Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C.[CH2:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=O)=O)=[CH:32][CH:31]=1)[C:26]#[C:27][CH3:28].Cl>ClCCl.[Cl-].[Na+].O>[CH2:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([SH:36])=[CH:34][CH:35]=1)[C:26]#[C:27][CH3:28]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CC#CCOc1ccc(S)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
To a solution of 11.8 g (0.045 mol) of triphenylphosphine dissolved in 10 mL of dichloromethane and 0.3 mL of DMF was added 3.67 g (0.015 mol) of the 4-but-2-ynyloxy-benzenesulfonyl chlorid, dissolved in 15 mL of dichloromethane and the resulting mixture was stirred for 2 h at room temperature. After the addition of 5 mL of 1N HCl solution the reaction was stirred for 0.5 h followed by the addition of 15 mL of brine. The organics were separated and concentrated in vacuo and the residue was diluted with ether and 2.5N sodium hydroxide solution. The resulting precipitate was filtered off and the aqueous layer was acidified to pH 2 and extracted with ether. The combined organics were washed with brine, dried over Na2SO4, filtered through Magnesol® and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexanes/ether (4:1) to provide 1.13 g (42%) of the thiol as a yellow oil. CI Mass Spec: 179 (M+H).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[C:11]([N+:23]([O-])=O)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].O1CCCC1.O>CO.[Fe]>[NH2:23][C:11]1[CH:10]=[C:9]([NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:14]=[CH:13][C:12]=1[S:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])c1cc(NCc2ccccc2)ccc1Sc1ccc(O)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Nc1cc(NCc2ccccc2)ccc1Sc1ccc(O)cc1
Yield: 66.5 %

Procedure:
A solution of the product of Example 62B (0.5 g, 1.4 mmol), iron powder (0.49 g, 8.74 mmol) and ammonium chloride (0.50 g, 9.3 mmol) in a methanol (10 mL), tetrahydrofuran (10 mL), and water (5 mL) solution was heated to reflux for 1.5 hours. The resultant mixture was diluted with methanol (50 mL) and filtered through a pad of celite. The filtrate was concentrated under vacuum to a volume of 10 mL, the solution diluted with water (50 mL) and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with 10% sodium chloride then dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (0.30 g, 66%).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:7]([O:9][CH3:10])=[O:8]>[Ru].[Co]>[CH:1]1([C:7]([O:9][CH3:10])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC=O
Reactant: C1=CCCCC1
Agent: [Co]
Agent: [Ru]
Product: COC(=O)C1CCCCC1
Temperature: 120 °C

Procedure:
In a pressure reactor made of stainless steel and having an internal volume of 50 ml, 0.05 mmol of [Ru(CO)3Cl2]2 as a ruthenium compound, 0.05 mmol of Co2(CO)8 as a cobalt compound, and 1.0 mmol of [bis(triphenylphosphine)iminium]iodide as a halide salt were introduced and mixed at room temperature, and thus a catalyst system was obtained. 5.0 mmol of cyclohexene and 5.0 mL of methyl formate were added to this catalyst system, subsequently the reactor was purged with nitrogen gas at 0.5 MPa, and the system was maintained for 15 hours at 120° C. Thereafter, the reactor was cooled to room temperature, and the pressure was released. A portion of the remaining organic phase was withdrawn, and the components of the reaction mixture were analyzed by using gas chromatography. According to the analysis results, the amount of methyl cyclohexanecarboxylate produced by the reaction was 2.47 mmol (yield in terms of cyclohexene 49.4%).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([CH:11]2[C@H:16]([O:17]CC3C=CC=CC=3)[C@@H:15]([O:25]CC3C=CC=CC=3)[C@H:14]([O:33]CC3C=CC=CC=3)[C@@H:13]([CH2:41][O:42]CC3C=CC=CC=3)[O:12]2)=[CH:4][C:3]=1[CH2:50][C:51]1[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][CH:52]=1>C1COCC1.CO.[Pd]>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([C@H:11]2[C@H:16]([OH:17])[C@@H:15]([OH:25])[C@H:14]([OH:33])[C@@H:13]([CH2:41][OH:42])[O:12]2)=[CH:4][C:3]=1[CH2:50][C:51]1[CH:52]=[CH:53][C:54]([O:57][CH3:58])=[CH:55][CH:56]=1
Reactant: COc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3c(c2Cl)OCC3)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A suspension of compound 68 (340 mg, 0.48 mmol) and Pd/C (10% wt., 45 mg) in THF (4.0 mL) and MeOH (2.0 mL) was stirred at room temperature under an atmosphere of H2 for 24 hours. The mixture was filtered through a Celite pad and concentrated in vacuo. The residue was purified by prep HPLC (C18) to afford the product E019 (15 mg, 7%) as a white solid.
Reaction SMILES: C(O[C:4](=[O:6])C)=O.C(O)=O.[C@H:10]1([NH2:20])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1>CCOCC>[C@H:10]1([NH:20][CH:4]=[O:6])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1
Reactant: CC(=O)OC=O
Reactant: N[C@@H]1CCCc2ccccc21
Solvent: CCOCC
Solvent: O=CO
Product: O=CN[C@@H]1CCCc2ccccc21
Temperature: 25 °C

