Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][CH2:11][CH:12]1[CH2:14][CH2:13]1>>[CH:12]1([CH2:11][NH:10][C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:14][CH2:13]1
Reactant: COc1cccnc1Cl
Reactant: NCC1CC1
Product: COc1cccnc1NCC1CC1
Temperature: 125 °C
Yield: 50 %

Procedure:
A mixture of 2.00 g (13.9 mmol) of 2-chloro-3-methoxypyridine (Lancaster) in 13.3 mL of aminomethylcyclopropane was heated at 125° C. in a sealed tube for 4 days. The mixture was then cooled to room temperature and partitioned between Et2O and water. The aqueous layer was washed with Et2O, and the combined extracts were washed with brine, dried with MgSO4, filtered, and concentrated. The residue was passed through a plug of silica gel with CH2Cl2 to provide 1.25 g (7.01 mmol; 50%) of 2-cyclopropylmethylamino-3-methoxypyridine. To a mixture of 2-cyclopropyl-methylamino-3-methoxypyridine (430 mg; 2.41 mmol) in 7.5 mL of 2:1 HOAc and water was added 612 mg (2.41 mmol) of I2. The mixture was heated to 100° C. for 4 h, and an additional 320 mg of I2 was added. The mixture was heated for 2 h, then cooled to room temperature and stirred for 12 h. Saturated NaHCO3 (20 mL) and water (20 mL) were added and the suspension was extracted with EtOAc. The extract was then washed with 10% Na2S2O3, water, and brine, dried with MgSO4, filtered, and concentrated. The pure fractions from chromatography (1–4% MeOH in CH2Cl2) were concentrated to provide 145 mg of 2-cyclopropylmethylamino-3-methoxy-5-iodopyridine.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=1>CN1C(=O)CCC1.O>[Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ncccc2Br)cc1
Reactant: Cc1ccc(F)nc1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc(Nc2ccc(Oc3ncccc3Br)cc2)nc1
Temperature: 170 °C

Procedure:
To a pressure vessel was added 4-(3-bromopyridin-2-yloxy)aniline (7.23 g, 27.3 mmol) and 2-fluoro-5-methylpyridine (3.03 mL, 27.2 mmol) in NMP (13.61 mL) to stir at 170° C. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, sat NaCl, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide N-(4-(3-bromopyridin-2-yloxy)phenyl)-5-methylpyridin-2-amine.
Reaction SMILES: C[S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[CH:14][S:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([Li])CCC.CCCCCC.C(B(CCCC)CCCC)CCC.C([O-])(=O)C.[Na+].[NH2:52]OS(O)(=O)=O>C1COCC1.C(OCC)(=O)C.O>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([NH2:52])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][S:13][CH:14]=2)=[CH:17][CH:18]=1
Reactant: NOS(=O)(=O)O
Reactant: CS(=O)(=O)c1ccc(-c2cscc2-c2ccc(F)cc2)cc1
Agent: CC(=O)[O-]
Agent: CCCCB(CCCC)CCCC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: NS(=O)(=O)c1ccc(-c2cscc2-c2ccc(F)cc2)cc1
Temperature: -70 °C
Reaction time: 0.33 h
Yield: 17.7 %

Procedure:
To a solution of 3-(4-methylsulfonylphenyl)-4-(4-fluorophenyl)thiophene (0.332 g, 1.0 mmol) from Step 5 in THF (8 mL) at -70° C. under nitrogen was added 1.6M n-butyllithium in hexane (0.66 mL, 1.05 mmol) slowly, via syringe, and the mixture stirred at -70° C. for 20 minutes and then at room temperature (25° C.) for 1 hour. After cooling to -70° C., a 1.0M solution of tri-n-butyl borane in THF (1.15 mL, 1.15 mmol) was added and the mixture allowed to warm slowly to 0° C. for 1 hour, warmed to room temperature for 2 hours, and finally stirred at reflux overnight (18 hours). After cooling to room temperature and stirring for 3 hours, water (0.8 mL) was added followed by sodium acetate (0.6 g) and hydroxylamine-O-sulfonic acid (0.41 g). After stirring at room temperature overnight, the mixture was poured into 3 volumes of ethyl acetate, and the organic layer washed with water and brine and dried over MgSO4. After solvent removal, the white solids (a mixture of product and starting material) were separated via flash chromatography on silica gel using a 15% ethyl acetate/85% toluene eluant to yield 4-[4-(4-fluorophenyl)thien-3-yl]benzenesulfonamide as a white solid (59 mg, mp 194°-195° C.). Anal. Calc'd for C16 H12NO2S2F: C, 57.64; H, 3.63; N, 4.20. Found: C, 57.37; H, 3.69; N, 3.99.
Reaction SMILES: [CH2:1]([C:7]1[C:8]2[S:19][CH:18]=[CH:17][C:9]=2[S:10][C:11]=1[C:12]([O:14]CC)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Li+].[OH-].C1COCC1.Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>[CH2:1]([C:7]1[C:8]2[S:19][CH:18]=[CH:17][C:9]=2[S:10][C:11]=1[C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1c(C(=O)OCC)sc2ccsc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCc1c(C(=O)O)sc2ccsc12
Temperature: 25 °C
Yield: 94.8 %

