Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:24])[C:6]=1[C:7]1[C:8]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:16]=2[F:23])=[N:9][N:10]([CH3:14])[C:11]=1[C:12]#[N:13].S(C)C>C(Cl)Cl.B(F)(F)F>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH3:24])[C:6]=1[C:7]1[C:8]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[F:23])=[N:9][N:10]([CH3:14])[C:11]=1[C:12]#[N:13]
Reactant: COc1ccc(-c2nn(C)c(C#N)c2-c2c(C)csc2C)c(F)c1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: Cc1csc(C)c1-c1c(-c2ccc(O)cc2F)nn(C)c1C#N
Temperature: 25 °C
Yield: 42.8 %

Procedure:
4-(2,4-dimethylthiophen-3-yl)-3-(2-fluoro-4-methoxyphenyl)-1-methyl-1H-pyrazole-5-carbonitrile (17 mg, 0.05 mmol) was dissolved in dry DCM (2 mL) and BF3.Me2S (1 M solution in DCM, 0.3 mL, 0.3 mmol) was added and the mixture was stirred at room temperature over night. The mixture was concentrated and MeOH was added to quench the reaction The crude product was purified on silica gel to give -(2,4-dimethylthiophen-3-yl)-3-(2-fluoro-4-hydroxyphenyl)-1-methyl-1H-pyrazole-5-carbonitrile (7.0 mg, 43%).
Reaction SMILES: [Cl:1][C:2]1[N:6]2[C:7]3[S:21][C:20]([CH2:22][CH3:23])=[CH:19][C:8]=3[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:10][CH2:11][C:5]2=[N:4][N:3]=1.Cl.C(=O)([O-])[OH:26].[Na+].[NH:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[C:31]1[C:39](Cl)=[O:40]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:6]([C:7]2[S:21][C:20]([CH2:22][CH3:23])=[CH:19][C:8]=2[C:9](=[O:26])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[C:5]([CH2:11][NH:10][C:39]([C:31]2[NH:30][C:38]3[C:33]([CH:32]=2)=[CH:34][CH:35]=[CH:36][CH:37]=3)=[O:40])=[N:4][N:3]=1
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Reactant: O=C([O-])O
Reactant: CCc1cc2c(s1)-n1c(Cl)nnc1CN=C2c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(Cl)nnc2CNC(=O)c2cc3ccccc3[nH]2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
9-Chloro-4-(2-chlorophenyl)-2-ethyl-6H-thieno[3,2-f] [1,2,4]triazolo[4,3-a] [1,4]diazepine (0.5 g) was stirred with 2M hydrochloric acid (12.5 ml) at 60° C. for 2.5 hours. The reaction mixture was cooled to room temperature. Sodium hydrogencarbonate was added to make the reaction mixture alkaline. Chloroform and indole-2-carbonyl chloride (0.33 g) were added, and the mixture was stirred for 0.5 hour. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, and the obtained residue was crystallized from ethyl acetate to give 0.2 g of N-(3-chloro-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl) [1,2,4]triazol-5-ylmethyl)indole-2-carboxamide.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3]([NH:5][C:6]1[N:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1)=[O:4].[CH:15]([Mg]Br)([CH3:17])[CH3:16].[NH4+].[Cl-]>C1COCC1.C(Cl)Cl>[CH3:16][CH:15]([C:11]1[CH:10]=[C:9]([CH3:12])[N:8]=[N:7][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:14])([CH3:13])[CH3:1])[CH3:17]
Reactant: CC(C)[Mg]Br
Reactant: Cc1ccc(NC(=O)C(C)(C)C)nn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C(C)C)c(NC(=O)C(C)(C)C)nn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.3 %

