Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[NH2:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18]>C(OCC)(=O)C>[CH3:12][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([NH:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[CH:3]=1
Reactant: N#Cc1cccc(N)c1
Reactant: COc1ccc([N+](=O)[O-])c(F)c1
Solvent: CCOC(C)=O
Product: COc1ccc([N+](=O)[O-])c(Nc2cccc(C#N)c2)c1

Procedure:
2 g of 3-fluoro-4-nitroanisole and 15 ml of 3-aminobenzonitrile were stirred for 65 hours at 140° C. The batch was then diluted with ethyl acetate, washed three times with water and once with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum, and the residue was chromatographed on silica gel.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[Cl:11]N1C(=O)CCC1=O>CC#N>[Cl:11][C:10]1[C:2](=[O:1])[NH:3][CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1ccc(O)nc1
Solvent: CC#N
Product: O=C(O)c1c[nH]c(=O)c(Cl)c1
Temperature: 80 °C

Procedure:
To a solution of 6-hydroxy nicotinic acid (0.500 g, 3.59 mmol, TCI) in MeCN (20 mL), was added N-chlorosuccinimide (0.436 mL, 5.39 mmol, Aldrich). The resulting mixture was then heated at 80° C. for 72 h. A white precipitate was present. The mixture was filtered and the white solid was washed with EtOAc (2×1 mL) and dried in vacuo to afford the title compound as a white solid. MS (ESI, positive ion) m/z: 174, 176 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][CH2:19][NH2:20].[OH-].[NH4+]>O>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[CH:4][CH:3]=[C:2]2[NH:20][CH2:19][CH2:18][C:14]1[S:13][CH:17]=[CH:16][CH:15]=1
Reactant: Fc1cccc2c(Cl)ccnc12
Reactant: NCCc1cccs1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc2c(NCCc3cccs3)ccnc12
Yield: 33.3 %

Procedure:
A mixture of 2.0 g of 4-chloro-8-fluoroquinoline and 2.8 g of 2-(2-thienyl)ethyl amine was heated under nitrogen to 160°-165° C. for two hours, then cooled and combined with 200 mL of a 50:50 mixture of ammonium hydroxide and water. The product was extracted into CH2Cl2, which was then concentrated to dryness. The residue was recrystallized from pentane/CH2Cl2 to give 1.0 g of the title product. Yield 34.5%. M.P. 157°-158° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH2:17][C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[N:14][C:13]=2[CH:37]=1)#[N:8].C1OCCOCCOCCOCCOCCOC1.Br[CH2:57][C:58]([O:60][CH3:61])=[O:59]>C1COCC1>[C:7]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([C:18]3[C:26]([O:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:57][C:58]([O:60][CH3:61])=[O:59])=[N:14][C:13]=2[CH:37]=1)#[N:8]
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1Cc1nc2cc(C#N)ccc2o1
Reactant: COC(=O)CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CC(c1nc2cc(C#N)ccc2o1)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C
Reaction time: 0.25 h

Procedure:
To a mixture of potassium tert-butoxide (108 mg, 0.958 mmol) in THF (0.715 mL) at −78° C. under nitrogen was added tert-butyl 4-((5-cyanobenzo[d]oxazol-2-yl)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 144-A) (200 mg, 0.479 mmol) in THF (4.3 mL) under nitrogen. After stirring for 15 min a solution of 18-crown-6 (12.66 mg, 0.048 mmol) in THF (1.430 mL) was added to the mixture at the same temperature and stirred for another 15 min. Then a solution of methyl bromoacetate (0.618 mL, 6.71 mmol) in THF (0.715 mL) was degassed and added dropwise and stirred at the same temp for 10 min. The reaction mixture was quenched with a saturated solution of ammonium chloride, extracted with EtOAc (2×), passed through a phase separator and concentrated to give the title compound. MS (ESI+) m/z 490.32 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([N:24]([C:32]2[N:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][N:33]=2)C(=O)OC(C)(C)C)[CH:8]=[C:9]([C:11]2[S:15][C:14]([N:16]3[CH2:22][CH2:21][CH2:20][NH:19][C:18](=[O:23])[CH2:17]3)=[N:13][CH:12]=2)[CH:10]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[O:23]=[C:18]1[NH:19][CH2:20][CH2:21][CH2:22][N:16]([C:14]2[S:15][C:11]([C:9]3[CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[C:7]([NH:24][C:32]4[N:37]=[C:36]([C:38]([F:39])([F:41])[F:40])[CH:35]=[CH:34][N:33]=4)[CH:8]=3)=[CH:12][N:13]=2)[CH2:17]1
Reactant: CC(=O)Nc1cc(-c2cnc(N3CCCNC(=O)C3)s2)cc(N(C(=O)OC(C)(C)C)c2nccc(C(F)(F)F)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(N3CCCNC(=O)C3)s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.1 %