Procedure:
Compound 61 (32.1 g, 0.11 mol) was mixed with LiOH (10% in water, 50 mL), THF (100 mL), MeOH (30 mL) and a catalytic amount (20 mg) tetrabutylammonium iodide in a 500 mL flask. This mixture was heated at reflux overnight, allowed to cool to room temperature, and acidified with concentrated HCl. The resultant yellow solid was collected by filtration and washed thoroughly with water. The solid then was heated with hexane (100 mL) allowed to cool to room temperature. After filtration, the solid was collected, dried over vacuum to yield compound 62 as a light yellow powder (28.0 g, 96.7%). Mp: 110.7-112.4° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([Cl:18])[CH:9]=2)=[CH:4][N:3]=1.Cl[CH:20]([C:23]1([C:26]2[CH:27]=[C:28]3[C:33](=[CH:34][CH:35]=2)[N:32]=[CH:31][CH:30]=[CH:29]3)[CH2:25][CH2:24]1)[CH:21]=O>C(O)C>[Cl:18][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[N:3][C:2]3[N:7]([C:20]([C:23]4([C:26]5[CH:27]=[C:28]6[C:33](=[CH:34][CH:35]=5)[N:32]=[CH:31][CH:30]=[CH:29]6)[CH2:25][CH2:24]4)=[CH:21][N:1]=3)[CH:6]=2)[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccc(-c2cnc(N)nc2)cc1Cl
Reactant: O=CC(Cl)C1(c2ccc3ncccc3c2)CC1
Solvent: CCO
Product: COC(=O)c1ccc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)cc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-(2-aminopyrimidin-5-yl)-2-chlorobenzoate (0.22 g, 0.83 mmol) and chloro(1-quinolin-6-ylcyclopropyl)acetaldehyde (0.20 g, 0.83 mmol) in ethanol (6 mL) was stirred at 100° C. overnight. The reaction mixture was concentrated to afford the crude product which was directly used for next step. LCMS: (M+H)=455.1/457.1.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15]([OH:17])=[O:16])[C:5]2=[O:22].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][CH2:31][Cl:32].[OH-].[Na+].Cl>CN(C=O)C>[Cl:32][CH2:31][CH2:30][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]([C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:15]([OH:17])=[O:16])[C:5]2=[O:22]
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(O)cc2c1=O
Reactant: ClCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCCl)cc2c1=O
Temperature: 50 °C

Procedure:
To a suspension of 3-(6-hydroxy-4-oxoquinazolin-3(4H)-yl)-4-methylbenzoic acid (7.2 g) in DMF (150 ml) was added K2CO3 (33 g) and 1-bromo-2-chloroethane (12 ml) and heated to 50° C. for 2 hours. 2N NaOH (24 ml) was added and the solution heated to 40° C. for a further 16 hours. The pH was adjusted to pH˜1 with 1N HCl and the resultant solid collected by filtration. The solid was washed with methylene chloride, methanol and dried in vacuo to yield 3-[6-(2-chloroethoxy)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (9.1 g); NMR Spectrum: (DMSOd6) 2.14 (s, 3H), 3.98 (m, 2H), 4.40 (m, 2H), 7.55 (m, 3H), 7.72 (d, 1H), 7.93 (s, 1H), 7.98 (d, 1H), 8.19 (s, 1H); Mass Spectrum: M+H+ 359.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([OH:28])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1.[OH-].[Na+]>C1COCC1>[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:28][S:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])(=[O:10])=[O:9])[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: CN1CCC(c2c[nH]c3ccc(O)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)c4ccccc4F)cc23)CC1
Yield: 115.3 %