Procedure:
A solution of 2,2-dimethyl-N-(6-methyl-pyridazin-3-yl)-propionamide (4.00 g, 20.73 mmol) in THF (50 mL) is stirred at 0° C. 2.0 M iPrMgBr (46.6 mL, 93.26 mmol) is then added dropwise. The reaction is stirred at 0° C. for 30 min, then it is refluxed for 2 h. It is cooled to rt, poured into ice-H2O; sat. NH4Cl is added and extracted with EtOAc; dried with Na2SO4, filtered and concentrated. The crude material is dissolved in CH2Cl2 (100 mL), treated with 12 (5.8 g, 22.80 mmol) and stirred at rt for 2 h. The reaction is diluted with CH2Cl2 (100 mL), washed with 5% Na2SO3 (3×100 mL); dried with Na2SO4, filtered and concentrated. Purification of the crude material gives the title compound (1.38 g, 5.87 mmol, 28%). ES-MS (m/z): calcd for C13H21N3O (M+H)+: 236.3. found: 236.1.
Reaction SMILES: [N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:31]=[C:32]([C:34](=[O:43])[NH:35][C:36]4[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=4)[CH:33]=3)[O:17][CH:18]([CH2:24][CH2:25]OS(C)(=O)=O)[C:19](OCC)=[O:20])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.[I-].[Na+].[CH2:46]([NH2:48])[CH3:47]>C(#N)C>[N:1]1([C:5]([C:7]2[N:12]=[CH:11][C:10]([O:13][C:14]3[CH:33]=[C:32]([CH:31]=[C:16]([O:17][CH:18]4[CH2:24][CH2:25][N:48]([CH2:46][CH3:47])[C:19]4=[O:20])[CH:15]=3)[C:34]([NH:35][C:36]3[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=3)=[O:43])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: CCN
Reactant: CCOC(=O)C(CCOS(C)(=O)=O)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2cnc(C)cn2)c1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCC(Oc2cc(Oc3ccc(C(=O)N4CCC4)nc3)cc(C(=O)Nc3cnc(C)cn3)c2)C1=O
Yield: 116.2 %

Procedure:
Ethyl 2-[3-[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy-5-[(5-methylpyrazin-2-yl)carbamoyl]phenoxy]-4-methylsulfonyloxy-butanoate (Intermediate 27) (27 mg, 0.04 mmol), sodium iodide (7 mg, 0.04 mmol) and ethylamine (2M in THF; 45 μL, 0.09 mmol) in acetonitrile (2 mL) were heated in a microwave at 120° C. for 90 minutes. Solvent evaporated under reduced pressure and the residue diluted with ethyl acetate (20 mL) and brine (20 mL). The organics were separated and the aqueous layer re-extracted with ethyl acetate (20 mL). The combined organics were dried (MgSO4) and concentrated and the residue purified by preparative HPLC, eluting with a gradient of 5 to 95% acetonitrile in water containing 0.2% trifluoroacetic acid on a Phenomenex Luna 10u C18(2) 100A column, to afford product (24 mg, 87%). 1H NMR δ (300 MHz, CDCl3) 1.19 (3H, t), 2.17-2.26 (1H, m), 2.34-2.44 (2H, m), 2.62-2.74 (4H, m), 3.39-3.59 (4H, m), 4.30 (2H, s), 4.76 (2H, s), 5.11 (1H, t), 6.95 (1H, t), 7.29 (1H, t), 7.39-7.42 (1H, m), 7.52 (1H, d), 8.10 (1H, d), 8.19 (1H, s), 8.36 (1H, d), 9.65 (1H, d); m/z 517 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH:5]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7](N)[CH:6]=1>O>[CH:9]1[C:10]([NH2:11])=[CH:5][CH:6]=[C:7]([NH:1][C:2]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([NH2:11])=[CH:5][CH:6]=2)=[O:3])[CH:8]=1
Reactant: Nc1ccc(N)cc1
Reactant: NC(N)=O
Solvent: O
Product: Nc1ccc(NC(=O)Nc2ccc(N)cc2)cc1

