Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[F:24][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:25])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(NCc2c(-c3cccc(F)c3)noc2C)nc1
Reactant: CC(C)N
Product: Cc1onc(-c2cccc(F)c2)c1CNc1ccc(C(=O)NC(C)C)cn1
Yield: 33 %

Procedure:
As described for example 168, 6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinic acid methyl ester (85 mg, 0.25 mmol) was converted using isopropylamine instead of 2,2,2-trifluoroethylamine to the title compound (30 mg, 33%) which was obtained as an off white foam. MS: m/e=369.1 [M+H]+.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N:19]2[CH2:24][CH2:23][N:22]([C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: C1CCC(N2CCNCC2)CC1
Product: CCCCCCC/C=C/C(=O)N1CCN(C2CCCCC2)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-cyclohexylpiperazine as starting raw materials, to produce an intended compound.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:38]3[CH:39]=[C:34]([CH3:33])[CH:35]=[CH:36][CH:37]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)c1
Yield: 81 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 3-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (81%).
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)=[O:5].[C:18]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>CO.C(OCC)(=O)C>[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:18]([CH3:20])([CH3:19])[CH3:21])=[CH:23][CH:24]=1
Reactant: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2C(=O)NCCc2ncc[nH]2)cc1
Yield: 64.5 %

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 6B using 1.50 g (0.00651 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)ethyl]benzamide, prepared as in Example 6A, and 2.61 g (0.01302 mol) of p-tert-butylbenzoyl chloride, with the exception that after reducing the initial reaction mixture to dryness, the resultant residue was dissolved in methanol and heated at reflux for 30 minutes. The methanol solution was then reduced to dryness under reduced pressure and the resultant residue was dissolved in an ethyl acetate/aqueous sodium bicarbonate mixture. The resulting layers were separated and the organic layer was washed with a saturated sodium chloride solution, dried with anhydrous sodium sulfate and reduced to dryness under reduced pressure to provide a yellow oil. This oil was purified by twice crystallizing the material from diethyl ether containing a small amount of ethyl acetate to provide 1.64 g of the desired titled compound (m.p. 127°-132° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=3)[CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[C:7]([CH3:35])[C:6]=2[CH:36]=1.C(N(CC)CC)C.[CH2:44]([N:46]=[C:47]=[O:48])[CH3:45]>O1CCCC1>[CH:11]1([CH:10]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([N:26]([CH3:34])[CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:25])=[CH:20][CH:19]=2)[C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:47](=[O:48])[NH:46][CH2:44][CH3:45])=[CH:36][C:6]=3[C:7]=2[CH3:35])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCN=C=O
