Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH:7]([CH3:11])[C:8](Cl)=[O:9].Cl.[CH2:13]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)Cl>[Cl:5][CH2:6][CH:7]([CH3:11])[C:8]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)=[CH:15][CH:16]=1)=[O:9]
Reactant: c1ccc(Cc2cccnc2)cc1
Reactant: CC(CCl)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(CCl)C(=O)c1ccc(Cc2cccnc2)cc1
Reaction time: 1 h
Yield: 96 %

Procedure:
In 25 ml of methylene chloride was suspended 13.3 g of anhydrous aluminum chloride, and 7.3 g of 3-chloro-2-methylpropionyl chloride was added to the suspension with ice-cooling, after which 8.2 g of 3-benzylpyridine hydrochloride was added in small portions to the suspension. The resulting mixture was subjected to reaction with ice-cooling for 2 hours and then at room temperature for one hour. The reaction mixture was added in small portions to a mixture of 246 ml of iced water and 49 ml of methylene chloride, and the organic layer was separated, while the aqueous layer was extracted with 40 ml of methylene chloride. The organic layers were combined and then 80 ml of water was added thereto after which the resulting mixture was neutralized with sodium hydrogencarbonate. The organic layer was separated, washed with 50 ml of water, and thereafter dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform:ethyl acetate (1:1 by volume)] to obtain 10.53 g (yield 96.0%) of colorless, oily 3-[p-(3-chloro-2-methylpropionyl)benzyl]pyridine.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:10]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.CCOCC>CCCCCC>[CH:10]1([NH:17][C:8]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[S:9])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: S=C=NC1CCCCC1
Reactant: NC1CCCCCC1
Solvent: CCOCC
Solvent: CCCCCC
Product: S=C(NC1CCCCCC1)NC1CCCCC1

Procedure:
The thiourea is prepared by reacting 14.1 gm. (0.1 mole) of cyclohexyl isothiocyanate and 11.5 gm. (0.1 mole) of cycloheptylamine in 200 ml. of ether for 1.5 hr. at room temperature. Reaction is diluted with an equal volume of Skellysolve B to give 19.5 gm. of product, m.p. 160°-161°.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[CH:8][N:7]([CH3:13])[N:6]=1)=[O:4]>C(O)C.[Pd]>[CH3:1][NH:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][N:7]([CH3:13])[N:6]=1)=[O:4]
Reactant: CNC(=O)c1nn(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNC(=O)c1nn(C)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.6 %

Procedure:
A solution of 1-methyl-4-nitro-1H-pyrazole-3-carboxylic acid methylamide (100 mg, 0.5 mmol) in ethanol (4 ml) was flushed with argon and treated with Pd/C 10% (40 mg, 0.04 mmol). The reaction vessel was evacuated and flushed with hydrogen three times and the reaction was stirred at ambient temperature overnight. The reaction mixture was filtrated and the solvent was evaporated to yield a brown viscous oil (76 mg, 91%) which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:24]1CCOCC1.ClC(OCC(C)C)=O.N>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:11])[NH2:24])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(N)=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 74 %

Procedure:
To a 0° C. solution of 2-(S)-tert-butoxycarbonylamino-3-(4-nitrophenyl)-propionic acid and N-methylmorpholine (1.1 mL, 9.65 mmol) in DMF (10 mL) is added dropwise iso-butyl chloroformate (1.25 mL, 9.65 mmol). The mixture is stirred at 0° C. for 20 minutes. after which NH3 (g) is passed through the reaction mixture for 30 minutes at 0° C. The reaction mixture is concentrated and the residue dissolved in EtOAc, washed successively with 5% citric acid, water, 5% NaHCO3, water and brine, dried (Na2SO4), filtered and concentrated in vacuo to a residue that is triturated with a mixture of EtOAc/petroleum ether to provide 2.2 g (74% yield) of the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](Cl)=[O:19])([CH3:14])([CH3:13])[CH3:12]>COCCOC>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:23]([OH:24])=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:16]=2)=[CH:3][CH:4]=1)([OH:8])=[O:7]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: Nc1ccc(C(=O)O)cc1
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 32.7 %

