Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:19]2[NH:28][C:27](=O)[C:26]3[C:21](=[CH:22][C:23]([O:32][CH3:33])=[CH:24][C:25]=3[O:30][CH3:31])[N:20]=2)=[CH:14][C:13]=1[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:37])=O>>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15]([C:19]2[N:28]=[C:27]([Cl:37])[C:26]3[C:21](=[CH:22][C:23]([O:32][CH3:33])=[CH:24][C:25]=3[O:30][CH3:31])[N:20]=2)=[CH:14][C:13]=1[CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCOCc4ccccc4)c(C)c3)nc2c1
Product: COc1cc(OC)c2c(Cl)nc(-c3cc(C)c(OCCOCc4ccccc4)c(C)c3)nc2c1

Procedure:
To a 100 mL round bottom flask was added 2-amino-4,6-dimethoxy-benzamide (318 mg, 1.6 mmol), 4-(2-benzyloxy-ethoxy)-3,5-dimethyl-benzaldehyde (461 mg, 1.6 mmol), p-toluenesulfonic acid monohydrate (32 mg, 0.16 mmol), sodium hydrogensulfite (318 mg, 1.8 mmol) and dimethylacetamide (5 mL). The mixture was stirred in a 150° C. oil bath under nitrogen overnight. Water (40 mL) and ether (30 mL) were added. The precipitate was filtered off, washed with water then ether, and air-dried. The intermediate 2-[4-(2-benzyloxyethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one was obtained as light brown/beige solid. Yield 474 mg (64%). 2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (474 mg, 1.03 mmol) was stirred in phosphorus oxychloride (10 mL) at 100° C. for 4 h. Excess phosphorus oxychloride was removed under reduced pressure. Ice was added and the solid was collected. The solid was washed with water and ether, and air-dried. 2-[4-(2-benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazoline was obtained as a light brown solid (yield: 356 mg, 72%). 2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazoline (192 mg, 0.4 mmol) was dissolved in a small amount of THF and 10% Pd/C (dry) (66 mg) was added. Anhydrous methanol (20 mL) and ammonium formate (955 mg) were added. The mixture was stirred in a 80° C. oil bath for 5 h. The mixture was filtered through Celite, washed with MeOH/DCM, purified by column chromatography to give 2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy)ethanol (36 mg, 25%) as an off-white solid. Selected data: MS (ES) m/z: 355.04; mp 169-170° C.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH2:18][C:19](Cl)=[O:20])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]>C1COCC1>[OH:20][C:19](=[C:4]([C:3]#[N:7])[C:5]#[N:6])[CH2:18][C:12]1[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([O:9][CH3:8])[CH:11]=1
Reactant: N#CCC#N
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CC(O)=C(C#N)C#N)cc1OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 110.3 %

Procedure:
To a 60% NaH/mineral oil dispersion (6.0 g, 0.15 moles) in THF (230 ml) in an ice-bath was added dropwise malononitrile (9.9 g, 0.15 mol). The reaction mixture was stirred for 2 hours at 0° C. and 3,4-dimethoxyphenyl acetylchloride (32.2 g, 0.15 mol) in THF (50 ml) was added dropwise over 2 hours. The reaction mixture was warmed to room temperature and stirred for 24 hours. The solvent was removed in vacuo, and the residue was partitioned between chloroform and 2N H2SO4. The organic layer was separated and the aqueous layer was extracted with chloroform (2×150 ml). The organic layers were combined and the solvent was removed in vacuo to afford 40.4 g (crude) of (1-hydroxy-(3,4-dimethoxyphenylethylidene))malononitrile as a brown oil, which was used directly in the following reaction without purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([O:11][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1ccc([N+](=O)[O-])c(C)c1
Temperature: 115 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a solution of 3-methyl-4-nitrophenol (45 g, 0.294 mol) in dimethylformamide (270 mL) there were added 1-bromodecane (65 g, 0.294 mol) and potassium carbonate (121.8 g, 0.882 mol). The reaction mixture was heated to 115° C. and stirred at that temperature for 48 hours. The reaction mixture was cooled and poured into water (4 L), stirred for 0.5 hour and extracted with two portions of ethyl acetate (1.5 L and 600 mL). The combined organic extracts were washed with 5% aqueous solution sodium bicarbonate (1 L), water (1 L and 0.5 L), dried over sodium sulfate and concentrated to give the crude product (90 g, 0.294 mol, 100% yield). This product was used in the next step without purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]3[C:17]([OH:18])=[N:16][CH:15]=[N:14][C:13]=23)=[CH:5][CH:4]=1)[CH3:2].[OH2:19]>C(O)(=O)C.[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]3[C:17]([OH:18])=[N:16][CH:15]=[N:14][C:13]=23)=[CH:7][CH:8]=1)(=[O:19])[CH3:2]
Reactant: CCc1ccc(-c2cnn3c(O)ncnc23)cc1
Reactant: O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: CC(=O)c1ccc(-c2cnn3c(O)ncnc23)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 8-(4-ethylphenyl)-4-hydroxypyrazolo[1,5-a]-1,3,5-triazine (240 mg) in acetic acid (5 ml) are added chromium trioxide (500 mg) and water (1 ml), and the mixture is stirred at room temperature for 14 hours. To the reaction mixture is added water, and the insoluble material is separated by filtration, washed with water and dried to give the title compound (150 mg).
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[NH2:14][NH2:15]>CCO>[NH:14]([C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[C:7]([Cl:12])[CH:8]=2)[N:3]=1)[NH2:15]
Reactant: NN
Reactant: Clc1cnc2cc(Cl)c(Cl)cc2n1
Solvent: CCO
Product: NNc1cnc2cc(Cl)c(Cl)cc2n1

