Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([N+:26]([O-])=O)=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][CH2:16][CH2:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:12][C:11]([NH2:26])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)c1[nH]c2ccc([N+](=O)[O-])cc2c1CCCNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1[nH]c2ccc(N)cc2c1CCCNC(=O)OC(C)(C)C

Procedure:
5-Nitro-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester (prepared by the procedure described in Example 2 for the 5-bromo analog) (426 mg) was dissolved in 20 mL of methanol. Palladium on carbon (85 mg) was added and the flask was seal with a rubber septum. A vacuum was pulled through a needle and the void was refilled from a balloon of hydrogen gas. The resulting mixture was stirred under 1 atm of hydrogen gas for 17 h. In the morning, LCMS analysis revealed consumption of the starting material and formation of the product. The reaction mixture was filtered through diatomaceous earth and concentrated under vacuum to yield 5-amino-3-[3-(t-butoxycarbonylamino)-propyl]-1H-indole-2-carboxylic acid ethyl ester as an orange foam (432 mg, solvent trapped within). This material was used without further manipulation.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[H-].[Na+].[CH3:25]I>O1CCCC1>[CH3:25][N:6]1[C:2]([CH3:1])=[C:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1[nH]c(C)c(C(=O)OCC)c1-c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccccc2)c(C(=O)OCC)n(C)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A solution of diethyl 5-methyl-3-phenyl-1H-pyrrole-2,4-dicarboxylate (85 g, 0.28 mol) in dry tetrahydrofuran (240 mL) was added to a suspension of sodium hydride (60% w/w; 17 g, 0.425 mol) in dry tetrahydrofuran (200 mL) at 0° C. over 45 min. The mixture was warmed to room temperature and stirred for 1 h before cooling back to 0 C. Methyl iodide (71 mL, 1.13 mol) was added dropwise over 30 min and the reaction mixture and then stirred at room temperature for 18 h. The mixture was quenched with ice-water (100 mL) and concentrated in vacuo to remove volatile organics. The aqueous phase was decanted off and the residual solid was extracted with dichloromethane (350 mL). The aqueous phase was extracted with dichloromethane (2×100 mL) and the combined extracts were washed successively with water (2×200 mL), brine (2×100 mL), dried over anhydrous sodium sulfate and concentrated to afford diethyl 1,5-dimethyl-3-phenyl-pyrrole-2,4-dicarboxylate (80 g, 90%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([S:19]([C:22]2[CH:23]=[N:24][CH:25]=[C:26]([CH:31]=2)[C:27]([NH:29][NH2:30])=[O:28])(=[O:21])=[O:20])[CH2:15][CH2:14]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](/[C:8](=[N:30]/[NH:29][C:27](=[O:28])[C:26]2[CH:31]=[C:22]([S:19]([N:16]3[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]3)(=[O:21])=[O:20])[CH:23]=[N:24][CH:25]=2)/[CH3:9])[CH:7]=1
Reactant: CC(=O)c1cc(Cl)ccc1O
Reactant: CN1CCN(S(=O)(=O)c2cncc(C(=O)NN)c2)CC1
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cncc(S(=O)(=O)N2CCN(C)CC2)c1)c1cc(Cl)ccc1O
Temperature: 70 °C