Procedure:
A solution of 8.6g (0.063 mole) of p-aminobenzoic acid in 100 ml of 1,2-dimethoxyethane was added to a suspension of 8.0g (0.0298 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then filtered. The filtrate was thereafter diluted with 200 ml of water and chilled. The resulting precipitate was collected, and was then recrystallized from a mixture of ethanol and water to give 3.6g of white needles of N-(4-carboxyphenyl)-3,5-di-t-butyl-4-hydroxybenzamide, m.p. 265°-266° C. Analysis: Calculated for C22H27NO4 : %C, 71.5; %H, 7.4; %N, 3.8; Found: %C, 71.7; %H, 7.3; %N, 3.6.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: Clc1nc2c(Cl)cccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5c(Cl)cccc5s4)cc3CC[C@@H]12
Yield: 49.1 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2,4-dichlorobenzothiazole (94 mg, 0.46 mmol) and 1 mL of anhydrous dimethyl formamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 48 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 80 mg (49%) of the title compound as an amorphous solid. mp 207°-209°. FDMS: m/e=429 α[D]589 =+63.86 (c=0.57, chloroform).
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[Br:13][C:14]1[CH:15]=[C:16]([NH2:28])[C:17]([NH:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:19]=1>C1COCC1.C([O-])(O)=O.[Na+]>[Br:13][C:14]1[CH:19]=[CH:18][C:17]2[N:20]([CH2:21][CH2:22][N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[C:6](=[O:7])[NH:28][C:16]=2[CH:15]=1
Reactant: Nc1cc(Br)ccc1NCCN1CCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c2cc(Br)ccc2n1CCN1CCCC1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
600 mg (3.70 mmol) CDI are added to a solution of 853 mg (3.00 mmol) 4-bromo-N1-(2-pyrrolidin-1-yl-ethyl)-benzene-1,2-diamine in 20 mL THF at RT. The reaction solution is heated to 40° C. and stirred for 30 min at this temperature. A further 600 mg (3.70 mmol) CDI are added and the reaction is stirred for a further 30 min at 40° C. The solution is diluted with semisaturated NaHCO3 solution and the aqueous phase is extracted twice with EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The residue is triturated with acetonitrile, the precipitate is filtered and dried in the air.
Reaction SMILES: [K].[CH2:2]([OH:4])[CH3:3].C(OC([CH:10]1[CH2:16][CH2:15][CH2:14][N:13]([CH2:17][C:18](OCC)=O)CC1)=O)C>C1(C)C=CC=CC=1>[N:13]12[CH2:14][CH2:15][CH:16]([CH2:18][CH2:17]1)[CH2:10][C:2](=[O:4])[CH2:3]2
Reactant: CCO
Reactant: CCOC(=O)CN1CCCC(C(=O)OCC)CC1
Agent: [K]
Solvent: Cc1ccccc1
Product: O=C1CC2CCN(CC2)C1
Reaction time: 14 h

Procedure:
To a 250 mL round-bottomed flask equipped with condenser and nitrogen inlet were added 1.55 g (39.69 g-atm.) potassium and 80 mL toluene. The mixture was heated to reflux and treated with 1.83 mL (39.69 mmol) ethanol. Refluxing continued until the potassium disappeared. Then 4.08 g (15.87 mmol) ethyl-N-ethoxycarbonylmethyl-perhydroazepine-4-carboxylate was added and refluxing was continued for 14 hours. The reaction was evaporated and the residue taken up in 100 mL 1N hydrochloric acid. This solution was refluxed for 22 hours, cooled, washed with methylene chloride, and adjusted to pH 12 with 6N sodium hydroxide. The aqueous layer was extracted with methylene chloride, which was dried over sodium sulfate and evaporated. The resulting foam, 700 mg (32%), was used directly below.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)=[C:7]([CH:14]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([O:17][CH3:18])=[O:16])[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.[CH3:32][N:33](C)C=O>O.[C-]#N.[C-]#N.[Zn+2].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:32]([C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)=[C:7]([CH:14]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])[C:15]([O:17][CH3:18])=[O:16])[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1)#[N:33]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(Br)cc2c(=O)n1C
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: O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(C#N)cc2c(=O)n1C
Yield: 82 %

