Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:26][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[C:4]([CH:27]2[CH2:30][N:29](C(=O)C(F)(F)F)[CH2:28]2)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH:29]1[CH2:30][CH:27]([C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:26][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:9])=[O:10])[CH2:28]1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2C2CN(C(=O)C(F)(F)F)C2)ccc2c1OCC1CC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2C2CNC2)ccc2c1OCC1CC21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.8 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-{4-fluoro-2-[1-(2,2,2-trifluoroacetyl)azetidin-3-yl]benzene-sulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 88, 0.294 g) and potassium carbonate (0.155 g) in methanol (5 mL) and water (0.5 mL) was stirred at room temperature for 45 minutes. The mixture was concentrated in vacuo and the residue was triturated with 10% methanol in DCM and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-40% to give methyl (1aRS,7bSR)-5-[2-(azetidin-3-yl)-4-fluoro-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.216 g) as a pale yellow foam.
Reaction SMILES: FC(F)(F)C(O)=[O:4].C([C@@H]1C(OC)=[N:15][C@@H:14]([CH2:19][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH3:22])[C:13]([O:29][CH3:30])=N1)(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O.C(#N)C>[CH3:30][O:29][C:13](=[O:4])[C@@H:14]([NH2:15])[CH2:19][C@@H:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:21][CH3:22]
Reactant: CC[C@@H](C[C@@H]1N=C(OC)[C@@H](C(C)C)N=C1OC)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC[C@@H](C[C@H](N)C(=O)OC)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of trifluoroacetic acid (3.4 ml) in water (440 ml) was added dropwise over 15 min a solution of (2R,5S)-2-isopropyl-3,6-dimethoxy-5-((S)-2-phenyl-butyl)-2,5-dihydro-pyrazine (4.69 g, 14.8 mmol) in acetonitrile (75 ml). The mixture was stirred overnight at room temperature then made basic by addition of saturated aqueous sodium carbonate solution and the mixture was extracted with ethyl acetate. The phases were separated and the organic phase was washed sequentially with water and with saturated brine, then dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, EtOAc/heptane) to yield a yellow oil (2.78 g, 85%); MS (ISP): 222.1 ([M+H]+).
Reaction SMILES: [OH-].[Na+].CO.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=O)=[CH:8][CH:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22]C#N)[CH:19]=[CH:20][CH:21]=1>O>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[C:10]([CH:11]=1)=[C:22]([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=1)[O:14][N:12]=2
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: N#CCc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Clc1cccc(-c2onc3ccc(Br)cc23)c1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
Sodium hydroxide (0.62 mol) was dissolved in methanol (100 mol) and the mixture was cooled till room temperature. 1-bromo-4-nitro-benzene (0.124 mol), followed by 3-chloro-benzeneacetonitrile (0.223 mol) were added dropwise, the temperature raised till 50° C. and the mixture was stirred at room temperature for one night. The mixture was poured into water and ice, the precipitate was filtered off, washed with water and extracted with DME and methanol. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The residue was taken up in diethylether, filtered off and dried, yielding 13.2 g (34.8%) of 5-bromo-3-(3-chlorophenyl)-2,1-benzisoxazole, mp. 163° C. (intermediate 1).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]([C:11](=O)[CH2:12]Br)=[N:8][CH:7]=1)=[O:5])C.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[C:21]([NH2:23])=[S:22])[CH3:16]>>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([C:21]2[S:22][CH:12]=[C:11]([C:9]3[NH:10][C:6]([C:4]([OH:3])=[O:5])=[CH:7][N:8]=3)[N:23]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH2:28][CH3:29])[CH3:16]
Reactant: CCOC(=O)c1cnc(C(=O)CBr)[nH]1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3ncc(C(=O)O)[nH]3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 5-ethoxycarbonyl-2-(α-bromoacetyl)imidazole and 3,4-diethoxythiobenzamide. Then, hydrolysis was conducted in the same manner as in Example 2 to obtain 2-(3,4-diethoxyphenyl)-4-(5-carboxy-2-imidazolyl)thiazole.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.O[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])([C:19]#[N:20])[C:17]#[N:18].O>C(Cl)(Cl)Cl>[F:7][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])([C:19]#[N:20])[C:17]#[N:18]
