Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[F:11][Sb-:12]([F:17])([F:16])([F:15])([F:14])[F:13].[Na+].[CH2:19]([S:37][CH3:38])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[Br-].[Na+]>C(C(C)=O)C>[F:11][Sb-:12]([F:17])([F:16])([F:15])([F:14])[F:13].[CH3:38][S+:37]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: O=C(CBr)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCSC
Agent: F[Sb-](F)(F)(F)(F)F
Agent: [Br-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCCCCCC[S+](C)CC(=O)c1ccccc1

Procedure:
In a 100 mL Erlenmeyer flask were combined 10 g (0.05 mol) phenacyl bromide, 12.93 g (0.05 mol) sodium hexafluoroantimonate, 15 g (0.05 mol) methyl octadecyl sulfide and 40 mL methyl ethyl ketone (2-butanone). The reaction mixture was heated to boiling and maintained at this temperature for 30 minutes. During this time, sodium bromide was observed to precipitate. The reaction mixture was filtered to remove the inorganic salts and the resulting solution placed on a rotary evaporator to remove solvents. The product crystallized to give the desired salt, m.p. 80-82° C. Recrystallization from isopropanol gave a very light tan salt with a melting point of 79-80° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C@H:10]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH2:11][CH:12]=C)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2].C(Cl)Cl.C1C=C(Cl)C=C(C(OO)=[O:32])C=1.[C:35]([O-:38])([O-])=O.[K+].[K+]>O>[C:1]([C:3]1[CH:4]=[C:5]([C@H:10]([NH:14][S:15]([C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:16])=[O:32])[CH2:11][CH:12]2[CH2:35][O:38]2)[CH:6]=[C:7]([F:9])[CH:8]=1)#[N:2]
Reactant: O=C([O-])[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC[C@@H](N[S@](=O)C(C)(C)C)c1cc(F)cc(C#N)c1
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)S(=O)(=O)N[C@H](CC1CO1)c1cc(F)cc(C#N)c1
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
A 22 L 4 neck round bottom flask was charged with (R)-N-((R)-1-(3-cyano-5-fluorophenyl)but-3-enyl)-2-methylpropane-2-sulfinamide (I-18) (441 g, 1.5 mol) and DCM (6 L). The solution was cooled to <0° C. and mCPBA (737 g, 3.0 mol) was added in portions over 60 minutes at a batch temperature <10° C. (Note: a mild exotherm and gas evolution were observed. A white suspension was obtained after the addition). The reaction mixture was stirred at 0-10° C. over 20 minutes and warmed to room temperature and stirred at room temperature for 3 hours. Additional mCPBA (387.5 g, 1.54 mol) was added and the mixture was stirred at room temperature for an additional 18 hours. The reaction was monitored by HPLC until deemed complete. The mixture was cooled to <10° C. and water (7.3 L) was added to the reaction mixture. (Note: exotherm from 5° C. to 12° C.) A saturated K2CO3 solution (1.94 L) was added until pH˜9.0 was reached. (Note: A suspension was initially obtained and a biphasic solution was obtained after stirring). The DCM layer was separated and to it was added 10% sodium bisulfite solution (2.9 L) over 15 minutes at 4 to 9° C. (aqueous layer pH 3-4). The mixture was stirred 30 minutes at 9 to 12° C. and the DCM layer was then washed with a mixture of brine (3 L) and aqueous saturated NaHCO3 (2 L) (aqueous layer pH=7). Aqueous saturated K2CO3 (150 mL) was added until pH=8.5 at 10 to 16° C. The DCM solution was concentrated under vacuum (250 to 50 torr) at 25° C. to give N-((1R)-1-(3-cyano-5-fluorophenyl)-2-(oxiran-2-yl)ethyl)-2-methylpropane-2-sulfonamide (I-19) as an oil (as a mixture of diastereoisomers). 1H NMR (400 MHz, CDCl3) δ 748-7.50 (m, 1 H), 7.30-7.40 (m, 1 H), 7.28-7.29 (m, 1 H), 5.28-5.37 (m, 1 H), 4.77-4.88 (m, 1 H), 2.89-3.00 (m, 1 H), 2.79-2.85 (m, 1 H), 2.48-2.62 (m, 1 H), 2.21-2.31 (m, 1 H), 1.86-1.84 (m, 1 H), 1.36 (s, 9 H).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([NH:14][C:15](=[O:17])[CH3:16])=[CH:12][CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]=1[OH:18])[CH:2]=[CH2:3].C(N(CC)CC)C.[CH3:26][O:27][CH2:28]Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:26][O:27][CH2:28][O:18][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[C:13]([NH:14][C:15](=[O:17])[CH3:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COCCl
Reactant: C=CCc1c(NC(C)=O)ccc(C(=O)OC)c1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCc1c(NC(C)=O)ccc(C(=O)OC)c1OCOC
Reaction time: 24 h

