Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:14][CH2:15][C:16]([OH:18])=O)=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.P(C#N)(OCC)(OCC)=O.Cl.[NH:30]1[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]1.C(N(CC)CC)C>O.CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]([CH2:14][CH2:15][C:16]([N:30]2[CH2:35][CH2:34][S:33](=[O:37])(=[O:36])[CH2:32][CH2:31]2)=[O:18])=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[N:6]=1
Reactant: Nc1nc(-c2ccc(Cl)cc2)c(CCC(=O)O)s1
Reactant: O=S1(=O)CCNCC1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1nc(-c2ccc(Cl)cc2)c(CCC(=O)N2CCS(=O)(=O)CC2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-[2-amino-4-(4-chlorophenyl)-5-thiazolyl]propionic acid (2.67 g), diethyl cyanophosphate (1.69 g), thiomorpholine-1,1-dioxide hydrochloride (1.62 g), triethylamine (2.9 ml) and N,N-dimethylformamide (40 ml) was stirred at room temperature for 3 hrs. The reaction mixture as poured into water, extracted with ethyl acetate, washed with 0.1N aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and concentrated. The precipitated solid was collected by filtration to give 4-{3-[2-amino-4-(4-chlorophenyl)-5-thiazolyl]propanoyl}thiomorpholine-1,1-dioxide as a colorless powder. Recrystallization from ethanol-isopropyl ether gave colorless prism crystals. melting point: 220–222° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=O)=[CH:5][CH:4]=1.[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][C:7]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)=[O:9])[CH:15]=1
Reactant: Cc1cc(Br)ccn1
Reactant: COC(=O)c1ccc(OC)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2cc(Br)ccn2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.5 %

Procedure:
In a 250 mL round-bottomed flask at 0° C. under nitrogen was added methyl 4-methoxybenzoate (Aldrich, 3.32 g, 20.00 mmol) and 4-bromo-2-methylpyridine (Frontier, 1.72 g, 10.00 mmol) in anhydrous tetrahydrofuran (40.0 mL) to give a yellow solution. Lithium hexamethyldisilazide (1 M in tetrahydrofuran, 20 mL, 20 mmol) was added dropwise over 15 minutes via a dropping addition funnel to produce an orange transparent solution that was stirred for 18 hours at ambient temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated to a reddish oil. Purification by flash chromatography on a silica 80 g cartridge eluting with 10-60% ethyl acetate in hexane gave the title compound (2.68 g, 88%). MS (APCI+) m/z 306/308 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]=2[OH:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:20][S:21]([N:24]=[C:25]=[O:26])(=[O:23])=[O:22]>C(OCC)C.CCCCCC>[C:13]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]=2[O:19][C:25](=[O:26])[NH:24][S:21]([Cl:20])(=[O:23])=[O:22])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1c(-c2ccccc2)cccc1-c1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCCCCC
Solvent: CCOCC
Product: O=C(NS(=O)(=O)Cl)Oc1c(-c2ccccc2)cccc1-c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 2,6-diphenyl phenol (25.0 g, 101 mmol) in 250 mL ethyl ether was added dropwise to a solution of chlorosulfonyl isocyanate (9.7 mL, 112 μmol) in 100 mL hexane at -15° C. under an atmosphere of nitrogen. The resulting white suspension was allowed to warm to room temperature over 2 hours. Concentrated in vacuo and triturated with ice cold hexane. Vacuum filtration afforded the title compound as a white solid, mp 159°-162° C.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:10])C1C=CC=CC=1.CO.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[CH2:30]([O:29][C:12]1[C:13]2[C:18](=[C:17]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:16]=[CH:15][CH:14]=2)[CH:19]=[CH:20][C:11]=1[C:9]([OH:10])=[O:8])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(OCc1ccccc1)c1ccc2c(OCc3ccccc3)cccc2c1OCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(OCc3ccccc3)cccc2c1OCc1ccccc1
Yield: 92 %

