Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:26]=[CH:25][C:5]2[S:6][C:7]([C:10]3[N:14]4[N:15]=[C:16]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:17]=[CH:18][C:13]4=[N:12][CH:11]=3)=[C:8]([CH3:9])[C:4]=2[CH:3]=1.[H][H]>CO.[Pd]>[CH3:9][C:8]1[C:4]2[CH:3]=[CH:2][CH:26]=[CH:25][C:5]=2[S:6][C:7]=1[C:10]1[N:14]2[N:15]=[C:16]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: [H][H]
Reactant: Cc1c(-c2cnc3ccc(NCCCCO)nn23)sc2ccc(Cl)cc12
Agent: [Pd]
Solvent: CO
Product: Cc1c(-c2cnc3ccc(NCCCCO)nn23)sc2ccccc12
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a solution of 4-(3-(5-chloro-3-methylbenzo[b]thiophen-2-yl)imidazo[1,2-b]pyridazin-6-ylamino)butan-1-ol (20 mg, 0.0517 mmol, 1.0 equiv) in methanol (2.00 mL) was added Pd/C and placed under a balloon of hydrogen. After 3 h, the reaction mixture was filtered through a plug of silica gel to provide 15 mg of the white solid, 82%.
Reaction SMILES: [OH:1][CH:2]([CH3:39])[CH2:3][O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:21][CH:20]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]3[N:36]=[CH:37][N:38]=[C:12]23)[CH2:7][CH2:6]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C(#N)C.C(=O)([O-])O.[Na+]>[O:17]=[C:16]1[C:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]2[N:36]=[CH:37][N:38]=[C:12]2[N:11]1[C@H:8]1[CH2:7][CH2:6][C@H:5]([O:4][CH2:3][C:2](=[O:1])[CH3:39])[CH2:10][CH2:9]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)O)CC2)c2ncnn12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4′-({4-[trans-4-(2-hydroxypropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (280 mg) in acetonitrile (5 mL) was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (293 mg) under ice-cooling, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=65/35→40/60 (volume ratio)] to give the title compound as a colorless amorphous compound (254 mg, 92%).
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2]O.[Cl:6][C:7]1[CH:8]=[C:9]([NH2:22])[C:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:11][CH:12]=1.C([O-])(O)=O.[Na+].C(Cl)Cl>Cl.O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]2[N:13]([CH2:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[C:2]([CH2:1][OH:5])=[N:22][C:9]=2[CH:8]=1
Reactant: Nc1cc(Cl)ccc1NCCCn1ccnc1
Reactant: O=C(O)CO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: OCc1nc2cc(Cl)ccc2n1CCCn1ccnc1
Temperature: 90 °C
Yield: 29.3 %

Procedure:
Glycolic acid (1.98 g, 26 mmol, 3 eq.) was added to a solution of 4-chloro-N1-[3-(1H-imidazol-1-yl)propyl]benzene-1,2-diamine (12, 2.18 g, 8.7 mmol) in HCl (6N, 20 mL) at room temperature. The reaction mixture was heated up until 90° C. during 16 hours. After cooling to ambient temperature the reaction mixture was diluted with 100 mL water followed by addition of NaHCO3 until the pH was approximately 7. CH2Cl2 (30 ml) was added and the organic layer was separated and the aqueous layer was further extracted with additional CH2Cl2 (20 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo and purified by flash chromatography (0 to 10% MeOH in CH2Cl2) to give {5-chloro-1-[3-(1H-imidazol-1-yl)propyl]-1H-benzimidazol-2-yl}methanol (13, 740 mg, 30%) as a white solid; LCMS m/z=291 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:12][CH3:13])=[CH:5][C:6]=1[C:7]([O:9]CC)=O.Cl[C:15]1[N:20]=[CH:19][C:18]([C:21]([OH:23])=[O:22])=[CH:17][CH:16]=1.C>C(O)(=O)C>[CH2:12]([C:4]1[S:3][C:2]2[N:1]=[C:15]3[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][N:20]3[C:7](=[O:9])[C:6]=2[CH:5]=1)[CH3:13]
Reactant: CCOC(=O)c1cc(CC)sc1N
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: CC(=O)O
Product: CCc1cc2c(=O)n3cc(C(=O)O)ccc3nc2s1

