 ml ether was refluxed for 48 hours. The resulting crude product was partitioned between 50% potassium carbonate solution and ethyl acetate. The organic phase was dried (MgSO4) and concentrated. Chromatography at the residue (silica, ether) afforded 3-(1-ethoxycarbonyl-3-phenylpropyl)amino-3-methyl-1,2-dihydro-2-oxo-3H-indole as a mixture of diastereomers.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([OH:9])=[CH:7][C:6]([OH:10])=[CH:5][C:4]=1[CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>CC(C)=O>[CH2:22]([O:9][C:8]1[C:3]([CH2:1][CH3:2])=[C:4]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([O:10][CH2:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:7]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrCc1ccccc1
Reactant: CCc1c(O)cc(O)cc1CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCc1c(CC(=O)OC)cc(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 131.7 %

Procedure:
Methyl 2-ethyl-3,5-dihydroxyphenylacetate (1.70 g, 8.09 mmol) was dissolved in acetone (20 mL), and potassium carbonate (6.43 g, 46.5 mmol) and benzyl bromide (4.00 mL, 33.6 mmol) were added thereto ad stirred at room temperature for 6 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through silica gel column chromatography (n-hexane/ethyl acetate=20/1 to 9/1) to obtain methyl 3,5-bis(benzyloxy)-2-ethylphenylacetate (2.08 g, 66%).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=[O:12])=[O:5])[CH3:2].C([Li])CCC.C[Si](Cl)(C)C.C([N-]C(C)C)(C)C.[Li+].[CH2:31]([O:33][C:34](=[O:37])[CH2:35]Br)[CH3:32]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1([CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:37])[CH2:11][CH2:10][CH2:9][NH:8][C:7]1=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCNC1=O
Reactant: CCOC(=O)CBr
Agent: CC(C)[N-]C(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1(C(=O)OCC)CCCNC1=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5 mmol of 2-oxo-piperidine-3-carboxylic acid ethyl ester [3731-16-6] in 30 ml dry of tetrahydrofuran is added dropwise 5.25 mmol of an n-butyl lithium solution (1.6M in hexane) at −78° C. After stirring for 15 minutes at −78° C., trimethylsilyl chloride (0.67 mL, 5.25 mmol) is added dropwise and stirring is continued for 30 minutes while the solution is allowed to warm to 0° C. The reaction mixture is then cooled to −78° C. and transferred (via cannula) to a solution of 5 mmol of freshly prepared lithium diisopropyl-amide in 20 ml of dry tetrahydrofuran at −78° C. After stirring for 30 minutes at −78° C., 5.25 mmol of 2-bromoacetic acid ethyl ester [105-36-2] are added drop wise and stirring is continued for 1 hour while the solution is allowed to warm to 0° C. The reaction is quenched by addition of aqueous saturated ammonium chloride solution and extracted with diethyl ether (3×). The combined organic phases are washed with brine, dried with sodium sulphate and evaporated. From the residue the title compound is identified by means of flash chromatography (SiO2 60 F) on the basis of the Rf value.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([F:21])[CH:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[Br:22]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:3]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])=[C:10]([F:21])[CH:9]=2)=[N:4][C:5]([Br:22])=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2nccnc2N)cc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CC(C)(C)OC(=O)c1ccc(-c2nc(Br)cnc2N)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
To a stirred solution of tert-butyl 4-(3-aminopyrazin-2-yl)-2-fluorobenzoate (37.7 g, 130 mmol) in acetonitrile (800 mL) at 0° C. was added N-bromosuccinimide (23.19 g, 130 mmol) in one portion. The reaction was stirred at 0° C. for 2 h, then quenched with saturated NaHCO3 solution (200 mL) and stirred at 0° C. for 30 min. The mixture was diluted with water (300 mL) and extracted with EtOAc (3×250 mL). The combined organics were washed with water (200 mL) and brine (2×200 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified using flash chromatography on silica gel (0 to 40% EtOAc in heptane over 40 min), giving tert-butyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (30.9 g, 64%) as a solid. LCMS (m/z): 368/370 (MH+), 1.03 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.14 (s, 1H) 7.97-7.74 (m, 1H) 7.62-7.39 (m, 2H) 6.64 (s, 2H) 1.54 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)[N:5]=[C:4]([CH3:18])[N:3]=1.[CH3:19][C:20]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:21]=1[NH2:22]>>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:6]2[N:5]=[C:4]([CH3:18])[N:3]=[C:2]([NH:22][C:21]3[C:23]([CH3:28])=[CH:24][C:25]([CH3:27])=[CH:26][C:20]=3[CH3:19])[CH:7]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: Cc1cc(C)c(N)c(C)c1
Reactant: COc1ccc(-c2cc(Cl)nc(C)n2)cc1OC
Product: COc1ccc(-c2cc(Nc3c(C)cc(C)cc3C)nc(C)n2)cc1OC
Temperature: 120 °C

