Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]2)[CH2:3]1.CN1CCOCC1.[Br:17][C:18]1[CH:19]=[C:20]([C:31](Cl)=[O:32])[C:21]2[O:26][CH:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[C:22]=2[CH:30]=1>C(Cl)(Cl)Cl>[Br:17][C:18]1[CH:19]=[C:20]([C:31]([NH:1][CH:2]2[CH:7]3[CH2:8][CH2:9][N:4]([CH2:5][CH2:6]3)[CH2:3]2)=[O:32])[C:21]2[O:26][CH:25]([CH3:27])[C:24](=[O:28])[N:23]([CH3:29])[C:22]=2[CH:30]=1
Reactant: CC1Oc2c(C(=O)Cl)cc(Br)cc2N(C)C1=O
Reactant: NC1CN2CCC1CC2
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: CC1Oc2c(C(=O)NC3CN4CCC3CC4)cc(Br)cc2N(C)C1=O

Procedure:
To a solution of 1.6 g of 3-aminoquinuclidine and 1.35 g of N-methylmorpholine in 25 ml of chloroform is added a solution of 4.0 g of 6-bromo-3,4-dihydro-2,4-dimethyl-3-oxo -2H-1,4-benzoxazine-8-carboxylic acid chloride in 20 ml of chloroform under cooling and stirring followed by stirring at room temperature for 3 hours. The resultant solution is washed with water, aqueous sodium hydrogen carbonate and then water, and dried over magnesium sulfate. After the solvent is distilled off under reduced pressure, the residue is recrystallized from ethanol-isopropyl ether to give 6-bromo-3,4-dihydro-2,4-dimethyl-3-oxo-N-(3-quinuclidinyl) -2H-1,4-benzoxazine-8-carboxamide, melting at 287°-288° C.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([Br:12])[C:9]2[C:4](=[C:5]([Br:22])[CH:6]=[C:7]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:14])[CH:8]=2)[N:3]=1.C1(C)C=CC=CC=1.[O:30]([CH3:32])[Na]>O1CCCC1>[Br:12][C:10]1[C:9]2[C:4](=[C:5]([Br:22])[CH:6]=[C:7]([C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[O:14])[CH:8]=2)[N:3]=[C:2]([O:30][CH3:32])[CH:11]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cc(Br)c2nc(Br)cc(Br)c2c1
Reactant: CO[Na]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1cc(Br)c2cc(C(=O)c3ccc(Cl)cc3)cc(Br)c2n1
Temperature: 66 °C
Reaction time: 2 h

Procedure:
Into a 100-mL round-bottom flask, was placed 2,4,8-tribromo-6-[(4-chlorophenyl)carbonyl]quinoline (2 g, 3.97 mmol, 1.00 equip), toluene (20 mL), and tetrahydrofuran (2 mL). To the resulting mixture was then added NaOCH3 (642 mg, 11.89 mmol, 3.00 equip). The resulting solution was stirred for 2 h at 66° C. Then another batch of NaOCH3 (642 mg, 11.89 mmol, 3.00 equip) was added to the solution. The resulting solution was allowed to react, with stirring, for an additional 2 h at 66° C. And then a final batch of NaOCH3 (642 mg, 11.89 mmol, 3.00 equip) was added to the solution. The resulting solution was allowed to react, with stirring, for an additional 2 h at 66° C. The reaction was then quenched by the addition of saturated sodium bicarbonate (200 mL). The resulting solution was extracted with DCM (2×100 mL) and the organic layers combined and dried over anhydrous sodium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 4,8-dibromo-6-[(4-chlorophenyl)carbonyl]-2-methoxyquinoline as a yellow solid. LCMS (ES, m/z) 456 [M+H]+
Reaction SMILES: CC([NH:8][C:9](=[O:12])[CH:10]=[CH2:11])(C)[CH2:3][C:4](=[O:6])[CH3:5].S(O)(O)(=O)=O.[OH:18][C:19]1([CH3:29])OC(C=C)=NC(C)(C)[CH2:20]1.N>O>[C:9]([NH2:8])(=[O:12])[CH:10]=[CH2:11].[CH3:3][C:4]([CH3:5])=[O:6].[CH3:20][C:19]([CH3:29])=[O:18]
Reactant: C=CC1=NC(C)(C)CC(C)(O)O1
Reactant: C=CC(=O)NC(C)(C)CC(C)=O
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: C=CC(N)=O
Product: CC(C)=O

Procedure:
A process for preparing N-(1,1-dimethyl-3-oxobutyl)acrylamide which comprises (1) contacting a dispersion of 5,6-dihydro-6-hydroxy-4,4,6-trimethyl-2-vinyl-1,3(4H)-oxazine sulfate (1:1) in a water-immiscible organic solvent with a neutralizing or alkalizing amount of gaseous ammonia at a temperature between about 10° C. and 30° C. to form a solution of diacetone acrylamide in said organic solvent and a precipitate of crystalline ammonium sulfate; (2) separating the crystals of ammonium sulfate; (3) cooling the organic mother liquors recovered from step (2) to about -10° C. to 20° C. to crystallize N-(1,1-dimethyl-3-oxobutyl)acrylamide therefrom; and (4) recovering the crystals of N-(1,1-dimethyl-3-oxobutyl)acrylamide, washing the recovered crystals with a cold water-immiscible organic solvent, and drying the same.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:2]2[N:7]=[C:6]([NH2:8])[CH:5]=[N:4][CH:3]=2)[CH:10]=1
Reactant: Nc1cncc(Cl)n1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Nc1cncc(-c2cccnc2)n1
Reaction time: 16 h
Yield: 85.9 %

Procedure:
An oven dried resealable Schlenk tube was charged with 6-chloropyrazin-2-amine (0.73 g, 5.71 mmol), 3-pyridineboronic acid (0.91 g, 7.42 mmol), dioxane (50 mL) and a 2M aqueous solution of cesium carbonate (8.5 mL, 17.13 mmol). The Schlenk tube was subjected to three cycles of evacuation-backfilling with argon, and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (290 mg, 0.35 mmol) was added. After three new cycles of evacuation-backfilling with argon, the Schlenk tube was capped and placed in a 90° C. oil bath. After 16 h, the mixture was cooled, partitioned between water and ethyl acetate, the aqueous phase extracted twice with ethyl acetate, the organic layers washed with brine, dried (MgSO4) and evaporated. The residue was purified by silica gel flash chromatography (95:5 dichloromethane/methanol) to give the title compound (845 mg, 86%) as a solid.
Reaction SMILES: C(O[C:4]([C:6]1[N:11]2[C:12]([C:15](=[O:20])C(Cl)(Cl)Cl)=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)=[O:5])C.[NH3:21]>C(#N)C>[N:14]1[CH:13]=[C:12]2[N:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=13)[C:4](=[O:5])[NH:21][C:15]2=[O:20]
Reactant: CCOC(=O)c1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Reactant: N
Solvent: CC#N
Product: O=c1[nH]c(=O)c2cnc3cccc1n32
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.8 %

Procedure:
To a solution of 2.64 g (7.55 mmol) of 5-ethoxycarbonyl-3-trichloroacetylimidazo[1,2-a]pyridine in 20 ml of acetonitrile was added 2.5 ml of 25% aqueous ammonia. The mixture was stirred for 5 hours at room temperature. The resulting crystals were collected by filtration and washed with acetonitrile to give 393 mg of the desired compound (27.8%, pale brown solid).
Reaction SMILES: Br[C:2]1[C:11]([OH:12])=[C:10]([CH3:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.[Cl:29]C1C=CC=CC=1Cl>CN(C)C1C=CN=CC=1>[Cl:29][C:2]1[C:11]([O:12][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:10]([CH3:13])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Clc1ccccc1Cl
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Cc1cc2ncccc2c(Br)c1O
Agent: CN(C)c1ccncc1
Product: COc1cc2nccc(Oc3c(C)cc4ncccc4c3Cl)c2cc1OC
Temperature: 140 °C
Reaction time: 6 h
Yield: 10 %

Procedure:
5-Bromo-6-hydroxy-7-methyl-quinoline (110 mg), 4-chloro-6,7-dimethoxyquinoline (330 mg), and 4-dimethylaminopyridine (240 mg) were suspended in o-dichlorobenzene (10 ml), and the mixture was stirred at 140° C. for 6 hr. The reaction solution was cooled to room temperature, and the solvent was removed therefrom by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (19 mg, yield 10%).
Reaction SMILES: [C:1]([O:5][CH:6]([O:10][C:11]([NH:13][CH2:14][C:15]1([CH2:21][C:22]([O:24]CC2C=CC=CC=2)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:12])[CH2:7][CH2:8][CH3:9])(=[O:4])[CH2:2][CH3:3]>C(O)C.[Pd]>[C:1]([O:5][CH:6]([O:10][C:11]([NH:13][CH2:14][C:15]1([CH2:21][C:22]([OH:24])=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:12])[CH2:7][CH2:8][CH3:9])(=[O:4])[CH2:2][CH3:3]
Reactant: CCCC(OC(=O)CC)OC(=O)NCC1(CC(=O)OCc2ccccc2)CCCCC1
Agent: [Pd]
Solvent: CCO
Product: CCCC(OC(=O)CC)OC(=O)NCC1(CC(=O)O)CCCCC1
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
A suspension of (135) (2.5 g, 5.77 mmol) and 10% Pd/C (250 mg) in ethanol (100 mL) was stirred under an atmosphere of hydrogen (balloon) for 30 minutes then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the crude product, which was purified by preparative LC-MS to give 1.21 g of the desired acid (131). (CDCl3, 400 MHz): 0.97 (t, J=7.2 Hz, 3H), 1.15 (t, J=7.2 Hz, 3H), 1.50–1.38 (m, 12H), 1.72 (m, 2H), 2.32 (m, 4H), 3.18 (dd, J=6.4, 4.4 Hz, 2H), 5.27 (t, J=6.4 Hz, 1H), 6.72 (t, J=5.6 Hz, 1H). MS (ESI) m/z 344.39 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[H][H]>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C.[OH-].[Pd+2].[OH-]>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:2]=1[F:1]
Reactant: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC

Procedure:
4-Chloro-6,7-dimethoxyquinazoline (10.23 g) and 2-fluoro-4-nitrophenol (14.37 g) were suspended in monochlorobenzene (100 ml), and the suspension was heated under reflux overnight. The solvent was removed by distillation under the reduced pressure, and the residue was washed with toluene, was filtered, and was dried. The crystal thus obtained was then suspended in an aqueous sodium hydroxide solution, and the suspension was filtered, followed by drying to give 4-(3-fluoro-4-nitrophenoxy)-6,7-dimethoxyquinoline (14.2 g, yield 90%). 4-(2-Fluoro-4-nitrophenoxy)-6,7-dimethoxy-quinoline (4.57 g) was dissolved in ethyl acetate/N,N-dimethylformamide/triethylamine (100 ml/100 ml/20 ml) to prepare a solution. Palladium hydroxide (1.2 g) was added to the solution, and the mixture was stirred in a hydrogen atmosphere at room temperature overnight. After filtration through Celite, the solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to quantitatively give 4.27 g of the title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([F:13])=[CH:5][C:6]([F:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[CH3:14]O>>[Br:2][C:3]1[C:4]([F:13])=[CH:5][C:6]([F:12])=[C:7]([CH:11]=1)[C:8]([O:10][CH3:14])=[O:9]
Reactant: CO
Reactant: O=C(O)c1cc(Br)c(F)cc1F
Agent: Cl
Product: COC(=O)c1cc(Br)c(F)cc1F
Temperature: 95 °C

Procedure:
Concentrated hydrochloric acid (10.4 mL, 127 mmol) was slowly added to a mixture of 5-bromo-2,4-difluorobenzoic acid (0.999 g, 4.21 mmol) in methanol (26 mL). The mixture was heated at 95° C. for 18 hours. The reaction was cooled and then concentrated in vacuo. The residue was diluted with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic extract was washed with brine (2×50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil (0.847 g). The crude product was purified by silica gel chromatography (Biotage®, 100 g SNAP cartridge, 5 to 50% EtOAc in Heptane) to afford the title compound as clear crystalline solid (0.544 g).
Reaction SMILES: [N:1]1[N:2]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=2)[CH:3]=[C:4]2[CH2:10][CH2:9][NH:8][CH2:7][CH2:6][C:5]=12.[C:20]1(=O)[CH2:24][CH2:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>ClCCl.C(O)(=O)C>[CH:20]1([N:8]2[CH2:9][CH2:10][C:4]3=[CH:3][N:2]([C:11]4[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=4)[N:1]=[C:5]3[CH2:6][CH2:7]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NC(=O)c1ccc(-n2cc3c(n2)CCNCC3)cc1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: NC(=O)c1ccc(-n2cc3c(n2)CCN(C2CCCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-(5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzamide (may be prepared as described in Description 37) (31 mg, 0.12 mmol) in dichloromethane (3 ml) was added cyclopentanone (20 mg, 0.24 mmol) and acetic acid (2 drops). The resulting mixture was stirred at room temperature, under argon, for 20 minutes. Sodium triacetoxyborohydride (51 mg, 0.24 mmol) was added and stirring continued for 2 hours. A further 6 eq. of cyclopentanone was added and stirring continued over the weekend. Methanol was added and the crude mixture was purified by SCX, eluting with methanol and then with 2M ammonia/methanol. The basic fractions were combined and solvent evaporated in vacuo to afford the title compound (E23). MS (ES+) m/e 325 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=O.[OH-].[K+].Br[CH:17](Br)[CH3:18]>O.C(O)C>[CH2:17]1[CH2:18][O:11][C:10]2[C:2](=[C:3]([CH:7]=[CH:8][CH:9]=2)[C:4]([OH:6])=[O:5])[O:1]1
Reactant: CC(Br)Br
Reactant: O=C(O)c1cccc(O)c1O
Agent: O=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cccc2c1OCCO2
Yield: 96.7 %

Procedure:
2,3-Dihydroxybenzoic acid (25 g, 0.16 mol) was heated under reflux in an oxygen-free atmosphere with potassium hydroxide (26.42 g, 0.47 mole) and dibromoethane (13.46 g, 0.07 mol) using 95% ethanol (60 ml) and water (142 ml as solvent as described in J. Org. Chem. (1948), 13, 489-95 to give 2,3-ethylenedioxybenzoic acid (12.2 g, 43%), m.pt. 195°-196° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[O:13].I[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[O:13])[CH3:16]
Reactant: CCI
Reactant: O=Cc1c(O)ccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc2ccccc2c1C=O
Temperature: 25 °C

Procedure:
2-Hydroxy-1-naphthaldehyde (10 g., 0.058 mole) was combined with acetone (120 ml.), iodoethane (9.9 g., 0.063 mole) and anhydrous potassium carbonate (8.0 g., 0.058 mole) and the mixture heated to reflux for 48 hours. The reaction mixture was cooled to room temperature, filtered and filtrate evaporated to solids (9.0 g.) Recrystallization from isopropyl ether afforded purified 2-ethoxy-1-naphthaldehyde in two crops (4.5 g. and 0.5 g., m.p. 106°-109° C.).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li:10])CCC.[S:11](=[O:14])(=[O:13])=[O:12]>CCCCCCC.CCCCCC.ClCCl>[S:11]([N+:1]1[CH:5]=[CH:4][N:3]([S:11]([O-:14])(=[O:13])=[O:12])[CH:2]=1)([O-:14])(=[O:13])=[O:12].[Li+:10]
Reactant: [Li]CCCC
Reactant: O=S(=O)=O
Reactant: c1c[nH]cn1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCCCCC
Product: O=S(=O)([O-])n1cc[n+](S(=O)(=O)[O-])c1
Product: [Li+]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 1.34 g of imidazole in suspension in heptane is added 1 ml of 2M butyllithium in hexane and the mixture is stirred at room temperature for 24 hours. To this suspension, are added 3.2 g of sulfur trioxide in dichloromethane. The slurry is stirred further for 24 hours and the solids are separated by centrifugation to yield lithium [1,3 disulfonatoimidazolium].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[S:10][C:3]=12.[CH3:16][NH:17][C:18]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([OH:29])=[CH:26][CH:27]=2)[N:22]([CH3:30])[C:21]=1[CH3:31])=[O:19].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:30][N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[C:25]([O:29][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[S:10][C:3]=34)[CH:24]=2)[C:20]([C:18]([NH:17][CH3:16])=[O:19])=[C:21]1[CH3:31]
Reactant: CNC(=O)c1c(C)n(C)c2cc(O)ccc12
Reactant: CN(C)C(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(C)n(C)c2cc(Oc3ccnc4cc(C(=O)N(C)C)sc34)ccc12
Yield: 72.5 %

Procedure:
This material was prepared by the reaction 7-chloro-N,N-dimethylthieno[3,2-b]pyridine-2-carboxamide 33a (0.077 g, 0.32 mmole) and 6-hydroxy-N,1,2-trimethyl-1H-indole-3-carboxamide 16e (0.070 g, 0.32 mmole) and Cs2CO3 (0.104 g, 0.32 mmole) in a manner as previously described for example 1 to give a pale yellow solid (0.098 g, 73%). 1H NMR (300 MHz, CD3OD) δ 8.38 (1H, d, J=5.5 Hz), 7.75 (1H, d, J=8.7 Hz), 7.66 (1H, s), 7.28 (1H, d, J=2.1 Hz), 6.94 (1H, dd, J=2.1, 8.7 Hz), 6.60 (1H, d, J=5.5 Hz), 3.61 (3H, s), 3.21 (6H, m), 2.87 (3H, s), 2.56 (3H, s). ESIMS (MH+): 423.05.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:3]=1[C:4]([NH:6][C:7]([N:9]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=1)[NH:10]C(OC(C)(C)C)=O)=[O:8])=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:9]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[C:20]([O:28][CH3:29])[CH:19]=2)[N:10]=1
Reactant: COC(=O)c1ccc(N(NC(=O)OC(C)(C)C)C(=O)NC(=O)c2c(F)cccc2Cl)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1OC
Yield: 87.4 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-((2-chloro-6-fluorobenzoyl)carbamoyl)-2-(3-methoxy-4-(methoxycarbonyl)phenyl)hydrazinecarboxylate (3.0 g, 6.06 mmol), DCM (30 mL) and trifluoro acetic acid (2.0 mL) to afford 2.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.81 (s, 3H), 3.85 (s, 3H), 7.34-7.73 (m, 6H), 12.80 (s, 1H); MS (m/z): 376.16 (M−H)−.
Reaction SMILES: [F:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([C@@H:9]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C@H:10]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH3:11])=[O:8])[CH2:3]1.[OH:35]O.[OH-].[Na+].Cl>C1COCC1.O>[C:30]([O:29][C:28](=[O:34])[NH:27][C@H:9]([C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([F:1])[CH2:3]1)=[O:8])[C@H:10]([C:12]1[CH:13]=[CH:14][C:15]([OH:35])=[CH:16][CH:17]=1)[CH3:11])([CH3:31])([CH3:32])[CH3:33]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](c1ccc(O)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1

Procedure:
To a solution of the material from Step A (0.5 g, 1.0 mmol) in THF (10 mL) at 0° C. was added sequentially 30% hydrogen peroxide (0.18 mL, 1.5 mmol) and 3N aqueous sodium hydroxide (0.35 g, 1.0 mmol). After 2 h at this temperature water (30 mL) was added, and the resulting solution was adjusted to pH 5 by the addition of 1N hydrochloric acid. The mixture was extracted with ethyl acetate, and the combined extracts were washed with saturated sodium thiosulfate until the organic phase showed a negative peroxide test. The combined organics were washed with brine, dried (magnesium sulfate), and concentrated in vacuo. The residue was purified by silica gel chromatography (50% ethyl acetate in hexane) to give the title compound as a white foam. LC/MS 389.3 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]#[C:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br.[I-:13].[Na+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]#[C:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][I:13]
Reactant: [I-]
Reactant: COC(=O)C#CCCCCCBr
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)C#CCCCCCI
Yield: 98.6 %

Procedure:
To a solution of 4.05 g of 8-bromo-2-octynoic acid methyl ester (prepared as described hereafter) in 24 ml of acetone was added 3.9 g of sodium iodide, the mixture was refluxed with heating for one hour, and concentrated under reduced pressure. The residue was dissolved in water, extracted with diethyl ether, the extract was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure to give 4.80 g of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][C:2]([O-:5])(C)C.[K+].[CH3:7][O:8][C:9](=[O:25])[CH2:10][N:11]=C(C1C=CC=CC=1)C1C=CC=CC=1.C([Cl:29])(=O)C.Cl>C1COCC1>[ClH:29].[CH3:7][O:8][C:9](=[O:25])[CH:10]([C:2](=[O:5])[CH3:1])[NH2:11]
Reactant: COC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(N)C(C)=O
Reaction time: 0.5 h

Procedure:
Potassium tert-butylate (17.8 g, 157.9 mmol) was introduced into THF (120 ml), and a solution of N-diphenylmethylideneglycine methyl ester (40 g, 157.9 mmol) in THF (60 ml) was added at −70° C. After the yellowish solution had been stirred for 30 minutes at this temperature, it was added dropwise at −70° C. to a solution of acetyl chloride (12.4 g, 157.9 mmol) in THF (70 ml). After the mixture had been stirred at this temperature for 1.75 hours, 3N HCl (160 ml) was added, and the yellowish suspension was stirred for a further 10 minutes at room temperature. The THF was removed at room temperature on a rotary evaporator, and the remaining aqueous phase was washed 3× with diethyl ether. The aqueous phase was freeze-dried and the residue was extracted by stirring with methanol. The methanolic solution of the product was concentrated on a rotary evaporator at 35° C. Yield: 26.4 g (157.9 mmol, quant., yellowish solid).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][NH:14][C:15]2[CH:20]=[CH:19][C:18](C(C)C)=[CH:17][CH:16]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:28]=1[N:36]=[C:37]=[O:38])([CH3:26])[CH3:25].[C:39]1(C)[CH:44]=CC=C[CH:40]=1>>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][N:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=2[CH:39]([CH3:44])[CH3:40])[C:37]([NH:36][C:28]2[C:29]([CH:33]([CH3:34])[CH3:35])=[CH:30][CH:31]=[CH:32][C:27]=2[CH:24]([CH3:25])[CH3:26])=[O:38])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1ccc(NCc2cnn(Cc3ccccc3)c2)cc1
Reactant: Cc1ccccc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1ccccc1N(Cc1cnn(Cc2ccccc2)c1)C(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [(1-benzylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.17 g) in toluene (5 mL) was added 2,6-diisopropylphenyl isocyanate (0.12 mL) and the mixture was stirred overnight at room temperature. The reaction mixture was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give N-[(1-benzylpyrazol-4-yl)methyl]-N′-(2,6-diisopropylphenyl)-N-(isopropylphenyl)urea (0.24 g).