Procedure:
To a solution of tert-butyl {3-(acetylamino)-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}[4-(trifluoromethyl)pyrimidin-2-yl]carbamate (79 mg, 0.134 mmol) in dichloromethane (1 mL) at room temperatrue, under nitrogen, was added trifluoroacetic acid (1 mL, 13 mmol). The mixture was stirred at room temperature for 1 h and concentrated to dryness. The residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The solid product precipitated in the two phases. The organic layer was concentrated to dryness and the residue was transferred into the aqueous with a small amount of EtOH. The resulting aqueous suspension was filtered, the solids collected, and washed with water, a small amount of ethanol, then hexane, and dried to afford 48 mg (0.098 mmol, 73% yield) of N-(3-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)acetamide as an off-white solid. MS APCI: [M+H]+ m/z 492.1. 1H NMR (400 MHz, d6-dmso): δ 10.25 (s, 1H); 9.98 (s, 1H); 8.82 (d, J=4.9 Hz, 1H); 7.75 (m, 2H); 7.61 (br t, J=5.0 Hz, 1H); 7.43-7.37 (m, 2H); 7.28 (d, J=4.9 Hz, 1H); 4.19 (s, 2H); 3.81 (m, 2H); 3.24 (m, 2H); 2.05 (s, 3H); 1.80 (m, 2H). rhSyk=+++.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15](F)[CH2:16][CH:17]([F:26])[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CS(C)=O>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15]([NH:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH:17]([F:26])[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: O=C(c1ccccc1)C(F)CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccccc1)C(F)CC(NCc1ccccc1)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reaction time: 8 h

Procedure:
A mixture of γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone hydrochloride (4.0 g), benzylamine (20.0 g) and dimethylsulfoxide (100 ml) was stirred at 70° to 80°C for 8 hours. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was sufficiently washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Treatment of the residue with ethanol afforded γ-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]-4-benzylamino-2-fluorobutyrophenone. M.P. 158° - 165°C. IR νmaxNujol 3350, 1650 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[CH2:9][C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:5]2=[CH:4][CH:3]=1.C(O)C.[ClH:28]>[Fe].O>[ClH:1].[ClH:28].[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[N:8]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:7]=2)[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:9]1
Reactant: O=[N+]([O-])c1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccccc1N1CC2(CCNCC2)c2ccc(Cl)cc21

Procedure:
A mixture of 2.1 g of 6-chloro-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine], free base of Example 33, 95 ml of 95% ethyl alcohol, 7.5 ml of water and 4.4 g of iron powder is acidified with 0.2 ml of concentrated hydrochloric acid and then refluxed under nitrogen for 10 minutes. Thereafter, the mixture is permitted to cool before being filtered through celite. The filtrate is concentrated under vacuum leaving an oily residue which is basified. The alkaline mixture is extracted with ether and then dried. The product is converted to a solid dihydrochloric acid salt which is recrystallized from a methyl alcohol-ether mixture to provide off-white prisms, mp 270°-273° C. (after darkening) of 1-(2-aminophenyl)-6-chlorospiro[indoline-3,4'-piperidine]dihydrochloride.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][NH:10][CH2:11][CH2:12][N:13]2[CH:22]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14]2)=[CH:7][CH:6]=1)=[O:4].Cl>[OH-].[Na+].C(O)C>[F:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][CH:22]2[CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][N:13]2[CH2:12][CH2:11][NH:10][CH2:9][C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:32][CH:31]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(CNCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc(CNCCN2Cc3ccccc3CC2Cc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 68.9 %