Procedure:
1-(5-chloro-2-hydroxyphenyl)ethanone (25.07 mg, 0.147 mmol) and 5-((4-methylpiperazin-1-yl)sulfonyl)nicotinohydrazide (40 mg, 0.134 mmol) was dissolved in Methanol (10 ml) in the presence of acetic acid as a catalyst and then the reaction mixture was refluxed for 12 h at 70° C. Reaction was monitored by TLC. After completion of the reaction, following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) afforded the title compound (E)-N′-(1-(5-chloro-2-hydroxyphenyl)ethylidene)-5-((4-methylpiperazin-1-yl)sulfonyl)nicotinohydrazide as a solid. 1HNMR (400 MHz, CDCl3): δ 9.21 (s, 1H), 9.00 (s, 1H), 8.48 (s, 1H), 7.41 (d, 1H, J=2.0 Hz), 7.20 (d, 1H, J=8.4 Hz), 6.90 (d, 1H, J=8.4 Hz), 3.08 (m, 4H), 2.48 (m, 4H), 2.40 (s, 3H), 2.25 (5, 3H). ESI-MS: 452.0 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19]Cl)[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1.[C:23]1([C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)[OH:26])[OH:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3[CH:18]=[C:17]([CH2:19][O:24][C:23]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[OH:26])[CH:16]=[N:15][C:9]=3[N:10]([CH2:13][CH3:14])[C:11]=2[N:12]=1
Reactant: Oc1ccccc1O
Reactant: CCN1c2ncc(CCl)cc2C(=O)N(C)c2ccc(Cl)nc21
Product: CCN1c2ncc(COc3ccccc3O)cc2C(=O)N(C)c2ccc(Cl)nc21
Yield: 58 %

Procedure:
Using a procedure analogous to that described in Example 104, the title compound, m.p. 172°-173° C., was prepared from 2-chloro-8-chloromethyl-5,11-dihydro-11-ethyl-5-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and catechol. The yield was 58% of theory.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:26]=[CH:25][C:9]([O:10][C:11]2[CH:12]=[CH:13][C:14]([F:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH:16]=2)=[C:8]([C:27]#[N:28])[CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[C:8]([C:27]#[N:28])=[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14]([F:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([F:21])([F:20])[F:22])[CH:16]=3)[CH:25]=[CH:26][C:6]=2[N:5]=1
Reactant: N#Cc1cc(N)ccc1Oc1ccc(F)c(NC(=O)C(F)(F)F)c1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: N#Cc1c(Oc2ccc(F)c(NC(=O)C(F)(F)F)c2)ccc2nc(N)sc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.1 %

Procedure:
Potassium thiocyanate (7.72 g, 79.4 mmol) was suspended in acetic acid (30 mL), and the suspension was stirred at room temperature for 10 min. A solution of N-[5-(4-amino-2-cyanophenoxy)-2-fluorophenyl]-2,2,2-trifluoroacetamide (5.4 g, 15.9 mmol) in acetic acid (200 mL) was added to the obtained solution, and the mixture was further stirred at room temperature for 10 min. A solution of bromine (5.05 g, 31.5 mmol) in acetic acid (30 mL) was slowly added dropwise to the obtained solution. After the completion of the dropwise addition, the mixture was stirred at room temperature for 12 hr. The resulting yellow insoluble material was filtered off and washed with acetic acid. The filtrate and washings were combined and the mixture was concentrated under reduced pressure. The obtained residue was suspended in ethyl acetate (500 ml), washed successively with saturated aqueous sodium hydrogen carbonate solution (250 mL×2) and saturated brine (250 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was purified by silica gel column chromatography (eluate: ethyl acetate). The obtained solution was concentrated under reduced pressure to give the title compound (5.36 g, 85%) as a pale-yellow powder.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](I)[N:17]=1>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[N:17]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Clc1cccc(I)n1
Product: Cc1onc(-c2ccccc2)c1C#Cc1cccc(Cl)n1
Yield: 87 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-chloro-6-iodopyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 129 mg, 87%) which was obtained as a light yellow oil. MS: m/e=295.1/297.3 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH:48]1[CH2:51][CH2:50][CH2:49]1>>[N:48]1([C:42](=[O:44])[CH2:41][N:38]2[CH2:39][CH2:40][N:35]([C:33]([N:13]3[C@@:14]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)([CH3:25])[C@@:15]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)([CH3:17])[N:16]=[C:12]3[C:9]3[CH:10]=[N:11][C:6]([C:2]([CH3:3])([CH3:5])[CH3:4])=[CH:7][C:8]=3[O:45][CH2:46][CH3:47])=[O:34])[CH2:36][CH2:37]2)[CH2:51][CH2:50][CH2:49]1
Reactant: C1CNC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCC2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with azetidine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H47Cl2N6O3 [(M+H)+] 705.3081, observed 705.3081.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)=[CH:23][CH:22]=2)[CH2:10]/[C:11](=[N:19]\[OH:20])/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[C:5]([CH3:40])[CH:4]=1>O1CCOCC1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C:21]2[CH:22]=[CH:23][C:24]([CH:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)=[CH:25][CH:26]=2)[CH2:10]/[C:11](/[C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:19]\[OH:20])=[C:5]([CH3:40])[CH:4]=1
Reactant: Cc1cc(/C(C[C@H](c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)c2ccc(Cl)cc2C)=N/O)ccn1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(/C(C[C@H](c2ccc(C3CCNCC3)cc2)c2ccc(Cl)cc2C)=N/O)ccn1
Temperature: 50 °C
Yield: 44.9 %