Procedure:
To a 1-liter, 3-neck round-bottom flask equipped with a mechanical stirrer, nitrogen inlet tube extending below the liquid level and a reflux condenser with a nitrogen exit to a gas bubbler, was added 500 ml. of distilled water. After the water was de-oxygenated by bubbling nitrogen gas through it for three hours, 15 g. (0.25 mole) of a commercial pre-dried urea and 60 g. (0.554 mole) of purified p-phenylenediamine were added and the solution which formed was refluxed for about 72 hours under a nitrogen atmosphere. The diamine to urea mole ratio utilized was 2.22.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[H][H].[Na].C[O:30][C:31](=[O:40])[C:32]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=1>CN(C)C=O.CCOCC>[CH3:3][N:4]([C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[N:5]([CH2:38][C:35]1[CH:36]=[CH:37][C:32]([C:31]([OH:40])=[O:30])=[CH:33][CH:34]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CN(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)N(Cc1ccc(C(=O)O)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
309 g. of a 27% suspension of sodium hydride in an inert solvent were treated with 300 ml. of dimethylformamide, and a solution of 1095 g. of 1-methyl-1,2-dicarbobenzoxy-hydrazine in dimethylformamide was added thereto. When all the material had been added and the hydrogen evolution had nearly come to a standstill, the mixture was heated for an hour at about 80° in order to carry the formation of the sodium salt to completion. A mixture of 759 g. of 4-(bromo-methyl)-benzoic acid methyl ester in 700 ml. of dimethylformamide was then dropped in, and finally the reaction mixture was heated for an hour at 80°. After cooling, the reaction mixture was poured into 10 liters of ice water and the condensation products taken up in ether. The thereby obtained crude methyl ester (nD24 = 1.1558) was used without further purification for the next step. It was dissolved in about 2200 ml. of dioxane, treated with a solution of 133 g. of sodium hydroxide in 870 ml. of water, and the resulting mixture stirred for about 24 hours at room temperature. It was then poured into about 10 liters of ice water and neutral materials were extracted with ether. The aqueous phase was rendered acid with concentrated hydrochloric acid (weak congo red) and the separated acid taken up in ether. The isolated crude acid was recrystallized from dibutyl ether, yielding colorless crystals of 4-[(2-methyl-1,2-dicarbobenzoxy-hydrazino)-methyl]-benzoic acid, which melted at 112°. The so-obtained product was sufficiently pure for further reaction.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([OH:3])=[O:2].[NH2:12][C:13]1[C:18]([NH2:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][N:14]=1.C(OCC)(=O)C.C(OCC)C>[N+](C1C=CC=CC=1)([O-])=O>[N+:20]([C:16]1[CH:17]=[C:18]2[N:19]=[C:7]([C:6]3[CH:5]=[C:4]([CH:11]=[CH:10][CH:9]=3)[C:1]([OH:3])=[O:2])[NH:12][C:13]2=[N:14][CH:15]=1)([O-:22])=[O:21]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: Nc1cc([N+](=O)[O-])cnc1N
Solvent: O=[N+]([O-])c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(-c2nc3cc([N+](=O)[O-])cnc3[nH]2)c1
Temperature: 25 °C

Procedure:
0.87 g 3-carboxybenzaldehyde and 0.866 g 2,3-diamino-5-nitropyridine in 50 ml nitrobenzene were heated to 160° C. for 30 hrs. The mixture was cooled to room temperature and 200 ml ethyl acetate and 100 ml ethyl ether were added. The precipitated product was collected by filtration and dried. Yield 1.135 g
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:23])(=[O:22])[NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH:6]=1)=[O:4].[CH2:24]([NH:26][C:27]([NH:29][CH2:30][CH3:31])=[S:28])[CH3:25]>>[ClH:1].[CH2:30]([N:29]1[C:3]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:23])(=[O:22])[NH:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[CH:6]=2)([OH:4])[CH2:2][S:28][C:27]1=[N:26][CH2:24][CH3:25])[CH3:31]
Reactant: O=C(CCl)c1ccc(Cl)c(S(=O)(=O)NCc2ccccc2Cl)c1
Reactant: CCNC(=S)NCC
Product: CCN=C1SCC(O)(c2ccc(Cl)c(S(=O)(=O)NCc3ccccc3Cl)c2)N1CC
Product: Cl