Procedure:
1,5-Bis-benzyloxy-naphthalene-2-carboxylic acid benzyl ester (0.556 g, 1.17 mmol), MeOH (6.4 mL) and NaOH (1.25 mL), H2O (65.0 mL) and citric acid (0.28 g, 1.5 mmol) Yield: 0.507 g creamy white solid (92% yield). 1H NMR (400 MHz CDCl3) δ 5.23 (s, 2H), δ 5.28 (s, 2H), δ 7.06 (d, J=7.3 Hz, 1H), δ 7.38-7.55 (m, 11H), δ 7.83 (d, J=8.7 Hz, 1H), δ 8.08 (d, J=8.7 Hz, 1H), δ 8.26 (d, J=8.7 Hz, 1H).
Reaction SMILES: C(=O)C.C(N[C:8]([C:10]1[N:11]=[C:12]2[C:18]([C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:17][NH:16][C:13]2=[N:14][CH:15]=1)=[O:9])(C)C.[CH:25](N)([CH3:27])[CH3:26].C(C1N=C2C(C(=O)C(C)(C)C)=CNC2=NC=1)(=O)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[OH:9][CH:8]([C:10]1[N:11]=[C:12]2[C:18]([C:19](=[O:24])[C:20]([CH3:21])([CH3:22])[CH3:23])=[CH:17][NH:16][C:13]2=[N:14][CH:15]=1)[CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)NC(=O)c1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1
Reactant: CC(C)N
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)c1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1
Agent: CC=O
Product: CC(C)C(O)c1cnc2[nH]cc(C(=O)C(C)(C)C)c2n1

Procedure:
Substituting isobutyraldehyde for acetaldehyde in Step 2. MP=148-150 C, (M+H)+=276. 7-(2,2-Dimethyl-propionyl)-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid isopropylamide Substituting carbon dioxide for acetaldehyde in Step 2. Then following general procedures described in these Examples, using isopropylamine and continuing with Step 3. MP=206-208 C, (M+H)+=289. 1-(2-Acetyl-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one. The product of Step 3 was treated with Dess-Martin periodinane, following general procedures described in these Examples. MP=221-223 C, (M+H)+=246.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH:3]=1.C(OO)(=[O:12])C>C(OCC)(=O)C>[CH3:1][C:2]12[O:12][CH:7]1[CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][CH2:3]2
Reactant: CC1=CCC(CO)CC1
Reactant: CC(=O)OO
Solvent: CCOC(C)=O
Product: CC12CCC(CO)CC1O2
Yield: 95 %

Procedure:
Epoxidation of 12.6 g (0.1 mol) of (4-methylcyclohex-3-enyl)methanol was performed with a 5 percent by weight solution of peroxyacetic acid in ethyl acetate at 65° C. The epoxidized product was purified by distillation and thereby yielded 12 g of (6-methyl-7-oxabicyclo[4.1.0]hept-3-yl)methanol with a purity of 98%.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[C:6](=[O:16])[NH:7][C:8]([CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:9][N:10]=1)[CH2:3][CH3:4].[CH:17]1([C:21](Cl)=[O:22])[CH2:20][CH2:19][CH2:18]1>>[CH:11]1([C:8]2[NH:7][C:6](=[O:16])[C:5]([CH:2]([NH:1][C:21]([CH:17]3[CH2:20][CH2:19][CH2:18]3)=[O:22])[CH2:3][CH3:4])=[N:10][N:9]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C(Cl)C1CCC1
Reactant: CCC(N)c1nnc(C2CCCC2)[nH]c1=O
Product: CCC(NC(=O)C1CCC1)c1nnc(C2CCCC2)[nH]c1=O

Procedure:
In analogy to the procedure for Example 36A, 200 mg (0.90 mmol) 6-(1-aminopropyl)-3-cyclopentyl-1,2,4-triazin-5(4H)-one, 110 mg (0.90 mmol) cyclobutanecarbonyl chloride and proportionate amounts of the other reagents are used. The crude product is used in the next step without further purification.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:37])([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([N:22]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:23][CH2:24][CH3:25])[CH:21]=1)[C:16](O)=[O:17])=O)(C)(C)C.[C:38]1([CH:44]2[CH2:48][CH2:47][CH2:46][NH:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.NC(C)(CC1C=CC=CC=1)COCC1C=C(C=C(N(S(C)(=O)=O)CCC)C=1)C(NC(C1C=CC=CC=1)C(F)(F)F)=O.N>CO>[NH2:8][C:9]([CH3:37])([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:21]=[C:20]([N:22]([CH2:23][CH2:24][CH3:25])[S:26]([CH3:29])(=[O:28])=[O:27])[CH:19]=[C:15]([C:16]([N:45]2[CH2:46][CH2:47][CH2:48][CH:44]2[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:17])[CH:14]=1
Reactant: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C(=O)O)c1)S(C)(=O)=O
Reactant: c1ccc(C2CCCN2)cc1
Agent: CCCN(c1cc(COCC(C)(N)Cc2ccccc2)cc(C(=O)NC(c2ccccc2)C(F)(F)F)c1)S(C)(=O)=O
Agent: N
Solvent: CO
Product: CCCN(c1cc(COCC(C)(N)Cc2ccccc2)cc(C(=O)N2CCCC2c2ccccc2)c1)S(C)(=O)=O