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(N)cc3c2C)C2CCCCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1ccc2oc(C(Nc3ccc(C(=O)N(C)CCC(=O)OCC)cc3)C3CCCCC3)c(C)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a solution (10 mL) of ethyl 3-{[(4-{[(5-amino-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl](methyl)amino}-propanoate (280 mg) synthesized in Example A110(5) in tetrahydrofuran were added triethylamine (95 μL) and ethyl isocyanate (54 μL), and the mixture was stirred at room temperature for 1 day. Triethylamine (95 μL) and ethyl isocyanate (54 μL) were additionally added, and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (60-100% ethyl acetate/hexane) to give the title object compound (304 mg, 95%) as a colorless oil.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].[C:10]([N:13]1[C:17](=[O:18])[CH:16]=[CH:15][C:14]1=[O:19])(=[O:12])[NH2:11]>>[C:17]([O:5][CH2:4][CH:3]([CH2:1][CH3:2])[CH2:6][CH2:7][CH2:8][CH3:9])(=[O:18])/[CH:16]=[CH:15]\[C:14](=[O:19])[NH:13][C:10](=[O:12])[NH2:11]
Reactant: CCCCC(CC)CO
Reactant: NC(=O)N1C(=O)C=CC1=O
Product: CCCCC(CC)COC(=O)/C=C\C(=O)NC(N)=O
Yield: 95 %

Procedure:
The addition of 2-ethylhexanol to N-carbamylmaleimide under the conditions of Example C afforded a 95% yield of 2-ethylhexyl maleurate. M.P.: 73°-6° C.; 1H NMR (CDCl3): δ10.6 (br s, 1H), 8.2 (br s, 1H), 6.3 (m, 2H), 5.8 (br s, 1H), 4.2 (m, 2H), 1.6 (m, 1H), 1.3 (m, 8H), 0.9 (t, 6H); HPLC (40% CH3CN/H2O, C8): Rt=14.2 minutes.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:26][CH2:27][CH3:28])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([CH:12]2[CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:13]2)[C:5]([O:26][CH2:27][CH3:28])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:9]=1
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOc1c(C(C)O)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a solution of benzyl 3-(3-acetyl-5-chloro-2-ethoxy-6-methylphenyl)azetidine-1-carboxylate (0.35 g, 0.87 mmol) in methanol (5 mL) cooled at 0° C. was added sodium tetrahydroborate (0.040 g, 1.0 mmol). The mixture was stirred at room temperature for 1 hour, then diluted with water, extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated to give the crude alcohol (0.31 g, 88%). LCMS calculated for C22H27ClNO4 (M+H)+: m/z=404.2; Found: 404.0,
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:21][C@H:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=2)[CH3:23])=[N:4][C:5]([NH:11][C:12]2[CH:16]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[NH:14][N:13]=2)=[C:6]([N+:8]([O-])=O)[CH:7]=1.[CH2:31](O)C.C(OCC)(=O)C>[Cl-].[Na+].O.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]2[N:8]=[CH:31][N:11]([C:12]3[CH:16]=[C:15]([O:17][CH:18]([CH3:20])[CH3:19])[NH:14][N:13]=3)[C:5]2=[N:4][C:3]=1[NH:21][C@H:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][N:25]=1)[CH3:23]
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cn3)c(Cl)cc2[N+](=O)[O-])n[nH]1
Reactant: CCO
Agent: [Pd]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(-n2cnc3cc(Cl)c(N[C@@H](C)c4ccc(F)cn4)nc32)n[nH]1
Temperature: 25 °C

Procedure:
3-Chloro-N2-[(1S)-1-(5-fluoropyridin-2-yl)ethyl]-N6-(5-isopropoxy-1H-pyrazol-3-yl)-5-nitropyridine-2,6-diamine (Intermediate 39, 0.5 g) was dissolved into ethanol (20 mL) with Pd—C (150 mg) and a hydrogen inlet. The mixture was stirred at room temperature until no starting material was detected with TLC or LCMS. Formylamidine acetate (0.5 g) was added to the filtrate after the filtration of resulting mixture. The mixture was stirred at 85° C. for 4 hours. Ethyl acetate (40 mL) was added into the resulting mixture, and brine (10 mL×3) was used to wash the organic layer. The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Ethyl acetate/MeOH) to afford 0.12 g desired product. MS (electrospray): 416 (M+1) for C19H19ClFN7O. 1H NMR (300 MHz, CD3OD) δ ppm 8.40 (s, 1H) 8.30 (s, 1H) 7.90 (d, 1H) 7.50 (m 2H) 6.70 (d, 1H) 6.00 (s, 1H) 5.40 (m, 1H) 4.60 (m, 1H) 1.60 (d, 3H) 1.40 (d, 6H).
Reaction SMILES: C[Si](C)(C)[Br:3].[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12]O)=[CH:10][C:9]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21]>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][Br:3])=[CH:10][C:9]=1[O:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21]
Reactant: COCCCOc1cc(CO)ccc1OC
Reactant: C[Si](C)(C)Br
Solvent: ClC(Cl)Cl
Product: COCCCOc1cc(CBr)ccc1OC

Procedure:
97 ml of trimethylbromosilane are added, with stirring at room temperature, to 113.1 g of 4-methoxy-3-(3-methoxypropyloxy)-benzyl alcohol in 1.31 liters of chloroform. After 10 minutes the solvent is evaporated off and the residue is immediately purified by means of FC (900 g of silica gel, eluant: ethyl acetate/hexane 1:3). The title compound is obtained: Rf (ethyl acetate/hexane=1:2)=0.34; m.p. 50°-51 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([CH:11]([CH:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CN1CCC(O)CC1
Reactant: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CN1CCC(C(c2ccncc2)S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 32.6 %

Procedure:
A toluene (5 ml) solution of the 4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained in Example 119, 1-methylpiperidin-4-ol (62 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (62 μl, 0.538 mol) was heated under reflux for 3 days under an argon atmosphere. After cooling to room temperature, the reaction mixture was added with 1-methylpiperidin-4-ol (62 μl, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol), followed by heating under reflux for 22 hours under an argon atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction obtained from the methanol:methylene chloride (=1:50) eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (using a mixed solvent of water/acetonitrile/formic acid) to give the title compound (31 mg, 33%) as a white solid. The resulting solid was washed with hexane-ether and then, collected by filtration, whereby the title compound was obtained as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:14][N:13]3[CH:25]=2)=[CH:6][C:4]=1[NH2:5])#[CH:2].N1C=CC=CC=1.[CH3:32][C:33]([CH3:38])([CH3:37])[C:34](Cl)=[O:35]>C(#N)C>[C:1]([C:3]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:14][N:13]3[CH:25]=2)=[CH:6][C:4]=1[NH:5][C:34](=[O:35])[C:33]([CH3:38])([CH3:37])[CH3:32])#[CH:2]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C#Cc1ccc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1N
Solvent: c1ccncc1
Solvent: CC#N
Product: C#Cc1ccc(-c2cn3nc(-c4ccccc4F)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
A solution of 2-ethynyl-5-(6-(2-fluorophenyl)imidazo[1,2-b]pyridazin-2-yl)aniline (0.030 g, 0.0913 mmol) in acetonitrile (1 mL) containing pyridine (0.273 mmol) is added trimethylacetylchloride (0.0958 mmol). The mixture is stirred at room temperature for 4 hours, then concentrated to dryness and residue purified via silica chromatography (hexanes to EtOAc) to afford the title compound (0.029 g, 78%) as a yellow solid: Rf 0.58 (1:1 EtOAc:hexanes); LCMS (m/z)=413.5 [M+H]+, tR=3.19 min. (compound same as Example 321)
Reaction SMILES: C(OC([O:8][CH2:9][CH:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=O)(C)(C)C>C(O)(C(F)(F)F)=O.ClCCl>[OH:8][CH2:9][CH:10]1[CH2:14][O:13][C:12](=[O:15])[N:11]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CCCCCCN1C(=O)OCC1COC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCCCCCN1C(=O)OCC1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
A solution of 1-4 (446 mg) in a mixture of 10% TFA in dichloromethane (10 mL) was stirred at room temperature for 2 h and concentrated. The residue was purified by column chromatography. Eluting with 70–100% ethyl acetate in hexanes afforded the alcohol 1-5 (264 mg). 1H NMR (400 MHz, acetone-d6): δ 4.33 (t, 1H), 4.19 (t, 1H, OH), 4.14 (dd, 1H), 4.09 (q, 2H), 3.95 (m, 1H), 3.78 (m, 1H), 3.65 (m, 1H), 3.38 (m, 1H), 3.16 (m, 1H), 2.29 (t, 2H), 1.70–1.55 (m, 4H), 1.45–1.30 (m, 4H), 1.21 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[C:14]([C:20]([F:23])([F:22])[F:21])[CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:16]([C:4]1[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][CH:5]=1)[C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][C:14]=1[C:20]([F:23])([F:22])[F:21])=[CH:5][NH:6]2
Reactant: Clc1cccc2[nH]ccc12
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Product: Fc1ccc(C(c2c[nH]c3cccc(Cl)c23)c2c[nH]c3cccc(Cl)c23)c(C(F)(F)F)c1

Procedure:
The compound Bis(4-chloroindol-3-yl)-(4-fluoro-2-trifluoromethylphenyl)methane was prepared following procedure A, starting from 4-chloro indole and 4-fluoro-2-(trifluromethyl) benzaldehyde. LC: Tr 2.52 min, MS: 477 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[CH:6][C:5]([C@H:28]2[CH2:32][C@@H:31]([CH2:33][OH:34])[NH:30][CH2:29]2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:41]#[C:42]Br>C(O)C.O>[NH2:1][C:2]1[C:7]([C:8]2[CH:26]=[CH:25][C:11]([C:12]([NH:14][C@@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=3)[CH2:16][OH:17])=[O:13])=[C:10]([F:27])[CH:9]=2)=[CH:6][C:5]([C@@H:28]2[CH2:29][N:30]3[C:42](=[NH:41])[O:34][CH2:33][C@@H:31]3[CH2:32]2)=[CH:4][N:3]=1
Reactant: Nc1ncc([C@@H]2CN[C@H](CO)C2)cc1-c1ccc(C(=O)N[C@H](CO)c2cccc(Cl)c2)c(F)c1
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Product: N=C1OC[C@@H]2C[C@H](c3cnc(N)c(-c4ccc(C(=O)N[C@H](CO)c5cccc(Cl)c5)c(F)c4)c3)CN12
Reaction time: 1 h

Procedure:
A room temperature mixture of 4-(2-amino-5-((3R,5S)-5-(hydroxymethyl)pyrrolidin-3-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide (12.5 mg, 0.026 mmol) (Example 7) and cesium carbonate (33.6 mg, 0.103 mmol) in ethanol (0.75 mL) was treated with cyanogen bromide (6.2 μL, 0.031 mmol). After 1 h, the reaction was diluted with water (1.0 mL) and extracted into ethyl acetate (10 mL). The organics were washed with brine (2 mL), then dried over Na2SO4 and concentrate and purified by reverse phase prep HPLC yielding 4-(2-amino-5-((6R,7aS)-3-iminohexahydropyrrolo[1,2-c]oxazol-6-yl)pyridin-3-yl)-N—((S)-1-(3-chlorophenyl)-2-hydroxyethyl)-2-fluorobenzamide. LCMS (m/z): 510.1, 512.1 (MH+), 0.52 min. 1H NMR (400 MHz, CD3OD) δ ppm 8.63-8.54 (m, 1H), 7.92-7.85 (m, 2H), 7.80 (t, J=7.83 Hz, 1H), 7.40-7.31 (m, 3H), 7.29-7.24 (m, 2H), 7.24-7.16 (m, 1H), 5.14-5.06 (m, 1H), 4.97-4.88 (m, 1H), 4.61-4.49 (m, 2H), 3.88-3.70 (m, 4H), 3.32 (s, 1H), 2.41-2.31 (m, 1H), 2.02-1.89 (m, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([N:6](CC2C=CC(OC)=CC=2)[S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[C:25]([OH:26])=[CH:24][C:23]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=4)=[C:22]([F:35])[CH:21]=2)[C:15](=[O:36])[CH:14]=[CH:13]3)(=[O:9])=[O:8])=[N:2]1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.CS(C)=O>[O:1]1[CH:5]=[CH:4][C:3]([NH:6][S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]2[C:25]([OH:26])=[CH:24][C:23]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=4)=[C:22]([F:35])[CH:21]=2)[C:15](=[O:36])[CH:14]=[CH:13]3)(=[O:8])=[O:9])=[N:2]1
Reactant: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(-c4cc(F)cc(F)c4)cc3O)c2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=c1ccc2cc(S(=O)(=O)Nc3ccon3)ccc2n1-c1cc(F)c(-c2cc(F)cc(F)c2)cc1O