Procedure:
To the 2,6,7-trichloroquinoxaline was added anhydrous EtOH (500 ml) to give a brown solution. 5.0 g (156 mmol) anhydrous hydrazine were added dropwise under N2, turning the solution red immediately. The solution was heated at reflux for 1 hour, cooled and the resulting solid was collected. Recrystallization from 1500 ml 95% EtOH yielded 13.0 g of 2-hydrazino-6,7-dichloroquinoxaline.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:19](=[O:20])[N:18]([CH2:21][CH2:22][CH3:23])[N:17]=[N:16]2)=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8]C)=[O:7].[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:19](=[O:20])[N:18]([CH2:21][CH2:22][CH3:23])[N:17]=[N:16]2)=[CH:10][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCCn1nnn(-c2cc(OCC(=O)OC)c(Cl)cc2Cl)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCn1nnn(-c2cc(OCC(=O)O)c(Cl)cc2Cl)c1=O
Yield: 41.2 %

Procedure:
A stirred solution of 0.5 g (0.0014 mole) of methyl 2,4-dichloro-5-(1,4-dihydro-5-oxo-4-propyltetrazol-1-yl)phenoxyacetate (compound 83) and 0.08 g (0.0021 mole) of sodium hydroxide in 10 mL of methanol was heated at reflux temperature for 1.5 hours. The reaction mixture was cooled, then evaporated under reduced pressure to leave a solid residue. The residue was dissolved in 20 mL of water, and the solution acidified with concentrated hydrochloric acid. A solid precipitate formed and was collected by filtration and washed with cold water. Recrystallization from diethyl ether:pentane provided 0.2 g of 2,4-dichloro-5-[1,4-dihydro-5-oxo-4-propyltetrazol-1-yl)phenoxyacetic acid, mp 134°-136° C.
Reaction SMILES: [O-]CC.[Na+].Cl.[CH2:6]([O:8][C:9](=[O:13])[CH2:10][NH:11][CH3:12])[CH3:7].C(O[C:17](=[C:20]([C:23]#[N:24])[C:21]#[N:22])[CH2:18][CH3:19])C.Cl>C(O)C>[CH2:6]([O:8][C:9]([C:10]1[N:11]([CH3:12])[C:17]([CH2:18][CH3:19])=[C:20]([C:21]#[N:22])[C:23]=1[NH2:24])=[O:13])[CH3:7]
Reactant: CCOC(CC)=C(C#N)C#N
Reactant: CCOC(=O)CNC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1c(N)c(C#N)c(CC)n1C
Temperature: 15 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
Alternatively the title compound may be prepared by the following procedure. Charge ethanol (3.40 L, denatured with 0.5% toluene) to a 22 L 3-neck reaction flask equipped with a mechanical stirrer, condenser, addition funnel and cooling bath. Cool the ethanol to 8° C. and add sodium ethoxide (805 grams, 11.35 mol) portion-wise over 20 minutes. In a separate flask, combine sarcosine ethyl ester hydrochloride (697 g, 4.54 mol), 2-(1-ethoxy-propylidene)-malononitrile (681 grams, 4.54 mol, prepared in preparation 35) and ethanol (3.0 L) and stir to dissolve the solids. Add the resulting solution to the 22 L flask over 33 minutes while maintaining about 11 C. Maintain the reaction mixture between 10-20° C. for 3.5 hours. Stir the mixture at room temperature overnight, then cool to 1° C. Adjust the pH to 7.0 by adding 1 N HCl (6.58 L) and stir the resulting suspension at 0-5° C. for 3 hours. Collect the precipitate by filtration, rinse the filter cake with deionized water (1.0 L) and vacuum-dry at 40° C., to afford the title compound in 66.7% yield. Mass spectrum (m/e): 222.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:13])=[C:4]([NH2:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:14][C:15]1[C:16]([N:20]=[C:21]=[S:22])=[CH:17][S:18][CH:19]=1>C1COCC1>[NH2:13][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=1[NH:12][C:21]([NH:20][C:16]1[C:15]([CH3:14])=[CH:19][S:18][CH:17]=1)=[S:22]
Reactant: Cc1cscc1N=C=S
Reactant: Nc1cc(C(F)(F)F)cc(Cl)c1N
Solvent: C1CCOC1
Product: Cc1cscc1NC(=S)Nc1cc(C(F)(F)F)cc(Cl)c1N