Procedure:
By a method similar to Example 31, using 2-fluorobenzenesulfonyl chloride (234 mg, 1.2 mmol) added dropwise to a solution of 3-(1-methylpiperidin-4-yl)-5-hydroxy-1H-indole (231 mg, 1.0 mmol) in 0.2 N sodium hydroxide (5.5 mL, 1.1 mmol) and THF (5 mL) gave 448 mg of the title compound as a crystalline solid. The product was recrystallized from ethyl acetate/hexanes to give 320 mg (82%) of the title compound an off white powder: mp=180-182° C.; MS(m/e): 389 (M+1); Calculated for C20H21FN2O3S: Calcd: C, 61.84; H, 5.45; N, 7.21. Found: C, 61.83; H, 5.57; N, 7.26.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][O:23]/[N:24]=[C:25](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)\[CH2:26][C:27]([O:29]CC)=[O:28])=[CH:20][CH:19]=1.O.Cl>O1CCCC1>[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][O:23][N:24]=[C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([OH:29])=[O:28])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CON=C(CC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
Lithium hydroxide monohydrate (402 mg) was added to a solution of ethyl E-3-[4-(5-methyl-2-phenyl4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionate (1.16 g) in tetrahydrofuran (60 ml)-water (40 ml) and stirred at room temperature for 18 hours. Dilute hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized to obtain 3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionic acid (1.08 g, yield 99%) as colorless crystals. m.p. 107-108° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.O>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:16]1[CH2:15][CH2:14][N:13]([C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:18][CH2:17]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCl)CC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 83.7 %

Procedure:
To an ice-cold solution of chloroacetyl chloride (1.27 g, 10 mmol) in 15 mL of methylene chloride was added N-tert-butoxycarbonylpiperazine (1.27 g, 11 mmol) in 10 mL of methylene chloride containing triethylamine (2.17 g, 20 mmol). The reaction mixture was stirred at 5° C. for 30 minutes, then warmed to room temperature and stirred for 24 hours. Water (20 mL) was added at 5° C., and the reaction mixture was diluted with methylene chloride (200 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (2×100 mL), brine (2×100 mL), dried over MgSO4, filtered, and concentrated at reduced pressure. The concentrated residue was purified by flash column chromatography on silica gel eluting with ethyl acetate to give 2.20 g (84.0%) of 1-(2-chloroacetyl)-4-(tert-butoxycarbonyl)piperazine as a yellow liquid. 1H NMR (300 MHz / CDCl3): δ 1.46 (s, 9H), 3.41-3.60 (m, 8H), 4.07 (s, 2H). HRMS: calcd for C11H19NO3 Cl1 262.1084, found 262.1079.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:18][C@@H:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[CH:33]1([O:39][C:40]2[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][C:45]=2[C:46]([O:48][CH3:49])=[O:47])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[C:13]([O:12][C:11]([N:10]([CH2:18][C@@H:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:42]2[CH:43]=[CH:44][C:45]([C:46]([O:48][CH3:49])=[O:47])=[C:40]([O:39][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:41]=2)=[CH:3][CH:4]=1)=[O:17])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)c1ccc(B(O)O)cc1OC1CCCCC1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Br)cc1)C[C@H](OC1CCCCO1)c1ccccc1
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: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](OC3CCCCO3)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1OC1CCCCC1
Temperature: 75 °C
Reaction time: 5 h
Yield: 83.1 %

Procedure:
To a solution of tert-butyl [2-(4-bromophenyl)ethyl]-[(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-carbamate (620 mg) in 1,2-dimethoxyethane (7 ml) were added [3-(cyclohexyloxy)-4-(methoxycarbonyl)phenyl]boronic acid (410 mg), tetrakis(triphenylphosphine)palladium (99 mg) and aqueous solution of sodium carbonate (2M, 1.35 ml), and the mixture was stirred at 75° C. for 5 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=9/1) to give methyl 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-phenyl-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]-3-(cyclohexyloxy)-4-biphenylcarboxylate (672 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[CH:10][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[CH:16](O)=[O:17].C(O)(=O)C.C(OC(=O)C)(=O)C>COCCOC>[CH:16]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[N:9]=[CH:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)=[O:17]
Reactant: O=CO
Reactant: Clc1ccc(NN=Cc2cccs2)cc1
Solvent: CC(=O)OC(C)=O
Solvent: COCCOC
Solvent: CC(=O)O
Product: O=CN(N=Cc1cccs1)c1ccc(Cl)cc1
Reaction time: 8 h

