Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].[CH:27]1([S:32][CH2:33][CH2:34]Cl)[CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.CO>[OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:34][CH2:33][S:32][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Reactant: ClCCSC1CCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)[C@H]1CN(CCSC2CCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Yield: 49.3 %

Procedure:
0.717 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 15 cm3 of acetonitrile and 15 cm3 of methanol was heated for 3½ h at a temperature in the region of the reflux temperature, with stirring and under an inert atmosphere, with 0.439 g of 90% 2-chloroethyl cyclopentyl sulfide in the presence of 0.332 g of potassium carbonate and 0.4 g of potassium iodide. After cooling the reaction mixture to a temperature in the region of 20° C., the insoluble material was filtered off and then washed with acetonitrile. The filtrate was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 100 kPa on a column of silica gel (particle size 40-63 μm; diameter 3.5 cm; height 45 cm), elution was carried out with a dichloromethane/methanol (95/5 by volume) mixture, and 35-cm3 fractions were collected. Fractions 25 to 45 were combined and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.48 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)-ethyl]piperidine-3-carboxylate was obtained in the form of a lacquer with a dark-green color.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.Cl.[CH:19]1([NH:22][C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[C:26]([CH3:36])[CH:25]=2)[CH2:21][CH2:20]1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH:19]1([NH:22][C:23](=[O:37])[C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][N:33]([CH2:2][C:3]4[CH:12]=[N:11][C:10]5[N:9]6[CH2:13][CH2:14][CH2:15][C@H:8]6[C:7](=[O:16])[NH:6][C:5]=5[CH:4]=4)[CH2:34][CH2:35]3)=[C:26]([CH3:36])[CH:25]=2)[CH2:21][CH2:20]1
Reactant: Cc1cc(C(=O)NC2CC2)ccc1N1CCNCC1
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Cc1cc(C(=O)NC2CC2)ccc1N1CCN(Cc2cnc3c(c2)NC(=O)[C@@H]2CCCN32)CC1
Temperature: 90 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
To a suspension of (S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (0.1 g, 0.456 mmol), N-cyclopropyl-3-methyl-4-(piperazin-1-yl)benzamide dihydrochloride (0.179 g, 0.538 mmol), and (cyanomethyl)trimethylphosphonium iodide (0.188 g, 0.775 mmol) in Propiononitrile (Volume: 2.0 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.556 mL, 3.19 mmol) at 23° C. The reaction was stirred at 90° C. for 8 hr. The reaction mixture was cooled to room temperature, filtered, and rinsed with propiononitrile (3×1 mL). The resulting solid was reconstituted in DMSO (Volume: 3.0 mL) and purified via preparative mass trigger LCMS using a gradient eluant of 25-65% ACN: 10 mM NH4HCO3 (aq). The collected fractions were combined and the ACN was removed via rotary evaporation to furnish a suspension. The suspension was filtered, rinsed with H2O (3×10 mL), and the resulting solid was dried in vacuo to provide (S)-N-cyclopropyl-3-methyl-4-(4-((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)b enzamide (0.0624 g, 0.135 mmol, 29.7% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.50-0.59 (m, 2 H) 0.60-0.70 (m, 2 H) 1.86-2.00 (m, 3 H) 2.14-2.20 (m, 1 H) 2.25 (s, 3 H) 2.47-2.50 (m, 4 H) 2.76-2.93 (m, 5 H) 3.34-3.44 (m, 3 H) 3.55-3.63 (m, 1 H) 3.93-4.02 (m, 1 H) 6.96-7.04 (m, 2 H) 7.56-7.67 (m, 3 H) 8.22 (d, J=4.29 Hz, 1 H) 10.45 (s, 1 H). ESI-MS: m/z 461.4 (M+H)+. mp=226.7-233.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH2:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[CH:12][N:11]=1>ClCCl>[CH3:7][O:8][CH2:9][C:10]1[N:15]=[C:14]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][N:11]=1
Reactant: COCc1nccc(Cl)n1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: COCc1nccc(N2CCCCC2)n1
Reaction time: 8 h

Procedure:
Piperidine (6.17 ml) in dichloromethane (40 ml) was added dropwise to a solution of 2-methoxymethyl-4-chloropyrimidine (4.71 g) in dichloromethane (40 ml). After standing overnight at room temperature the mixture was heated under reflux for 1 hour. After cooling the solution was washed with water, dried and stripped. The residue was chromatographed (silica gel, CHCl3) to give 2-methoxymethyl-4-piperidinopyrimidine (4.49 g) as an oil.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11].CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: OC1CN2CCC1CC2
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(-c2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
3-Quinuclidinol (Aldrich, 0.51 g, 4 mmol) coupled with 4′-nitro-1,1′-biphenyl-4-ol (TCl, 0.43 g, 2 mmol) with DIAD (di-isopropyl azadicarboxylate, Aldrich, 0.81 g, 4 mmol) and Ph3P (Aldrich, 1.04 g, 4 mmol) in THF (anhydrous, Aldrich, 40 mL) at ambient temperature for two days. The reaction mixture was concentrated. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.20) as solid (400 mg, yield, 62%). 1H NMR (300 MHz, CD3OD) δ 1.45–1.57 (m, 1H), 1.63–1.91 (m, 2H), 1.97–2.12 (m, 1H), 2.17–2.24 (m, 1H), 2.66–3.00 (m, 5H), 3.30–3.41 (m, 1H), 4.56–4.64 (m, 1H), 7.05 (dt, J=8.8, 2.6 Hz, 2H), 7.68 (dt, J=9.2, 2.6 Hz, 2H), 7.82 (dt, J=8.8, 2.7 Hz, 2H), 8.28 (dt, J=8.8, 2.8 Hz, 2H) ppm. MS (DCl/NH3) m/z 325 (M+H)+.
Reaction SMILES: [C:1]12([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[CH2:18][C:19]#[N:20]>>[C:1]12([N:11]3[CH2:16][CH2:15][N:14]([CH2:18][C:19]#[N:20])[CH2:13][CH2:12]3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: N#CCBr
Reactant: C1CN(C23CC4CC(CC(C4)C2)C3)CCN1
Product: N#CCN1CCN(C23CC4CC(CC(C4)C2)C3)CC1

Procedure:
The title compound is synthesized by coupling of 1-Adamantyl-piperazine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=260.3: 1HNMR(DMSO-d6) 3.65 (s, 2H), 2.60-2.50 (m, 4H), 2.45-2.40 (m, 4H), 2.00 (bs, 3H), 1.60-1.50 (m, 12H).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:19])=[N:11][N:12]([C:14]([CH3:18])([CH3:17])[CH2:15][CH3:16])[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1>>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=2)[C:9]2[C:10]([CH3:19])=[N:11][N:12]([C:14]([CH3:18])([CH3:17])[CH2:15][CH3:16])[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: CCC(C)(C)n1cc(C(O)C2CCCCC2)c(C)n1
Product: CCC(C)(C)n1cc(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)c(C)n1
Yield: 31.8 %

Procedure:
Using cyclohexyl[1-(1,1-dimethylpropyl)-3-methyl-1H-pyrazol-4-yl]methanol (1.0 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.67 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.41 g, 46%) was obtained as a white solid.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:35]=[CH:34][C:29]3[O:30][CH2:31][CH2:32][O:33][C:28]=3[CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.C(OCC)(=O)C>[CH:21]1([CH:20]=[C:19]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[C:26]2[CH:35]=[CH:34][C:29]3[O:30][CH2:31][CH2:32][O:33][C:28]=3[CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=S(=O)(c1ccccc1)n1c(C(=CC2CCCC2)c2ccc3c(c2)OCCO3)cc2cccnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C(=C(c1ccc2c(c1)OCCO2)c1cc2cccnc2[nH]1)C1CCCC1
Yield: 85.5 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (130 mg, 0.27 mmol) in ethanol (6 mL) and tetrahydrofuran (3 mL) and an aqueous sodium hydroxide solution (10%, 1 mL) was stirred at 40° C. for 48 h. The mixture was diluted with ethyl acetate (100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (80 mg, 87%) as a white solid: LC/MS m/e calcd for C22H22N2O2 [M+H]+ 347.43, observed 347.1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9](=[O:25])[CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:12]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Br:26]Br>C(O)(=O)C>[BrH:26].[Br:26][CH:10]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=1)[C:9]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=1)=[O:25]
Reactant: Cc1cc(C)cc(C(=O)Cc2ccnc(OCc3ccccc3)c2)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: Cc1cc(C)cc(C(=O)C(Br)c2ccnc(OCc3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 196 %

Procedure:
1-(3,5-Dimethylphenyl)-2-(2-phenylmethyloxy-4-pyridyl)ethanone (3.3 g, 10 mmol) was dissolved in acetic acid (10 mL) and bromine (0.51 mL, 10 mmol) was added to the solution and stirred at room temperature for 30 minutes. The precipitated crude crystals were collected by filtration and washed with diethyl ether to obtain 4.8 g of the title compound (9.8 mmol, yield 98%).
Reaction SMILES: [IH:1].C(=O)([O-])[O-:3].[Ca+2:6].[Ca]>[Pt]>[OH2:3].[OH2:3].[OH2:3].[OH2:3].[OH2:3].[OH2:3].[I-:1].[Ca+2:6].[I-:1]
Reactant: O=C([O-])[O-]
Reactant: I
Agent: [Pt]
Agent: [Ca+2]
Agent: [Ca]
Product: O
Product: [I-]
Temperature: 5 °C

Procedure:
In a suitable vessel of glass, stainless steel, or platinum, hydriodic acid (47 percent solution) 790 parts is added to calcium carbonate (215 parts) stoichiometrically in excess of the calcium, boiled to remove CO2, and made alkaline with calcium oxide. The resulting reaction mass in the form of a slurry is filtered for insolubles and made acid with additional 47 percent aqueous hydrogen iodide to a pH below 1. The filtrate is boiled to concentrate the solution through a continually rising boiling range to 146° C. The resulting highly concentrated liquor was cooled to 5° C. to form calcium iodide hexahydrate in crystalline form. The mother liquor is poured off and the crystals are spread loosely in an inert tray of quartz or a resinous material, such as polytetrafluoroethylene, to a depth of approximately 1 inch. The filled tray is then placed in a vacuum drying oven equipped with a vapor trap cooled with dry ice. The oven is then evacuated and pumping continued over a period of 24 to 48 hours, with no heat applied, until a pressure of 0.1 mm. Hg absolute or less is attained. The calcium iodide is then heated slowly to about 75° to 80° C. over an interval of 40 to 60 hours, and held at this temperature for approximately 24 hours, or until a pressure of about 0.1 to 0.03 mm. Hg absolute is attained as measured by a Pirani-type vacuum gauge.
Reaction SMILES: [CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([O:34]C)[C:7](=[O:33])[N:8]2[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[NH:32][N:31]=[N:30][N:29]=2)=[CH:18][CH:17]=1)[CH3:2].B(Br)(Br)[Br:37].CO>ClCCl>[BrH:37].[CH2:1]([C:3]1[N:12]=[C:11]([CH2:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([OH:34])[C:7](=[O:33])[N:8]2[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]2[NH:32][N:31]=[N:30][N:29]=2)=[CH:20][CH:21]=1)[CH3:2]
Reactant: BrB(Br)Br
Reactant: CCc1cc2c(cc(OC)c(=O)n2Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(CC)n1
Solvent: ClCCl
Solvent: CO
Product: Br
Product: CCc1cc2c(cc(O)c(=O)n2Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(CC)n1
Reaction time: 16 h

Procedure:
5,7-Diethyl-3-methoxy-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-1,6-naphthyridin-2(1H)-one (80 mg) was suspended in dichloromethane (1 ml) and a 1M solution of boron tribromide in dichloromethane (0.5 ml) was added. The mixture was stirred for 16 hours then methanol (3 ml) was added dropwise. The mixture was heated at reflux for 5 minutes and volatile material was then removed by evaporation. The residue was recrystallised from ethanol/ether to give 5,7-diethyl-3-hydroxy-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)-methyl]-1,6-naphthyridin-2(1H)-one hydrobromide as a solid (45 mg), m.p. 190°-194° C.; NMR (d6 -DMSO): 1.24(t, 3H), 1.30(t, 3H), 2.92(q, 2H), 3.22(q, 2H), 5.64(s, 2H), 7.07(d, 2H), 7.22(d, 2H), 7.45-7.75(m, 6H); mass spectrum (+ve FAB, methanol/NBA): 453 (M+H)+ ; microanalysis, found: C, 57.1; H, 4.9; N, 14.7%; C26H24N6O2.Hbr.1.5H2O requires: C, 56.7; H, 5.1; N, 15.2%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:6]([N+:19]([O-])=O)[CH:5]=1.[Cl-].[NH4+].CO.O1CCCC1>[Fe].O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[C:6]([NH2:19])[CH:5]=1
Reactant: COC(=O)c1ccc(Sc2ccc(OC)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Sc2ccc(OC)cc2)c(N)c1
Yield: 90 %

Procedure:
To a solution of the product from Example 136A, iron powder and ammonium chloride in a methanol, tetrahydrofuran, and water solution was heated to reflux. The resultant mixture was filtered, and the filtrate was concentrated. Then ethyl acetate was added, stirred, filtered and concentrated under vacuum to provide the title compound (7.16 g, 90%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][NH2:15])[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:34]=[C:35]([Cl:37])[CH:36]=1)[CH2:20][O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([CH2:30][C:31](O)=[O:32])[CH2:26][CH2:25]1)=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][NH:15][C:31](=[O:32])[CH2:30][CH:27]2[CH2:28][CH2:29][N:24]([C:22]([O:21][CH2:20][C:19]3[CH:18]=[C:17]([Cl:16])[CH:36]=[C:35]([Cl:37])[CH:34]=3)=[O:23])[CH2:25][CH2:26]2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1
Reactant: NCCc1cn(Cc2ccccc2)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(CC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)NCCc1cn(Cc2ccccc2)nn1

Procedure:
A reaction mixture comprising of 2-(1-benzyl-1H-1,2,3-triazol-4-yl)ethanamine (59.1 mg, 0.292 mmol), 2-(1-(((3,5-dichlorobenzyl)oxy)carbonyl)piperidin-4-yl)acetic acid (101 mg, 0.292 mmol), HATU (222 mg, 0.584 mmol) and TEA (122 μl, 0.877 mmol) in DMF (0.97 ml) was stirred for 3 hours at room temperature. The reaction mixture was diluted with water and ethyl acetate. The organic layer was removed and dried over MgSO4, filtered and concentrated under reduced pressure. Further purification was carried out using preparative LC-MS. The resulting product fractions were concentrated under reduced pressure to give aqueous solutions which were extracted with ethyl acetate. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:41])[C:5]([C:28]1[CH:40]=[CH:39][C:31]([O:32][CH2:33][C:34]([O:36]CC)=O)=[CH:30][CH:29]=1)=[CH:6][N:7]2[CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.[NH3:42].CO>>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:41])[C:5]([C:28]1[CH:29]=[CH:30][C:31]([O:32][CH2:33][C:34]([NH2:42])=[O:36])=[CH:39][CH:40]=1)=[CH:6][N:7]2[CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: N
Reactant: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OCC(=O)OCC)cc3)cn(CC(=O)NCCN3CCOCC3)c12
Solvent: CO
Product: CCCOc1ccc(F)c2c(=O)c(-c3ccc(OCC(N)=O)cc3)cn(CC(=O)NCCN3CCOCC3)c12
Temperature: 70 °C
Reaction time: 43 h
Yield: 35 %

Procedure:
Ethyl (4-{5-fluoro-1-[(2-morpholin-4-yl-ethylcarbamoyl)methyl]-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl}phenoxy)acetate (300 mg) was added to a 7N ammonia-methanol solution (15 ml) and then stirred at 70° C. for 43 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified using silica gel column chromatography (dichloromethane:methanol=50:1→9:1→ethyl acetate:methanol=10:1). The purified product was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-n-hexane, giving a pale yellow powder of 2-(4-{5-fluoro-1-[(2-morpholin-4-yl-ethylcarbamoyl)methyl]-4-oxo-8-propoxy-1,4-dihydroquinolin-3-yl}phenoxy)acetamide (100 mg, yield: 35%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[O:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:11][C:10]=2[CH2:21]O)=[N:6][CH:7]=1.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:48]>C(Cl)Cl.O>[Br:48][CH2:21][C:10]1[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:13][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: OCc1nc(-c2ccc(F)cc2)oc1Sc1ccc(Cl)cn1
Reactant: BrC(Br)(Br)Br
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: Fc1ccc(-c2nc(CBr)c(Sc3ccc(Cl)cn3)o2)cc1
Reaction time: 1 h

Procedure:
To a solution of {5-[(5-chloropyridin-2-yl)sulfanyl]-2-(4-fluorophenyl)-1,3-oxazol-4-yl}methanol (intermediate B1.1, 0.30 g, 0.89 mmol) in 3.3 mL of DCM at 0° C. was added imidazole (0.02 g, 0.36 mmol), Ph3P (0.28 g, 1.07 mmol) and CBr4 (0.36 g, 1.07 mmol). After 1 h at 0° C., water was added and the reaction mixture was extracted with EtOAc. The combined organics were washed with 10% KHSO4, satd. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated. The reaction was purified by flash chromatography (silica, 0-25% EtOAc/hexanes) to give 2-{[4-(bromomethyl)-2-(4-fluorophenyl)-1,3-oxazol-5-yl]sulfanyl}-5-chloropyridine as white solid. LCMS [M+H]+=401.2.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.[NH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([OH:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=N)C>CN(C)C=O.O>[OH:30][C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][NH:19][C:9](=[O:11])[C:8]2[CH:12]=[CH:13][CH:14]=[N:15][C:7]=2[O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([S:2][CH3:1])[CH:4]=2)=[CH:22][CH:23]=1)([CH3:29])[CH3:28]
Reactant: CSc1cccc(Oc2ncccc2C(=O)O)c1
Reactant: CC(C)(O)c1ccc(CN)cc1
Agent: CCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cccc(Oc2ncccc2C(=O)NCc2ccc(C(C)(C)O)cc2)c1
Yield: 14.1 %

Procedure:
To a stirred solution 2-(3-Methylsulfanyl-phenoxy)-nicotinic acid (2.5 grams, 9.58 mmole), 2-(4-Aminomethyl-phenyl)-propan-2-ol (1.896 grams, 11.50 mmole) and 1-hydroxybenzotriazole hydrate (1.55 grams, 11.50 mmole) in dry dimethylformamide (60 ml) was added 1-(3-dimethylamino)-propyl)-3-ethylcarbodiimide hydrochloride (2.39 grams, 12.45 mmole) and stirred over night. The mixture was diluted with 300 ml water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated to give a yellow oil that was purified by chromatography on silica eluting with 3.5% methanol/methylene chloride to give a white solid. Recrystalization from ethyl acetate/hexane gave a solid (0.550 g). M.P. 107-109° C.; Anal. calcd. for C23H24N2O3S: C, 67.62; H, 5.92; N, 6.86. Found: C, 67.53, H, 5.76; N, 6.91.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27]([CH:38]([CH3:40])[CH3:39])=[CH:26][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:50])=CC=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:29]=[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27]([CH:38]([CH3:40])[CH3:39])=[CH:26][C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1)=[S:50])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=O)Nc2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)c1cc(C(=S)Nc2ccc(N3CCOCC3)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 161.3 %

Procedure:
2,4-bis-benzyloxy-5-isopropyl-N-[4-(morpholin-4-yl)phenyl]benzamide (F370-IM2, 2.45 g, 4.60 mmol) was suspended in toluene (50 mL), mixed with Lawesson's reagent (2.05 g, 5.06 mmol) and the mixture was heated at 110° C. for 1 hour. As the reaction proceeded, the suspension changed to a yellow solution. The reaction mixture was cooled to room temperature, mixed with 5% aqueous sodium hydrogencarbonate (50 mL), and the organic layer was separated. The organic layer thus obtained was dried over anhydrous sodium sulfate. Sodium sulfate was removed by filtration, and the solvent was distilled off under reduced pressure. To the residue were added toluene (20 mL) and hexane (10 mL), and the resulting suspension was stirred at room temperature for 1 hour, crystals (F370-IM3) were collected by filtration. The mother liquor was concentrated and purified by silica gel column chromatography (ethyl acetate:hexane 2:1), to afford F370-IM3. The combined title compound (F370-IM3, about 4.1 g) was subjected to the next reaction.