Procedure:
is obtained analogously to the procedure described in example 25 a) by reacting 3-chloro-5-trifluoromethyl-1,2-diaminobenzene and 4-methyl-3-thienyl isothiocyanate in anhydrous THF at room temperature for 3 days. The solvent is distilled off and water is added to the residue, and the mixture is then extracted with ethyl acetate, the solvent is again distilled off and the amorphous residue is crystallized under diisopropyl ether. M.p.: >310° C.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:2].[O:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:1]([N:3]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[CH:7][C:6]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:25]1[CH2:26][CH2:27][O:22][CH2:23][CH2:24]1)[CH3:2]
Reactant: CCNCc1cc(C(=O)OCC)ccc1-c1ccccc1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(-c2ccccc2)c(CN(CC)C2CCOCC2)c1

Procedure:
Ethyl 2-[(ethylamino)methyl]biphenyl-4-carboxylate and tetrahydro-4H-pyran-4-one were treated with sodium triacetoxyborohydride in the presence of acetic acid to obtain ethyl 2-{[ethyl(tetrahydro-2H-pyran-4-yl)amino]methyl}biphenyl-4-carboxylate.
Reaction SMILES: ClC(Cl)(Cl)C(O)=O.C[O:9][CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[O:20][CH3:21]>ClCCl.O>[CH3:21][O:20][C:13]1[C:14]([O:18][CH3:19])=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][CH:10]=[O:9]
Reactant: COC=Cc1cccc(OC)c1OC
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1cccc(CC=O)c1OC
Reaction time: 2 h
Yield: 104.1 %

Procedure:
Trichloroacetic acid (817 mg, 5.00 mmol) was added to a solution (10 mL) of 2-(2,3-dimethoxyphenyl)ethenyl methyl ether (808 mg, 4.16 mmol) in dichloromethane at room temperature and stirred for 2 hours. The reaction mixture was diluted with water and extracted twice with ethyl acetate. The extract solution was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 2-(2,3-dimethoxyphenyl)acetaldehyde (780 mg, 100%) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)C(C)C)(C)C.[CH:34]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]2[C:18]([CH3:19])([CH3:20])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([O:23][CH3:24])=[O:22])[CH:15]=3)[NH:10]2)=[CH:3][C:2]=1[NH:1][C:40]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:41]
Reactant: O=C(Cl)C1CCCCC1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(N)c1)N2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1ccc(Cl)c(NC(=O)C3CCCCC3)c1)N2
Reaction time: 1.5 h
Yield: 94.7 %

Procedure:
To a solution of methyl 2-(3-amino-4-chlorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (200 mg, 0.58 mmol) in 8 mL of dichloromethane, was added N,N-diisopropylethylamine (150 mg, 1.16 mmol) under nitrogen atmosphere. Then a solution of cyclohexanecarbonyl chloride (127 mg, 0.87 mmol) was added via syringe with an ice bath. The mixture was stirred for 1.5 h. The mixture was purified by column chromatography to afford 250 mg of methyl 2-(4-chloro-3-(cyclohexanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a crude product. (Yield: 95%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][F:19])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>N1CCCCC1.C(#N)C.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.[Cu]I>[NH2:17][C:13]1[N:12]=[C:11]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:29]#[C:28][C:26]([C:21]4[N:20]=[CH:25][CH:24]=[CH:23][N:22]=4)([OH:30])[CH3:27])[CH:10]=3)[C:6]([CH2:18][F:19])=[N:7]2)[CH:16]=[CH:15][N:14]=1
Reactant: Nc1nccc(-n2nc(CF)c3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1ncccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: CC#N
Product: CC(O)(C#Cc1ccc2c(CF)nn(-c3ccnc(N)n3)c2c1)c1ncccn1
Temperature: 66 °C