Procedure:
N-{3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-[(2-phenylpyrrolidin-1-yl)carbonyl]phenyl}-N-propylmethanesulfonamide was prepared from 3-({2-[(tert-butoxycarbonyl)amino]-2-methyl-3-phenylpropoxy}methyl)-5-[(methylsulfonyl)(propyl)amino]benzoic acid (intermediate XI) and 2-phenylpyrrolidine following a similar procedure as described for the preparation of 3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-5-[(methylsulfonyl)(propyl)amino]-N-(2,2,2-trifluoro-1-phenylethyl)benzamide with additional purification by ion exchange chromatography (Varian Bond Elut SCX, eluting with MeOH followed by 2.0M.NH3 in MeOH). HRMS (ES, M+H) calculated for C32H41N3O4S: 564.2891, found: 564.2891.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]1[C:9]([OH:10])=[C:8]([C:11]([CH3:13])=O)[CH:7]=[CH:6][C:5]=1[OH:14].Cl.[NH2:16]O.C([O-])(=O)C.[Na+]>CO>[CH3:13][C:11]1[C:8]2[CH:7]=[CH:6][C:5]([OH:14])=[C:4]([CH2:3][CH2:2][CH3:1])[C:9]=2[O:10][N:16]=1
Reactant: NO
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1c(O)ccc2c(C)noc12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 2,4-dihydroxy-3-propylacetophenone (1.008 grams) in dry methanol (10 mL) was treated with hydroxylamine hydrochloride (1.803 grams) and anhydrous sodium acetate (2.127 grams). The mixture was refluxed 4 hours. HPLC analysis indicated the complete disappearance of starting material. The reaction was partitioned between isopropyl acetate and pH 7 buffer. The organic was dried over magnesium sulfate, filtered and evaporated to a solid. Acetic anhydride (11 mL) was added and the solution stirred at ambient temperature for 14 hours. The solvent was removed in vacuo and the residue partitioned between isopropyl acetate and pH 7 buffer. The organic was dried over magnesium sulfate, filtered and concentrated to a residue. Pyridine (12 mL) was added and the solution refluxed for 3 hours. The solvent was removed in vacuo and the residue partitioned between isopropyl acetate and 0.1 N HCl. The organic was washed with 0.1 N HCl and dried over magnesium sulfate. The organic was filtered and concentrated to a residue which was chromatographed over silica gel to afford the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:21]([O:22][CH3:23])=[CH:20][C:19]([N+:24]([O-])=O)=[C:18]2[C:13]=1[C:14]([CH3:27])=[CH:15][CH:16]=[N:17]2.O(CCCC)CCCC.O>[Fe].CC(O)=O>[NH2:24][C:19]1[CH:20]=[C:21]([O:22][CH3:23])[C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[C:14]2[CH3:27]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OCCCCCc1ccco1
Agent: [Fe]
Solvent: O
Solvent: CCCCOCCCC
Solvent: CC(=O)O
Product: COc1cc(N)c2nccc(C)c2c1OCCCCCc1ccco1