Procedure:
Hydrogen chloride solution (4 M in 1,4-dioxane, 0.4 mL, 1.6 mmol) was added at room temperature to a solution of (R,E)-tert-butyl 4-(4-(1-(4-chloro-2-methylphenyl)-3-(hydroxy-imino)-3-(2-methylpyridin-4-yl)propyl)phenyl)piperidine-1-carboxylate (example 387; 90 mg, 164 μmol) in 1,4-dioxane (5 mL). The reaction mixture was heated at 50° C. for 17 h, then partitioned between sat. aq. sodium hydrogencarbonate solution and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and evaporated to produce the title compound (33 mg, 45%). White solid, MS (ESI+): m/z=448.0 ([M+H]+).
Reaction SMILES: CS(O[CH:6]([C:24]1[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[C:31]([C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([CH:6]2[CH2:7][CH2:8][CH:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[N:39]2[C:38]2[CH:40]=[CH:41][C:35]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:36][CH:37]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc(Br)cc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(N2C(c3ccc(Br)cc3)CCC2c2ccc([N+](=O)[O-])cc2)cc1
Yield: 50.2 %

Procedure:
The product from Example 39C (10.86 g, 20.79 mmol), DMF (65 mL) and 4-tert-butylaniline (26.5 mL, 166 mmol) was reacted according to the procedure in Example 39D to provide the title compound (5.0 g, 50%, yellow solid) as a mixture of cis and trans pyrrolidine stereoisomers.
Reaction SMILES: [CH:1]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22]#[C:23][CH2:24][CH2:25][OH:26])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C=O)C>[CH:1]([N:14]1[C:15]2[C:16](=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH:22]=[C:23]1[CH2:24][CH2:25][OH:26])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC#Cc1cc(Cl)ccc1NC(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: OCCc1cc2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1

Procedure:
A solution of the crude 4-[2-(benzhydryl-amino)-5-chloro-phenyl]-but-3-yn-1-ol (25.5 g) and Cul (2.7 g, 14.1 mmol) in DMF (200 mL) was heated at 125° C. for 24 hours. The reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated, redissolved in EtOAc, washed with water (3×) and brine, and dried over MgSO4. Silica gel column chromatography (30% EtOAc/hexanes) yielded the desired 2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethanol as a yellow solid (14.5 g, 73% over 2 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[N:25]1([CH:30]2[CH:39]3[CH:34]([CH2:35][CH2:36][CH2:37][NH:38]3)[CH2:33][CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:38]2[CH:39]3[CH:34]([CH2:33][CH2:32][CH2:31][CH:30]3[N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:35][CH2:36][CH2:37]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: C1CNC2C(C1)CCCC2N1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)c(Cl)c1)N1CCCC2CCCC(N3CCCC3)C21
Temperature: 25 °C
Reaction time: 4 h
Yield: 113.6 %