Procedure:
To a solution of acetic formic anhydride (0.056 mol) (prepared by stirring acetyl anhydride (7.36 ml, 78.0 mmol) and formic acid (2.94 ml, 78.0 mmol) at 50-60° C. for 2 h then cooling to room temperature) was added (r)-1,2,3,4-tetrahydro-1-naphthylamine (8.20 g, 55.7 mmol) dropwise with stirring at such a rate that the temperature never rose above 40° C. After stirring for 30 min, 300 mL of ether was added, and the solution was stirred at room temperature overnight. The reaction was diluted with ether, washed twice with water, twice with Sat. NaHCO3, with 5% HCl, and finally with water. The organic layer was dried with Na2SO4, filtered, and evaporated to dryness. flash chomatograph (SiO2, hexane/EtOAc=1:1 to pure EtOAc) afforded (R)—N-(1,2,3,4-tetrahydronaphthalen-1-yl)formamide as a white solid.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[OH:26])[O:22][CH2:21][CH2:20][CH:19]2[C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].C>O1CCOCC1.C(OCC)(=O)C>[C:9]([O:8][C:6]([C:5]1[CH:13]=[CH:14][C:2]([O:26][C:25]2[CH:24]=[C:23]3[C:18]([CH:19]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][CH2:21][O:22]3)=[CH:17][C:16]=2[Cl:15])=[CH:3][CH:4]=1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)C1CCOc2cc(O)c(Cl)cc21
Agent: CN(C)CC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)OC(C)(C)C)cc3)c(Cl)cc21
Temperature: 96 °C
Yield: 102.2 %

Procedure:
Tert-butyl 4-bromobenzoate (210.4 g, 818.2 mmol) was dissolved in 1 L of dioxane, which was previously degassed with argon, in a 4-neck 5 L round bottom flask equipped with a mechanical stirrer and a reflux condenser. Under argon flow and with stirring, ethyl 6-chloro-7-hydroxychroman-4-carboxylate (176.4 g, 687.2 mmol), N,N-dimethyl glycine hydrochloride (35.7 g, 346.2 mmol) and cuprous chloride (34.0 g, 342.9 mmol) were added via a funnel. Cesium carbonate then added and an additional 0.5 L of dioxane was added to the reaction mixture. The mixture was then heated at 95-97° C. for 20 hours. After cooling to ambient temperature, the reaction mixture was poured into 3 L of a 3:1 mixture of hexanes:ethyl acetate and activated charcoal (300 g) was added. After stirring periodically for 1 hour, the mixture was filtered thru GF/F paper, washing the filter cake with 2 L of a 3:1 mixture of hexanes:ethyl acetate. The resulting golden brown solution was concentrated to provide 304 g of crude ethyl 7-(4-(tert-butoxycarbonyl)-phenoxy)-6-chlorochroman-4-carboxylate. The crude product was dissolved in dichloromethane, concentrated onto silica gel and purified by flash column chromatography, eluting with a gradient of 10 to 25% ethyl acetate in hexanes to give ethyl 7-(4-(tert-butoxycarbonyl)phenoxy)-6-chlorochroman-4-carboxylate as a colorless, viscous oil (221 g, 74.3% yield). 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.8 Hz, 2H), 7.37 (s, 1H), 6.94 (d, J=8.8 Hz, 2H), 6.54 (s, 1H), 4.21-4.29 (m, 4H), 3.74 (t, J=5.3 Hz, 1H), 2.30-2.36 (m, 1H), 2.05-2.14 (m, 1H), 1.58 (s, 9H), 1.31 (t, J=7.0 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:16]=1[C:10]1([CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:9](=[O:17])[C:8]([C:18]([NH:20][CH2:21][C:22]([O:24]C(C)(C)C)=[O:23])=[O:19])=[C:7]2[OH:29].C(O)(C(F)(F)F)=O>O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:16]=1[C:10]1([CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:9](=[O:17])[C:8]([C:18]([NH:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[C:7]2[OH:29]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccc(F)c2C2(CCOCC2)C1=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CNC(=O)C1=C(O)c2cccc(F)c2C2(CCOCC2)C1=O
Reaction time: 0.25 h

Procedure:
In a flask was combined 1,1-dimethylethyl N-((8-fluoro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-yl)carbonyl)glycinate (1.7 g, 4.2 mmol) and TFA (50 mL). The reaction was stirred for 15 minutes and then concentrated to afford an oil. Water was added, affording a white precipitate that was filtered off and washed with water and ether. The solid was dried under vacuum at 50° C. (1.4 g, 98%). MS m/e=348 (M−1)−. Calculated for C17H16FNO6 349.1.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[O:11][CH3:12].[OH-].[Na+].O.Cl>CO.C(OCC)(=O)C>[F:1][C:2]1[C:3]([CH2:13][C:14]([OH:16])=[O:15])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[O:11][CH3:12]
Reactant: COC(=O)Cc1cc2ccsc2c(OC)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(F)c(CC(=O)O)cc2ccsc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.6 %

Procedure:
In 39 mL of methanol is dissolved 3.87 g of methyl 2-(6-fluoro-7-methoxybenzo[b]thiophen-5-yl)-acetate, to which is added 6.6 mL of 3 mol/L aqueous solution of sodium hydroxide. The mixture is stirred at ambient temperature for 4 hours. The reaction mixture is concentrated under reduced pressure, the residue thus obtained is mixed with water and ethyl acetate, and pH is adjusted to 1 with 6 mol/L hydrochloric acid. The organic layer is separated, washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. Thus, 2.80 g of 2-(6-fluoro-7-methoxybenzo[b]thiophen-5-yl)-acetic acid is obtained as a brown-colored crystalline product.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[OH-].[Na+]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4occc4c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2occc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a solution of methyl 2-(1-benzofuran-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (105 mg, crude) in methanol (30 mL) was added sodium hydroxide (59.7 mg, 1.49 mmol) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and adjusted to pH 5 with HCl (3N), extracted with ethyl acetate (3×80 mL) and the organic layers combined, dried over anhydrous magnesium sulfate and concentrated under vacuum to give the residue, which was purified by Prep-HPLC under the following conditions [(Agilent 1200 prep HPLC): Column, SunFire Prep C18, 19*50 mm 5 um; mobile phase, water with 0.05% NH3H2O and CH3CN (10% CH3CN up to 45% in 10 min); Detector, UV 220 nm] to afford 2-(1-benzofuran-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a yellow solid (26.3 mg).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.Br>C(Cl)(Cl)(Cl)Cl>[Br:19][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:13][CH:12]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)Cc1ccc(Oc2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Br)c1ccc(Oc2ccccc2)cc1

Procedure:
A mixture of 22.68 g of methyl [p-(phenoxy)phenyl]acetate, 17.195 g of N-bromosuccinimide and 20 drops of carbon tetrachloride saturated with HBr in 300 ml of carbon tetrachloride is heated at reflux for 28 hours. After cooling, the mixture is filtered through aluminum oxide, concentrated and distilled at 0.15 mm to give the product as a colorless oil (bp 162.5°-165° C).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[CH3:32].Cl>C(O)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[CH3:32])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: Cc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Product: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Yield: 23.9 %

Procedure:
A mixture of 1.0 g (3.15 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-20), 0.572 g (3.78 mmole) of 4-amino-3-methylbenzoic acid, 10 mL of ethanol and 40 mL of 1M hydrochloric acid was heated at reflux for 14 hours. The mixture was cooled and the white precipitate was collected by filtratration, washed with cold water and dried in vacuum to give 0.3251 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) as off-white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([F:17])[CH:11]=2)[CH2:4][CH2:3]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=2)[N:23]=[C:22]([C:31]([F:34])([F:33])[F:32])[CH:21]=1>CN1C(=O)CCC1>[F:16][C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([F:17])[CH:13]=1)[C:9]([NH:8][C@H:5]1[CH2:4][CH2:3][C@@H:2]([NH:1][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=3)[N:23]=[C:22]([C:31]([F:32])([F:33])[F:34])[CH:21]=2)[CH2:7][CH2:6]1)=[O:18]
Reactant: Fc1ccc2nc(C(F)(F)F)cc(Cl)c2c1
Reactant: NC1CCC(NC(=O)c2cc(F)cc(F)c2)CC1
Solvent: CN1CCCC1=O
Product: O=C(N[C@H]1CC[C@@H](Nc2cc(C(F)(F)F)nc3ccc(F)cc23)CC1)c1cc(F)cc(F)c1

Procedure:
A solution of N-(4-Amino-cyclohexyl)-3,5-difluorobenzamide (30 mg, 0.12 mmol) in NMP (1.0 mL) was treated with 4-chloro-6-fluoro-2-trifluoromethyl-quinoline (1 eq) and 3 eq (0.045 mL) TEA. The reaction was heated to 220 C in the microwave for 15 minutes. The crude compound was purified by reverse phase HPLC to provide the desired compound. MS (ESI (+)) m/e 468 (M+H)+; 1H NMR (500 MHz, DMSO) δ ppm 8.32 (m, 2 H), 7.98 (m, 1 H), 7.67 (m, 1 H), 7.58 (m, 2 H), 7.44 (m, 1 H), 7.15 (d, 1 H), 6.82 (s, 1 H), 1.95 (m, 4 H), 1.65-1.88 (m, 4 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:27]([NH:26][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:28])[CH:15]=[CH:14][C:13]=2[Cl:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2Cl)cc1
Reactant: O=C=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)NC3CCCCC3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
A mixture of 5′-amino-2′-chloro-biphenyl-4-carboxylic acid ethyl ester (350 mg) and cyclohexyl isocyanate (0.32 ml) in dry THF (15 ml) containing triethylamine (0.62 ml) was stirred at room temp for 48 h. The mixture was then evaporated and the residue partitioned between water and DCM. The dried extracts were evaporated giving the crude title compound as a white solid (616 mg, >100%, contaminated with dicyclohexyl-urea)
Reaction SMILES: [OH:1][C@H:2]([C@@H:13]([NH:18][C:19](=[O:42])[O:20][C@H:21]([CH2:26][N:27]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[N:28]1)[C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:14][CH2:15][CH2:16][CH3:17])[CH2:3][NH:4][C:5]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:6].O[C@@H]([C@@H](NC(=O)O[C@H](CN1C=CC(C2C=CC(C(F)(F)F)=CC=2)=N1)C(C)(C)C)CCCC)CNC(N1CCOCC1)=O.O[C@H]([C@@H](NC(=O)O[C@H](CN1C=CC(C2C=CC(C(F)(F)F)=CC=2)=N1)C(C)(C)C)CCCC)CNS(C1C=CC=CN=1)(=O)=O.O[C@@H]([C@@H](NC(=O)O[C@H](CN1C=CC(C2C=CC(C(F)(F)F)=CC=2)=N1)C(C)(C)C)CCCC)CNS(C1C=CC=CN=1)(=O)=O>>[N:7]1([C:5]([NH:4][CH2:3][C:2]([C@@H:13]([NH:18][C:19](=[O:42])[O:20][C@H:21]([CH2:26][N:27]2[CH:31]=[CH:30][C:29]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:39])([F:41])[F:40])=[CH:36][CH:37]=3)=[N:28]2)[C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:1])=[O:6])[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1
Reactant: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@@H](O)CNC(=O)N1CCOCC1
Agent: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@H](O)CNC(=O)N1CCOCC1
Agent: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@H](O)CNS(=O)(=O)c1ccccn1
Product: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)C(=O)CNC(=O)N1CCOCC1
Yield: 50 %

Procedure:
(1S)-2,2-Dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{[(4-morpholinylcarbonyl)amino]acetyl}pentylcarbamate was prepared (50% yield) as in example 3g except that (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1 S)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate & (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1R)-1-hydroxy-2-[(4-morpholinylcarbonyl)amino]ethyl}pentylcarbamate were substituted for (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate & (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate. 1H-NMR (300 MHz, DMSO-d6): δ 8.00 (d, J=8 Hz, 2H), 7.74 (m, 3H), 7.47 (d, J=8 Hz, 1H), 6.81–6.72 (m, 2H), 4.87 (d, J=9 Hz, 1H), 4.48 (m, 1H), 4.22 (m, 1H), 3.88-3.75 (m, 2H), 3.53 (t, J=4 Hz, 4H), 3.38 under water peak (m, 1H), 3.24 (t, J=4 Hz, 4H), 1.55 (m, 1H), 1.33 (m, 1H), 1.15–0.85 (m, 13H), 0.72 (t, J=6 Hz, 3H); ES-LCMS m/z 596 (M+H); HRMS C29H40N5O5F3 m/Z 596.3060 (M+H)+Cal; 596.3047 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(O[CH2:33][C@@H:34]2[CH2:38][O:37][C:36](=[O:39])[NH:35]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.[I-].C([N+](CC)(CC)CC)C.C1(C)C=CC=CC=1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])/[N:7]([CH2:33][C@H:34]2[CH2:38][O:37][C:36](=[O:39])[NH:35]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COC(=O)N2)cc1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CC[N+](CC)(CC)CC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1COC(=O)N1
Yield: 42.9 %

Procedure:
A mixture of Example 244A (180 mg, 0.55 mmol), (S)-(2-oxo-oxazolidin-4-yl)methyl 4-methylbenzenesulfonate (180 mg, 0.67 mmol), potassium carbonate (153 mg, 1.1 mmol), tetrabutylammonium iodide (10 mg, 0.03 mmol), tetrabutylammonium hydrogen sulfate (10 mg, 0.03 mmol) and tetraethylammonium iodide (10 mg, 0.04 mmol) in toluene (35 mL) was refluxed for 14 h. The mixture was washed with water, brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography over silica gel (EtOAc as eluent) to afford 100 mg of the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.36 (s, 9H), 3.92 (s, 3H), 4.11-4.26 (m, 2H), 4.30-4.41 (m, 2H), 4.57 (t, J=8.6 Hz, 1H), 6.33 (s, 1H), 6.62 (s, 1H), 6.93 (d, J=8.8 Hz, 1H), 7.35 (dd, J=9.0, 2.9 Hz, 1H), 7.79 (d, J=2.7 Hz, 1H). MS (DCI/NH3) m/z 424 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]2[CH2:6][O:7][CH2:8][CH:4]2[O:3]S1(=O)=O.[Br:11][C:12]1[CH:24]=[C:23]2[C:15]([C:16]3[C:17](=[O:32])[C:18]4[CH:30]=[CH:29][C:28](O)=[CH:27][C:19]=4[C:20]([CH3:26])([CH3:25])[C:21]=3[NH:22]2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].S(=O)(=O)(O)O>CN(C=O)C.O.C1COCC1>[Br:11][C:12]1[CH:24]=[C:23]2[C:15]([C:16]3[C:17](=[O:32])[C:18]4[CH:30]=[CH:29][C:28]([O:3][CH:4]5[CH:5]([OH:1])[CH2:6][O:7][CH2:8]5)=[CH:27][C:19]=4[C:20]([CH3:25])([CH3:26])[C:21]=3[NH:22]2)=[CH:14][CH:13]=1
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(Br)ccc21
Reactant: O=S1(=O)OC2COCC2O1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)c2cc(OC3COCC3O)ccc2C(=O)c2c1[nH]c1cc(Br)ccc21
Temperature: 80 °C
Reaction time: 15 h
Yield: 72.2 %

Procedure:
Under nitrogen atmosphere, tetrahydro-furo[3,4-d][1,3,2]dioxathiol 2,2-dioxide (71.5 mg, 0.420 mmol) was dissolved in DMF (1.40 mL), added with 3-bromo-8-hydroxy-6,6-dimethyl-5,6-dihydro-benzo[b]carbazol-11-one (Compound A5-1, 50.0 mg, 0.140 mmol) and cesium carbonate (228 mg, 0.700 mmol), and stirred at 80° C. for 15 hr. Subsequently, sulfuric acid (0.10 mL, 18 M), THF (3.00 mL) and water (0.50 mL) were added to the mixture, which was then stirred at room temperature for 24 hr and further at 60° C. for 24 hr. The reaction solution was added to water, extracted with ethyl acetate, washed with water, saturated aqueous solution of sodium bicarbonate, and saturated brine, and dried over sodium sulfate. After filtering and concentration under reduced pressure, the resulting residues were washed with dichloromethane and purified by NH silica gel column chromatography (ethyl acetate/THF) to obtain the target compound (44.7 mg, 72%).
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]2[C:12]=1I)([CH3:3])[CH3:2].[F:14][C:15]1[CH:16]=[CH:17][C:18]2=[C:19]([CH:35]=1)[O:20][CH2:21][C:22]1[CH:32]=[C:31]([CH:33]=[O:34])[CH:30]=[CH:29][C:23]=1/[C:24]/2=[C:25](/[CH3:28])\[C:26]#[N:27]>>[F:14][C:15]1[CH:16]=[CH:17][C:18]2=[C:19]([CH:35]=1)[O:20][CH2:21][C:22]1[CH:32]=[C:31]([CH:33]([OH:34])[C:12]3[N:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]4=[N:5][C:4]=3[CH:1]([CH3:3])[CH3:2])[CH:30]=[CH:29][C:23]=1/[C:24]/2=[C:25](/[CH3:28])\[C:26]#[N:27]
Reactant: CC(C)c1nc2ccccn2c1I
Reactant: C/C(C#N)=C1/c2ccc(C=O)cc2COc2cc(F)ccc21
Product: C/C(C#N)=C1/c2ccc(C(O)c3c(C(C)C)nc4ccccn34)cc2COc2cc(F)ccc21
Yield: 45.2 %

Procedure:
[step 3] Using 2-isopropyl-3-iodoimidazo[1,2-a]pyridine (366 mg, 1.28 mmol) obtained in step 2 and (E)-2-(3-fluoro-8-formyldibenzo[b,e]oxepin-11(6H)-ylidene)propanenitrile (250 mg, 0.853 mmol) obtained in Reference Example 5, and in the same manner as in Reference Example 8A, step 3, (E)-2-{3-fluoro-8-[hydroxy(2-isopropylimidazo[1,2-a]pyridin-3-yl)methyl]dibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (175 mg, 45%) was obtained.