Procedure:
A mixture of methyl [7-bromo-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate (160 mg, 0.329 mmol) and Zn(CN)2 (38.6 mg, 0.329 mmol) in N,N-Dimethylformamide (DMF) (3289 μl) was degassed with N2 for 5 min, treated with Pd(Ph3P)4 (38.0 mg, 0.033 mmol), and irradiated in microwave at 120° C. for 30 min. The mixture was diluted with water, extracted with EtOAc, washed with water, brine, dried with Na2SO4, filtered, and concentrated. the residue was purified by column chromatography (SiO2, 0-60% EtOAc/Hexane) to afford methyl [7-cyano-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl][(1,1-dimethylethyl)oxy]acetate (116.8 mg, 0.270 mmol, 82% yield) as colorless oil that slowly became a white solid: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.85-8.76 (m, 1 H), 7.65 (ddd, J=1.9, 6.1, 8.3 Hz, 1 H), 7.30-7.24 (m, 1 H), 7.23-7.09 (m, 2 H), 7.07-6.96 (m, 1 H), 5.22 (s, 1 H), 3.80 (s, 1.5 H), 3.78 (s, 1.5 H), 3.70 (s, 1.5 H), 3.69 (s, 1.5 ; H), 2.37 (s, 3 H), 2.32 (s, 3 H), 1.02 (s, 4.5 H), 1.01 (s, 4.5 H); LCMS (m/z) ES+=433 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1)=[O:5].C(N(CC)CC)C.[CH:27]1[CH:28]=[CH:29][N:30]2[CH2:36][C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[NH:33][CH2:32][C:31]=12>C(Cl)Cl>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([N:33]2[C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[CH2:36][N:30]3[CH:29]=[CH:28][CH:27]=[C:31]3[CH2:32]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 131.1 %

Procedure:
To a mixture of 1.93 g of 4-[(2-methylbenzoyl)amino]benzoyl chloride in 15 ml of methylene chloride, cooled to 0° C. is added 1.13 ml of triethylamine. After stirring for 3 minutes, a mixture of 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 5 ml of methylene chloride is added. The cooling bath is removed and after about 30 minutes a complete solution is obtained. The reaction mixture is allowed to stir at room temperature for 48 hours and the volatiles are concentrated in vacuo to a residue. The residue is dissolved in 100 ml of ethyl acetate and washed with water, 2N citric acid, aqueous NaHCO3 and brine. The solution is dried with Na2SO4 and the volatiles concentrated in vacuo to give 3.0 g of a residue. A 300 mg sample of the residue is purified by thick layer chromatography using 10% ethyl acetate-methylene chloride to give 160 mg of the desired product. The remainder of the crude material is purified by flash chromatography using 10% ethyl acetate in methylene chloride to give the desired product as a residue which is crystallized from ethyl acetate to give 800 mg of the desired product as white crystals, m.p. 212°-215° C.
Reaction SMILES: [F:1][C:2]1[C:22](F)=[CH:21][C:5]2[C:6]3[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][N:10]([CH3:14])[C:11]=3[CH:12]=[N:13][C:4]=2[CH:3]=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:32]2[CH2:37][NH:36][CH2:35][CH2:34][NH:33]2)[CH:28]=[CH:29][C:30]=1[CH3:31].O>CS(C)=O>[CH3:24][C:25]1[CH:26]=[C:27]([CH:32]2[NH:33][CH2:34][CH2:35][N:36]([C:22]3[C:2]([F:1])=[CH:3][C:4]4[N:13]=[CH:12][C:11]5[N:10]([CH3:14])[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=5[C:5]=4[CH:21]=3)[CH2:37]2)[CH:28]=[CH:29][C:30]=1[CH3:31]
Reactant: Cc1ccc(C2CNCCN2)cc1C
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(F)c(F)cc3c2c1=O
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2cnc3cc(F)c(N4CCNC(c5ccc(C)c(C)c5)C4)cc3c2c1=O
Temperature: 100 °C
Yield: 42 %