Reactant: N#CC(C#N)(CCCCCO)CCC(F)(F)F
Reactant: CCN(CC)S(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: N#CC(C#N)(CCCCCF)CCC(F)(F)F
Temperature: 25 °C
Reaction time: 9 h
Yield: 29.8 %

Procedure:
0.29 g of diethylaminosulfur trifluoride was dissolved in 5 ml of chloroform and thereto was added dropwise at 0° C. 0.40 g of 2-(5-hydroxypentyl)-2-(3,3,3-trifluoropropyl)malononitrile dissolved in 3 ml of chloroform. The mixture was stirred at room temperature for 9 hours. Thereafter, water was added to the reaction mixture, followed by extraction with methyl tert-butyl ether. The organic layer was washed successively with water, aqueous saturated sodium hydrogen carbonate and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.12 g of 2-(5-fluoropentyl)-2-(3,3,3-trifluoropropyl)malononitrile (hereinafter, referred to as the present compound (55)).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=2[OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].N1C=CC=CC=1>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][S:24]([CH2:23][Cl:22])(=[O:26])=[O:25])[C:15]=2[OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)CCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2O)CC1
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(NS(=O)(=O)CCl)c2O)CC1
Yield: 46.8 %

Procedure:
In a dry roundbottom flask, 4-(3-amino-2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (293 mg., 1 mmol) was dissolved in dry THF (3 mL) under nitrogen. While stirring, chloro-methanesulfonyl chloride (149 mg., 1 mmol) was added dropwise over 10 minutes and the solution was stirred 30 minutes. Pyridine (0.121 mL., 1.5 mmol) was then added dropwise over 5 minutes and the solution was stirred for 18 hours. The reaction mixture was diluted with 40 mL Et2O and washed with 40 mL of 10% aqueous HCl, 50 mL water, and 50 mL brine. The organic fraction was dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (20% to 40% EtOAc in hexanes) to give 190 mg of 4-(3-Chloromethanesulfonylamino-2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as an amber oil (45%). (M−H)−=404.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:7])[CH2:5][NH2:6].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:22]([C:24]1[CH:37]=[CH:36][C:27]([CH2:28][N:29]2[C:33]([CH:34]=O)=[CH:32][N:31]=[CH:30]2)=[CH:26][CH:25]=1)#[N:23].CCOC(C)=O>ClCCCl>[C:22]([C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]2[C:33]([CH2:34][NH:6][CH2:5][C:4]([O:3][CH3:2])=[O:7])=[CH:32][N:31]=[CH:30]2)=[CH:36][CH:37]=1)#[N:23]
Reactant: COC(=O)CN
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)CNCc1cncn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of glycine methyl ester hydrochloride (595 mg, 4.74 mmol) in 1,2-dichloroethane at 0° C. was added 4 Å powdered molecular sieves (3 g), followed by sodium triacetoxyborohydride (1.51 g, 7.1 mmol). The 1-(4-cyanobenzyl)-5-imidazolecarboxaldehyde from Step E of Example 1 (1.00 g, 4.74 mmol) was added, and the reaction was stirred overnight, allowing it to warm to room temperature. The reaction was poured into EtOAc, washed with sat. aq. NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting product was taken up in CH2Cl2, and propylamine (20 vol %) was added. The reaction was stirred for one hour, then concentrated in vacuo, and purified by silica gel chromatography (95:5; CHCl3:MeOH) to provide the titled amine product.
Reaction SMILES: [CH:1]1([N:7]([C:34](=[O:48])[CH2:35][CH2:36][NH:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=2[F:47])[CH2:8][CH2:9][N:10]([CH2:21][CH2:22][C:23]2[C:31]3[S:30][C:29](=[O:32])[NH:28][C:27]=3[C:26]([OH:33])=[CH:25][CH:24]=2)C(=O)OCC2C=CC=CC=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[BrH:49].C(O)(=O)C.C1(C)C=CC=CC=1>C(O)(=O)C>[BrH:49].[BrH:49].[CH:1]1([N:7]([CH2:8][CH2:9][NH:10][CH2:21][CH2:22][C:23]2[C:31]3[S:30][C:29](=[O:32])[NH:28][C:27]=3[C:26]([OH:33])=[CH:25][CH:24]=2)[C:34](=[O:48])[CH2:35][CH2:36][NH:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=2[F:47])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(OCc1ccccc1)N(CCc1ccc(O)c2[nH]c(=O)sc12)CCN(C(=O)CCNCCc1cccc(F)c1F)C1CCCCC1
Agent: Br
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: O=C(CCNCCc1cccc(F)c1F)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)C1CCCCC1
Reaction time: 1 h

Procedure:
A solution of the carbamate from step (i) (0.4 g) in acetic acid (2 mL) was treated with hydrogen bromide/acetic acid (33%, 2 mL) and stirred for 1 h. Toluene (10 mL) was added, the mixture was evaporated in vacuo, the residue purified by reverse phase HPLC with 0.2% aqueous TFA/acetonitrile as eluent and the pure fractions evaporated in vacuo. The solid residue was dissolved in a mixture of ethanol (5 mL) and acetonitrile (15 mL) and treated with hydrobromic acid in aqueous acetonitrile (16%, 1.8 mL). A solid gradually precipitated and was filtered off, washed with acetonitrile and slurried in ethanol. The solid was filtered off, washed with a little ethanol and dried to afford the title product (0.036 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[S:11]([C:15]1[CH:16]=[C:17]([NH:21][C:22]([C:24]2[C:25](ON3C4=NC=CC=C4N=N3)=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:23])[CH:18]=[CH:19][CH:20]=1)(=[O:14])(=[O:13])[NH2:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:25]2[C:24]([C:22]([NH:21][C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([S:11](=[O:13])(=[O:14])[NH2:12])[CH:16]=3)=[O:23])=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=2)=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: NS(=O)(=O)c1cccc(NC(=O)c2cc3ccccc3nc2On2nnc3cccnc32)c1
Reactant: COc1cc(F)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Oc1nc2ccccc2cc1C(=O)Nc1cccc(S(N)(=O)=O)c1
Temperature: 90 °C
Yield: 34 %

Procedure:
4-Fluoro-2-methoxy-phenol (6.17 μL, 0.05 mmol), N-(3-sulfamoylphenyl)-2-(triazolo[4,5-b]pyridin-3-yloxy)quinoline-3-carboxamide (25 mg, 0.05 mmol) and K2CO3 (22.46 mg, 0.16 mmol) were combined in DMF (0.5 mL) and heated at 90° C. for 1 h. The reaction was diluted with DMF (0.5 mL), filtered, and purified by reverse phase HPLC (30-99% CH3CN/5 mM aqueous HCl) to provide 2-(4-fluoro-2-methoxy-phenoxy)-N-(3-sulfamoylphenyl)quinoline-3-carboxamide (61) (7.95 mg, 30%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 8.73 (s, 1H), 8.40-8.35 (m, 1H), 8.07 (dd, J=7.8, 1.6 Hz, 1H), 7.88 (td, J=4.4, 2.1 Hz, 1H), 7.72 (ddd, J=8.4, 6.9, 1.5 Hz, 1H), 7.64-7.52 (m, 4H), 7.42 (s, 2H), 7.38 (dd, J=8.9, 6.0 Hz, 1H), 7.12 (dd, J=10.8, 2.9 Hz, 1H), 6.87 (td, J=8.5, 2.9 Hz, 1H), 3.70 (s, 3H), 8.76-8.68 (m, 1H) ppm. ESI-MS m/z calc. 467.09, found 468.3 (M+1)+; Retention time: 1.78 minutes (3 minutes run).
Reaction SMILES: C(OC(=O)C[N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[N:14]=1)(C)(C)C.F[C:22](F)(F)[C:23]([OH:25])=[O:24]>ClCCl>[F:19][C:15]1([CH2:22][C:23]([OH:25])=[O:24])[CH:16]=[CH:17][CH:18]=[C:13]([C:9]2[NH:8][CH:12]=[CH:11][N:10]=2)[NH:14]1
Reactant: CC(C)(C)OC(=O)Cn1ccnc1-c1cccc(F)n1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CC1(F)C=CC=C(c2ncc[nH]2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of [2-(6-fluoropyridin-2-yl)-imidazol-1-yl]acetic acid tert-butyl ester (630 mg; 2.27 mmol) and trifluoroacetic acid (4 mL) in dichloromethane (4 mL) is stirred at room temperature for 5 hr. The reaction mixture is concentrated. The residue is treated with 3M HCl in ethyl acetate (10 mL) and the suspension stirred at room temperature for 1 hr. The precipitate is collected, washed with ethyl acetate, and dried to give 2-Fluoro-6-(1H-imidazol-2-yl)-pyridine acetic acid as a tan solid (581 mg), 1H NMR (d6DMSO) δ 8.35-8.26 (m, 2H), 7.83 (s, 1H), 7.76 (s, 1H), 7.44-7.41(m. 1H), 5.40 (s, 2H). LCMS: 222.1 (MH+).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[OH:14][CH2:15][CH:16]1[CH2:19][C:18]([CH2:42][C:43]#[N:44])([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:17]1.C(N(CC)CC)C>>[CH:15]([CH:16]1[CH2:17][C:18]([CH2:42][C:43]#[N:44])([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:41])[CH3:40])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:19]1)=[O:14]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CO)C4)c3)ncnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(C=O)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
Dimethyl sulfoxide (0.194 mL, 0.00274 mol) was added to a solution of oxalyl chloride (0.145 mL, 0.00171 mol) in methylene chloride (6.384 mL, 0.09959 mol) at −78° C. After 10 min, 3-(hydroxymethyl)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.500 g, 0.00114 mol) in methylene chloride (12.77 mL, 0.1992 mol) was added and the resultant mixture was stirred at −78° C. for 30 min. Triethylamine (0.794 mL, 0.00570 mol) was then added and the mixture was stirred for 5 h with the temperature allowed to gradually warm up to rt. After quenching with water, the mixture was extracted with methylene chloride. The organic layers were combined, washed with brine, dried and evaporated to dry. The residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexane, to give the desired aldehyde (430 mg, 86%). LCMS calculated for C22H29N6O2Si(M+H)+: 437.2; Found: 437.4.