Procedure:
5.29 g of 1 was dissolved in 25 ml of 1,2-dimethoxyethane. The solution was treated with 5.4 g of the mixed anhydrides of formic acid and acetic acid, prepared by mixing the appropriate amounts of formic acid and acetic anhydride, and distilling the product. The resulting mixture was held overnight at room temperature. The solvent was evaporated and the residue was extracted with chloroform. The extract was washed with sodium bicarbonate solution, dried and the solvent evaporated. The residue was treated with charcoal in hexane; the mixture was filtered and the filtrate let stand. 2 crystallized out, mp 103°-105° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])=[CH:2]1.CCN(C(C)C)C(C)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[C:36]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]([N:14]([CH:24]([CH3:26])[CH3:25])[NH:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:13])=[CH:2]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1c[nH]c2ccccc12
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)/C=C/c1cn(C(=O)c2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a round bottom flask, (E)-N′-(3-(1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide (50 mg, 0.14 mmol, 1.0 equivalent), and DMAP (cat, 4.0 mg, 0.14 equivalent) were introduced and dissolved in CH2Cl2, after which DIPEA (0.04 ml, 0.20 mmol, 1.5 equivalent) was introduced. After introducing benzoyl chloride (0.02 ml, 0.17 mmol, 1.2 equivalent) at 0° C. and stirring at room temperature for 24 hr, the reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (n-hexane:EtOAc:=1:1) and dried so that solid form of (E)-N′-(3-(1-benzoyl-1H-indol-3-yl)acryloyl)-N′-isopropylbenzohydrazide was obtained. (48.0 mg, 77%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3][CH2:2]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:33]([C:37]1[O:41][N:40]=[C:39]([NH:42][C:43]([CH:45]2[CH2:50][CH2:49][CH2:48][NH:47][CH2:46]2)=[O:44])[CH:38]=1)([CH3:36])([CH3:35])[CH3:34].Cl.C(N(CC)CC)C>CN(C=O)C.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:33]([C:37]1[O:41][N:40]=[C:39]([NH:42][C:43]([CH:45]2[CH2:50][CH2:49][CH2:48][N:47]([C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[O:9])[CH2:46]2)=[O:44])[CH:38]=1)([CH3:36])([CH3:34])[CH3:35]
Reactant: O=C(O)C1CCOCC1
Reactant: CC(C)(C)c1cc(NC(=O)C2CCCNC2)no1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)C2CCCN(C(=O)C3CCOCC3)C2)no1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of tetrahydro-pyran-4-carboxylic acid (54.66 mg; 0.42 mmol) and 1-hydroxybenzotriazole hydrate (56.76 mg; 0.42 mmol) in anhydrous DMF (1.5 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (80.52 mg; 0.42 mmol) and the reaction mixture is stirred at room temperature for 15 minutes. After this time, piperidine-3-carboxylic acid (5-tert-butyl-isoxazol-3-yl)-amide; hydrochloride (90 mg; 0.313 mmol), triethylamine (0.044 mL; 0.313 mmol) and 4-dimethylaminopyridine (4.1 mg; 0.034 mmol) are added. The reaction mixture is stirred at room temperature for 18 hours. The mixture is diluted with ethyl acetate and then washed with water, saturated NaHCO3 aqueous solution then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica using methanol/methylene chloride then recrystallization from hot ethyl acetate provides the title compound, m/z 364 [M+H+].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[C:5]([Cl:21])=[CH:4][N:3]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH3:33])[CH:27]=1)([CH3:25])=[O:24].[OH-].[Na+]>COCCO>[Cl:21][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])=[N:7][C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([P:23]([CH3:25])([CH3:22])=[O:24])=[CH:27][C:28]=2[CH3:33])=[N:3][CH:4]=1
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Cc1cc(P(C)(C)=O)ccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: Cc1cc(P(C)(C)=O)ccc1Nc1ncc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 90 °C
Yield: 17.6 %

Procedure:
To a solution of 2,5-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (as prepared in Example 17: 0.083 g, 0.24 mmol) in 1.5 mL of 2-methoxyethanol was added 4-(dimethylphosphoryl)-2-methylaniline (0.050 g, 0.23 mmol) as its hydrochloride salt. The mixture was heated in a sealed tube at 90° C. for 16 h. The mixture was basified with 1N NaOH solution, and extracted with ethyl acetate. The organic layers were combined, washed with saturated sodium chloride solution, dried with sodium sulfate, filtered and concentrated. The crude residue was purified by prep-HPLC to afford the final compound (20 mg, 18% yield). MS/ES+: m/z=493.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[Cl:20])[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: ClCc1ccccc1Cl
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(Cc3ccccc3Cl)n2)ccc1F
Yield: 76.4 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 2-chlorobenzyl chloride were reacted. Without purification, the reaction product was reacted further following the procedure of Example 1(7) to yield the title compound as pale yellow needles (yield: 76.4%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:10][S:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])=[CH:14][CH:13]=1
Reactant: N#Cc1ccccc1F
Reactant: CSc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ccc(Oc2ccccc2C#N)cc1
Temperature: 100 °C
Yield: 99.1 %

Procedure:
2-Fluorobenzonitrile (15.7 mL, 149 mmol) and 4-(methylsulfanyl)phenol (25 g, 178 mmol) were dissolved in DMF (500 mL) and K2CO3 (61.8 g, 447 mmol) was then added. The mixture was heated at 100° C. for 16 h under a nitrogen atmosphere. After cooling to room temperature the mixture was evaporated to dryness and then partitioned between ether (1 L) and water (2 L). The organic layer was separated, washed with 2M NaOH (500 mL), 10% (aq) K2CO3 (500 mL), dried (MgSO4) and evaporated to give a light brown solid (35.62 g, 92%); δH (CDCl3, 400 MHz) 2.50 (3H, s), 6.82 (1H, d), 7.05 (2H, d), 7.15 (1H, t), 7.30 (2H, m), 7.43 (1H, t), 7.62 (1H, d); MS m/z (TS+) 259 (MNH4+).
Reaction SMILES: [N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]([NH2:22])[C:14]=2[CH:13]=[CH:12][CH:11]=1.[Cl:23][C:24]1[CH:25]=[C:26]([C:33](O)=[O:34])[C:27]2[CH:32]=[CH:31][NH:30][C:28]=2[N:29]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[NH:3][C:2]=1[C:10]1[C:18]2[N:17]3[CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]([NH:22][C:33]([C:26]3[C:27]4[CH:32]=[CH:31][NH:30][C:28]=4[N:29]=[C:24]([Cl:23])[CH:25]=3)=[O:34])[C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1cc(Cl)nc2[nH]ccc12
Reactant: NC1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NC1c2cccc(-c3nc4ccncc4[nH]3)c2-n2cccc21)c1cc(Cl)nc2[nH]ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.8 %

Procedure:
In a 100 ml round-bottomed flask, a mixture of 69 mg of 5-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-pyrrolo[1,2-a]indol-9-ylamine obtained according to stage 4 of Example 3, 48 mg of 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid obtained according to the preceding stage, 51 mg of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) and 36 mg of 1-hydroxybenzotriazole (HOBt) in 5 ml of dimethylformamide is stirred for 3 hours under argon at ambient temperature. The reaction medium is evaporated to dryness under vacuum and the residue is chromatographed on silica gel (15-40 μm), elution being carried out with a gradient of methanol (4% to 6% v/v) in dichloromethane. The valuable fractions are combined and evaporated to dryness under vacuum, the residue is triturated from a solution of sodium bicarbonate and filtered, and the solid is washed with water. The precipitate is dissolved in methanol and the solvent is evaporated to dryness under vacuum. 11 mg of 6-chloro-1H-pyrrolo[2,3-b]pyridine-4-carboxylic acid [5-(3H-imidazo[4,5-c]pyridin-2-yl)-9H-pyrrolo[1,2-a]indol-9-yl]amide are obtained in the form of a solid, the characteristics of which are the following: