Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21]3[C:22]4=[C:23]5[C:18](=[CH:19][CH:20]=3)[CH:17]=[CH:16][CH:15]=[C:14]5[CH:13]=[CH:12][C:11]4=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:24][C:15]1[C:14]2[C:23]3=[C:22]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[C:21]4[CH:20]=[CH:19][C:18]3=[CH:17][CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccc3ccc4cccc5ccc2c3c45)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2ccc3ccc4c(Br)ccc5ccc2c3c54)cc1
Temperature: 40 °C
Reaction time: 7 h
Yield: 22.4 %

Procedure:
Next, a mixed solution of 40.0 g of 1-(4-methylphenyl)pyrene, 24.4 g of N-bromosuccinimide and 1.4 L of dimethylformamide was heated with stirring under a nitrogen gas flow at 40° C. for 7 hours. After cooling the solution to room temperature, 1.0 L of water was injected, followed by extraction with 500 ml of dichloromethane. The organic layer was washed twice with 200 ml of water, dried over magnesium sulfate, evaporated and then filtered using Celite. The filtrate was evaporated and the residue was washed twice with 200 ml of ethyl acetate. The precipitated solid was collected by filtration and then vacuum-dried to obtain 11.4 g of 1-bromo-6-(4-methylphenyl)pyrene.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.C([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C>N1C=CC=CC=1>[C:36]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2)(=[O:35])[CH2:37][OH:38]
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(N)sc2n1
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)CO)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.7 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-3-(trifluoromethyl)benzamide (200 mg, 0.450 mmol) produced in Example C8(iv) in pyridine (5 mL) was added acetoxyacetyl chloride (121 μL, 1.12 mmol), and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and a mixture of the obtained residue, methanol (3 mL), pyridine (2 mL) and 0.5N aqueous sodium hydroxide solution (3 mL) was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was precipitated with ethyl acetate and hexane to give the title compound (92 mg, 41%) as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)(=O)C>C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Reaction time: 24 h
Yield: 18.8 %

Procedure:
1-tert-Butoxycarbonyl-4-piperidone (2.29 g, 0.0114 mol, 1.15 eq) and 4-hydroxypiperidine (1 g, 0.0099 mol, 1 eq) were stirred at room temperature in THF (10 ml) and acetic acid (0.6 ml) for 20 hours. To the solution was added 0.17 g of 5% palladium on carbon type 87L Johnson Matthey catalyst. The reaction was then hydrogenated under a pressure of 3 bar at room temperature for 24 hours. The catalyst was filtered off through CELITE™ and washed with THF (20 ml). The 4-(hydroxy)-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester (18.8% purity by HPLC area %) was not isolated.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1.Cl.[BrH:16]>>[BrH:16].[NH:11]1[CH2:12][CH2:13][CH2:14][CH:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[CH2:10]1
Reactant: COc1ccccc1C1CCCNC1
Agent: Br
Agent: Cl
Product: Oc1ccccc1C1CCCNC1

Procedure:
HBr was prepared by heating 3-(2-methoxyphenyl)piperidine.HCl (46 mg, 0.20 mmol) with 48% HBr in a microwave reactor at 120° C. for one hour. After evaporation, 61 mg of the title compound was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.[H-].[Na+].[CH2:22](I)[CH3:23]>CN(C=O)C>[CH2:22]([N:11]1[C:12]2[C:8](=[C:7]([N:3]3[CH2:4][CH2:5][CH2:6][C:2]3=[O:1])[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=2)[CH:9]=[CH:10]1)[CH3:23]
Reactant: CCI
Reactant: COC(=O)c1cc(N2CCCC2=O)c2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2c(N3CCCC3=O)cc(C(=O)OC)cc21
Reaction time: 0.25 h
Yield: 72 %