Procedure:
A stirred suspension of 2.5 g of ethyl 8,9-difluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate and 2.6 g of 2-(3,4-dimethylphenyl)piperazine in 45 cm3 of dimethyl sulphoxide was heated at a temperature in the region of 100° C. for about 100 hours. The reaction mixture was treated with 400 cm3 of water and filtered. The residue obtained was chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 5.5 cm, height 45 cm), eluted at an argon pressure of 120 kPa with a mixture of dichloromethane and ethanol (92/8 mixture by volume) and 50 cm3 fractions were collected. Fractions 37 to 80 were combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.61 g of ethyl 9-[3-(3,4-dimethylphenyl)piperazin-1-yl]-8-fluoro-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate was obtained in the form of a yellow solid, which melted at 290° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:18][NH:19][CH2:20][CH3:21]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:19]([CH2:20][CH3:21])[CH3:18])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Reactant: CCNC
Solvent: CO
Product: CCN(C)c1nc(Cl)nc2c1CCC2c1ccccc1
Yield: 100 %

Procedure:
A solution of 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (150 mg, 0.566 mmol) and excess N-methylethanamine (0.486 mL, 5.66 mmol) in MeOH (2 mL) was stirred at rt for 1 h. The solvent was removed in vacuum to afford 2-chloro-N-ethyl-N-methyl-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (163 mg, 0.566 mmol, 100% yield). LC-MS (M+H)+=288.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:29])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[C:15]([CH3:28])[C:16]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43](O)=[O:44])[C:38]2=[O:46])=[CH:33][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:29][C:43]([C:39]2[C:38](=[O:46])[N:37]([C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=3)[CH:42]=[CH:41][CH:40]=2)=[O:44])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[C:15]([CH3:28])[C:16]([O:18][CH2:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine 30 mg, 0.075 mmol) and 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid in DMF (1.0 mL) at room temperature were added HATU (57 mg, 0.15 mmol, Perseptive Biosystem), and DIEA (0.05 mL, 0.3 mmol, Aldrich). The reaction mixture was stirred at rt for 1 h, and was then quenched by the addition of 2 mL of methanol. The reaction mixture was purified by preparative HPLC. The desired fractions were combined, concentrated in vacuo, and neutralized to pH 8 with aq. K2HPO4. The title compound (30 mg, 64%) was obtained as a white solid which was collected by filtration and dried under vaccum. 1H NMR (DMSO-d6) δ 12.09 (br s, 1H), 8.58 (dd, 1H, J=7.15, 2.20 Hz, 1H), 8.12 (dd, 1H, J=6.60, 1.65 Hz), 7.98 (s, 1H), 7.95 (d, 2H, J=3.85 Hz), 7.62-7.59 (m, 2H), 7.45-7.40 (m, 4H), 6.72 (t, 1H, J=9.90 Hz), 4.13 (t, 2H, J=5.5 Hz), 2.71 (d, 2H, J=5.5 Hz), 2.60-2.25 (m, 8H), 2.35 (s, 3H), 2.16 (s, 3H); MS(ESI30) m/z 616.40 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[K+].[K+].Br[C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][C:29]([S:35]([N:38](CC1C=CC(OC)=CC=1OC)[C:39]1[S:43][N:42]=[CH:41][N:40]=1)(=[O:37])=[O:36])=[CH:30]2>O1CCOCC1.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>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH:27]=[CH:28][C:29]([S:35]([NH:38][C:39]1[S:43][N:42]=[CH:41][N:40]=1)(=[O:37])=[O:36])=[CH:30]2
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Reactant: CC1(C)OB(c2ccc(Cl)cc2Br)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(Cl)cc3Br)cccc2c1
Temperature: 100 °C