Procedure:
The mixture of 4-chloro-6-(3,4-dimethoxyphenyl)-2-methylpyrimidine (2.0 g) and 2,4,6-trimethylaniline (5.3 ml) was stirred at 120° C. for an hour. After cooled, the mixture was triturated with ethyl acetate. The precipitates were collected, and dissolved in chloroform. The solution was washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate, and evaporated to give 6-(3,4-dimethoxyphenyl)-2-methyl-4-(2,4,6-trimethylphenylamino)pyrimidine (2.39 g).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH:18]([OH:19])[CH2:17][N:16]([C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[O:21])[CH2:15]3)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:33]I>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:9][CH2:10][N:11]([CH:14]3[CH:18]([O:19][CH3:33])[CH2:17][N:16]([C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[O:21])[CH2:15]3)[CH2:12][CH2:13]2)=[O:7])=[CH:29][CH:30]=1
Reactant: CI
Reactant: O=C(c1ccc(Cl)cc1)N1CCN(C2CN(C(=O)c3ccc(Cl)cc3)CC2O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COC1CN(C(=O)c2ccc(Cl)cc2)CC1N1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: 4 °C
Reaction time: 0.25 h

Procedure:
To a cold (3-5° C.) solution of starting material {3-[4-(4-Chloro-benzoyl)-piperazin-1-yl]-4-hydroxy-pyrrolidin-1-yl}-(4-chloro-phenyl)-methanone in 1 mL of NMP was added NaH (4 mg, 0.17 mmol). The mixture was then stirred at 3-5° C. for 15 mins. MeI (7.5 uL) was then added. After 2 hours, the reaction was quenched by adding 50 μL AcOH. The mixture was then partitioned in EtOAc and 1M K2CO3. The separated organic phase was washed with brine, dried over Na2SO4 and concentrated down to dryness. The resulting crude residue was purified by column chromatography on silica (Methanol 1 CH2Cl2: 0%-10%). The pure product was converted to it HCl salt by precipitation in a mixture of ethanol 1 ether and conc. HCl, to give 43 mg of salt of {3-[4-(4-Chloro-benzoyl)-piperazin-1-yl]-4-methoxy-pyrrolidin-1-yl]-(4-chloro-phenyl)-methanone as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]([NH:16][CH:17]1[C:23](=[O:24])[N:22]2[CH:25]([C:28]([OH:30])=[O:29])[CH2:26][S:27][CH:21]2[CH2:20][CH2:19][CH2:18]1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].ClC1C=C(C=CC=1)C(OO)=[O:36]>C(O)C>[CH2:2]([O:4][C:5]([CH:7]([NH:16][CH:17]1[C:23](=[O:24])[N:22]2[CH:25]([C:28]([OH:30])=[O:29])[CH2:26][S:27](=[O:36])[CH:21]2[CH2:20][CH2:19][CH2:18]1)[CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C(CCc1ccccc1)NC1CCCC2SCC(C(=O)O)N2C1=O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(CCc1ccccc1)NC1CCCC2N(C1=O)C(C(=O)O)CS2=O
Reaction time: 3 h

Procedure:
To a solution of [3R-[3α,6α(S*R*),9aα]]-6-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]octahydro-5-oxothiazolo[3,2-a]azepine-3-carboxylic acid hydrochloride (1 mmole) in 50 ml of absolute ethanol at 0° under nitrogen, purified meta-chloroperoxybenzoic acid (1.05 mmole) can be added. The reaction mixture can be stirred for 3 hours at 0° and then absorbed onto a Dowex 50 X-2 ion-exchange column. Elution with ethanol-water (1:1) and then 4% pyridine-water will permit recovery of the product. The product can then be freeze-dried to afford a mixture of diastereomeric sulfoxides which can be separated by preparative chromatography on a reverse-phase column.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:22]#[N:23])=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=3)[N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.[CH2:24]([N:26]=[C:27]=[O:28])[CH3:25]>ClCCl>[C:22]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([NH:1][C:27]([NH:26][CH2:24][CH3:25])=[O:28])=[CH:3][CH:4]=2)[N:8]([CH2:11][CH3:12])[C:7]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=1)#[N:23]
Reactant: CCN=C=O
Reactant: CCOc1ccc(-c2c(C#N)c3ccc(N)cc3n2CC)cc1
Solvent: ClCCl
Product: CCNC(=O)Nc1ccc2c(C#N)c(-c3ccc(OCC)cc3)n(CC)c2c1
Yield: 95.6 %

Procedure:
6-Amino-2-(4-ethoxyphenyl)-1-ethyl-1H-indole-3-carbonitrile (31 mg, 0.1 mmol) is treated with ethyl isocyanate (14 mg, 0.2 mmol) in dichloromethane (1.0 mL) at 40° C. overnight. The precipitate is collected via filtration, washed with dichloromethane and dried in air to furnish 1-[3-cyano-2-(4-ethoxy-phenyl)-1-ethyl-1H-indol-6-yl]-3-ethyl-urea (36 mg, 95%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Nc2ccccc2)ccc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.5 %