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of N-(isoxazol-3-yl)-N-(4-methoxybenzyl)-2-oxo-1-(2,3′,5′-trifluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide (39.3 mg, 0.062 mmol) in DCM (620 μl) at room temperature was added trifluoromethanesulfonic acid (16.52 μl, 0.186 mmol). The resulting solution was stirred for 1 hour. The solution was then dissolved in 1.5 ml of DMSO and passed through a 0.20 micron filter. An additional 0.5 ml was used to sinse the reaction vial and the solution was passed through the same filter. The resulting DMSO solution was purified by reverse-phase HPLC (Waters XBridge Prep Shield RP18 10 μm OBD 19×100 mm) gradient, 5 to 50% MeCN in water (containing 0.1% ammonium hydroxide as an additive), flow rate 40 mL/min to yield N-(isoxazol-3-yl)-2-oxo-1-(2,3′,5′-trifluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)-1,2-dihydroquinoline-6-sulfonamide (10.2 mgs, 32% yield over two steps).1H NMR (500 MHz, DMSO-d6) □=ppm 6.37 (s, 1 H) 6.78 (d, J=9.17 Hz, 1 H) 6.83 (d, J=8.45 Hz, 1 H) 7.17 (d, J=7.20 Hz, 1 H) 7.30-7.43 (m, 4 H) 7.84 (dd, J=8.95, 2.01 Hz, 1 H) 8.19 (d, J=7.88 Hz, 1 H) 8.31 (s, J=8.04 Hz, 1 H) 8.59 (s, 1 H) 10.06 (br. s., 1 H). m/z (ESI) 513.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1([CH2:26]O)[CH2:25][CH2:24][CH2:23]1.CO>ClCCl>[CH:22]1([CH2:26][O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OCC1CCC1
Solvent: CO
Solvent: ClCCl
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCC1CCC1
Yield: 92 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using cyclobutanemethanol (32 μL, 0.34 mmol) as the coupling partner. Chromatography (1:1 methanol:dichloromethane) through SiO2 yielded 56 mg (92%) of the titled compound. ESI-MS m/z 360 (MH+), 358 (M−H−).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:24]1([C:35](O)=[O:36])[CH:25]=[CH:26][CH:27]=[C:28]2[CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:29]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:35]([C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[CH2:34][CH2:33][CH2:32][CH:31]=[CH:30][C:29]=23)=[O:36])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)thio]phenyl}propan-1-ol (450 mg, 1.51 mmol) in acetonitrile (20 ml) were added 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (284 mg, 1.51 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (435 mg, 2.27 mmol) and 1-hydroxybenzotriazole hydrate (231 mg, 1.51 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (396 mg, 51%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([C:14]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[O:22][C:23]3[CH:28]=[C:27]([Cl:29])[C:26]([OH:30])=[CH:25][C:24]=3[Cl:31])=[O:15])[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>CN(C)C=O>[CH2:39]([O:38][C:36](=[O:37])[CH2:35][O:30][C:26]1[CH:25]=[C:24]([Cl:31])[C:23]([O:22][C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:14]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:4]([CH:1]3[CH2:2][CH2:3]3)[CH2:5][CH2:6]2)=[O:15])=[CH:28][C:27]=1[Cl:29])[CH3:40]
Reactant: CCOC(=O)CBr
Reactant: O=C(c1cnccc1Oc1cc(Cl)c(O)cc1Cl)N1CCN(C2CC2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
To a solution of 0.15 g (0.33 mmol) (4-cyclopropyl-3,4-dihydro-2H-quinoxalin-1-yl)-[4-(2,5-dichloro-4-hydroxy-phenoxy)-pyridin-3-yl]-methanone (Example 57) in 2 mL N,N-dimethylformamide was added 0.016 g (0.37 mmol) sodium hydride (60% dispersion in mineral oil, Aldrich, CAS RN 7646-69-7). The reaction mixture was stirred for 15 min. at room temperature before 0.04 mL (0.36 mmol) ethyl bromoacetate (commercially available, CAS RN 105-36-2) were added. After stirring at room temperature for 3 hours the solution was poured on water and extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting powder was purified by silica gel chromatography using a MPLC system (10 g silica gel column, CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:ethyl acetate (100:0 to 30:70) to give 0.144 g (81%) of the desired compound as a light yellow foam. MS (ESI): m/z=542.123 [M+H]+.