Procedure:
To a solution of 4-[6-bromo-3-(fluoromethyl)-1H-indazol-1-yl]pyrimidin-2-amine (49 mg, 0.12 mmol) in piperidine (2 mL) was introduced tetrakis(triphenylphosphine)palladium (0) (11.5 mg, 0.01 mmol), copper(I) iodide (1.9 mg, 0.01 mmol) and 2-(pyrimidin-2-yl)but-3-yn-2-ol (39 mg, 0.25 mmol). The reaction mixture was warmed to 66° C. for 2 hr. After cooling to RT, the reaction mixture was concentrated in vacuo, DCM (10 mL) was added and the solution re-evaporated to dryness in vacuo (re-evaporation process repeated twice). Purification of the residue by column chromatography (Biotage, DCM containing a 0-10% gradient of methanol) furnished a brown oil which was suspended in acetonitrile and concentrated in vacuo. The residue was re-suspended in acetonitrile (1 mL), whereupon a brown solid precipitated and was collected by filtration to furnish the title compound as a brown solid: 1H NMR (500 MHz, METHANOL-d4) delta 1.99 (3H, s), 5.75 (2H, d, J=47.92 Hz), 7.23 (1H, d, J=5.36 Hz), 7.42 (1H, dd, J=8.28, 1.02 Hz), 7.48 (1H, t, J=4.89 Hz), 7.85 (1H, d, J=8.20 Hz), 8.25 (1H, d, J=4.73 Hz), 8.88 (2H, d, J=4.89 Hz), 9.06 (1H, s); LC-MS: m/z=+390.05 (M+H)+.
Reaction SMILES: C([N:4]1[C:16]2[CH:15]=[CH:14][C:13]3[C:17]([O:19][C:20](=[O:21])[C:12]=3[C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)=O)(=O)C.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>C1(C)C=CC=CC=1>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][N:26]1[C:20](=[O:21])[C:12]2[C:11]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[NH:4][C:16]=3[CH:15]=[CH:14][C:13]=2[C:17]1=[O:19]
Reactant: CN(C)CCN
Reactant: CC(=O)n1c2ccccc2c2c3c(ccc21)C(=O)OC3=O
Solvent: Cc1ccccc1
Product: CN(C)CCN1C(=O)c2ccc3[nH]c4ccccc4c3c2C1=O
Yield: 77.9 %