Procedure:
A pressure vessel was charged with 2-(2-bromo-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.732 g, 2.306 mmol), potassium carbonate (1.328 g, 9.61 mmol), 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D) (1 g, 1.922 mmol), tetrakis(triphenylphosphine)palladium(0) (0.222 g, 0.192 mmol) in dioxane (12.81 mL) and water (6.41 mL). The reaction was heated in an oil bath at 100° C. for 35 min. LC/MS indicated that the desired product (M+H=479.8) was generated. Water was added to the mixture and washed with EtOAc. The water layer was acidified with 5% HCl (15 mL) and washed with EtOAc again to afford a light yellow solid. The product was used in the next reaction without further purification. m/z (ESI) 480.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([O:16]CC)=[O:15])=[CH:12][N:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:9]=1.[OH-].[K+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[C:10]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:9]=1
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1-c1ccccc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cnc(-c2ccccc2)nc1-c1ccccc1Cl
Yield: 99.5 %

Procedure:
A mixture of 5.70 g of compound E and 2.83 g of potassium hydroxide in 40 cc of ethanol and 0.5 cc of water was heated under reflux for 3 hours. After cooling, the reaction mixture was acidified with 1N HCl, and extracted with chloroform. The extract was dried over magnesium sulfate, and distilled to remove the solvent. Thus, 5.20 g of 4-(2-chlorophenyl)-2-phenyl-5-pyrimidinecarboxylic acid was obtained. Yield: 99.6%.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([OH:28])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][C:20]=2[C:29](=[O:31])[NH2:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:33][C:34]([O:36][CH3:37])=[O:35]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([O:28][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][C:20]=2[C:29](=[O:31])[NH2:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1ccccc1Cc1ccccc1
Reaction time: 0.05 h
Yield: 34.9 %

Procedure:
40% Methanolic Triton B (0.12 mL, 0.26 mM) was added to a solution of the 9-[(2-benzylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (701 mg, 0.17 mM) in 10 mL DMF at 25° C. After 3 minutes, methyl bromoacetate (55 mg, 0.34 mM) was added and the resultant mixture stirred at room temperature for 25 hours. The mixture was diluted with ethyl acetate, washed with 1 N HCl, H2O, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 60 mg (73%) of the {9-[(2-benzylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a white solid. 1H NMR (CDCl3) δ 7.4-7.00 (m, 14H), 6.65 (d, 1H, J=8 Hz), 6.55 (d, 1H, J=8 Hz), 6.4 (d, 1H, J=8 Hz), 5.4 (s, 2H), 4.95 (s, 2H), 4.2 (s, 2H), and 3.80 (s, 3H). IR (KBr, cm−1) 3414, 3186, 1759, 1625, 1583, 1500, 1452, 1424, 1340, 1325, 1213, 1199, and 1108. MS (ES) m/e 477, 479.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]1(CCCCO)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(P(CCCC)CCCC)CCC.N(C(N(C)C)=O)=NC(N(C)C)=O>ClCCl.O1CCCC1>[C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Reactant: Oc1ccccc1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 139.9 %

Procedure:
To the phenol resin (100 mg), 4-phenylbutan-1-ol (0.42 mmol) was added at room temperature, followed by the addition of dry tetrahydrofuran (0.4 mL) and dichloromethane (0.4 mL). At room temperature, tri-n-butylphosphine (0.42 mmol) was added dropwise thereto and further 1,1′-azobis(N,N-dimethylformamide) (0.42 mmol) was added. The mixture was shaken at room temperature for 5 hours. The resin was taken up by filtration, washed with a mixed solvent (dichloromethane:tetrahydrofuran=1:1) 4 times and dichloromethane 2 times and then dried to give a phenyl ether resin (about 100 mg).