Procedure:
A solution of 873 mg of 3,4-dichlorophenyl-acetic acid and 690 mg of carbonyldiimidazole in tetrahydrofuran was stirred for 1 hour at 20° to 25° C. and then 645 mg of the product of Step C in solution in 3 ml of tetrahydrofuran was added. After stirring for 4 hours at ambient temperature, the tetrahydrofuran was eliminated under reduced pressure at less than 40° C. and the residue was taken up in 20 ml of ether. The solution was washed with a saturated solution of sodium bicarbonate, then with water saturated with sodium chloride and the ethereal phase was dried and distilled to dryness under reduced pressure to obtain 1.39 g of the crude product.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[H-].[Na+].Cl.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17]Cl>CN(C=O)C>[CH3:10][C:8]1[N:9]=[C:5]([N:4]([CH2:17][CH2:16][N:15]([CH3:19])[CH3:14])[C:1](=[O:3])[CH3:2])[S:6][CH:7]=1
Reactant: CC(=O)Nc1nc(C)cs1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)N(CCN(C)C)c1nc(C)cs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The reaction is run under a nitrogen atmosphere. To a stirred solution of 31.2 g. (0.20 mole) of 2-acetamido-4-methylthiazole in 300 ml. of DMF is added 9.6 g. (0.20 mole) of a 50% suspension of sodium hydride in mineral oil. The reaction is stirred for 1/2 hour as the temperature spontaneously rises to 50° C. The reaction is cooled to 35° to 40° C. and a further 12.0 g. (0.25 mole) of sodium hydride suspension added followed by 36.0 g. (0.25 mole) of 2-dimethylaminoethyl chloride HCl, added portionwise for 10 to 15 minutes. The mixture is stirred at room temperature for about 1 hour and then at steam bath temperature for 20 hours. The tan mixture is cooled to ambient temperature and filtered to remove salts. The filtrate is concentrated under reduced pressure at steam bath temperature. This gives 46.4 g. of crude product as a brown oil (containing mineral oil (10.8 g.).
Reaction SMILES: [C:1]1([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21]CC3C=CC=CC=3)=O)[CH2:14]2)[N:2]=[CH:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2.[C:29]([CH2:31]C(O)=O)#[N:30].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(O)C.[OH-].[Pd+2].[OH-].[C].C(Cl)(Cl)Cl.CO.O>[C:1]1([CH:13]2[CH2:18][CH2:17][CH2:16][N:15]([C:19](=[O:21])[CH2:31][C:29]#[N:30])[CH2:14]2)[N:2]=[CH:3][N:4]2[C:9]=1[C:8]1[CH:10]=[CH:11][NH:12][C:7]=1[N:6]=[CH:5]2
Reactant: N#CCC(=O)O
Reactant: O=C(OCc1ccccc1)N1CCCC(c2ncn3cnc4[nH]ccc4c23)C1
Agent: [Pd+2]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#CCC(=O)N1CCCC(c2ncn3cnc4[nH]ccc4c23)C1
Yield: 9.3 %

Procedure:
Benzyl 3-(7H-imidazo[1,5-c]pyrrolo[3,2-e]pyrimidin-1-yl)piperidine-1-carboxylate (13.3 mg, 0.0354 mmol) and 10% palladium hydroxide-carbon (small amount) in ethanol (1.5 mL) was stirred at room temperature for 2.5 hours under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in N,N-dimethylformamide (1 mL) and stirred with 2-cyanoacetic acid (5.0 mg, 0.054 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (27.5 mg, 0.0722 mmol) and N,N-diisopropylethylamine (19.0 μL, 0.11 mmol) at room temperature for one day. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (NH-PLC05 plate manufactured by Fuji Silysia Chemical Ltd.: chloroform/methanol=15/1 (v/v)) to give the title compound as a pale yellow oil (1.02 mg, yield 11%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:20])[CH:9](C(OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].CS(C)=O.[Cl-].[Li+]>O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:20])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C(=O)OCC)C(C)c1ccccc1Br
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CC(C)c1ccccc1Br
Temperature: 150 °C
Yield: 61.5 %