Procedure:
To 100 ml of toluene were added 1.12 g of 9-acetylcarbazole-3,4-dicarboxylic anhydride and 1.06 g of N,N-dimethylethylenediamine. The mixture was azeotropically refluxed for 2 hours. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from n-propanol to obtain 960 mg (yield: 78%) of N-(2-dimethylaminoethyl)-carbazole-3,4-dicarboximide as light yellow needles.
Reaction SMILES: C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:31]([O:35][C:36](=[O:56])[CH2:37][C@H:38]([NH:42][S:43]([C:46]1[C:51]([CH3:52])=[CH:50][C:49]([O:53][CH3:54])=[CH:48][C:47]=1[CH3:55])(=[O:45])=[O:44])[C:39](O)=[O:40])([CH3:34])([CH3:33])[CH3:32].[CH3:57][O:58][CH:59]([O:62][CH3:63])[CH2:60][NH2:61]>C(Cl)Cl>[CH3:57][O:58][CH:59]([O:62][CH3:63])[CH2:60][NH:61][C:39](=[O:40])[C@@H:38]([NH:42][S:43]([C:46]1[C:51]([CH3:52])=[CH:50][C:49]([O:53][CH3:54])=[CH:48][C:47]=1[CH3:55])(=[O:44])=[O:45])[CH2:37][C:36]([O:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:56]
Reactant: COC(CN)OC
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)NCC(OC)OC)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
Diisopropylethylamine (2.5 eq) followed by HOBT (1.0 eq) and EDCI (1.5 eq) was added to a solution of (S)-4-tert-butoxy-2-(4-methoxy-2,6-dimethylphenyl-sulfonamido)-4-oxobutyric acid (1.91 mmol, 1.0 eq) in DCM (10 ml/mmol) at 0° C. The resulting solution was stirred for 15 min at 25° C., cooled to 0° C. again and 2,2-dimethoxyethanamine (1.2 eq) was added. The reaction mixture was stirred for 16 h at 15° C. It was then diluted with DCM and extracted with saturated ammonium chloride solution, saturated sodium chloride solution, saturated sodium bicarbonate solution and finally saturated sodium chloride solution. The organic phase was dried (Na2SO4) and concentrated to low volume under vacuum. The crude product was processed by column chromatography. Yield: 70%
Reaction SMILES: [Li]CCCC.[F:6][C:7]([F:16])([F:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].CN([CH:20]=[O:21])C.O>C1COCC1>[Cl:14][C:9]1[C:8]([C:7]([F:6])([F:15])[F:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:20]=[O:21]
Reactant: FC(F)(F)c1ccccc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1cccc(C(F)(F)F)c1Cl
Temperature: -70 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
BuLi (1.6 M in hexane, 173 mL, 277 mmol) was added to a sol. of 2-trifluoromethyl-chlorobenzene (50.0 g, 277 mmol) in THF (500 mL) at −70° C. The sol. was stirred for 2 h at −70° C., and DMF (21.3 mL, 277 mmol) in THF (100 mL) was added. The mixture was allowed to warm to rt overnight. Water was added (200 mL), and the mixture was extracted with Et2O (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane/EtOAc 20:1) yielded the title compound (37.4 g, 65%). LC-MS: tR=0.96 min.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:19][O:20][CH3:21]>CC#N>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:19][O:20][CH3:21])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5]
Reactant: COCCl
Reactant: O=Cc1c(O)cc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COCOc1cc(O)c(C=O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Fluoro-4,6-dihydroxybenzaldehyde (12 g) was dissolved in MeCN (250 mL), and cesium carbonate (25.1 g) and chloromethylmethylether (6.95 mL) were added thereto, followed by stirring at room temperature for 1 hour. The insoluble materials were removed by filtration through celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 94:6) to obtain 2-fluoro-6-hydroxy-4-(methoxymethoxy)benzaldehyde (11.89 g) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[NH:12]1[CH:16]=[CH:15][N:14]=[CH:13]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:12]1[CH:16]=[CH:15][N:14]=[CH:13]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(-n2ccnc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
A mixture of 3,4-difluoronitrobenzene (1.00 mL, 9.03 mmol), imidazole (0.615 g, 9.04 mmol) and K2CO3 (2.50 g, 18.1 mmol) in DMF (10 mL) was stirred at room temperature overnight. Water (20 mL) was added to induce precipitation. The precipitate was collected, dried on vacuum to give 1-(2-fluoro-4-nitrophenyl)-1H-imidazole as a solid (1.81 g). MS 208.2 (M+H)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[CH2:12][CH2:13][O:14][CH3:15])=[CH:4][CH:3]=1.[C:16]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:21]=[CH:20][C:19]([C:22](O)=[O:23])=[CH:18][CH:17]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:15][O:14][CH2:13][CH2:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:17][CH:18]=3)=[O:23])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: COCCN1CCCc2ccc(N)cc21
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COCCN1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-amino-1-(2-methoxyethyl)-1,2,3,4-tetrahydroquinoline (D13) (72 mg, 0.35 mmol) in DCM (2.5 ml) was added 4-biphenylcarboxylic acid (104 mg, 0.53 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (97 mg, 0.53 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) and the reaction stirred at ambient temperature overnight. The mixture was diluted with DCM, washed with 2M sodium hydroxide solution, dried over MgSO4 and concentrated in vacuo to give the crude product which was purified by silica SPE chromatography. Elution with 20% EtOAc/60-80° C. petroleum ether gave the title compound as a pale yellow solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.93 (d, 2H), 7.77 (br, 1H), 7.69 (d, 2H), 7.62 (d, 2H), 7.47 (t, 2H), 7.39 (t, 1H), 7.06 (d, 1H), 6.91 (d, 1H), 6.73 (dd, 1H), 3.63 (t, 2H), 3.49 (t, 2H), 3.37 (s, 3H), 3.36 (t, 2H), 2.73 (t, 2H), 1.91 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: Nc1ccc(-c2ccc(O)cc2)c2c1C(=O)NC2
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(N)c3c2CNC3=O)cc1
Yield: 67.5 %

Procedure:
In a similar manner to Step 1 of Example 304, 7-amino-4-(4-hydroxyphenyl)isoindolinone (182 mg, 0.760 mmol) was dissolved in acetonitrile (9.1 mL), and the solution was treated with tert-butyldimethylsilyl chloride (206 mg, 1.37 mmol) and DBU (0.205 mL, 1.37 mmol), followed by purification by flash column chromatography (chloroform) to obtain 7-amino-4-(4-tert-butyldimethylsilyloxyphenyl)isoindolinone (182 mg, yield 68%).