Procedure:
To a solution of 10 g (40.2 mmol) of methyl 3-allyl-4-acetylaminosalicylate in 50 ml of CH2Cl2 is added 7.9 ml (56.3 mmol) of triethylamine in one portion at room temperature, followed by 3.3 ml (44.2 mmol) of chloromethyl methyl ether dropwise at room temperature. Stirring is continued for 24 hours at room temperature. The reaction mixture is diluted with ethyl acetate and washed with water. The organic layer is dried over MgSO4, filtered and concentrated. Flash chromatography (10% EtOAc/hexanes) affords pure methyl 2-methoxymethyloxy-3-allyl-4-acetylaminobenzoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH2:13])[CH:5]=1.N1C=CC=CC=1.[Cl:21][CH2:22][CH2:23][CH2:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH3:12])[CH:7]=[C:6]([NH:13][S:25]([CH2:24][CH2:23][CH2:22][Cl:21])(=[O:27])=[O:26])[CH:5]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCOc1cc(N)cc(C(=O)OC)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1cc(NS(=O)(=O)CCCCl)cc(C(=O)OC)c1
Reaction time: 16 h
Yield: 97.3 %

Procedure:
A suspension of 3-amino-5-ethoxy-benzoic acid methyl ester (D49) (4.0 g, 20.5 mmol, 1 equiv) in CH2Cl2 (100 ml) was treated with DMAP (400 mg, 3.2 mmol,) and pyridine (1.74 g, 22 mmol, 1.1 equiv) followed by 3-chloropropanesulfonyl chloride (3.89 g, 22 mmol, 1.1 equiv) dropwise. The resulting mixture was stirred for 16 h then concentrated in vacuo. The residue was dissolved in AcOEt (200 ml) and the resulting solution was washed with 2N aqueous HCl solution (100 ml) followed by saturated aqueous NaHCO3 solution (100 ml), then dried over MgSO4 and concentrated in vacuo to give 3-(3-chloro-propane-1-sulfonylamino)-5-ethoxy-benzoic acid methyl ester (D53) (6.7 g, 98%) as a pale orange solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][CH:8]([OH:10])[CH2:9][CH:3]1[CH2:4][CH2:5]2.[C:11](Cl)(=[O:17])[CH2:12][CH2:13][C:14](Cl)=[O:15].[OH2:19].[OH-].[Na+]>C(Cl)Cl>[C:11]([O:17][CH:8]1[CH2:7][C@H:6]2[N:2]([CH3:1])[C@H:3]([CH2:4][CH2:5]2)[CH2:9]1)(=[O:19])[CH2:12][CH2:13][C:14]([O:10][CH:8]1[CH2:9][C@H:3]2[N:2]([CH3:1])[C@H:6]([CH2:5][CH2:4]2)[CH2:7]1)=[O:15]
Reactant: O=C(Cl)CCC(=O)Cl
Reactant: CN1C2CCC1CC(O)C2
Reactant: O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN1[C@@H]2CC[C@H]1CC(OC(=O)CCC(=O)OC1C[C@H]3CC[C@@H](C1)N3C)C2
Temperature: 25 °C
Yield: 65 %

Procedure:
To a solution of 14.1 g (100 mmol) of tropine in 50 mL of methylene chloride is added dropwise 7.75 g (50 mmol) of succinyl chloride in 100 mL of methylene chloride with cooling in an ice bath. Then the mixture is allowed to warm to room temperature. After the reaction mixture is poured into 200 mL of cold water, the aqueous layer is adjusted to pH 10-11 with 6 N NaOH aqueous solution and extracted with chloroform. The resulting oil is purified by column chromatography (silica gel, 20% methanol in chloroform) to yield 11.8 g (65%) of bis-tropan-3-yl succinate as a thick oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:7]1[C:15]2[O:14][C:13](=O)[CH2:12][C:11]=2[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=1)([CH3:6])[CH3:5].I[CH3:20].CN(C)[CH:23]=[O:24]>O>[CH3:13][C:12]1([CH3:20])[C:11]2[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=[C:7]([C:4]([CH3:6])([CH3:5])[CH3:3])[C:15]=2[O:14][C:23]1=[O:24]
Reactant: COc1cc2c(c(C(C)(C)C)c1)OC(=O)C2
Reactant: CN(C)C=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc(C(C)(C)C)c2c(c1)C(C)(C)C(=O)O2
Reaction time: 0.5 h

Procedure:
In 400 ml of N,N-dimethylformamide (DMF) was suspended 60.7 g of 60% sodium hydride followed by dropwise addition of a solution of 7-(1,1-dimethylethyl)-5-methoxy-2(3H)-benzofuranone (160 g) in DMF (1000 ml) at a temperature not exceeding 50° C. and the mixture was stirred for 30 minutes. Then, a solution of iodomethane (230 g) in DMF (100 ml) was added and the mixture was stirred at ambient temperature for 3 hours. The reaction mixture was poured in water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated. The resultant crude product was purified by silica gel column chromatography ( ethyl acetate-hexane =1:10) and washed with cold hexane to give 104 g of 3,3-dimethyl-7-(1,1-dimethylethyl)-5-methoxy-2(3H)-benzofuranone as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:21][CH2:20][C:19](=[CH:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)=[CH:12][C:11]=2[F:25])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[FH:26].C(=O)([O-])O.[Na+]>ClCCl.N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]3[CH2:17][CH2:18][C:19]([F:26])([CH2:22][CH2:23][CH3:24])[CH2:20][CH2:21]3)=[CH:12][C:11]=2[F:25])[CH:5]=[C:6]([F:9])[C:7]=1[F:8]
Reactant: CCC=C1CCC(c2ccc(-c3cc(F)c(F)c(F)c3)c(F)c2)CC1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1(F)CCC(c2ccc(-c3cc(F)c(F)c(F)c3)c(F)c2)CC1
Temperature: -25 °C
Reaction time: 1 h

Procedure:
8.0 g of 3,4,5,2'-tetrafluoro-4'-(4-propylidenecyclohexyl)biphenyl in 16 ml of dichloromethane were introduced into a Teflon apparatus and cooled to -25° C. 80 ml of a 70% solution of hydrogen fluoride in pyridine were then added dropwise with stirring, and the mixture was stirred for 30 minutes at -25° C. and then for a further 1 hour at room temperature. The reaction solution was poured into a suspension of 10 g of sodium hydrogencarbonate and 200 g of ice-water. The mixture was then extracted with 3×80 ml of hexane. The combined organic extracts were washed once with 50 ml of sodium chloride solution, dried using sodium sulfate, filtered and evaporated to a residue. The crude product was purified by means of a silica-gel frit and the eluate was evaporated to a residue, giving 3,4,5,2'-tetrafluoro-4'-(4-fluoro-4-propylcyclohexyl)-biphenyl (C 73 N (48.8) I, Δε=15.3, Δn=+0.111).
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[CH:5][CH:4]=1)=O.Cl.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1.C(N(CC)CC)C.[BH4-].[Na+]>CO>[F:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][N:31]([CH2:1][C:3]3[CH:18]=[CH:17][C:6]([O:7][C:8]4[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=4)=[CH:5][CH:4]=3)[CH2:30][CH2:29]2)=[CH:26][CH:27]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: NC(=O)c1ccc(Oc2ccc(CN3CCN(c4ccc(F)cc4)CC3)cc2)nc1
Reaction time: 23 h
Yield: 21.4 %

Procedure:
Combine 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.299 g, 1.23 mmol), 1-(4-fluoro-phenyl)-piperizine, bis hydrochloride salt (0.314 g, 1.24 mmol), triethylamine (0.36 mL, 2.58 mmol) in methanol (12 mL) and stir. After 23 h, add sodium borohydride (0.108 g, 2.85 mmol). After 1 d, concentrate and purify the residue by silica gel chromatography (25:1→4:1 methylene chloride:methanol) to provide 0.107 g (21%) of the title compound as a white solid: high resolution mass spectrum (electrospray): m/z calc for C23H24FN4O2 407.1883, found 407.1883; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.4 Hz), 8.30 (dd, 1H, J=2.4; 8.8 Hz), 7.52-7.47 (m, 2H), 7.20-7.15 (m, 2H), 7.05 (d, 1H, J=7.8 Hz), 7.01 (d, 1H, J=6.3 Hz), 3.66 (s, 2H), 3.21-3.16 (m, 4H), 2.74-2.68 (m, 4H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:26]=[C:27]=[O:28])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[OH:29][CH2:30][CH:31]1[CH:36]([C:37]([NH:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:38])[CH2:35][CH:34]=[CH:33][CH2:32]1>C(Cl)Cl>[CH2:8]([NH:26][C:27](=[O:28])[O:29][CH2:30][CH:31]1[CH:36]([C:37]([NH:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[O:38])[CH2:35][CH:34]=[CH:33][CH2:32]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=C(NCCN1CCCCC1)C1CC=CCC1CO
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC1CC=CCC1C(=O)NCCN1CCCCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Triethylamine (0.96 ml) and octadecyl isocyanate (2.2 ml) were added to a solution of 6-(hydroxymethyl)-N-(2-piperidinoethyl)-3-cyclohexene-1-carboxamide (1.65 g) in methylene chloride (22 ml). After being stirred for 15 hours at room temperature, triethylamine (0.96 ml) and octadecyl isocyanate (2.2 ml) were further added to the reaction mixture and stirred for 5 hours at room temperature. The insoluble matters were filtrated out under a vacuum and washed with chloroform. The filtrate and washings were combined together and the mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 100 g, chloroform:methanol=30:1-10:1), thereby yielding the entitled compound (2.59 g) as white solid.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)[C:10]([N:12]1[CH2:17][CH2:16][NH:15][C:14](=[O:18])[C@H:13]1[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:11])C)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:19]([C@H:13]1[N:12]([C:10](=[O:11])[C@H:9]([NH:7][CH3:6])[CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH2:17][CH2:16][NH:15][C:14]1=[O:18])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N1CCNC(=O)[C@H]1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N1CCNC(=O)[C@H]1Cc1ccccc1
Yield: 93.1 %

Procedure:
N-((1R)-2-((2R)-2-Benzyl-3-oxopiperazin-1-yl)-1-((2-naphthyl)methyl)- 2-oxoethyl)-N-methylcarbamic acid tert-butyl ester (0.405 g; 0.808 mmol) was dissolved in methylene chloride (5 ml) and trifluoroacetic acid (5 ml) and stirred 10 min at room temperature. Water (10 ml) and sodium hydrogencarbonate were added to pH 8. The reaction mixture was extracted with methylene chloride (2×30 ml), dried over magnesium sulfate and evaporated in vacuo to afford 0.302 g of (3R)-3-benzyl-4-((2R)-2-methylamino-3-(2-naphthyl)propionyl)piperazin-2-one.
Reaction SMILES: [C:1](=[O:3])=[O:2].[CH2:4]([S:12][CH2:13][CH2:14][NH2:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C(#N)C>[C:1](=[O:3])([OH:2])[NH2:15].[CH2:4]([S:12][CH2:13][CH2:14][NH2:15])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=C=O
Agent: CCCCCCCCSCCN
Solvent: CC#N
Product: NC(=O)O

Procedure:
Carbon dioxide is bubbled through an acetonitrile (60 ml) solution of 10 g (52.8 mmoles) of 2-(octylthio)ethylamine to afford a white precipitate which is isolated by suction filtration. The product is washed three times with 10 ml portions of acetonitrile and is then washed three times with 20 mls portions of methyl t-butyl ether. The product is air dried to give 7.77 g of octylthioethylamine carbamic acid derivative as a white powder (yield, 62.1%). The product is further characterized by IR. proton NMR, and elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[C:62]([O:65][CH:66]1[CH2:69][CH:68]([C:70](O)=[O:71])[CH2:67]1)(=[O:64])[CH3:63]>CN(C=O)C.O>[C:62]([O:65][CH:66]1[CH2:69][CH:68]([C:70](=[O:71])[NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[CH:14]=[N:13][C:12]([NH:15][C:16]([C:18]4[C:19](=[O:31])[N:20]([C:25]5[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=5)[N:21]([CH3:24])[C:22]=4[CH3:23])=[O:17])=[CH:11][CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:67]1)(=[O:64])[CH3:63]
Reactant: CC(=O)OC1CC(C(=O)O)C1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cn2)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC1CC(C(=O)Nc2cc(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)nc3)ccn2)C1
Temperature: 120 °C
Yield: 30 %