Procedure:
To a solution of crude ethyl 3-(2-bromophenyl)-2-ethoxycarbonyl-3-methyl-propionate (52.96 g, 168.13 mmole) in the mixture of dimethylsulfoxide (250 ml) and water (3 ml) was added lithium chloride (14 g), and the resulting mixture was heated at 150° C. for 2.5 hours. After cooling, dimethylsulfoxide was removed by distillation under reduced pressure, an aqueous sodium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous ammonium chloride solution, dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residual concentrate was further purified by distillation to give ethyl 3-(2-bromophenyl)-3-methylpropionate (28.04 g, 65%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1CBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
A stirred mixture of methyl 2-methyl-3-nitrobenzoate (17.6 g, 87.1 mmol) and N-bromosuccinimide (18.9 g, 105 mmol) in carbon tetrachloride (243 mL) was heated under gentle reflux with a 100 W light bulb situated 2 cm away shining on the reaction mixture overnight. After 18 hours, the reaction mixture was cooled to room temperature and filtered. The filtrate was washed with water (2×120 mL), brine (120 mL), and dried (MgSO4). The solvent was removed in vacuo to give a yellow solid. The product was purified by flash chromatography (hexane:ethyl acetate 8:2) to give 22 g (93%) of methyl 2-bromomethyl-3-nitrobenzoate as a yellow solid: mp 69-72° C.; 1H NMR (CDCl3) δ 8.13-8.09 (dd, J=1.36 and 7.86 Hz, 1H), 7.98-7.93 (dd, J=1.32 and 8.13 Hz, 1H), 7.57-7.51 (t, J=7.97 Hz, 1H), 5.16 (s, 2H), 4.0 (s, 3H); 13C NMR (CDCl3) δ 65.84, 150.56, 134.68, 132.64, 132.36, 129.09, 53.05, 22.70; HPLC: Waters Nova-Pak C18 column, 4 micron, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4(aq), 8.2 min 99%. Anal. Calcd for C9H8NO4Br: C, 39.44; H, 2.94; N, 5.11, Br, 29.15. Found: C, 39.51; H, 2.79; N, 5.02; Br, 29.32.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[NH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>CC([O-])=O.CC([O-])=O.[Pd+2].CN1CCCC1=O>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:5]2
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: COc1ccc2c(Nc3ccc(C#N)cc3)nc(Nc3cc(C)[nH]n3)cc2c1
Temperature: 150 °C

Procedure:
(1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (100 mg), 4-amino-benzonitrile (85 mg), Cs2CO3 (376 mg), 2,2′-Bis(diphenylphosphino)-1′1-binaphthyl (BINAP) (44 mg), Pd(OAc)2 (8 mg), 1,4-dioxane (2 ml), N-methyl-pyrrolidone (NMP) (0.2 ml), were placed in a microwave bottle. The mixture was heated at 150° C. for 30 minutes under microwave irradiation and purified by preparative LC-MS to give 4-[6-methoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-ylamino]-benzonitrile. LC-MS m/e 371 (MH+). 1H NMR(DMSO): δ 2.26(s, 3H), δ 3.86(s, 3H), δ 5.75(s, 1H), δ 6.52(m, 1H), δ 6.79(d, 1H), δ 7.12(s, 1H), δ 7.65(d, 2H), δ 8.20(m, 3H), δ 8.65(s,1H), δ 9.30(s, 1H), δ 11.75(s,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[C:21]([C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[S:32])[CH:27]=[CH:28][CH:29]=1)([OH:23])=[O:22]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][C:31](=[S:32])[NH:30][C:26]3[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=3)[C:21]([OH:23])=[O:22])[CH:17]=1)=[CH:5]2
Reactant: COc1ccc(-c2cc3cc(Cl)c(Cl)cc3[nH]2)cc1N
Reactant: O=C(O)c1cccc(N=C=S)c1
Product: COc1ccc(-c2cc3cc(Cl)c(Cl)cc3[nH]2)cc1NC(=S)Nc1cccc(C(=O)O)c1

Procedure:
3-{3-[5-(5,6-Dichloro-1H-indol-2-yl)-2-methoxy-phenyl]-thioureido}-benzoic acid was prepared from the product of Example 18, Step D, 5-(5,6-dichloro-1H-indol-2-yl)-2-methoxy-phenylamine (0.64 g, 1.72 mmol) and 3-carboxyphenyl isothiocyanate (0.359 g, 2.0 mmol) to give the product as a reddish-tan solid (0.104 g), mp 216-218° C.