Procedure:
9 mg of N-(4-methoxycarbonylbenzyl)-2-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethanamine obtained in Example 108 was dissolved in 1 mL of 2.5 N aqueous sodium hydroxide solution and 1 mL of ethanol, followed by stirring at 0° C. for 3 hours. After completion of the reaction, 2N hydrochloric acid was added to the reaction liquid, followed by extraction with chloroform, and the organic layer was then washed with saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 6 mg (yield 76%) of a title compound as a pale yellow oily substance.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[OH:35].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[O:35][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=1
Reactant: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Oc1cccc(Cl)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1cccc(OCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1Cl
Temperature: 80 °C
Yield: 66.5 %

Procedure:
To a stirred solution of 4-chloromethyl-1-trityl-1H-imidazole (400 mg; CAS 103057-10-9) at r.t. in DMF (5 ml) under an argon atmosphere were added 2,3-dichlorophenol (273 mg) and K2CO3 (385 mg). The reaction mixture was heated to 80° C. for 5 hours, then cooled to r.t., diluted with EtOAc and washed with 1 N NaOH. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 1:1) to give 4-(2,3-dichloro-phenoxymethyl)-1-trityl-1H-imidazole (360 mg) as white solid. MS (ISP): 243.3 ([Trt]+)
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[O:9][CH2:10][C:4]=2[C:3]=1[OH:18].C([O-])([O-])=O.[Cs+].[Cs+].[C:25](=O)([O:41]C1C=CC([N+]([O-])=O)=CC=1)[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([O:37][N+:38]([O-:40])=[O:39])[CH2:32][O:33][N+:34]([O-:36])=[O:35]>CN(C=O)C.O>[C:25](=[O:41])([O:18][C:3]1[C:4]2[CH2:10][O:9][CH:8]([C:11]3[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=3)[C:5]=2[CH:6]=[N:7][C:2]=1[CH3:1])[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH:31]([O:37][N+:38]([O-:40])=[O:39])[CH2:32][O:33][N+:34]([O-:36])=[O:35]
Reactant: O=C(OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ncc2c(c1O)COC2c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncc2c(c1OC(=O)OCCCCC(CO[N+](=O)[O-])O[N+](=O)[O-])COC2c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of cicletanine (120 mg, 0.55 mmol) in DMF (10 mL) was added Cs2CO3 (373 mg, 1.15 mmol) and followed by 5,6-bis(nitrooxy)hexyl 4-nitrophenyl carbonate (210 mg, 0.54 mmol). The mixture was stirred at rt over night and diluted with H2O, extracted with CH2Cl2 and the organic layer was washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (Biotage SP1; column 25M; TLC method: n-hexane/ethyl acetate 5/5; Rf=0.35), affording product. 1H NMR (500 MHz, CDCl3) δ 8.08 (s, 1H), 7.36-7.27 (m, 4H), 6.21 (s, 1H), 5.34 (m, 1H), 5.26 (m, 1H), 5.13 (m, 1H), 4.77 (m, 1H), 4.48 (m, 1H), 4.32 (m, 2H), 2.51 (s, 3H), 1.84 (m, 4H), 1.69-1.55 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9]([CH3:11])=[O:10])=[CH:6][C:5]([N+:12]([O-])=O)=[C:4]([CH3:15])[CH:3]=1.[H][H].[S]>C(O)C.[Ni]>[CH3:15][C:4]1[C:5]([NH2:12])=[CH:6][C:7]([NH:8][C:9]([CH3:11])=[O:10])=[C:2]([CH3:1])[CH:3]=1
Reactant: CC(=O)Nc1cc([N+](=O)[O-])c(C)cc1C
Reactant: [H][H]
Agent: [Ni]
Agent: [S]
Solvent: CCO
Product: CC(=O)Nc1cc(N)c(C)cc1C

