Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.Cl[C:9]1[CH:10]=[CH:11][C:12]([N+:28]([O-:30])=[O:29])=[C:13]([NH:15][C@@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH:14]=1>CN1C(=O)CCC1>[CH:25]([NH:24][C:22]([C@H:19]1[CH2:18][CH2:17][C@@H:16]([NH:15][C:13]2[CH:14]=[C:9]([N:3]3[CH:7]=[N:6][CH:5]=[N:4]3)[CH:10]=[CH:11][C:12]=2[N+:28]([O-:30])=[O:29])[CH2:21][CH2:20]1)=[O:23])([CH3:27])[CH3:26]
Reactant: c1nc[nH]n1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ccc2[N+](=O)[O-])CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(-n3cncn3)ccc2[N+](=O)[O-])CC1

Procedure:
To a suspension of sodium hydride (70.6 mg, 2.94 mmol) and 1H-1,2,4-triazole (203 mg, 2.94 mmol) in NMP (1 mL) was added cis-4-(5-chloro-2-nitrophenylamino)-N-isopropylcyclohexanecarboxamide (100 mg, 0.294 mmol). The resulting suspension was irradiated in a microwave reactor for 1 hour at 150° C. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layers were then washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide a yellow oil that crystallized upon standing to provide cis-N-isopropyl-4-(2-nitro-5-(1H-1,2,4-triazol-1-yl)phenylamino)cyclohexanecarboxamide as a yellow solid (100 mg, 91% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([CH2:23][CH3:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:17]2[CH:22]=[C:21]([CH2:23][CH3:24])[S:20][C:18]=2[N:19]=1
Reactant: CCc1cc2c(Cl)nc(Cl)nc2s1
Reactant: COc1ccc(CN)cc1OC
Product: CCc1cc2c(NCc3ccc(OC)c(OC)c3)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dimethoxybenzylamine with 2,4-dichloro-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-ethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[S:10]([N:13]=C=O)(=[O:12])=[O:11].C1C=CC=CC=1>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]([O:8][S:10](=[O:12])(=[O:11])[NH2:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(I)c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: NS(=O)(=O)Oc1cccc(I)c1
Yield: 78 %

Procedure:
This compound was prepared using the procedure of Example 84 from 27.8 g (0.126 mole) of 3-iodophenol and 11.7 ml (0.135 mole) of chlorosulfonyl isocyanate in 100 ml of toluene to obtain 29.4 g (78%) of the title compound as white flakes, mp 106°-108° C. (benzene).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:11][NH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([CH:8]1[CH2:9][N:10]([C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CC2CNC2)cc1
Reactant: O=C(Cl)CCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCc1ccccc1)N1CC(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.6 %

Procedure:
A solution of 3-benzylazetidine (294 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 4-phenylbutyryl chloride (456.6 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:5). The fractions containing 1-(3-benzylazetidin-1-yl)-4-phenylbutan-1-one are collected and the solvent is removed in vacuo to give 479 mg of colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28].CI.[C:31](=O)([O-])[O-].[K+].[K+]>[Cu].CN(C=O)C>[CH3:31][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][C:3]=1[C:15]1[CH:20]=[C:19]([CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:18]=[CH:17][C:16]=1[OH:28]
Reactant: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2O)c1
Reactant: O=C([O-])[O-]
Agent: [Cu]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(O)c(-c2cc(CCC(=O)OCC)ccc2OC)c1
Yield: 91.2 %

Procedure:
To 5 ml of a DMF solution containing 200 mg (0.5181 mmol) of 2,2'-dihydroxy-5,5'-bis (2-ethoxycarbonylethyl) biphenyl and 0.3292 ml (5.181 mmol) of methyl iodide, there were added 85.8 mg (0.6217 mmol) of anhydrous potassium carbonate and a small amount of copper powder and the resulting mixture was agitated for 2 hours at room temperature. The reaction mixture was filtered by suction through Celite to remove the solid matter and the filtrate was washed with ethyl acetate. After the solvent in the filtrate was evaporated off under reduced pressure, the evaporated residue was dissolved in chloroform. This solution was washed with dilute hydrochloric acid, dilute aqueous sodium bicarbonate, water and aqueous sodium chloride solution in this sequence and was dried by adding anhydrous sodium sulfate. The residue obtained after the solvent had been evaporated off was purified by a silica gel column chromatography (with 20 g of WAKO-gel C-200, eluent: toluene and toluene/ethyl acetate of 25/1) to obtain 188.9 mg (0.4723 mmol, 91%) of 2-methoxy-2'-hydroxy-5, 5'-bis(2-ethoxycarbonylethyl) biphenyl as an oily product. 1H-NMR (CDCl3) δ (ppm): 1.24 (6H, t, 2CH3), 2.62 (4H, t, 2CH2), 2.9-3.0 (4H, m, 2CH2), 3.87 (3H, s, CH2), 4.13 (4H, q, 2CH2), 6.13 (1H, s, OH), 6.9-7.3 (6H, m, arom-H) MS (FAB): 400 (M)+
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18].[CH3:19][N:20]([CH3:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][N:22]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([N:20]([CH3:19])[CH3:30])=[N:22][CH:23]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:16][CH2:17][CH3:18]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: CN(C)c1ccc(C(=O)O)cn1
Product: CCOc1cc(CN2CCC(NC(=O)c3ccc(N(C)C)nc3)CC2)ccc1Cl
Yield: 26 %

Procedure:
The title compound (11 mg, 26%) was prepared analogously to example 1 by coupling of 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine with 6-dimethylamino nicotinic acid (J. Org. Chem. 1999, 9, 2293). MS: 417.4 (MH+)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=1.[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([OH:28])=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[N:18][CH:17]=1>CN(C=O)C.O>[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:8][C:9]3[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[N:18][CH:17]=1
Reactant: COc1cc2c(Cl)cnnc2cc1O
Reactant: Cn1ccnc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)cnnc2cc1OCc1nccn1C
Temperature: 40 °C
Reaction time: 8 h
Yield: 28.5 %

Procedure:
The starting material, 4-chloro-6-methoxy-7-[(1-methylimidazol-2-yl)methoxy]-cinnoline was obtained by adding potassium carbonate (531 mg, 3.8 mmol) followed by 2-chloromethyl-1-methylimidazole (232 mg, 1.4 mmol) to a suspension of 4-chloro-7-hydroxy-6-methoxycinnoline (270 mg, 1.28 mmol), (prepared as described for the starting material in Example 10), in DMF (6 ml). After stirring overnight at 40° C. the mixture was diluted with water and adjusted to pH7. After extraction with ethyl acetate the organic layer was washed with water and then brine, dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography using methylene chloride/methanol (98/2) as eluent to give 4-chloro-6-methoxy-7-[(1-methylimidazol-2-yl)methoxy]cinnoline (111 mg, 29%).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[C:22]([CH3:34])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1.O>CN(C)C=O>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:24]2[N:23]=[C:22]([CH3:34])[C:21]([CH2:20][O:18][C:15]3[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]4[CH:7]=[CH:6][N:5]=[N:4]4)=[CH:17][CH:16]=3)=[CH:26][CH:25]=2)=[CH:28][CH:29]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: Cc1nc(-c2ccc(Cl)cc2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2ccc(Cl)cc2)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
33 mg (0.83 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 172 mg (0.85 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.85 mmol) 3-chloromethyl-6-(4-chloro-phenyl)-2-methyl-pyridine (EP 0 284 174) were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, water/methanol 1:1, and ether. The residue was dried at 40° C. in vacuum to give 305 mg (89%) of the title compound as white powder.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])[NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:15]1([N:21]=[C:22]=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:22]([NH:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:23])[CH:9]=[C:10]([I:14])[C:11]=1[O:12][CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=Nc1ccccc1
Reactant: COc1c(I)cc(N)cc1C(C)(C)C
Product: COc1c(I)cc(NC(=O)Nc2ccccc2)cc1C(C)(C)C

Procedure:
3-tert-Butyl-5-iodo-4-methoxyaniline (305 mg, 1 mmol) and phenyl isocyanate (0.109 mL, 1.000 mmol) were reacted in the same manner as Example 15 Part A to give the title compound.
Reaction SMILES: [OH2:1].[Cl:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][CH:10]2[C:15]([CH3:17])([CH3:16])[S:14][C:13](=[S:18])[N:12]([CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[C:11]2=[O:24])=[O:8])=[CH:5][CH:4]=1>C(OCC)(=O)C>[Cl:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C@H:10]([C:11]([OH:1])=[O:24])[C:15]([S:14][C:13](=[S:18])[NH:12][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])([CH3:17])[CH3:16])=[O:8])=[CH:5][CH:4]=1
Reactant: CN(C)CCN1C(=O)C(NC(=O)c2ccc(Cl)cc2)C(C)(C)SC1=S
Reactant: O
Solvent: CCOC(C)=O
Product: CN(C)CCNC(=S)SC(C)(C)[C@H](NC(=O)c1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Water (10 ml) is added to a solution of 30 g of 5-(p-chlorobenzamido)-3-(2-dimethylaminoethyl)-6,6-dimethyl-2-thioxo-tetrahydro-2H-1,3-thiazin-4-one in 600 ml of ethyl acetate. The resulting mixture is stirred at room temperature for 5 days. The precipitate is collected by filtration, and washed with ethyl acetate. Thus is obtained N-(p-chlorobenzoyl)-S-(2-dimethylaminoethylthiocarbamoyl)-penicillamine as white crystals, melting at 142°-143° C. with decomposition.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1)=[CH2:2].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]2=[N:22][N:23]=[C:24]([C:25]3[CH:29]=[C:28]([CH3:30])[O:27][N:26]=3)[N:14]2[N:13]=1>>[CH3:30][C:28]1[O:27][N:26]=[C:25]([C:24]2[N:14]3[N:13]=[C:12]([O:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=4)[C:21]4[C:16]([C:15]3=[N:22][N:23]=2)=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:29]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Reactant: C=Cc1ccc(CO)cn1
Product: C=Cc1ccc(COc2nn3c(-c4cc(C)on4)nnc3c3ccccc23)cn1
Yield: 92.1 %

Procedure:
The reaction was carried out according to Example 1 step 4 using (6-vinylpyridin-3-yl)methanol (500 mg, 3.7 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (1.05 g, 3.7 mmol). The crude residue was purified by column chromatography on silica using 2-4% MeOH/CH2Cl2 to yield the desired phthalazine (1.31 g, 92%). 1H NMR (360 MHz, CDCl3) δ 8.86 (1H, s), 8.68 (1H, d, J=8.0 Hz), 8.21 (1H, d, J=8.0 Hz), 8.03 (1H, dd, J=8.0, 2.2 Hz), 7.95 (1H, t, J=8.0 Hz), 7.80 (1H, t, J=8.0 Hz), 7.40 (1H, d, J=8.0 Hz), 6.88-6.78 (2H, m), 6.23 (1H, dd, J=17.5, 1.1 Hz), 5.68 (2H, s), 5.51 (1H, dd, J=10.8, 1.1 Hz), 2.59 (3H, s). m/z (ES+) 385 (M+2H+).
Reaction SMILES: [NH:1]([C:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[NH:13][CH:14]=[C:6]([C:7]=23)[CH2:5][N:4]=1)[NH2:2].C.[CH3:16][C:17]([CH3:19])=O>>[C:17](=[N:2][NH:1][C:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[NH:13][CH:14]=[C:6]([C:7]=23)[CH2:5][N:4]=1)([CH3:19])[CH3:16]
Reactant: CC(C)=O
Reactant: NNC1=NCc2c[nH]c3cccc1c23
Product: CC(C)=NNC1=NCc2c[nH]c3cccc1c23

Procedure:
5-Hydrazino-1,3-dihydropyrrolo[4,3,2-de]isoquinoline (4.5 g), described in Example 8, is boiled in acetone (ca. 50 ml) for 10 minutes. The reaction mixture is treated with charcoal, filtered and concentrated. Addition of ether-hexane gives a precipitate. The precipitate is recrystallized from benzenemethanol-ether to give the title compound, mp 200° - 201°C, νmaxnujol 3450, 3100, 1625, 1565, 1540 and 1510 cm-1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][C:11]([O:13]CC)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[C:1]1([CH2:7][CH2:8][CH:9]([CH3:16])[CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CC(C)CCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(CCc1ccccc1)CC(=O)O
Yield: 91.8 %

Procedure:
A mixture of ethyl 5-phenyl-3-methylpentanoate (0.30 g, 1.36 mmol), a 1N-aqueous sodium hydroxide solution (3 ml), methanol (3 ml) and tetrahydrofuran (3 ml) was stirred at room temperature for 5 hours. The reaction mixture was adjusted to pH 1 with a 1N-aqueous hydrochloric acid solution and extracted with ethyl acetate. The extract solution was washed with water and a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.24 g of 5-phenyl-3-methylpentanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][CH:7]([C:11]([OH:13])=[O:12])[C:6]=2[CH:14]=1.S(=O)(=O)(O)O.[CH2:20](O)[CH3:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][CH:7]([C:11]([O:13][CH2:20][CH3:21])=[O:12])[C:6]=2[CH:14]=1
Reactant: CCO
Reactant: O=C(O)C1CCSc2ccc(Cl)cc21
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCSc2ccc(Cl)cc21

Procedure:
A mixture of 6-chloro-3,4-dihydro-2H-1-benzothiopyran-4-carboxylic acid (12.56 g, 0.055 mol) and concentrated sulfuric acid (20 mL) in ethanol is heated at reflux for 29 hours, cooled, concentrated in vacuo and diluted with a water/methylene chloride mixture. The aqueous phase is separated and extracted with methylene chloride. The organic phase and organic extracts are combined, dried, decolorized with activated carbon and concentrated in vacuo to give the title product as a pale yellow oil (12.34 g) which is identified by 1H and 13CNMR spectral analyses.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:13][N:14]([C@@H:22]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]1)[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)C(C)C)C>CN1C(=O)CCC1>[NH2:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[C:3]=2[N:24]2[CH2:25][CH2:26][CH2:27][C@@H:22]([N:14]([CH3:13])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:23]2)[NH:8][CH:9]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(N)c23)C1
Temperature: 125 °C
Reaction time: 20 h

Procedure:
A 250 mL round bottom flask was charged with 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (1.00 g, 4.35 mmol; Example 1, Step H), (R)-tert-butyl methyl(piperidin-3-yl)carbamate (1.86 g, 8.69 mmol), N-ethyl-N-isopropylpropan-2-amine (2.27 mL, 13.0 mmol), and NMP (10.8 mL). Nitrogen was bubbled through the mixture for 5 minutes. The reaction was stirred at 125° C. (oil bath) under positive nitrogen atmosphere for 20 hours to provide the crude (R)-tert-butyl 1-(3-amino-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-yl(methyl)carbamate.
Reaction SMILES: C(CC1C=CC(C[CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C@@H:19]2[CH2:28][CH2:27][C:26]3[CH:25]=[C:24]([O:29]C(=O)C(C)(C)C)[CH:23]=[CH:22][C:21]=3[CH2:20]2)=CC=1)(O)=O.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH2:11]([N:12]([CH2:25][C:26]1[CH:27]=[CH:28][C:19]([CH2:14][CH2:13][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[CH:20][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:19]1[CH2:28][CH2:27][C:26]2[CH:25]=[C:24]([OH:29])[CH:23]=[CH:22][C:21]=2[CH2:20]1)[CH3:10]
Reactant: C1CCNC1
Reactant: CC(C)(C)C(=O)Oc1ccc2c(c1)CC[C@@H](c1ccccc1NCCCc1ccc(CC(=O)O)cc1)C2
Product: CCN(Cc1ccc(CCN2CCCC2)cc1)c1ccccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 86.3 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]phenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (28 mg) and pyrrolidine (20 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (11 mg) was obtained.
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10](=[O:25])[NH:11][C:12]2[N:17]=[CH:16][C:15]3[C:18]([NH:21][C:22](=[O:24])[CH3:23])=[N:19][NH:20][C:14]=3[CH:13]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B-](F)(F)(F)[F:27].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CC(N(C)C)=O.CO>[F:27][C:13]1[C:14]2[NH:20][N:19]=[C:18]([NH:21][C:22](=[O:24])[CH3:23])[C:15]=2[CH:16]=[N:17][C:12]=1[NH:11][C:10]([NH:9][C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])=[O:25]
Reactant: CC(=O)Nc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CC(=O)Nc1n[nH]c2c(F)c(NC(=O)N[C@H](C)c3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)—N-(6-(3-(1-Phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide (Example 47; 75 mg, 0.222 mmol) was dissolved in DMA (0.5 mL) and methanol (0.5 mL), charged with powdered Selectfluor® (86 mg, 0.244 mmol), and stirred at room temperature overnight. The reaction was then heated to 65° C. for 2 h. The resulting crude residue was purified by mass-triggered reverse phase HPLC. Fractions containing pure compound were filtered through a PS-HCO3 cartridge and the filtrate was concentrated in vacuo to give (R)—N-(7-fluoro-6-(3-(1-phenylethyl)ureido)-1H-pyrazolo[4,3-c]pyridin-3-yl)acetamide. MS ESI calc'd. for C17H17FN6O2 [M+1]+ 357. found 357. 1H NMR (500 MHz, DMSO-d6) δ 13.83 (s, 1H) 11.15 (s, 1H), 10.79 (s, 1H), 9.86 (s, 1H), 8.28 (d, J=7.3, 1H) 7.34 (m, 4H), 7.34 (m, 1H), 4.88 (m, 1H), 2.20 (S, 3H), 1.43 (d, J=6.9, 3H).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[CH3:6][C@@H:7]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)=[C:25]([CH3:37])[CH:24]=1)=[N:15][CH:16]=[N:17]2)[CH2:8][NH:9][CH3:10]>>[OH:3][CH2:2][C:1]([N:9]([CH3:10])[CH2:8][C@H:7]([O:11][C:12]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:13]=1[C:14]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=3)=[C:25]([CH3:37])[CH:24]=1)=[N:15][CH:16]=[N:17]2)[CH3:6])=[O:5]
Reactant: O=C(O)CO
Reactant: CNC[C@@H](C)Oc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(O[C@H](C)CN(C)C(=O)CO)c34)cc2C)cn1
Yield: 86 %

Procedure:
The procedure described in Example 1 was repeated using glycolic acid and 5-[(1R)-1-methyl-2-(methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine to give the title compound in 86% yield; NMR spectrum (CDCl3) 1.55 (d, 3H), 2.30 (s, 3H), 2.53 (s, 3H), 2.96 (s, 3H), 3.59 (dd, 1H), 4.16-4.07 (m, 3H), 5.08 (m, 1H), 6.92 (d, 1H), 7.02 (d, 1H), 7.09 (d, 1H), 7.14 (d, 1H), 7.50 (m, 2H), 7.65 (m, 2H), 8.28 (s, 1H), 8.61 (s, 1H), 9.87 (s 1H); Mass spectrum: MH+ 488.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:21])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH2:19][CH3:20])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:22][C:23]1[N:24]=[CH:25][N:26](COCC[Si](C)(C)C)[C:27]=1[C:28](O)=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:22][C:23]1[N:24]=[CH:25][NH:26][C:27]=1[C:28]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:18]=[C:17]([CH2:19][CH3:20])[CH:16]=[C:13]([C:14]#[N:15])[CH:12]=2)[C:4]=1[F:21])=[O:29]
Reactant: CCc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCc1cc(C#N)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Yield: 26.5 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-ethylbenzonitrile (0.055 g, 0.181 mmol), 4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylic acid (0.050 g, 0.181 mmol) and DIPEA (0.063 mL, 0.361 mmol) were combined in THF (2 mL) and treated with HATU (0.076 g, 0.199 mmol) at 25° C. overnight with stirring. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with water, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in DCM (2.5 mL) and treated with TFA (2.5 mL) at 25° C. for 3 days. The reaction mixture was concentrated to dryness, dissolved in DCM, washed with saturated aqueous NaHCO3, dried over MgSO4, filtered and concentrated to dryness. The resultant solid was recrystallized from boiling IPA, cooled in an ice bath and filtered to give 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.021 g, 0.048 mmol, 26.8% yield) as a white solid. The mother liquor was concentrated to dryness and purified on an XTerra™ C-18 column eluted with 5 to 75% CH3CN/H2O (0.2% NH4OH buffer). Appropriate fractions were combined, concentrated to dryness, chased twice with ethanol and twice with toluene to remove residual water to give additional 4-chloro-N-({4-chloro-3-[(3-cyano-5-ethylphenyl)oxy]-2-fluorophenyl}methyl)-1H-imidazole-5-carboxamide (0.043 g, 0.099 mmol, 54.9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.19 (br. s., 1H), 8.30 (br. s., 1H), 7.76 (s, 1H), 7.43-7.54 (m, 2H), 7.29-7.42 (m, 1H), 7.18 (m, 2H), 4.53 (d, J=5.22 Hz, 2H), 2.64 (q, J=7.23 Hz, 2H), 1.15 (t, J=7.48 Hz, 3H). LC-MS (ES−) m/z 431.16, 433.15 [M−1]. LC-MS (ES+) m/z 433.08, 435.07 [M+H].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[S:12][C:3]=12.C(OCCO)C.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1.Cl.N1C=CC=CC=1>>[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:2]2[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]3[C:10]4[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=4[S:12][C:3]=23)=[C:26]([F:31])[CH:25]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: N#Cc1cnc2c(sc3ccccc32)c1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: N#Cc1cnc2c(sc3ccccc32)c1Nc1ccc(Cl)cc1F
Temperature: 25 °C
Yield: 66 %

Procedure:
A solution of 237 mg (0.97 mmol) of 4-chlorobenzo[4,5]thieno[3,2-b]pyridine-3-carbonitrile in 6 mL of 2-ethoxyethanol containing 0.15 mL (1.36 mmol) of 4-chloro-2-fluoroaniline and 112 mg of pyridine hydrochloride is heated at reflux temperature for 30 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the resultant solid is collected by filtration, washing with hexane to give 225 mg (66%) of an off-white solid, mp 250-251° C.