Procedure:
A mixture of 2-amino-5-ethyl-3-thiophenecarboxylic acid, ethyl ester (Chemische Berichte, Vol. 99, pages 94-100, 1966), 2.0 g (0.01 mol) and 6-chloro-3-pyridinecarboxylic acid (Aldrich Chemical Company), 1.6 g (0.01 mol) is heated in an oil bath at 180°-185° C. for six hours. The mixture is cooled, dissolved in hot glacial acetic acid, activated charcoal (Darco G-60, Matheson, Coleman and Bell) added and the hot suspension filtered through Supercell Hyflo® (Johns-Manville). The filtrate is cooled and 0.33 g of 2-ethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxylic acid is collected; mp 255°-257° C. after recrystallization from methanol.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])(C(C)(C)C)(C)C.FC(F)(F)S(O[CH2:45][CH:46]([F:48])[F:47])(=O)=O.C(N(CC)CC)C>C1COCC1>[F:48][CH:46]([F:47])[CH2:45][N:29]1[CH2:30][CH2:31][CH:26]([N:25]([CH3:32])[C:23]([N:11]2[CH2:12][C:13]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[F:22])=[CH:14][C:10]2([CH2:9][OH:8])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:24])[CH2:27][CH2:28]1
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO[Si](C)(C)C(C)(C)C)c1ccccc1)C1CCNCC1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1)C1CCN(CC(F)F)CC1
Temperature: 70 °C
Reaction time: 2.5 h

Procedure:
To 87 mg (0.16 mmol) of amine 7-2 in THF in a sealed tube was added 41 mg (0.19 mmol) of 2,2-difluoroethyl trifluoromethane sulfonate and 67 μL (0.48 mmol) of triethylamine. After stirring 2.5 h at 70° C., the mixture was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was dissolved in 5 mL CH2Cl2 and 1 mL of trifluroacetic acid was added. After stirring for 30 min at room temperature, the solvents were removed by rotary evaporation, the residue was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with brine, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by column chromatography on silica gel with MeOH/CHCl3 to provide 10-1 as a white solid. Data for 10-1: 1HNMR (500 MHz, CDCl3) δ 7.7-7.3 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.8 (m, 1H), 5.4 (m, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.7 (m, 1H), 3.0 (m, 2H), 2.9 (s, 3H), 2.75 (m, 2H), 2.3 (m, 2H), 1.9 (m, 2H), 1.6 (m, 1H) ppm. HRMS (ES) calc'd M+H for C26H29F4N3O2: 492.2269. Found: 492.2250.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:10])=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([C:20](Cl)=[O:21])=[C:16]([F:23])[CH:15]=1>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:11][O:12][C:13](=[O:24])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:5][C:4]2[CH:6]=[C:7]([F:9])[CH:8]=[C:2]([Br:1])[C:3]=2[CH3:10])=[O:21])=[C:16]([F:23])[CH:15]=1
Reactant: Cc1c(N)cc(F)cc1Br
Reactant: COC(=O)c1ccc(C(=O)Cl)c(F)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2cc(F)cc(Br)c2C)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Bromo-5-fluoro-2-methylaniline (515 mg, 2.53 mmol) was dissolved in pyridine (20 ml). Then Intermediate 33 (547 mg, 2.53 mmol) and DMAP (3.09 mg, 0.025 mmol) were added and the resulting mixture was stirred at r.t. for 2 hrs. The solvents were removed in vacuo and the residue was taken up with EtOAc and H2O. The organic layer was washed with sat. NaHCO3 solution and brine, and then dried over Na2SO4. The solvents were removed in vacuo and the resulting residue was recrystallized with MeOH to afford Intermediate 34 as colorless solid.
Reaction SMILES: [Cl-].[Li+].[CH2:3]([O:7][C:8]1[C:13]([C:14]2[NH:15][C:16](=[O:29])[C:17]3[C:18](=[C:20]([CH2:27][CH3:28])[N:21]([CH2:23][CH2:24][O:25][CH3:26])[N:22]=3)[N:19]=2)=[CH:12][C:11](I)=[CH:10][N:9]=1)[CH2:4][CH2:5][CH3:6]>O1CCOCC1.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>[CH2:3]([O:7][C:8]1[C:13]([C:14]2[NH:15][C:16](=[O:29])[C:17]3[C:18](=[C:20]([CH2:27][CH3:28])[N:21]([CH2:23][CH2:24][O:25][CH3:26])[N:22]=3)[N:19]=2)=[CH:12][C:11]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:10][N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCOc1ncc(I)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CCCCOc1ncc(-c2ccccn2)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Reaction time: 0.17 h
Yield: 58 %

Procedure:
2-Tributyltin pyridine (192 mg, 0.52 mmol), lithium chloride (170 mg, 4.00 mmol), cuprous iodide (11.5 mg, 0.06 mmol), Pd(PPh3)4 (46.5 mg, 0.04 mmol) and the title compound of Example 1 (200 mg, 0.40 mmol) were stirred together in dioxan (10 mL) under a nitrogen atmosphere. The mixture was heated at reflux for 3.5 h, allowed to cool and the solvent removed in vacuo. The residue was taken up in ethyl acetate and shaken vigorously with 5% aqueous potassium fluoride solution for 10 min and the mixture filtered through Arbocel®. The organic layer was separated, washed with 5% aqueous potassium fluoride solution, saturated sodium bicarbonate solution and brine. The organics were dried (MgSO4) and concentrated. The solid was partially purified by trituration with cold ethyl acetate and further purified by flash column chromatography (elution with 50:1 dichloromethane/methanol) to give the title compound (52 mg, 29%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]=O)=[CH:14][C:13]=2[C:19]=1[C:20]([CH3:23])([CH3:22])[CH3:21])C1C=CC=CC=1.C(OCC)(=O)C.[H][H]>[Pd].C(O)(=O)C>[C:20]([C:19]1[C:13]2[CH:14]=[C:15]([CH3:17])[O:16][C:12]=2[CH:11]=[CH:10][C:9]=1[OH:8])([CH3:23])([CH3:22])[CH3:21]
Reactant: [H][H]
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc2c(C(C)(C)C)c(O)ccc2o1
Yield: 16.6 %

Procedure:
A solution of 1.0 g of 5-benzyloxy-4-t-butyl-2-formylbenzofuran in a mixed solvent of 50 ml of ethyl acetate and 2 ml of acetic acid was vigorously stirred with 1.0 g of 10% palladium on carbon for 20 hours in a hydrogen atmosphere. After the palladium on carbon was filtered out, the filtrate was concentrated and the concentrate was purified by silica gel column chromatography (in n-hexane containing 20% ethyl acetate) to give 0.11 g of 4-t-butyl-5-hydroxy-2-methylbenzofuran as a white crystal (yield 17%).
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:22](O)=[O:23])[C:19]([F:21])=[CH:20][C:15]=2[O:14][C:13]([CH3:26])([CH3:25])[C:12]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][C@@H:36]1[C@@H:41]([C:42]2[CH:47]=[C:46]([F:48])[C:45]([F:49])=[CH:44][C:43]=2[F:50])[CH2:40][CH2:39][N:38]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:37]1>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:22]([NH:35][C@@H:36]3[C@@H:41]([C:42]4[CH:47]=[C:46]([F:48])[C:45]([F:49])=[CH:44][C:43]=4[F:50])[CH2:40][CH2:39][N:38]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:37]3)=[O:23])[C:19]([F:21])=[CH:20][C:15]=2[O:14][C:13]([CH3:26])([CH3:25])[C:12]1=[O:27])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC1(C)Oc2cc(F)c(C(=O)O)cc2N(CCN(Cc2ccccc2)Cc2ccccc2)C1=O
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2cc(F)c(F)cc2F)[C@@H](N)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](c2cc(F)c(F)cc2F)[C@@H](NC(=O)c2cc3c(cc2F)OC(C)(C)C(=O)N3CCN(Cc2ccccc2)Cc2ccccc2)C1

Procedure:
Using 4-[2-(dibenzylamino)ethyl]-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carboxylic acid and tert-butyl (3R,4R)-3-amino-4-(2,4,5-trifluorophenyl)piperidine-1-carboxylate, the title compound was obtained in a similar manner to Reference Example 541.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:18][C:19]1[CH:24]=[C:23]([Br:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[OH:27].CC([O-])(C)C.[K+]>CN1C(=O)CCC1>[Br:25][C:23]1[CH:24]=[C:19]([CH3:18])[C:20]([O:27][C:2]2[N:10]=[C:9]([CH3:11])[CH:8]=[C:7]([NH:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[C:3]=2[C:4]([NH2:6])=[O:5])=[C:21]([CH3:26])[CH:22]=1
Reactant: CCC(CC)Nc1cc(C)nc(Cl)c1C(N)=O
Reactant: Cc1cc(Br)cc(C)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C(N)=O
Temperature: 160 °C

Procedure:
To a mixture of 2-chloro-4-(1-ethyl-propylamino)-6-methyl-nicotinamide and 2,6-dimethyl-4-bromo-phenol in NMP was added t-BuOK. The resulting mixture was heated in a 160° C. oil bath overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated, then purified through silica gel Biotage to give the title compound. 1H NMR(CDCl3) d 9.69(d,1H), 7.89(brs,1H), 7.20(s,2H), 6.13(s,1H), 5.5(brs,1H), 3.3(m,1H), 2.10(s,3H), 2.09(s,6H), 1.6(m,4H), 0.95(t,6H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:25])[NH:7][CH2:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(=O)c1ccc(O)cc1

Procedure:
The compound of example 27b (6.0 g; 17.6 mmol) was dissolved in methanol (60 ml) and hydrogenated using 10% Pd—C (50 mg) at 40 psi for 2 h. The reaction mixture was filtered, concentrated and purified using flash chromatography (silica gel, 3% CH3CN in chloroform) to obtain the title compound. Yield, 2.6 g (59%); mp, 183-85° C.; MS (CI): 252 (M++1), 196, 178, 152; analysis: C13H17NO4 requires: C, 62.14; H, 6.82; N, 5.57. found: C, 62.23; H, 6.44; N, 5.57%.
Reaction SMILES: [CH3:1][NH2:2].[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[C@H:11]3[O:16][C@@H:10]3[C:9]=2[CH:17]=1)#[N:4]>C(O)C>[C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[C@@H:11]([OH:16])[C@H:10]([NH:2][CH3:1])[C:9]=2[CH:17]=1)#[N:4]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H]2O[C@@H]21
Reactant: CN
Solvent: CCO
Product: CN[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methylamine in dry ethanol was added to a solution of (3S,4R)-6-cyano-3,4-dihydro-3,4-epoxy-2,2-dimethyl-2H-1-benzopyran* (1.0 g) in dry ethanol, and the resulting solution stirred at room temperature for 2 days. Evaporation of solvent in vacuo gave the title compound as a gum (1.0 g) which was used without further purification.
Reaction SMILES: Cl.[OH:2][NH2:3].C(=O)(O)[O-].[Na+].[OH:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[C:14]#[N:15]>CO>[OH:2][N:3]=[C:14]([C:13]1[CH:16]=[CH:17][CH:18]=[C:11]([CH2:10][OH:9])[CH:12]=1)[NH2:15]
Reactant: NO
Reactant: N#Cc1cccc(CO)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: NC(=NO)c1cccc(CO)c1
Temperature: 25 °C
Yield: 105.7 %