Procedure:
To a solution of N-(5-((2-aminopyridin-4-yl)oxy)pyridin-2-yl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (50 mg, 0.12 mmol), HOAT (19 mg, 0.24 mmol), EDCI (28 mg, 0.14 mmol) and DIPEA (0.1 mL, 0.6 mmol) in DMF (5 mL) was added a solution of 3-acetoxycyclobutanecarboxylic acid in DMF (5 mL) at 0° C. The reaction was heated at 120° C. for 5 hours, then cooled to rt, diluted with water (50 mL) and extracted with EtOAc (30 mL×3). The combined organic phases were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulted residue was purified by a silica gel column chromatography (DCM/EtOAc (v/v)=1/2) to give the title compound as a white solid (20 mg, 30%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](C(=NN)C)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:14]1([CH2:20][CH2:21][CH2:22][N:23]2[CH2:27][C:26](=O)[CH2:25][C:24]2=[O:29])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O:30]1[CH2:35][CH2:34]OCC1>[O-2].[Mn+4].[O-2]>[CH3:27][C:26]1([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[CH:34]2[CH:25]1[C:24](=[O:29])[N:23]([CH2:22][CH2:21][CH2:20][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:35]2=[O:30]
Reactant: CC(=NN)c1cccc([N+](=O)[O-])c1
Reactant: O=C1CC(=O)N(CCCc2ccccc2)C1
Reactant: C1COCCO1
Agent: [Mn+4]
Agent: [O-2]
Product: CC1(c2ccccc2[N+](=O)[O-])C2C(=O)N(CCCc3ccccc3)C(=O)C21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of 1-(3-nitrophenyl)-1-ethanone hydrazone (Preparation 135, 100 g, 0.56 mol) in dioxan (1 l) was added manganese (IV) oxide (200 g, 2.3 mol) and the reaction mixture was stirred at room temperature for 30 min. The suspension was filtered through Celite™ washing with dioxan (ca. 200 ml). 1-(3-Phenylpropyl)-1H-pyrrole-2,4-dione (Preparation 80, 110 g, 0.54 mol) was added to the filtrate and the reaction mixture was stirred at room temperature for 4 h before heating under reflux for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was triturated in methanol (500 ml) and the precipitate was collected by filtration to afford the title compound as a white crystalline solid (121 g, 65%).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6].[NH2:24][CH2:25][CH2:26][CH:27]1[O:31][CH2:30][CH2:29][O:28]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:28]1[CH2:29][CH2:30][O:31][CH:27]1[CH2:26][CH2:25][NH:24][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6]
Reactant: NCCC1OCCO1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCC2OCCO2)c1
Yield: 98 %

Procedure:
A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide prepared according to Example A1 (1.86 g, 1 eq), 2-(2-aminoethyl)-1,3-dioxolane (0.8 g, 1.2 eq) and potassium carbonate (1.58 g, 2 eq) in acetonitrile (150 ml) is heated under reflux for 3 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (150 ml) and water (60 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent:heptane/ethyl acetate 8:2 to 7:3) produces the expected compound in the form of an orange-yellow oil (2.4 g; 98% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N:12]=[C:13]=[O:14].C(N(CC)CC)C.[CH3:22][C:23]1([CH3:37])[C:27]([CH3:29])([CH3:28])[O:26][B:25]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[O:24]1.CO>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]([NH:34][C:33]1[CH:32]=[CH:31][C:30]([B:25]2[O:26][C:27]([CH3:29])([CH3:28])[C:23]([CH3:37])([CH3:22])[O:24]2)=[CH:36][CH:35]=1)=[O:14]
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1(C)OB(c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.9 %

Procedure:
936 mg of 2-fluoro-5-trifluoromethylphenylisocyanate and then 0.64 ml of triethylamine are added to a solution of 1 g of 4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)aniline in 15 ml of tetrahydrofuran, at ambient temperature. The reaction medium is stirred at ambient temperature for 18 h, and then treated with methanol and then, finally, evaporated to dryness under reduced pressure. The residue thus obtained is purified by chromatography on silica using, as eluent, a (99.5/0.5 then 90/10) methylene chloride/methanol mixture. The fractions containing the expected product are concentrated to dryness so as to give 1.45 g of 1-(2-fluoro-5-trifluoromethylphenyl)-3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]urea in the form of a white solid. MS (ES) MH+ m/z=425.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH:37]1(O)[CH2:42][CH2:41]C[CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:41][CH2:42][CH2:37][CH2:38][CH2:39]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: COc1cc2ncnc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: OC1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCCC4)c(C)c3C)c2cc1OC
Yield: 72.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cyclohexanol (23 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (50 mg, yield 64%).