Procedure:
2,4-Dimethyl-5-nitroacetanilide (20.8 g., 100 mmole) in ethanol (400 ml.) was reduced over Raney nickel at about 45 psi of hydrogen gas. After the hydrogen uptake was complete, the mixture was deactivated with elementary sulfur, filtered, and the filtrate was evaporated under reduced pressure to give the product as a solid, m.p. 163°-164° C.
Reaction SMILES: [S:1]1[CH2:5][C@@H:4]([C:6]([OH:8])=[O:7])[NH:3][CH2:2]1.CCN(C(C)C)C(C)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>CN(C=O)C>[CH2:22]([O:21][C:19]([N:3]1[C@H:4]([C:6]([OH:8])=[O:7])[CH2:5][S:1][CH2:2]1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1CSCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)[C@@H]1CSCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
(R)-Thiazolidine-4-carboxylic acid (309.9 mg, 2.33 mmol) was dissolved in DMF (10 mL) and distilled water (10 mL). The solution was cooled to 0° C., and DIEA (0.590 mL, 3.39 mmol) was added followed by benzyl chloroformate (0.485 mL, 3.40 mmol). The reaction was stirred at 0° C. and allowed to warm to ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:18]3[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:25])=[N:12][O:13][C:14]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[CH:4][C:3]=1[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([C:36]([O:38]C)=[O:37])=[CH:31][CH:30]=[CH:29]2.C1COCC1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:11]([C:18]3[C:19]([Cl:25])=[CH:20][CH:21]=[CH:22][C:23]=3[Cl:24])=[N:12][O:13][C:14]=2[CH:15]([CH3:17])[CH3:16])[CH:5]=[CH:4][C:3]=1[C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[C:32]([C:36]([OH:38])=[O:37])=[CH:31][CH:30]=[CH:29]2
Reactant: COC(=O)c1cccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3Cl)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cccc3c2)c(Cl)c1
Temperature: 65 °C
Yield: 42.7 %