Procedure:
Hydroxyl amine hydrochloride (2.29 g, 32.9 mmol) and sodium bicarbonate (5.52 g, 65.8 mmol) were added to 3-(hydroxymethyl)benzonitrile (2.19 g, 16.4 mmol) and methanol (30 mL) and stirred at reflux for 18 hours. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo to give the title compound (2.88 g, 100% yield) as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N+:13]([O-:15])=[O:14].CN(C=O)C.[Cl:21]N1C(=O)CCC1=O>O>[Cl:21][C:8]1[CH:7]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([N+:13]([O-:15])=[O:14])[C:3]=1[NH:2][CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1c(Cl)cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.8 %

Procedure:
To a mixture of methyl-(2-nitro-4-trifluoromethylphenyl)-amine (4.40 g) and DMF (20 ml), N-chlorosuccinimide (3.67 g) was added under ice-cooling, and stirred for 3 hours. The mixture was heated to room temperature, and allowed to stand. Water was poured thereinto under ice-cooling, and then the precipitated solid was collected by filtration. The obtained solid was washed with water, and dried to give 3.96 g of (2-chloro-6-nitro-4-trifluoromethylphenyl)-methylamine.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C@H:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(Cl)Cl>C(N(CC)CC)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C@H:12]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: O=C(Cl)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(Br)cc1)C(=O)OCC
Reaction time: 8 h

Procedure:
To a mixture of 0.92 g of of 4-bromobenzoyl chloride and 1.0 g of diethyl L-glutamate in 50 ml to dry methylene chloride is added 1.16 ml of triethylamine. The reaction mixture is stirred overnight under nitrogen. After a standard workup, the methylene chloride solution is concentrated under reduced pressure, and the residue recrystallized from hexanes to give 0.68 g (46%) of analytically pure diethyl N-(4-bromobenzoyl)-L-glutamate as a white solid: m.p. 82.5°-83.5° C.; NMR (CDCl3, 300 MHz) delta 1.26 (t, 3H, J=6.9 Hz), 1.33 (t, 3H, J=6.9 Hz), 2.11°-2.60 (m, 4H), 4.14 (q, 2H, J=6.9 Hz), 4.27 (q, 2H, J=6.9 Hz) 4.78 (m, 1H), 7.14 (d, 1H, J=7.2 Hz), 7.61 (d, 2H, J=8.4 Hz), 7.73 (d, 2H, J= 8.4 Hz); IR (KBr) 3320, 2980, 1745, 1720, 1635, 1520, 1375, 1300, and 1200 cm-1.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17]>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:11](/[CH:12]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([F:14])=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=Cc1cc2ccc(F)cc2nc1Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C/c1cc2ccc(F)cc2nc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.7 %