Procedure:
7.8 g of 2,4'-dichloro-3'-o-chlorobenzylsulfamoylacetophenone and 2.5 g of 1,3-diethylthiourea were reacted as prescribed in Example 12 and worked up. Colorless crystals, decomposition beginning at 94° C., γ C=N 1615 cm-1.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1C=C(CO)C(=O)N(CC(C)C)N=1.[F:22][C:23]1[CH:24]=[C:25]([C:31]2[CH:32]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[C:34](=[O:37])[NH:35][N:36]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH3:30].FC1C=CC(CCl)=CC=1>>[F:8][C:6]1[CH:7]=[CH:2][C:3]([CH2:9][N:35]2[C:34](=[O:37])[C:33]([C:38]([O:40][CH3:41])=[O:39])=[CH:32][C:31]([C:25]3[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([F:22])[CH:24]=3)=[N:36]2)=[CH:4][CH:5]=1
Reactant: COC(=O)c1cc(-c2ccc(OC)c(F)c2)n[nH]c1=O
Reactant: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CO)c1=O
Agent: Fc1ccc(CCl)cc1
Product: COC(=O)c1cc(-c2ccc(OC)c(F)c2)nn(Cc2ccc(F)cc2)c1=O
Yield: 86.6 %

Procedure:
Following the procedure of Example 1 (6), 6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 4-fluorobenzyl chloride were reacted to yield the title compound as a slightly-yellow crystalline powder (yield: 86.6%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15](Cl)[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18].[N:24]#[C:25][NH2:26].O1CCCC1.C(N(CC)CC)C>O>[NH2:26][C:25]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:15]([C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])[N:24]=1
Reactant: N#CN
Reactant: FC(F)(F)c1cc(Cl)c(NN=C(Cl)C(F)(F)C(F)(F)F)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Nc1nc(C(F)(F)C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Yield: 60.2 %

Procedure:
20.5 g (0.05 mol) of pentafluoropropionyl chloride 2,6-dichloro-4-trifluoromethylphenylhydrazone and 2.5 g (0.06 mol) of cyanamide were added to 50 ml of tetrahydrofuran, and 6.1 g (0.06 mol) of triethylamine was dropwise added thereto under reflux and stirring. After completion of the dropwise addition, the mixture was stirred at the same temperature for 1 hour to complete the reaction. After cooling, the reaction solution was poured into water, and the precipitate was extracted with ethyl acetate. The organic layer was washed with water and dried. Then, the solvent was distilled off under reduced pressure, and the residue was washed with n-hexane to obtain 12.5 g (yield: 60.1%) of the desired compound as white powder. Melting point: 181°-183° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]3[CH:12]=[C:13]([CH3:16])[CH2:14][CH2:15][CH:9]3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=1.Cl.[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH2:27][CH2:26]1.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)[Cl:53]>CO.C(Cl)(Cl)Cl>[ClH:53].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([O:1][C:2]2[C:11]3[CH:10]4[CH:12]=[C:13]([CH3:16])[CH2:14][CH2:15][CH:9]4[C:8]([CH3:17])([CH3:18])[O:7][C:6]=3[CH:5]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=2)=[O:35])[CH2:27][CH2:26]1
Reactant: O=C(O)CCCN1CCOCC1
Reactant: ClCCl
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)C1CCC(C)=CC21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCc1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1CCC(C)=CC21