Procedure:
A solution of methyl 6-[2-chloro-4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylate (0.36 g, 0.62 mmol), 6.5 mL of THF, 3.5 mL of methanol and 1.3 mL of 1 N NaOH was stirred for 18 h at rt. The reaction mixture was heated to 65° C. for 2 hours. The solution was allowed to cool to room temperature and the pH was adjusted with 1N HCl. The solution was concentrated and the residue was extracted with ethyl acetate. The organic layer was dried with MgSO4, filtered, and the filtrate was concentrated to give the crude product as oil. The crude material was purified by flash chromatography (silica gel, gradient hexane to hexanes/ethyl acetate, 1:1) to afford the title compound as a white foam (0.15 g, 67%). 1H NMR (DMSO-d6): δ 13.13 (s, 1H), 8.87 (d, J=9 Hz, 1H), 8.19-8.14 (m, 2H), 7.97 (m, 1H), 7.64-7.53 (m, 5H), 7.36 (d, J=9 Hz, 1H), 7.04 (m, 1H), 6.86-6.84 (m, 1H), 4.92 (s, 2H), 3.48 (septet, J=7 Hz, 1H), 1.33 (d, J=7 Hz, 6 H). HRMS C30H22Cl3NO4 m/z 566.0693 (M+H)+Cal; 566.0687 (M+H)+Obs.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][P:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([O:21][CH3:22])[CH:15]=1)(=[O:12])[O:6][CH2:7][C:8]([F:11])([F:10])[F:9].Cl[C:26]1[N:31]=[C:30]([NH:32][C:33]2[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=2[C:35]([NH:37][CH3:38])=[O:36])[C:29]([C:43]([F:46])([F:45])[F:44])=[CH:28][N:27]=1>>[F:24][C:2]([F:1])([F:23])[CH2:3][O:4][P:5]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:26]2[N:31]=[C:30]([NH:32][C:33]3[CH:42]=[CH:41][CH:40]=[CH:39][C:34]=3[C:35](=[O:36])[NH:37][CH3:38])[C:29]([C:43]([F:46])([F:44])[F:45])=[CH:28][N:27]=2)=[C:16]([O:21][CH3:22])[CH:15]=1)(=[O:12])[O:6][CH2:7][C:8]([F:9])([F:10])[F:11]
Reactant: COc1cc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)ccc1N
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)cc2OC)ncc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedure for Example 102 bis(2,2,2-trifluoroethyl)(4-amino-3-methoxybenzyl)phosphonate (Compound 114A, 38 mg, 0.1 mmol) and 2-(2-chloro-5-(trifluoromethyl)pyrimidin-4-ylamino)-N-methylbenzamide (33 mg, 0.1 mmol). The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to afford the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ=2.73 (s, 3 H), 3.52 (d, J=21.6 Hz, 2 H), 3.73 (s, 3 H), 4.60-4.65 (m, 4 H), 6.81 (d, J=7.6 Hz, 1 H), 6.98 (s, 1 H), 7.05 (t, J=7.6 Hz, 1 H), 7.34 (t, J=7.2 Hz, 1 H), 7.57 (d, J=8.0 Hz, 1 H), 7.65 (dd, J=1.2, 7.6 Hz, 1 H), 8.34 (s, 1 H), 8.38 (s, 1 H), 8.68 (d, J=4.4 Hz, 1 H), 8.71 (s, 1 H), 11.42 (s, 1 H). MS (ES+): m/z 676.05 [MH+]; HPLC: tR=3.69 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:33]([O:32][C:30]([N:26]1[CH2:27][CH2:28][CH2:29][C@H:24]([NH:23][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:25]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 110 °C
Yield: 84.9 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.6769 g, 2.004 mmol), (S)-3-amino-1-Boc-piperidine (0.4269 g, 2.132 mmol), and diisopropylethylamine (0.45 mL, 2.6 mmol) in propan-2-ol (12 ml) was heated in a microwave reactor at 110° C. for 20 minutes. The solvent was evaporated in vacuo and then purified by column chromatography on silica gel (gradient: 0 to 30% ethyl acetate in heptanes) affording 853.7 mg (85%) of (S)-3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester. LCMS (Method F, ESI): RT=1.19 min, m+H=502.3.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:39][C:38]1[CH:42]=[CH:43][C:35]([Cl:34])=[CH:36][CH:37]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Br)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc(Cl)cc3)c3c(Br)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The titled compound was prepared from 4-bromo-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 22-(1) and 4-chlorobenzoyl chloride in a manner similar to Example 27 as a colorless powder. APCI-Mass m/Z 482/484 (M+H). 1H-NMR (DMSO-d6) δ 3.21-3.28 (m, 1H), 3.33-3.39 (m, 3H), 3.62-3.71 (m, 2H), 4.28 (s, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.11 (d, J=5.3 Hz, 1H), 5.17 (d, J=5.1 Hz, 1H), 5.23 (d, J=5.8 Hz, 1H), 5.41 (d, J=9.0 Hz, 1H), 7.04 (t, J=7.9 Hz, 1H), 7.19-7.24 (m, 3H), 7.30-7.35 (m, 2H), 7.33 (brs, 1H), 7.60 (d, J=8.3 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23]([CH:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]1)=[O:24])[NH2:22].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23]([CH:25]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26]1)=[O:24])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.304 g, 1.10 mmol) in DCM (20.0 mL) were added tert-butyl 3-(hydrazinecarbonyl)pyrrolidine-1-carboxylate 221 (0.380 g, 1.65 mmol), 1-hydroxybenzotriazole (0.223 g, 1.65 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.315 g, 1.65 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, concentrated to provide a residue which was subjected to chromatography to give 222 (0.48 g, slightly impure) as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH3:12])[C:3]=1[NH2:13].[N:14]#[C:15]Br>CO>[NH2:14][C:15]1[NH:13][C:3]2[C:4]([CH3:12])=[C:5]([N+:9]([O-:11])=[O:10])[C:6]([CH3:8])=[CH:7][C:2]=2[N:1]=1
Reactant: N#CBr
Reactant: Cc1cc(N)c(N)c(C)c1[N+](=O)[O-]
Solvent: CO
Product: Cc1cc2nc(N)[nH]c2c(C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1,2-diamino-3,5-dimethyl-4-nitrobenzene (0.87 g, 4.83 mmol) and cyanogen bromide (0.87 g, 7.73 mmol) in methanol (50 mL) is stirred at room temperature for 16 hours. The mixture is rotary evaporated to afford 2-amino-4,6-dimethyl-5-nitrobenzimidazole. The product is used in the next step without further purification.