Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:23]3[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][N:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1COCC1>[CH:10]1([O:16][C:17]2[N:22]=[CH:21][C:20]([C:23]3[C:24]4=[N:29][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:25]4[CH:26]=[CH:27][N:28]=3)=[CH:19][CH:18]=2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Nc1nccnc1-c1ccc(OC2CCCCC2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S1(=O)CCN2C=CN=C(c3ccc(OC4CCCCC4)nc3)C2=N1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 246 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.388 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-[6-(cyclohexyloxy)pyridin-3-yl]pyrazin-2-amine (332 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 1 day. The mixture was quenched with water at 0° C. carefully. EtOAc and THF were added and the organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was crystallized from MeCN-THF/IPE to give the title compound (104 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.C(N(CC)CC)C>O1CCOCC1>[N:11]1([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: c1c[nH]cn1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnccc1-n1ccnc1
Yield: 96.4 %

Procedure:
4-Chloro-3-nitropyridine (2.00 g, 12.6 mmol) and imidazole (2.25 g, 33.0 mmol) were dissolved in 10 ml of 1,4-dioxane, and 2 ml of triethylamine was added thereto. followed by reaction at 90° to 100° C. for 1.5 hours. Then, the solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: dichloromethane:methanol=10:1 (v/v)] to obtain 2.31 g of a yellow liquid (yield: 96.4%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:12]([O:14]CC)=O)=[N:9][O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:1]1([C:7]2[C:8]([C:12]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:14])=[N:9][O:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1nocc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Product: CC(C)(C)OC(=O)NCCNC(=O)c1nocc1-c1ccccc1
Yield: 84.1 %

Procedure:
3.9 g (17.95 mmol) of ethyl 4-phenyl-3-isoxazolecarboxylate and 5.8 g (36.2 mmol) of t-butyl (2-aminoethyl)carbamate were heated together to 110° for 2 hours under reduced pressure. Chromatography on silica gel and elution with methylene chloride which contained 5% and, respectively, 10% of ethyl acetate yielded an oil which crystallized from ethyl acetate/hexane. In this manner there were obtained 5.0 g (84%) of t-butyl [2-(4-phenyl-3-isoxazolecarboxamido)ethyl]carbamate as white crystals, melting point 170°-171°.
Reaction SMILES: Cl[CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:10]=2)[CH2:4]1.[I-:22].[Na+]>S1(CCCC1)(=O)=O.O>[I:22][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][C:16]3=[O:21])=[CH:11][CH:10]=2)[CH2:4]1
Reactant: O=C1COCCN1c1ccc(N2C[C@H](CCl)OC2=O)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: O=C1COCCN1c1ccc(N2C[C@H](CI)OC2=O)cc1
Temperature: 110 °C
Reaction time: 20 h
Yield: 81.1 %

Procedure:
Under an atmosphere of nitrogen to a solution of 1.00 g of 4-[4-[(5R)-5-(chloromethyl)-2-oxo-3-oxazolidinyl]phenyl]-3-morpholinone (MW=310.74; 1 eq.) in 5.3 mL sulfolane were added 0.97 g of sodium iodide (MW=149.89; 2 eq.). The resulting reaction mixture was stirred for 20 h at 110° C. Then the resulting slurry was cooled to room temperature and diluted with 30 mL of water. After stirring for 1 h at ambient temperature, the crystal suspension was isolated by filtration and the filter cake was washed with 20 mL of water. After drying in vacuo at 30° C., 1.05 g of the crystalline title compound (MW=402.19) were isolated. Yield=81.4%.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10]2=[O:18])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:19]([O:21][C:22](=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]Cl)[CH3:20]>CN(C=O)C>[CH2:19]([O:21][C:22](=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]1=[O:18])[CH3:20]
Reactant: O=c1[nH]c2ccccc2n1-c1ccccc1
Reactant: CCOC(=O)CCCCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCn1c(=O)n(-c2ccccc2)c2ccccc21

Procedure:
The product is produced as described in example 1 from 1.9 g. of NaH (80% suspension in mineral oil), 13.2 g. of 1-phenylbenzimidazolin-2-one (produced in usual manner by subjecting N-phenyl-o-phenylenediamine to reaction with phosgene), 120 cc. of DMF, 12.1 g. of 7-chloroenanthic acid ethyl ester and 1.9 g. of NaJ. Eluant in chromatographic purification: hexane/ethylacetate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:31].[C:32]1(=O)[O:37][C:35](=[O:36])[CH:34]=[CH:33]1>N1C=CC=CC=1>[OH:24][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:15](=[O:30])[C:14]=1[C:8]1[NH:7][C:6]2[CH:5]=[CH:4][C:3]3[O:31][C:32]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[N:1][C:2]=3[C:11]=2[S:10](=[O:12])(=[O:13])[N:9]=1
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc(O)c3N)N2)c(O)c2ccccc21
Reactant: O=C1C=CC(=O)O1
Solvent: c1ccncc1
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc4oc(CCC(=O)O)nc34)N2)c(O)c2ccccc21
Yield: 30.6 %

Procedure:
A solution of the product of Example 354 (15 mg, 0.033 mmol) and maleic anhydride (100 mg, 1.0 mmol) in pyridine (2 mL) was heated at 160° C. in a microwave reactor for 1 hour. The crude mixture was cooled to 25° C. and purified by preparative HPLC on a Waters Symmetry C8 column (25 mm×100 mm, 7 μm particle size) using a gradient of 10% to 100% acetonitrile:0.1% aqueous trifluoroacetic to yield the title compound (5.3 mg, 30%). The disodium salt was made by the procedure of Example 1D using 2 equivalents of sodium hydroxide. MS (ESI−) m/z 524 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.03 (d, J=6.25 Hz, 6 H) 1.86 (m, 1 H) 2.27 (m, 4 H) 2.66 (m, 2 H) 5.94 (t, J=7.54 Hz, 1 H) 6.81 (m, 2 H) 7.05 (t, J=7.91 Hz, 1 H) 7.53 (m, 2 H) 8.06 (d, J=6.62 Hz, 1 H) 15.74 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:4]=1[CH2:5][NH:6][CH2:7][C:8]1([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11][CH2:10][CH2:9]1.CCN(CC)CC.[Br:34][CH2:35][C:36](Br)=[O:37]>C1COCC1>[Br:34][CH2:35][C:36]([N:6]([CH2:7][C:8]1([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9][CH2:10][CH2:11][CH2:12]1)[CH2:5][C:4]1[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:3]=1[O:2][CH3:1])=[O:37]
Reactant: COc1ccc(CNCC2(NC(=O)OC(C)(C)C)CCCC2)c(OC)c1
Reactant: O=C(Br)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CN(CC2(NC(=O)OC(C)(C)C)CCCC2)C(=O)CBr)c(OC)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 1-{[(2,4-dimethoxybenzyl)amino]methyl}cyclopentyl-carbamate (3.20 g, 8.78 mmol) in anhydrous THF (25 mL) was added Et3N (1.35 mL, 9.65 mmol). The solution was cooled to 0° C., treated with bromoacetyl bromide (0.84 mL, 9.65 mmol), and stirred for 3 h. The reaction was poured into ice water and extracted three times into Et2O. The combined organics were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude material was subjected to column chromatography eluting with a gradient of 0-100% EtOAc/hexanes. Collection and concentration of the appropriate fractions afforded the product.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([O:12]C)=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20].[OH-].[Na+]>CCO>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[CH:7]=[CH:6][C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20]
Reactant: COCc1cc(C(=O)OC)ccc1-c1ccccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 92.5 %

Procedure:
A solution of methyl 2-(methoxymethyl)-2′-methylbiphenyl-4-carboxylate (40.0 g, 148 mmol) in EtOH (1.2 L) at RT was treated with a 5N aqueous solution of NaOH (90 mL, 450 mmol). The reaction mixture was stirred at 60° C. for 1 hour, and then concentrated under reduced pressure. The yellow solid was taken up with water (800 mL) and washed twice with EtOAc. The aqueous layer was acidified with a concentrated aqueous solution of HCl until pH=2 and was extracted with EtOAc (2×400 mL). The combined organic layers were washed with brine, dried (MgSO4) and concentrated affording the title compound as a yellow solid (35.1 g, 92%). HPLC (Method A), Rt 4.5 min (Purity: 96.4%). UPLC/MS, M−(ESI): 255.2. 1H NMR (DMSO-d6, 300 MHz) δ 12.99 (br s, 1H), 8.09 (s, 1H), 7.91 (m, 1H), 7.33-7.22 (m, 4H), 7.09 (m, 1H), 4.11 (m, 2H), 3.18 (s, 3H), 1.99 (s, 3H).
Reaction SMILES: C(OC(N[C:9]1[CH2:10][C:11](C(O)=O)=[CH:12][C:13]2[CH:19]=CC(C3C=CC(C(N4CCCC4)=O)=CC=3)=C[C:14]=2[N:15]=1)=O)(C)(C)C.N[OH:37]>>[CH3:12][C:13]([OH:37])([CH3:19])[CH2:14][NH:15][CH2:9][CH2:10][CH3:11]
Reactant: NO
Reactant: CC(C)(C)OC(=O)NC1=Nc2cc(-c3ccc(C(=O)N4CCCC4)cc3)ccc2C=C(C(=O)O)C1
Product: CCCNCC(C)(C)O

Procedure:
The following examples 115 and 117 were prepared by the procedures as described in Example 101 (Steps H and I) using (1E,4E)-2-(tert-butoxycarbonylamino)-8-(4-(pyrrolidine-1-carbonyl)phenyl)-3H-benzo[b]azepine-4-carboxylic acid and the appropriate amines (2-methyl-1-(propylamino)propan-2-ol was prepared by the procedure reported in J. Am. Chem. Soc. 1939, 61, 3562) or the hydroxylamine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[CH2:50]([CH2:52][NH2:53])[OH:51]>C(Cl)Cl.O1CCCC1>[NH2:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:53][CH2:52][CH2:50][OH:51])=[CH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCO)cn2)CC1
Reaction time: 2 h
Yield: 78 %

Procedure:
6-[1-(3-Amino-2-pyridyl)piperazine-4-yl-carbonyl]nicotinic acid (0.5 g) was added to a co-solvent of tetrahydrofuran (10 ml) and methylene chloride (10 ml) and with the successive addition of 1,3-dicyclohexylcarbodimide (0.65 g) and 1-hydroxybenzotriazole (0.23 g) at 15˜20° C., the mixture was stirred for 2 hours. With the addition of ethanolamine (0.18 ml), the mixture was stirred again at 20˜25° C. for 2 hours. Methylene chloride (30 ml) was added again to the mixture, washed with water 3 times, dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was treated with ether for crystallization. The solid was recrystallized with ethanol and hexane to give a desired compound of 0.44 g (yield: 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([OH:20])=O.[CH3:21][N:22]([CH3:39])[CH2:23][CH2:24][CH2:25][N:26]([CH3:38])[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=1[C:34]([F:37])([F:36])[F:35]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=[CH:9]2)[CH:5]=[CH:4][C:3]=1[CH2:17][C:18]([NH:33][C:30]1[CH:31]=[CH:32][C:27]([N:26]([CH2:25][CH2:24][CH2:23][N:22]([CH3:21])[CH3:39])[CH3:38])=[C:28]([C:34]([F:35])([F:36])[F:37])[CH:29]=1)=[O:20]
Reactant: CN(C)CCCN(C)c1ccc(N)cc1C(F)(F)F
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1Cl
Solvent: CO
Solvent: ClCCl
Product: CN(C)CCCN(C)c1ccc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2Cl)cc1C(F)(F)F

Procedure:
The title compound is prepared as described in Example 1 but using (2-chloro-4-imidazo[4,5-b]pyridin-3-yl-phenyl)-acetic acid (Step 16.1) and 4-[(3-dimethylamino-propyl)-methyl-amino]-3-trifluoromethyl-phenylamine (Step 5.1). Title compound: ES-MS: 544.9 [M+H]+; single peak at tR=3.66 min (System 1); Rf=0.28 (CH2Cl2/MeOH+1% NH3aq, 9:1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13]([Br:30])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (600 mg, 1.55 mmol) and N-bromosuccinimide (291 mg, 1.63 mmol) in CH2Cl2 (4.2 mL) was refluxed for 3 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography (0-60% EtOAc/hexanes+2% AcOH) to give 560 mg of the title compound as a yellow solid. MS: (+) m/z 464.97, 466.94 (M+H, 79/81Br)
Reaction SMILES: [CH3:1][C:2]([OH:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1.[NH2-].[Na+].C1C=CC=CC=1>O>[CH2:28]([O:27][C:25]([N:22]1[CH2:21][CH2:20][N:19]([CH2:18][CH2:17][O:15][C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:1])[CH2:24][CH2:23]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)N1CCN(CCCl)CC1
Reactant: CC(O)(c1ccccc1)c1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)N1CCN(CCOC(C)(c2ccccc2)c2ccccc2)CC1
Yield: 71.8 %

Procedure:
A mixture of 1.8 g (9.1 mmole) of α-methylbenzhydrol, 2.0 g (9.1 mmole) of 1-(2-chloroethyl)-4-(ethoxycarbonyl)piperazine, 0.36 g (9.2 mmole) of sodium amide and 20 ml of benzene was heated under reflux overnight. At the end of this time, water was poured onto the reation mixture, and the mixture was extracted with ethyl acetate. The solvent was then removed from the mixture by distillation under reduced pressure, and the residue was subjected to column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to obtain 2.5 g (yield 75%) of the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.[CH3:11][O:12][C:13](OC)(OC)OC.C(O)(=O)C>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:13]([O:12][CH3:11])[N:8]([CH3:9])[C:5]2=[N:6][CH:7]=1
Reactant: CNc1ncc(Br)cc1N
Reactant: COC(OC)(OC)OC
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1nc2cc(Br)cnc2n1C

Procedure:
A solution of 5-bromo-N*2*-methyl-pyridine-2,3-diamine (Stage 67.1.4, 960 mg, 4.75 mmol) and tetramethylorthocarbonate (Aldrich, Buchs, Switzerland, 2 ml, 14.7 mmol) and acetic acid (0.273 ml, 4.75 mmol) was stirred for 90 min at 100° C. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. The aqueous layer was extracted with EtOAc and the combined organic layers washed with saturated aqueous NaHCO3 and with brine, then dried over Na2SO4, filtered and evaporated. The crude product was dry loaded on silica gel and purified by MPLC (DCM/MeOH 0%-4%) to give the title compound as a green solid. (HPLC: tR 2.83 min (Method A); M+H=242, 244 MS-ES).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[CH:12][C:11]=1[NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=1>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:19]=2)=[CH:12][C:11]=1[NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[CH:34]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(O)c1
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(Oc2cc(Cl)ncn2)c1
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 47, 4,6-dichloropyrimidine was reacted with N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-hydroxybenzamide to give the title compound in 42% yield; NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 3.14 (t, 4H), 3.73 (t, 4H), 7.22 (d, 1H), 7.34 (m, 2H), 7.47 (m, 3H), 7.57 (m, 1H), 7.63 (t, H), 7.81 (d, 1H), 7.93 (d, 1H), 8.66 (s, 1H), 9.96 (s, 1H), 10.14 (s, 1H); Mass Spectrum: M+H+ 544.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][C:24]([CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:25][CH:26]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH:27]5[CH2:32][CH2:31][N:30]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:29][CH2:28]5)=[N:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:40])=[CH:41][CH:42]=3)(=[O:34])=[O:35])[CH:13]=2)[CH:9]=[N:8]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)nc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Yield: 98 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperidin-4-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (85 mg. 0.132 mmol) was alkylated using (S)-2-methyloxirane (16 mg, 0.264 mmol), DIPEA (68 mg, 0.528 mmol) and ethanol (5 mL) to get 86 mg (97.8% yield) of the titled compound. MS: m/z=665.2 (M+1).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[C:22]1([CH2:28][S:29](Cl)(=[O:31])=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C>ClCCl>[CH2:1]([N:5]([CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[S:29]([CH2:28][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:31])=[O:30])[CH:2]([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)Cc1ccccc1

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with alpha-toluenesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-C-phenyl-methanesulfonamide as an off-white solid. MS: 495.2 ([M+NH4]+)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:4][CH2:3]1.[N:23]#CBr.O>C1C=CC=CC=1>[C:1]([N:2]1[CH2:3][CH2:4][C:5](=[C:8]2[C:14]3[CH:15]=[N:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)[CH2:6][CH2:7]1)#[N:23]
Reactant: CN1CCC(=C2c3ccccc3CCc3ccncc32)CC1
Reactant: N#CBr
Solvent: c1ccccc1
Solvent: O
Product: N#CN1CCC(=C2c3ccccc3CCc3ccncc32)CC1
Yield: 36.9 %

Procedure:
To a solution of 400 mg (1.35 mmole) of 11-(1-methyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta [1,2-c]pyridine in 5.0 mL of benzene at room temperature and under an argon atmosphere was added dropwise a solution of 168 mg (1.59 mmole) of cyanogen bromide in 4 mL of benzene. After 30 min. the mixture was poured into water and extracted once with EtOAc. The organic layer was isolated, washed once with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via flash chromatography [21/2% MeOH in CH2Cl2 ] to give 150 mg (37%) of the title compound as a solid: m.p. 212°-214° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]2[C:7]3[C:12]([C:13](=[O:22])[N:14]([CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:5]2=[N:4][N:3]=1)=[CH:11][C:10]([Br:23])=[CH:9][CH:8]=3.CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1>C(O)(=O)C>[CH2:15]([N:14]1[C:13](=[O:22])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:23])[CH:11]=2)[N:6]2[C:2]([N:1]3[CH:26]=[CH:30][CH:29]=[CH:28]3)=[N:3][N:4]=[C:5]12)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1nnc2n(Cc3ccccc3)c(=O)c3cc(Br)ccc3n12
Solvent: CC(=O)O
Product: O=c1c2cc(Br)ccc2n2c(-n3cccc3)nnc2n1Cc1ccccc1
Yield: 59.5 %

Procedure:
In a 25 ml balloon flask, we resuspend 0.7 g (1.8 mmol) of 1-amino-4-benzyl-7-bromo-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (intermediate 10 compound of example 271) in 5 ml of acetic acid. We add 0.25 g (1.9 mmol) of 2.5-dimethoxytetrahydrofuran then heat the mixture by reflux for 1 hour. After cooling down and evaporation of acetic acid under vacuum, we obtain 0.8 g of highly colored solid which is purified by chromatography on silica column by elution with the mixture CH2Cl2/CH3OH (99,4/0,6 then 99/1). The solid obtained from pure fractions is recrystallized in ethanol to give 0.45 g of compound from example 217.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([NH2:12])=[CH:4][CH:3]=1.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:12][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=2)(=[O:21])=[O:20])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(Cl)ccc1N
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(C)cc1
Temperature: 5 °C
Yield: 95 %

Procedure:
To a solution of methyl 5-chloroanthranilate (10.50 g (56.6 mmol) in pyridine (30 ml), p-toluenesulfonyl chloride (12.00 g (62.9 mmol)) was added with stirring at 5° C. The mixture was stirred at room temperature for 18 hours, and then, 200 ml of water was added to the resulting mixture. The crystals separated were filtered and washed to give 18.20 g (95%) of 4′-chloro-2′-methoxycarbonyl-p-toluenesulfonanilide as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[Cl:18][C:19]1[CH:24]=[C:23]([N:25]=[C:26]=[O:27])[CH:22]=[C:21]([Cl:28])[N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH:13][C:26]([NH:25][C:23]2[CH:22]=[C:21]([Cl:28])[N:20]=[C:19]([Cl:18])[CH:24]=2)=[O:27])[CH2:7]1
Reactant: O=C=Nc1cc(Cl)nc(Cl)c1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1cc(Cl)nc(Cl)c1
Yield: 39.1 %

Procedure:
Example 24 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 2,6-dichloro-4-isocyanatopyridine (0.0258 g) to give the title compound (0.0165 g). LC-MS (System A): Rt 2.46 mins, Mass Spectrum m/z 463 [MH+].