Procedure:
0.7 g. (2.23 mmoles) of 1-Hydroxy-3-n-pentyl-6,6,9-trimethyl-10a,6a,7,8 -tetrahydrodibenzo[b,d]pyran, 0.48 g. (2.28 mmoles) of γ-morpholinobutyric acid hydrochloride (Cruickshank and Sheehan, J. Am. Chem. Soc. 83, 2891 (1961), m.p. 180°-182°), and 0.48 g. (2.35 mmoles) of dicyclohexylcarbodiimide (Aldrich) were combined with 35 ml. of methylene chloride and stirred at room temperature for a total of 40 hours. The insoluble by-product of dicyclohexylurea was separated by filtration and the methylene chloride was removed using a rotary evaporator. The resulting residue was dissolved in about 20 ml. of benzene and a small amount of insoluble material was removed by filtration. The benzene was evaporated and the residue dried in vacuo to give 0.7 g. of fluffy, white material. Crystallization from benzene/pet ether gave 0.4 g. of product as colorless crystals, m.p. 99°-101°. The material was pure by thin layer chromatography (10% MeOH/CHCl3); the infrared and nmr spectra are in agreement with the proposed structure.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][NH2:40])=[CH:34][CH:33]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:40][CH2:39][CH2:38][C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Reactant: NCCc1ccc(Cl)cc1
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(Cl)cc3)n2)c1

Procedure:
Intermediate 4 was coupled to 2-(4-chloro-phenyl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 474. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.30 ppm) δ 8.7 (m, 1H) 8.16 (m, 4H) 7.65 (m, 6H) 4.45 (s, 2H) 3.95 (m, 2H) 3.4 (m, 2H) 3.18 (m, 4H) 3.0 (m, 2H) 2.9 (s, 3H) 1.75 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[C:7]([C:24]([OH:26])=O)=[CH:6]2)#[N:2].S(Cl)(Cl)=O.[CH3:31][O:32][CH2:33][CH2:34][NH2:35].C(N(CC)CC)C>C(Cl)Cl>[CH3:31][O:32][CH2:33][CH2:34][NH:35][C:24]([C:7]1[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:22])([F:23])[F:21])[CH:14]=2)[C:9]2[C:5]([CH:6]=1)=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[O:26]
Reactant: COCCN
Reactant: N#Cc1ccc2c(c1)cc(C(=O)O)n2Cc1cccc(OC(F)(F)F)c1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNC(=O)c1cc2cc(C#N)ccc2n1Cc1cccc(OC(F)(F)F)c1
Reaction time: 2 h

Procedure:
5-Cyano-1-(3-trifluoromethoxybenzyl)-1H-indole-2-carboxylic acid (1.00 g, 2.77 mmol) was suspended in anhydrous DCM (20 ml) and thionyl chloride (0.5 ml, 6.85 mmol) added. The reaction was heated under reflux for 3 h then evaporated to dryness. The residue was dissolved in anhydrous DCM and spit into 4 aliquots, one aliquot was added to a solution of methoxyethylamine (0.075 ml, 1.00 mmol) and triethylamine (0.14 ml, 1.00 mmol) in DCM (5 ml). After stirring for 2 h the reaction was washed with water (2 ml) then evaporated to dryness. Crude product was purified by silica chromatography using DCM as eluent then crystallised from DCM:diethyl ether to provide crystalline title compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH3:10][C:11]1[C:12]([N:19]2[CH2:24][CH2:23][C:22]3[CH:25]=[CH:26][S:27][C:21]=3[CH:20]2[CH3:28])=[N:13][C:14]([Cl:18])=[N:15][C:16]=1[CH3:17]>CN(C)C=O>[ClH:18].[CH3:10][C:11]1[C:12]([N:19]2[CH2:24][CH2:23][C:22]3[CH:25]=[CH:26][S:27][C:21]=3[CH:20]2[CH3:28])=[N:13][C:14]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][C:4]=2[CH3:9])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(Cl)nc(N2CCc3ccsc3C2C)c1C
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1Nc1nc(C)c(C)c(N2CCc3ccsc3C2C)n1
Product: Cl
Yield: 12.5 %

Procedure:
After 4-fluoro-2-methylaniline(0.5 ml, 4.6 mmol) was added to a mixture solution of 5,6-dimethyl-4-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl)-2-chloropyrimidine(0.68 g, 2.3 mmol) and dimethylformamide(5 ml), 0.12 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.CN(C(ON1N=N[C:21]2[CH:22]=[CH:23][CH:24]=[N:25][C:20]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N1CCCCC1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:25]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[O:10])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Br)cn1)N1CCCCC1
Reaction time: 18 h
Yield: 364.1 %

Procedure:
5-bromo-2-pyridinecarboxylic acid (501 mg, 2.480 mmol, available from Apollo) was mixed with HATU (2358 mg, 6.20 mmol), DIPEA (1.625 mL, 9.30 mmol) and piperidine (0.307 mL, 3.10 mmol), dissolved in N,N-dimethylformamide (DMF) (22.5 mL) and stirred under nitrogen for 18 hours. The reaction was partitioned between distilled water (30 mL) and DCM (100 mL). The aqueous layer was extracted with DCM (2×70 mL) and the organic fractions were combined, washed (brine (2×50 mL)), dried (sodium sulfate), filtered and evaporated to dryness to give a dark brown solid (2.43 g). The crude product was purified on a 40+M Biotage silica column, eluting with cyclohexane:EtOAc (1:0 to 3:2, 19 CV). Product-containing fractions were evaporated to dryness to give a dark yellow solid (573 mg). LCMS (Method C): Rt=0.83, MH+=271
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:25])[N:6]2[C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:14]=[CH:15][CH:16]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.N1C=CC=CC=1>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Cu+2]>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:30]1[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=1)[C:5](=[O:25])[N:6]2[C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)[nH]c3c(N)ncnc32)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)n(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Temperature: 35 °C
Yield: 58.7 %

Procedure:
To a mixture of tert-butyl 3-(6-amino-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (5) (300 mg, 0.88 mmol) and 4 A MS (300 mg) in dry DMF (10 mL) were added 4-chlorophenylboronic acid (413 mg, 2.64 mmol), Cu(OAc)2 (160 mg, 0.88 mmol) and pyridine (1 mL). The reaction mixture was heated to 35° C. overnight under an O2 atmosphere, and filtered through a Celite pad. The filtrate was diluted with water (50 mL), extracted with EtOAc (30 mL×3). The combined organic layer was washed with water and brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (silica gel, 0 to 5% methanol in methylene chloride) to give tert-butyl 3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (12) (234 mg, 59.1%). LC-MS (ESI): m/z (M/M+2) 453/455.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21]C(C)(C)C)=[O:20])=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>C(Cl)Cl>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(-c2ccc(/C=C/C(=O)OC(C)(C)C)cn2)cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2ccc(/C=C/C(=O)O)cn2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of tert-butyl ester 39 (0.45 g, 1.3 mmol) in DCM (5 mL) was added neat trifluoroacetic acid (1.7 mL). The reaction was allowed to stir at room temperature for 18 h then concentrated; the residue was triturated with diethyl ether, to give title compound 40 (0.376 g, 92% yield).
Reaction SMILES: [NH:1]([C:8](=[O:28])[CH:9]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[CH:40]1[CH:41]=[CH:42][C:43]2[N:48](O)N=[N:46][C:44]=2[CH:45]=1.C1(N)C=CC=CC=1N>CN(C=O)C>[NH2:46][C:44]1[CH:45]=[CH:40][CH:41]=[CH:42][C:43]=1[NH:48][C:23]([C:22]1[CH:26]=[CH:27][C:19]([CH:9]([C:8]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:28])[C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:11])=[N:20][CH:21]=1)=[O:25]
Reactant: O=C(O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)nc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)nc1
Reaction time: 0.5 h
Yield: 37 %

Procedure:
To a solution of 6-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]nicotinic acid (35 mg, 0.093 mmol) in DMF (1 mL) at room temperature was added EDCI (22 mg, 0.11 mmol) and HOBT (14 mg, 0.10 mmol). The solution was stirred for 30 min and 1,2-phenylenediamine (34 mg, 0.31 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 18 h and purified by reverse phase HPLC (5% to 80% MeCN in water) to give 2-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-N,N′-diphenylmalonamide (16 mg, TFA salt, 21% from methyl 6-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]nicotinate) as a white solid: ESIMS calcd 466.2 (M++H), found 466.1 (M++H).