Procedure:
To a solution of 2-chloro-7-fluoroquinoline-3-carboxaldehyde (6.3 g, 30 mmol) in dry THF (200 mL) under nitrogen was added titanium(IV) isopropoxide (17.0 g, 60 mmol) and the reaction mixture stirred at r.t. for 10 minutes. (R)-(−)-2-Methyl-2-propane-sulfinamide (3.6 g, 30 mmol) was added to the reaction mixture, which was stirred at r.t. for 72 h and partitioned between water (20 mL) and DCM (150 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo to give the title compound (7.2 g, 76%) as a pale yellow solid. δH (CDCl3) 9.09 (1H, s), 8.83 (1H, s), 7.96 (1H, dd, J=6.0 Hz), 7.69 (1H, d, J=7.2 Hz), 7.42 (1H, t, J=8.4 Hz), 1.32 (9H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:24]([N:31]=[C:32]=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[CH2:24]([NH:31][C:32]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:16][C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:11][CH2:12]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)NCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
To a cold (0° C.), stirred solution of COMPOUND 249 (69 mg, 0.22 mmol) in CH2Cl2 (2 mL) was added benzyl isocyanate (35 μL, 0.28 mmol). After 15 minutes, the cooling bath was removed and the reaction mixture was warmed to room temperature. After an additional 45 minutes, the mixture was concentrated under reduced pressure. Purification of the crude material by radial chromatography on silica gel (1 mm plate, 25:1:1 CH2Cl2-MeOH—NH4OH) provided 93 mg (87%) of COMPOUND 271 as a white solid. 1H NMR (CDCl3) δ 1.60-1.71 (m, 2H), 1.88-1.93 (m, 2H), 2.08 (s, 6H), 2.61-2.69 (m, 3H), 3.81 (s, 4H), 4.05 (d, 2H, J=12.9 Hz), 4.42 (d, 2H, J=5.4 Hz), 4.74 (br t, 1H, J=5.4 Hz), 7.08 (dd, 2H, J=7.5, 5.1 Hz), 7.25-7.38 (m, 7H), 8.34 (d, 2H, J=3.6 Hz); 13C NMR (CDCl3) δ 18.36, 27.35, 44.58, 45.30, 54.99, 57.83, 122.81, 127.47, 128.03, 128.87, 133.82, 138.45, 140.13, 146.20, 157.52, 157.83; ES-MS m/z 444 (M+H). Anal. Calcd. For C27H33N5O.0.4.CH2Cl2: C, 68.91; H, 7.13; N, 14.66. Found: C, 69.19; H, 7.37; N, 14.64.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH:12]1[C:20]#[N:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:29][NH:30][OH:31].Cl>CCO>[OH:31][N:30]([C:20](=[NH:21])[CH:12]1[CH2:13][C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:29]
Reactant: CNO
Reactant: N#CC1Cc2ccccc2N1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(O)C(=N)C1Cc2ccccc2N1C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
1-Benzyloxycarbonyl-2-cyanoindoline was added to a solution of triethylamine (2 eq.) and MeNHOH.HCl (2 eq.) in EtOH. After stirring overnight the reaction mixture was evaporated, dissolved in EtOAc, washed with water, dried over Na2SO4 and evaporated to afford the title compound.
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:20]=[C:19]([C:21](=[O:26])[NH:22][CH2:23][CH2:24][CH3:25])[CH:18]=[C:17]([Cl:27])[C:16]=1[C:28](Cl)=[O:29]>>[C:11]([NH:10][C:6]1[N:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:28]([C:16]3[C:17]([Cl:27])=[CH:18][C:19]([C:21]([NH:22][CH2:23][CH2:24][CH3:25])=[O:26])=[CH:20][C:15]=3[Cl:14])=[O:29])=[CH:2][NH:1][C:5]=12)(=[O:13])[CH3:12]
Reactant: CCCNC(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Reactant: CC(=O)Nc1nccc2cc[nH]c12
Product: CCCNC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3c(NC(C)=O)nccc23)c(Cl)c1

Procedure:
4-{[7-(Acetylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl]carbonyl}-3,5-dichloro-N-propylbenzamide was prepared from N-(1H-pyrrolo[2,3-c]pyridin-7-yl) acetamide and 2,6-dichloro-4-(1-propylcarbamoyl)benzene carbonyl chloride (Compound No. 15).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[CH:9][C:10]2[C:15]([CH:16]=1)=[C:14]([NH:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[N:13]=[CH:12][CH:11]=2)(=O)=O.[CH3:26][O:27][C:28]1[CH:34]=[C:33]([C:35]2[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=2)[CH:32]=[CH:31][C:29]=1[NH2:30]>>[CH:18]1([NH:17][C:14]2[C:15]3[C:10](=[CH:9][N:8]=[C:7]([NH:30][C:29]4[CH:31]=[CH:32][C:33]([C:35]5[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=5)=[CH:34][C:28]=4[O:27][CH3:26])[CH:16]=3)[CH:11]=[CH:12][N:13]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COc1cc(-c2cnn(C)c2)ccc1N
Reactant: O=S(=O)(Oc1cc2c(NC3CCCCC3)nccc2cn1)C(F)(F)F
Product: COc1cc(-c2cnn(C)c2)ccc1Nc1cc2c(NC3CCCCC3)nccc2cn1

Procedure:
The title compound was prepared according to Method 6 (Example 103) using 5-(cyclohexylamino)-2,6-naphthyridin-3-yl trifluoromethanesulfonate (Preparation 93) and 2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)aniline (Preparation 19) for 18 hours. The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM.