Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](F)[C:5]([F:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:11].[CH3:19][OH:20].C[O-].[Na+]>C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([O:20][CH3:19])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[O:11]
Reactant: CO
Reactant: Nc1cc(F)c(F)cc1C(=O)c1ccccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(N)c(C(=O)c2ccccc2Cl)cc1F

Procedure:
A solution of 2.01 g (0.0075 mole) of (2-amino-4,5-difluorophenyl)-(2-chlorophenyl)-methanone (Xmm), 24 mL of methanol and 2.08 mL of 25% sodium methoxide solution was heated to reflux under an inert atmosphere for 80 minutes. The mixture was then cooled, taken up in ethyl acetate and washed twice with brine. The ethyl acetate extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 2.04 g of aminobenzopheneone (2-amino-5-fluoro-4-methoxyphenyl)-(2-chlorophenyl)-methanone (Xa) as a crystalline yellow solid. MH+/Z=280.
Reaction SMILES: [CH:1]1([C:7](=[O:27])[CH2:8][CH2:9][CH:10]2[CH2:18][CH2:17][C:12]3(OCC[O:13]3)[CH:11]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Cl>[CH:1]1([C:7](=[O:27])[CH2:8][CH2:9][CH:10]2[CH2:18][CH2:17][C:12](=[O:13])[CH:11]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][OH:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(CCC1CCC2(OCCO2)C1CCCCCCCO)C1CCCCC1
Agent: Cl
Product: O=C(CCC1CCC(=O)C1CCCCCCCO)C1CCCCC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
A mixture of 7-(3-cyclohexyl-3-oxopropyl)-6-(7-hydroxyheptyl)-1,4-dioxaspiro[4,4]nonane (0.5 g.) in hydrochloric acid (20 ml; 1N) was stirred at 60° C. for 2 hours, cooled to ambient temperature and extracted with diethyl ether. The ethereal extract was washed with water, then dried over sodium sulphate. Removal of the solvent under reduced pressure gave a crude product (0.4 g.) which was purified by preparative thin layer chromatography on silica gel, using a mixture of diethyl ether, ethyl acetate and hexane (2:1:1 v/v) as eluant, to give 7-[2-(3-cyclohexyl-3-oxopropyl)-5-oxocyclopentyl]heptan-1-ol (0.16 g.), νmax 3450 cm-1, 1730 cm-1, 1700 cm-1, 1060 cm-1 ; Elemental analysis: Found: C, 74.6; H, 10.7%; C21H36O3 requires C, 74.95; H, 10.78%.
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:41].C(O)C.C(=O)([O-])[O-].[NH4+:49].[NH4+]>ClCCl.C(O)C>[ClH:41].[C:1]1([N:7]([CH2:30][CH2:31][CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[NH:49])[NH2:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCOCc3ccccc3)c3ccccc3)ccc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(C(=O)N(CCCOCc3ccccc3)c3ccccc3)ccc21
Yield: 61 %

Procedure:
Prepared analogously to Example 25 from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(3-benzyloxy-n-propyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 61% of theory, C33H34N6O2 (546.7) Rf value: 0.19 (silica gel; dichloromethane/ethanol=4:1) ##EQU134##
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:37])[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]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:37])[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]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)NCCCSc1ccncc1
Yield: 73.8 %

Procedure:
To a solution of 1.21 g (5.00 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.79 ml (20.0 mmol) of triethylamine in 50 ml of methylene chloride was added 1.65 ml (6.00 mmol)of palmitoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with hexane and dried to obtain 1.50 g of the desired compound (73.8%, colorless powder), mp: 84.0°-85.0° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11].[H-].[Na+].Cl[C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1>CN(C=O)C.[Cl-].[Na+].O>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[O:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[C:9](=[N:14]\[O:15][CH3:16])/[C:10]([NH:12][CH3:13])=[O:11]
Reactant: Clc1ccc2ccccc2n1
Reactant: CNC(=O)/C(=N/OC)c1ccccc1CO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)/C(=N/OC)c1ccccc1COc1ccc2ccccc2n1
Reaction time: 0.17 h
Yield: 65.8 %

Procedure:
(E)-2-[2-(hydroxymethyl)phenyl]-2-methoxyimino-N-methylacetamide (0.44 g, 2 mmol) was dissolved in dry DMF (4 ml). 60% sodium hydride (0.10 g, 2.4 mmol) was added at room temperature, the mixture was stirred for 10 minutes, and then 2-chloroquinoline (0.36 g, 2.2 mmol) was added at room temperature. The resulting mixture was allowed to stand at room temperature overnight, and saturated brine was added. The mixture was extracted with ethyl acetate and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by column chromatography on silica gel (ethyl acetate--n-hexane) to give the title compound (0.46 g) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[NH2:12]>C(O)=O.CO>[CH3:9][C:10]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:11]=1[N:12]=[CH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: Cc1cccc(C)c1N
Reactant: O=Cc1ccccn1
Solvent: CO
Solvent: O=CO
Product: Cc1cccc(C)c1N=Cc1ccccn1
Reaction time: 5 h

Procedure:
A mixture of 2-pyridine-carboxaldehyde (10 ml, 0.1 mole), 2,6-dimethylaniline (12.9 ml, 0.1 mole), 3 drops of formic acid and 30 ml methanol was stirred for five hours. The methanol was removed under vacuum. An oil-like residue was recrystallized from n-hexane. 2-(N-(2,6-dimethylphenyl)-iminomethyl)-pyridine was isolated as yellow crystals. Yield: 13.6 g (62%). 1H NMR (200 MHz; CDCl3; δ, ppm; J, Hz): 2.17 s (6H, CH3), 6.94-7.12 m (3H, C6H3), 7.39 d,d,d (1H, H(5) 3J4,5=7.5, 3J5,6=4.9, 4J3,5=1.3); 7.83 t,d,d (1H, H(4) 3J=7.7, 4J4,6=1.8, 5J=0.6); 8.28 d,t (1H, H(3) 3J3,4=7.9, J=1.1); 8.35 s (1H, HC═N); 8.71 d,d,d (1H, H(6) 3J5,6=4.9, 4J4,6=1.6, 5J3,6=1.0). 13C NMR, DEPT (50 MHz; CDCl3; δ, ppm): 18.3 (CH3), 121.2 (C(3)H), 124.0 (C(4′)H), 125.3 (C(5)H), 126.8 (C(2′,6′)), 128.1 (C(3′,5′)H), 136.7 (C(4)H), 149.6 (C(6)H), 150.3 (C(1′)), 154.4 (C(2)), 163.4 (HC═N).
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]1[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:5]([OH:7])=O.C(OC(=O)C)(=O)C>>[C:1]1(=[O:12])[O:13][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1
Reactant: O=C(O)Cc1ccccc1C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1Cc2ccccc2C(=O)O1
Temperature: 80 °C

Procedure:
A 100 mL round-bottomed flask containing a stirring bar was charged with homophthalic acid (2.0 g, 11.101 mmol). Acetic anhydride (25.0 mL) was added, the flask was fitted with a condenser and the reaction mixture was heated at 80° C. for 2 h. The excess acetic anhydride was removed in vacuo and the solid obtained was triturated with Et2O (10.0 mL), filtered and dried to obtain homophthalic anhydride as an off white solid (1.53 g, 85%). Spectral data for this compound were consistent with those in the literature. M.p. 140-144° C. (lit. m.p. 140-145° C.); 1H NMR (400 MHz, DMSO-d6): δ=8.05 (d, J=8.2 Hz, 1H), 7.75 (app. t, 1H), 7.52 (app. t, 1H), 7.44 (d, J=7.8 Hz, 1H), 4.27 (s, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[CH2:13][CH:12]([O:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]2)(=[O:3])[CH3:2].[Br:19]Br>C(O)(=O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([Br:19])=[C:9]2[C:14]=1[CH2:13][CH:12]([O:15][C:16](=[O:18])[CH3:17])[CH2:11][CH2:10]2)(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)Nc1cccc2c1CC(OC(C)=O)CC2
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c2c1CC(OC(C)=O)CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A mixture of acetic acid 8-acetylamino-1,2,3,4-tetrahydronaphthalen-2-yl ester (2.2 g, 8.9 mmol) and bromine (1.7 g, 10.7 mmol) in 50 mL of acetic acid was stirred at room temperature for 18 h. The solvent was removed by rotoevaporation, and the residue was taken up in an diethyl ether/water mixture. The resulting solid was collected by filtration, and washed with diethyl ether. After drying the product (2.75 g) was obtained in 95% yield.
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]#[C:12][CH2:13][CH2:14]O)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1.[B-](F)(F)(F)[F:23].CCN([S+](F)F)CC.C([O-])(O)=O.[Na+]>ClCCl>[F:1][C:2]1[C:10]([C:11]#[C:12][CH2:13][CH2:14][F:23])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1
Reactant: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Reactant: F[B-](F)(F)F
Agent: CCN(CC)[S+](F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FCCC#Cc1ccc2c(cnn2C2CCCCO2)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
To a solution of 4-(4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-3-yn-1-ol (3.4 g, 11.8 mmol; Intermediate 29, Step 1) in dry dichloromethane (100 mL), was added triethylamine-3HF (7.6 g, 47.2 mmol). XtalFluor-E (8.0 g, 34.9 mmol) was then added. The resulting solution was stirred at room temperature for 30 minutes. Upon completion, the reaction solution was neutralized by slow addition of saturated NaHCO3 (30 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0˜20% EtOAc in petroleum ether), and then re-crystallized from petroleum ether to afford the title compound (1.3 g). 1H NMR (300 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.58 (d, 1H), 7.44 (dd, 1H), 5.89 (dd, 1H), 4.60 (dt, 2H), 3.91-3.85 (m, 1H), 3.80-3.69 (m, 1H), 2.93 (dt, 2H), 2.46-2.28 (m, 1H), 2.06-1.95 (m, 2H), 1.78-1.67 (m, 1H), 1.60-1.52 (m, 2H); LCMS: 291 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH:13]=O.[NH:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]3[O:28][CH2:29][CH2:30][O:31][C:26]=3[CH:25]=2)=[O:23])[CH2:17][CH2:16]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)C.C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:1]=[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]([C:24]2[CH:33]=[CH:32][C:27]3[O:28][CH2:29][CH2:30][O:31][C:26]=3[CH:25]=2)=[O:23])[CH2:17][CH2:16]1
Reactant: O=C(NC1CCNCC1)c1ccc2c(c1)OCCO2
Reactant: O=CCn1c(=O)cnc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NC1CCN(CCn2c(=O)cnc3ccccc32)CC1)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To 3 mL of dichloromethane solution containing 70 mg of (2-oxoquinoxalin-1(2H)-yl)acetaldehyde, 98 mg of N-(piperidin-4-yl)-2,3-dihydro-1,4-benzodioxin-6-carboxamide and 21 μl of acetic acid were added and stirred at room temperature for 2 hours. To the reaction mixture, 0.12 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 min. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=20:1], and to the residue thus obtained, diethyl ether was added, and the resulting solid was filtered to give 0.12 g of N-(1-(2-(2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)-2,3-dihydro-1,4-benzodioxin-6-carboxamide as a light brown solid.
Reaction SMILES: [CH2:1]([NH:3][CH:4]([CH3:8])[CH:5]([CH3:7])[CH3:6])[CH3:2].[CH2:9]=O>>[CH3:9][N:3]([CH:4]([CH3:8])[CH:5]([CH3:7])[CH3:6])[CH2:1][CH3:2]
Reactant: CCNC(C)C(C)C
Reactant: C=O
Product: CCN(C)C(C)C(C)C
Yield: 97.4 %

Procedure:
In a similar manner to Example 1, 230.4 g (2.0 mol) of N-ethyl-1,2-dimethylpropylamine and 330.2 g (3.2 mol) of formaldehyde (29.1%) are reacted in a 1 l autoclave; a maximum pressure of 2.3 MPa is established at a temperature of 120° C. After the crude amine (aqueous and organic phase) has been degassed at a maximum temperature of 94° C., the water is removed on a water separator. The remaining organic phase is subsequently fractionally distilled. 251.7 g of N-methyl-N-ethyl-1,2-dimethylpropylamine having a purity of 98.6% are isolated, corresponding to a yield of 96.0% of theory.
Reaction SMILES: C([O:4][C:5]1[CH:14]=[CH:13][C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[CH:6]=1)(=O)C.[OH-].[Na+].CCOC(C)=O>CO>[O:9]1[C:8]2[CH:13]=[CH:14][C:5]([OH:4])=[CH:6][C:7]=2[O:12][CH2:11][CH2:10]1
Reactant: CC(=O)Oc1ccc2c(c1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: Oc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1 g of 2,3-dihydro-1,4-benzodioxin-6-yl acetate (5.149 mmol) is dissolved in a solution of methanol (7.5 ml) and, under an argon atmosphere, the mixture is made basic, dropwise, with a 10% sodium hydroxide solution. The mixture is stirred at ambient temperature for 4 hours. At the end of the reaction, the methanol is evaporated and the reaction medium is acidified (to pH=1) with a 2N HCl solution and then washed with ethyl acetate. After extraction, drying over MgSO4 is carried out and the product is concentrated in vacuo. Purification on a silica column allows an oil to be obtained (eluant:PE/AcOEt 8/2 then 7/3).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[CH3:24][O:25][C:26]([CH:28]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[NH:29]1)=[O:27]>>[CH3:24][O:25][C:26]([CH:28]1[CH2:32][CH2:31][S:30](=[O:34])(=[O:33])[N:29]1[C:20]1[CH:21]=[CH:22][C:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])=[CH:18][CH:19]=1)=[O:27]
Reactant: COC(=O)C1CCS(=O)(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: COC(=O)C1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ccc(C)cc3C)CC2)cc1
Yield: 4.7 %

Procedure:
Using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (781 mg) described in Preparation Example 108 and 1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid methyl ester (580 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (41 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])[CH:5]=[CH:4][C:3]=1[NH:33][C:34](=[O:48])[NH:35][C@@H:36]1[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37]1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([C:8]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:23]([OH:32])([C:24]([F:26])([F:27])[F:25])[C:28]([F:29])([F:30])[F:31])=[CH:21][CH:22]=3)[CH2:14][CH2:15]2)=[O:9])[CH:5]=[CH:4][C:3]=1[NH:33][C:34]([NH:35][C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)=[O:48]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C(=O)N3CCN(Cc4ccc(C(O)(C(F)(F)F)C(F)(F)F)cc4)CC3)cc2F)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F)N[C@@H]1CCNC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
To a stirring solution of (R)-tert-butyl 3-(3-(2-fluoro-4-(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-1-carbonyl)phenyl)ureido)pyrrolidine-1-carboxylate (0.289 mmol, 200 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (7.23 mmol, 824 mg) and the mixture allowed to stir at room temperature for 5 hours. The reaction mixture was purified by strong cation exchange column chromatography to afford the title compound (146 mg). MS (ESI) m/z 592.3 [M+H]+
Reaction SMILES: [N:1]([CH:4]([CH3:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:18][CH2:17][CH:16]([O:19]C(OCC)C)[CH2:15][C:13]3=2)[CH:8]=[N:7]1)=[N+:2]=[N-:3].Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[N:1]([CH:4]([CH3:25])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]3[O:18][CH2:17][CH:16]([OH:19])[CH2:15][C:13]3=2)[CH:8]=[N:7]1)=[N+:2]=[N-:3]
Reactant: CCOC(C)OC1COc2ccc3cnn(CC(C)N=[N+]=[N-])c3c2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(Cn1ncc2ccc3c(c21)CC(O)CO3)N=[N+]=[N-]
Yield: 96.5 %

Procedure:
To a mixture of the product from Step H (0.40 g, 1.1 mmol) in THF (60 mL) was added 1 N HCl (26 mL). After stirring for 40 min a saturated solution of sodium bicarbonate (150 mL) was added and the mixture was extracted with EtOAc (3×100 mL). The combined extracts were dried and evaporated to a residue, which was purified by chromatography (silica, 50% EtOAc/hexane) to give an oil (0.29 g, 92%): LC/MS (+APCI) m/z 374 (M+H).
Reaction SMILES: BrBr.[F:3][C:4]1[CH:17]=[CH:16][C:7]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[S-:18][C:19]#[N:20].[NH4+]>C(O)(=O)C>[NH2:20][C:19]1[S:18][C:14]2[CH:15]=[C:9]([O:8][C:7]3[CH:16]=[CH:17][C:4]([F:3])=[CH:5][CH:6]=3)[CH:10]=[CH:11][C:12]=2[N:13]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Agent: BrBr
Agent: [NH4+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Oc3ccc(F)cc3)cc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
13 ml of acetic acid containing 6.5 ml of bromine were added dropwise at 13 to 15° C. to a solution of 25.6 g of 4-(4-fluorophenoxy)aniline and 19.2 g of ammonium thiocyanate in 185 ml of acetic acid. After completion of the addition, the mixture was stirred at room temperature for 1 hour and then the solvent was distilled off under reduced pressure. The residue was mixed with 300 ml of ethyl acetate and 200 ml of water, and the mixture was neutralized by adding powered potassium carbonate. The ethyl acetate layer was then separated and dried over anhydrous magnesium sulfate, and then the residue was concentrated by evaporation under reduced pressure. The crystalline residue was washed with diisopropyl ether to afford 26.7 g of the title compound, melting at 126-128° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=[O:9])[C:7]=1[Cl:8])=O.[F:10][CH:11]([F:20])[O:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16]>O1CCOCC1>[Cl:8][C:7]1[C:6]([N:16]([C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([O:12][CH:11]([F:10])[F:20])[CH:14]=2)[C:3](=[O:5])[C:2]=1[Cl:1])=[O:9]
Reactant: Nc1cccc(OC(F)F)c1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Solvent: C1COCCO1
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1cccc(OC(F)F)c1
Yield: 94.8 %

Procedure:
16.7 g (0.1 mole) of 2,3-dichloromaleic anhydride is dissolved in 100 ml of dioxane, and a solution of 15.9 g (0.1 mole) of m-difluoromethoxyaniline in 30 ml of dioxane is added dropwise to it at room temperature over 20 minutes with stirring. Thereafter, the resulting solution is stirred at 70°-80° C. for 2 hours and the dioxane is then distilled off under a reduced pressure. Water is added to the residue to precipitate crystals. The precipitated crystals are filtered off and recrystallized to give 29.2 g (yield: 95%) of 2,3-dichloro-N-(m-difluoromethoxyphenyl)maleimide melting at 122°-124° C. in the form of light yellow plate crystals.
Reaction SMILES: C([N:4]1[C:12]2[CH:11]=[CH:10][C:9]3[C:13](=[O:16])[CH2:14][CH2:15][C:8]=3[C:7]=2[CH:6]=[N:5]1)(=O)C.[OH-].[Na+]>CO>[CH:6]1[C:7]2[C:8]3[CH2:15][CH2:14][C:13](=[O:16])[C:9]=3[CH:10]=[CH:11][C:12]=2[NH:4][N:5]=1
Reactant: CC(=O)n1ncc2c3c(ccc21)C(=O)CC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1CCc2c1ccc1[nH]ncc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-acetyl-7,8-dihydrocyclopenta[e]indazol-6(3H) -one (9.19 g, 42.9 mmol) in methanol (250 mL) was added 1N aqueous sodium hydroxide (55.6 mL, 55.6 mmol). The resulting brown solution was stirred at room temperature for 1 hour. The methanol was evaporated under vacuum and the residue was diluted with water (250 mL) and adjusted to pH 4 with 6N aqueous HCl. The resulting precipitate was isolated by filtration, washed thoroughly with water and dried under vacuum to give 7,8-dihydrocyclopenta[e]indazol-6(3H)-one as a yellow solid.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@@H:13]([CH3:37])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:34]([O:33][CH:29]([O:30][CH2:31][CH3:32])[C@@H:28]([N:16]([CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)[C:14](=[O:15])[C@@H:13]([NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[CH3:37])[CH3:36])[CH3:35]
Reactant: CCNC(=O)NOCC(=O)O
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](C)N
Product: CCNC(=O)NOCC(=O)N[C@@H](C)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 68 mg (0.42 mmol) was coupled with (S)-2-amino-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-10) 100 mg (0.28 mmol) to obtain the title compound.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[C@@H:7]([CH3:8])[CH2:6][CH2:5][N:4]1C(OC(C)(C)C)=O.CO.[ClH:18]>C(Cl)Cl.O1CCOCC1>[ClH:18].[CH3:8][C@H:7]1[CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:2][OH:1]
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)[C@@H]1CO
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H]1CCN[C@@H]1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The crude 1,1-dimethylethyl(2S,3S)-2-(hydroxymethyl)-3-methyl-1-pyrrolidinecarboxylate from step 3 was dissolved in a 1:1 mixture of methylene chloride:methanol. Excess 4N HCl in dioxane was added, and the reaction stirred at room temperature for 1 hour, concentrated under reduced pressure, and then used in the final step (see Scheme 1a (g) to (h)). 1H NMR (400 MHz, DMSO-D6) δ ppm 1.1 (d, J=6.2 Hz, 3 H) 1.5 (m, 1 H) 2.1 (m, 2 H) 3.1 (m, 1 H) 3.3 (m, 1 H) 3.4 (m, 1 H) 4.5 (dd, J=12.1, 8.1 Hz, 1 H) 4.7 (dd, J=12.3, 3.1 Hz, 1 H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=[NH:13])OC.[C:14](OCC)(=[O:17])[NH:15][NH2:16]>O1CCOCC1>[NH:13]1[C:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[N:16][NH:15][C:14]1=[O:17]
Reactant: CCOC(=O)NN
Reactant: COC(=N)c1nc2ccccc2o1
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2nc3ccccc3o2)[nH]1

Procedure:
Methyl benzoxazole-2-imidate, 8.0 g. and 5.2 g. of ethyl carbazate in 60 ml. of dioxane was heated at 110° overnight. After evaporation of solvent, the residue was suspended in 45 ml. of Dowtherm A and heated at 220° for 15 minutes. The precipitated product was filtered, washed with CH2Cl2, CH3OH, and dried to give 3.6 g. of solid, mp. >300°.