Procedure:
A mechanically stirred mixture of 5-[5-(2-furyl)pentoxy]-6-methoxy-4-methyl-8-nitroquinoline (2.20 g, 0.0059 mol), Fe-filings (3.0 g), Bu2O (8 ml), H2O (30 ml) and HOAc (0.5 ml) was heated at 95°-100° C. for 2 h, allowed to cool and filtered. The residue was washed with Et2O (100 ml) and the filtrate and the washings were combined. The organic layer was separated and the aqueous layer was extracted with Et2O (2×50 ml). The combined organic layers were washed with saturated NaCl solution (1×50 ml), dried (Na2SO4), treated with Darco and concentrated to an oil which on trituration with cold hexane produced 8-amino-5-[5-(2-furyl) pentoxy]-6-methoxy-4-methylquinoline as a crude greenish-yellow solid 1.35 g (65%), mp 41°-42° C. This material was used without further purification.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:30])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.[CH3:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(=O)([O-])O.[Na+]>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH3:30][C:10]1([CH2:9][OH:8])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:36]5[CH:35]=[CH:34][CH:33]=[C:32]([CH3:31])[CH:37]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(Cl)cc4)CC3)n2CCS1
Reactant: Cc1cccc(B(O)O)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)c1
Temperature: 25 °C
Yield: 296.9 %

Procedure:
A solution of the compound (232 mg, 0.5 mmol) obtained in Example 1-2), 3-methylphenylboronic acid (105 mg, 0.77 mmol), tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.05 mmol), tricyclohexylphosphine (17 mg, 0.12 mmol), and tripotassium phosphate (186 mg, 0.85 mmol) in dioxane (2 mL) and water (1 mL) was stirred at 140° C. for 2 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was partially purified by silica gel chromatography (Isco Combiflash, 12 g, ethyl acetate:hexane=0:100 to 100:0, gradient). A solution of the obtained partially purified product (602 mg) and 4 M hydrochloric acid (1,4-dioxane solution, 0.69 mL) in methanol (2 mL) was stirred at room temperature for 14 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (331 mg, quant.) as a colorless solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[C:10]([NH:14][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:7])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)N
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thiophene-2-sulfonyl chloride (15 g, 0.082 mol) was dissolved in CHCl3 (200 mL) under N2 atmosphere and then cooled to 0° C. tert-Butylamine (25.9 mL, 0.246 mol) dissolved in CHCl3 (50 mL) was then added dropwise to the reaction mixture. The reaction mixture was stirred for 1 h at room temperature and then at reflux for 10 min. Toluene (700 mL) was added and the organic phase was washed with water (3×50 mL), dried, and concentrated in vacuo. The sub-title product was used without further purification in the next step.
Reaction SMILES: CN(C(O[N:9]1N=NC2C=[CH:13][CH:14]=[CH:15][C:10]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH3:32][N:33]1[C:37]([C:38](=[O:55])[NH:39][C:40]2[CH:45]=[CH:44][N:43]3[CH:46]=[C:47]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[N:48]=[C:42]3[CH:41]=2)=[C:36]([C:56](O)=[O:57])[CH:35]=[N:34]1.N1CCCC1>CN(C=O)C.O>[C:49]1([C:47]2[N:48]=[C:42]3[CH:41]=[C:40]([NH:39][C:38]([C:37]4[N:33]([CH3:32])[N:34]=[CH:35][C:36]=4[C:56]([N:9]4[CH2:10][CH2:15][CH2:14][CH2:13]4)=[O:57])=[O:55])[CH:45]=[CH:44][N:43]3[CH:46]=2)[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2c1
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ncc(C(=O)N2CCCC2)c1C(=O)Nc1ccn2cc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.6 %

Procedure:
TBTU (75 mg) and diisopropylethylamine (75 mg) were added to a solution of 1-methyl-5-(2-phenyl-imidazo[1,2-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (70 mg) in DMF (2 ml), and the mixture was stirred at r.t. (30 min). Pyrrolidine (14 mg) was added to the brown solution, and the reaction mixture was stirred at r.t. overnight. Water was added and the mixture was extracted several times with ethyl acetate. The combined organic layers were dried (Na2SO4), and evaporated. The title compound (43 mg, 54%) was isolated from the residue by preparative, inverse-phase HPLC (Agilent Zorbax XdB-C18 column, time per run ˜7 min, flow rate 30 ml/min, solvent gradient H2O/CH3CN=95:5-5:95). MS (m/e)=415.3 [M+H+].
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:32][C:33]1[CH:38]=[C:37]([N:18]2[C:19]3[C:15](=[CH:14][C:13]([C:11]([N:8]4[CH2:7][CH2:6][N:5]([CH:1]5[CH2:2][CH2:3][CH2:4]5)[CH2:10][CH2:9]4)=[O:12])=[CH:21][CH:20]=3)[CH:16]=[C:17]2[C:22]([N:24]2[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH:36]=[CH:35][CH:34]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCS(=O)(=O)CC1)n2-c1cccc(Cl)c1)N1CCN(C2CCC2)CC1
Yield: 72 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-chlorophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (72%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH3:3].[NH2:28][C:29]1[N:34]=[C:33](Cl)[C:32]([C:36]#[N:37])=[C:31]([CH3:38])[N:30]=1.CCN(C(C)C)C(C)C>CC(O)=O.C(#N)C>[NH2:28][C:29]1[N:34]=[C:33]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][CH2:16]2)[CH3:3])[C:32]([C:36]#[N:37])=[C:31]([CH3:38])[N:30]=1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1NC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2NC2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To crude tert-butyl (S)-4-((5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)amino)piperidine-1-carboxylate was added HOAc (2 drops), followed by ACN (2 mL), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.083 g, 0.493 mmol), and DIPEA (0.344 mL, 1.970 mmol). The reaction mixture was stirred at 75° C. for 1 hour. LCMS showed the reaction was complete, though messy. The volatiles were removed by N2 flow. The crude title compound was used without further purification. ESI-MS m/z [M+H]+ calc'd for C26H35N9O2, 506. found 506.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[O:12])[N:7]=[C:6]1[C:25]([OH:27])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.O.[N:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][NH2:48])[CH:42]=1>CN(C=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:23])([F:22])[F:24])=[CH:18][CH:19]=2)=[O:12])[N:7]=[C:6]1[C:25]([NH:48][CH2:47][C:43]1[CH:42]=[N:41][CH:46]=[CH:45][CH:44]=1)=[O:27]
Reactant: NCc1cccnc1
Reactant: COCCn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
38.8 mg (0.1 mmol) of 1-(2-methoxyethyl)-4-[({[4-(trifluoromethoxy)phenyl]amino}-carbonyl)amino]-1H-imidazole-2-carboxylic acid (Example 9A) are dissolved in 0.4 ml of DMF and, after addition of 81 mg (0.5 mmol) of N,N-carbonyldiimidazole, stirred at room temperature for 50 minutes. Then 18 μl (18 mg; 1 mmol) of water are added, and the mixture is stirred at room temperature for 30 minutes. Addition of 21.6 mg (0.2 mmol) of 3-picolylamine is followed by stirring at room temperature for 90 minutes. After filtration, the reaction mixture is purified by preparative HPLC (column: Macherey-Nagel VP 50/21 Nucleodur C18 gravity, 5 μm; flow rate: 25 ml/min; eluent A: acetonitrile, eluent B: water+0.1% conc. aqueous ammonia solution, gradient: 0 min 10% A, 2.00 min 10% A, 6.00 min 90% A, 7.00 min 90% A, 7.10 min 10% A, 8 min 10% A; running time: ca. 10 min per separation; wave length: 220 nm). The correct fractions are evaporated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([Cl:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].Cl.[CH3:15][S:16]([CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:18])=[O:17].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:24]1[CH2:23][CH2:22][N:21]([CH2:20][CH2:19][S:16]([CH3:15])(=[O:17])=[O:18])[CH2:26][CH2:25]1
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: COc1cc(F)c(Cl)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(Cl)cc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 91.3 %

Procedure:
To 1-chloro-2-fluoro-4-(methyloxy)-5-nitrobenzene (Example 104, Step B) (0.822 g, 4.0 mmol), 4-[2-(methylsulfonyl)ethyl]piperazine hydrochloride (Example 148, Step B) (0.915 g, 4.0 mmol), and K2CO3 (1.7 g, 12 mmol) was added DMSO (8 mL). The reaction was heated to 100° C. for two days. The reaction was determined to be complete by TLC. The reaction mixture was diluted with H2O and extracted with DCM and EtOAc sequentially for two iterations. The organic was dried (MgSO4), filtered, and rotovapped down. Purification by flash chromatography provided the title compound of Step A (1.38 g, 91%). MS (M+H, ES+) 378.