Reaction SMILES: [N:1]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:34])[CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[NH2:33])[CH2:22][CH2:21]3)=[CH:13][CH:12]=2)=[N:3][CH:2]=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[N:1]1[C:6]2[CH2:7][CH2:8][CH2:9][C:5]=2[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17](=[O:34])[CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[NH:33][C:35](=[O:37])[CH3:36])[CH2:22][CH2:21]3)=[CH:13][CH:12]=2)=[N:3][CH:2]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1CN1CCC(CCC(=O)c2ccc(Nc3ncnc4c3CCC4)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccccc1CN1CCC(CCC(=O)c2ccc(Nc3ncnc4c3CCC4)cc2)CC1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
To 0.17 g of N-(5,6-dihydro-7H-cyclopenta[d]pyrimidin-4-yl)-4-(3-[1-(2-aminobenzyl)piperidin-4-yl]propanoyl)aniline were added 30 ml of chloroform, 1 ml of acetic anhydride and 0.38 g of 4-dimethylaminopyridine, and the mixture was stirred at 50° C. for 10 minutes. Then, the solvent was removed by distillation under reduced pressure and the obtained residue was applied to silica gel column chromatography to obtain 0.06 g of the title compound as white crystal.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9](=[O:14])[N:8]3[CH2:15][CH2:16][O:17][C:7]3([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[N:10]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:9](=[O:14])[N:8]3[CH2:15][CH2:16][O:17][C:7]3([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: BrCc1ccccc1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2C2(c3ccccc3)OCCN12
Agent: [H-]
Agent: [Na+]
Product: O=C1N(Cc2ccccc2)c2ccc([N+](=O)[O-])cc2C2(c3ccccc3)OCCN12
Temperature: 60 °C
Yield: 83.4 %

Procedure:
To a solution of 0.93 g of 9-nitro-2,3,6,10b-tetrahydro-10b-phenyl-5H-oxazolo[3,2-C]quinazolin-5-one in 10 ml. of dimethylfomamide was added 0.18 g of 52.9% sodium hydride. The mixture was stirred with heating at 60°C for 1 hr. then, 0.68 g of benzyl bromide was added thereto. The resulting mixture was heated at 100°C for 4 hours. After cooling, the reaction mixture was poured into 50 ml. of water and the resulting precipitates were collected by filtration, washed with water and dried. The crude product was recrystallized from a mixture of methanol and carbon tetrachloride to give 1.0 g of 9-nitro-2,3,6,10b-tetrahydro-6-benzyl-10b-phenyl-5H-oxazolo[3,2-C]quinazolin-5-one as yellowish brown prisms, having a melting point of 96°-98°C (decomp.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[CH:2].Cl.[O-]S([O-])(=O)=O.[Mg+2].CC(C)([O-])C.[Na+].Br[C:23]1[C:31]2[NH:30][C:29]3[CH2:32][CH2:33][N:34]([CH3:36])[CH2:35][C:28]=3[C:27]=2[CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>O1CCOCC1.C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:36][N:34]1[CH2:33][CH2:32][C:29]2[NH:30][C:31]3[C:23]([C:2]#[C:1][C:3]4[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=4)=[CH:24][CH:25]=[CH:26][C:27]=3[C:28]=2[CH2:35]1
Reactant: CN1CCc2[nH]c3c(Br)cccc3c2C1
Reactant: C#Cc1ccncc1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN1CCc2[nH]c3c(C#Cc4ccncc4)cccc3c2C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Bis(tri-t-butylphosphino)palladium (58 mg, 0.11 mmol; Aldrich), 4-ethynylpyridine, hydrochloric acid (316 mg, 2.26 mmol; Aldrich), MgSO4 (340 mg, 2.83 mmol), sodium t-butoxide (272 mg, 2.83 mmol; Aldrich), the product of Example 1A (300 mg, 1.131 mmol) and triethylamine (0.40 mL, 2.83 mmol) were suspended in dioxane (10 mL). The mixture was purged with a nitrogen stream for 2 minutes, then stirred under nitrogen at 100° C. for 2 hours in a sealed tube. The mixture was cooled to room temperature, filtered though a glass microfiber frit, rinsed with CH3OH (5 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 40-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.56 (s, 3H), 2.90 (t, J=5.8 Hz, 2H), 2.99 (t, J=5.5 Hz, 2H), 3.69 (s, 2H), 7.00-7.06 (m, 1H), 7.29 (dd, J=7.6, 0.9 Hz, 1H), 7.46 (dd, J=7.9, 0.9 Hz, 1H), 7.61-7.66 (m, 2H), 8.53-8.57 (m, 2H); MS (APCI) m/z 288 (M+H)−.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][NH:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH3:2].[NH2:24][CH2:25][C@@H:26]([C:28]1[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[OH:27]>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][NH:7][C:8](=[O:22])[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([NH:24][CH2:25][C@H:26]([OH:27])[C:28]3[CH:29]=[CH:30][C:31]([OH:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=3)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)CCNC(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: CCOC(=O)CCNC(=O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from 3-[4-(4-oxo-piperidine-1-yl)-benzoylamino]-propionic acid ethyl ester (which was obtained in Example 158) and N-[5-((1R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 179 as a white solid; mp >95° C. (decomposed); 1H NMR (300 MHz, DMSO-d6) δ 1.17 (t, J=7.1 Hz, 3H), 1.40-1.60 (m, 2H), 1.90-2.10 (m, 2H), 2.54 (t, J=7.0 Hz, 2H), 2.70-2.95 (m, 5H), 2.94 (s, 3H), 3.35-3.50 (m, 2H), 3.80-3.95 (m, 2H), 4.05 (q, J=7.1 Hz, 2H), 4.65-4.75 (m, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.95 (d, J=8.9 Hz, 2H), 7.05 (dd, J=8.2, 1.9 Hz, 1H), 7.22 (d, J=1.9 Hz, 1H), 7.69 (d, J=8.9 Hz, 2H), 8.26 (t, J=5.2 Hz, 1H); MS (ES) m/z: 549.2 (MH+); HRMS Calcd. for C26H37N4O7S(MH+): 549.2377. Found: 549.2369.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:17][C:18]1[CH:19]=[C:20]([N:25]=[C:26]=S)[CH:21]=[CH:22][C:23]=1[F:24].CN(C)CCCN=C=NCC>>[F:17][C:18]1[CH:19]=[C:20]([NH:25][C:26]2[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:16]=2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: Nc1ccccc1Nc1ccc(F)c(F)c1
Reactant: Fc1ccc(N=C=S)cc1F
Agent: CCN=C=NCCCN(C)C
Product: Fc1ccc(Nc2nc3ccccc3n2-c2ccc(F)c(F)c2)cc1F

Procedure:
The title compound was prepared by Procedure G from N-(3,4-difluorophenyl)-benzene-1,2-diamine (Scheme 5), 3,4-difluorophenyl isothiocyanate and, in the last step, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The reaction mixture was evaporated to dryness and the remaining crude product purified by preparative LCMS to give the title compound as the free base (solid, mp 115-117° C.). MS(ES+) m/z 358 ([M+1]+, 100).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[NH:13][CH2:12][CH:11]([CH2:14][CH3:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[F:24][C:25]([F:33])([F:32])[CH:26]([CH3:31])[CH2:27][C:28](Cl)=[O:29].[OH-].[Na+]>C(Cl)Cl.O>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]2[N:13]([C:28](=[O:29])[CH2:27][CH:26]([C:25]([F:33])([F:32])[F:24])[CH3:31])[CH2:12][CH:11]([CH2:14][CH3:15])[O:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(CC(=O)Cl)C(F)(F)F
Reactant: CCC1CNC(c2cccc(C(F)(F)F)c2)O1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCC1CN(C(=O)CC(C)C(F)(F)F)C(c2cccc(C(F)(F)F)c2)O1
Reaction time: 8 h

Procedure:
Three and eight-tenths grams of 2-(m-trifluoromethylphenyl)-5-ethyl-1,3-oxazolidine was combined with 1.3 g of pyridine in 25 ml of methylene chloride and 2.7 g of 3-trifluoromethylbutyroyl chloride in 10 ml of methylene chloride was added dropwise with stirring. The mixture was allowed to stand overnight and was stand overnight and was worked up with 50 ml of 5% NaOH and 200 ml of water. The mixture was dried and stripped under vacuum on the rotary evaporator. The structure was confirmed by NMR and infrared spectroscopy.