Procedure:
A mixture of the 4-fluoro-3-nitroaniline (5.00 g, 32.03 mmol), phenylboronic acid (7.81 g, 64.05 mmol), copper(II) acetate (5.82 g, 32.03 mmol) and 4 Å molecular sieves (5.00 g) in dichloromethane (200.0 mL) and triethylamine (22.3 mL, 160 mmol) was placed in a round bottomed flask. The resulting suspension was stirred at room temperature under a dry ambient atmosphere for 48 h. The mixture was filtered through diatomaceous earth and the solvent was removed via rotary evaporation. The resulting residue was re-dissolved in EtOAc, adsorbed on silica gel and flash chromatographed (15% EtOAc/hexanes) to give 4-fluoro-3-nitro-N-phenylaniline as an orange solid (5.24 g, 70.5 % yield). M−, 231.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:5]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].I[CH2:28][CH2:29][O:30]C1CCCCO1.O>O1CCCC1>[Cl:1][CH2:2][CH2:3][C:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:5]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:28][CH2:29][OH:30])=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Oc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Reactant: ICCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCOc1ccc(C(=C(CCCl)c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
4-(4-Chloro-1,2-diphenyl-but-1-enyl)phenol (0.23 g, 0.689 mmol) was dissolved in tetrahydrofuran (3 ml) under nitrogen atmosphere. Sodium hydride (0.025 g, 1.03 mmol) was added to the solution and the mixture was stirred at room temperature for an hour. 2-(2-iodo-ethoxy)-tetrahydropyran (0.3 g, 1.17 mmol) was added and the mixture was refluxed for 2 hours. Additional portions of 2-(2-iodo-ethoxy)-tetrahydro-pyran (0.5 g, 2 mmol) were added to the mixture during seven hours. After cooling and adding water, THF was evaporated and the mixture was extracted three times with ethyl acetate. The organic phase was washed with 2 N aqueous sodium hydroxide and water, dried with sodium sulphate and evaporated to dryness. The residue (which is Compound (IV) where Pr is tetrahydropyranyl) was dissolved in ethanol and acidified with 2 N aqueous hydrogen chloride solution. The mixture was stirred at room temperature over night, evaporated and extracted with dichloromethane. After washing with water the organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography with dichloromethane/methanol 9.5/0.5 as eluent. Yield 0.17 g, 59%.
Reaction SMILES: [F:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=O.O=P(Cl)(Cl)Cl.[NH2:21][C:22](=[C:24]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:23].C([O-])(O)=O.[Na+].O>ClCCCl>[F:1][C:2]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7]/[C:6]/1=[N:21]\[C:22](=[C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH3:23]
Reactant: O=C1CCCN1Cc1cccc(F)c1F
Reactant: CCOC(=O)C(C(=O)OCC)=C(C)N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)C(C(=O)OCC)=C(C)/N=C1\CCCN1Cc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 1-(2,3-difluorobenzyl)pyrrolidin-2-one (17.05 mL, 89 mmol) in 1,2-dichloroethane (DCE) (240 mL) under nitrogen atmosphere was added dropwise in 15 min POCl3 (12.39 mL, 133 mmol) and the mixture was stirred at ambient temperature for 1 h. Then diethyl 2-(1-aminoethylidene)malonate (19.62 g, 97 mmol) was added and the mixture was heated to 40° C. under nitrogen atmosphere for 22 h. Saturated NaHCO3/water was carefully added (400 mL) and the mixture was stirred at ambient temperature for 1 h then extracted with dichloromethane. The aqueous phase was extracted with dichloromethane and the combined organic phase was washed brine, dried (Na2SO4), concentrated, dried in vacuo to provide (E)-diethyl 2-(1-((1-(2,3-difluorobenzyl)pyrrolidin-2-ylidene)amino)ethylidene)malonate (36.48 g, 70.3 mmol, 79% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.07-1.36 (m, 6 H), 1.88-2.10 (m, 2 H), 2.18-2.27 (m, 3 H), 2.35-2.61 (m, 2 H), 3.13-3.43 (m, 2 H), 3.98-4.30 (m, 4 H), 4.45-4.64 (m, 2 H), 6.94-7.20 (m, 3 H); LCMS (m/z) ES+=395 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.Cl>C1(O)CCCCC1.CCOCC>[Cl:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:13][CH3:14])=[C:9]([OH:12])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Cl)c2cc1O
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Solvent: OC1CCCCC1
Solvent: CCOCC
Product: COc1cc2nccc(Nc3ccc(Cl)cc3F)c2cc1O
Temperature: 155 °C
Yield: 25.1 %

Procedure:
A solution of 4-chloro-6-hydroxy-7-methoxyquinoline (3.0 g, 14 mmol) and 4-chloro-2-fluoroaniline (3.5 g, 23 mmol) in cyclohexanol (100 ml) containing 1M ethereal hydrogen chloride (16 ml) was heated at 155° C. for 18 hours. After cooling the mixture was diluted with ether and isohexanes and the precipitate was collected by filtration. The crude product was dissolved in a mixture of methylene chloride/methanol/ammonia (100/10/1) and silica (10 g) was added. The solvent was removed by evaporation and the resulting powder was purified by flash chromatography eluting with methylene chloride/methanol/ammonia (95/5/1 increasing to 80/20/1) to give 4-(4-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinoline (1.12 g, 25%).