Procedure:
To a solution of methyl 4-(2-oxo-1-pyrrolidinyl)-1H-indole-6-carboxylate (B154) (500 mg, 1.94 mmol, 1 equiv) in DMF (10 ml) at room temperature was added NaH (60% dispersion in mineral oil, 84 mg, 2.1 mmol, 1.1 equiv) and the resulting mixture was stirred 15 min. Ethyl iodide (200 μl, 2.5 mmol, 1.3 equiv) was added and the resulting solution was stirred for 30 min then concentrated in vacuo. The residue was dissolved in AcOEt and the organic phase was washed with a 2N aqueous HCl solution, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (AcOEt/iso-hexane: 1/4 to 1/1) gave methyl 1-ethyl-4-(2-oxo-1-pyrrolidinyl)-1H-indole-6-carboxylate (B140) (400 mg, 72%) as an off-white solid. [M+H]+=287.0, RT=2.73 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[C:13]([CH3:22])[C:14]([O:20]C)=[C:15]([CH3:19])[C:16]=3[CH3:18])[CH2:11][C:10]3([CH2:25][CH2:24][CH2:23]3)[CH2:9]2)=[CH:4][CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[C:13]([CH3:22])[C:14]([OH:20])=[C:15]([CH3:19])[C:16]=3[CH3:18])[CH2:11][C:10]3([CH2:25][CH2:24][CH2:23]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: COc1c(C)c(C)c2c(c1C)CC1(CCC1)CN2c1ccc(Cl)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CC1(CCC1)CN2c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 89.5 %

Procedure:
1′-(4-chlorophenyl)-6′-methoxy-5′,7′,8′-trimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinoline] (200 mg) was dissolved in dichloromethane (15 mL) cooled in a bath (−78° C.). To this solution was added BBr3 (4 mL, 1 M in dichloromethane). The temperature was then raised to 10° C. After another 1.5 h, the mixture was quenched with 3 mL saturated NaHCO3, and extracted with ethylacetate. The organic phase was washed with brine, dried and evaporated to an oil, which was passed through a silica column (EtOAc in Hexane: 5-16% in 30 min) to give 1′-(4-chlorophenyl)-5′,7′,8′-trimethyl-2′,4′-dihydro-1′H-spiro[cyclobutane-1,3′-quinolin]-6′-ol (172 mg) as an off-while oil. 1H-NMR (300 MHz, CDCl3): δ=7.18-6.94 (d, 2H), 6.74-6.54 (d, 2H), 4.54 (s, 1H), 3.63 (s, 2H), 2.72 (s, 2H), 2.19 (s, 3H), 2.13 (s, 3H), 1.79 (s, 3H), 1.97-1.54 (m, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=150.31, 148.19, 134.19, 129.01, 128.71, 128.23, 123.3, 120.69, 119.34, 119.25, 60.83, 40.61, 38.49, 32.91, 15.82, 15.56, 12.6, 11.57 ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([CH2:14][NH:15][C:16](=[O:26])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][N:3]=1.[C-]#N.[K+].[N:30]12CCN(CC1)C[CH2:31]2>CS(C)=O.O>[C:31]([C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([CH2:14][NH:15][C:16](=[O:26])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][N:3]=1)#[N:30]
Reactant: COc1ccc(CC(=O)NCc2cnc(Cl)nc2NCC(C)(C)C)cc1
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CC(=O)NCc2cnc(C#N)nc2NCC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of 0.036 g (0.096 mmol) of N-[2-chloro-4-(2,2-dimethyl-propylamino)-pyrimidin-5-ylmethyl]-2-(4-methoxy-phenyl)acetamide, 0.013 g (0.192 mmol) of KCN and 0.011 g (0.096 mmol) of 1.4-diazabicyclo[2.2.2]octan in 1 ml of DMSO/H2O (85:15) is stirred for 45 minutes at 60° C. The reaction mixture is cooled to r.t. and subjected to preparative HPLC. N-[2-cyano-4-(2,2-dimethyl-propylamino)-pyrimidin-5-ylmethyl]-2-(4-methoxy-phenyl)-acetamide is obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[C:13]([O:15]C)=[O:14].[OH-].[Na+].Cl>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[C:5]2[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1c[nH]c(=O)c2ccc(F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1c[nH]c(=O)c2ccc(F)cc12
Temperature: 80 °C
Yield: 95.3 %

Procedure:
To a solution of methyl 6-fluoro-1-oxo-1,2-dihydroisoquinoline-4-carboxylate (1.3 g) in methanol (3 ml) was added a aqueous solution (3 ml) of sodium hydroxide (1 g) and the reaction mixture was heated at 80° C. for 3 h. The reaction was cooled to 20° C. and carefully acidified with concentrated hydrochloric acid. The white precipitate was isolated by filtration, washed with water and methanol to yield the title compound (1.16 g)
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:26]=[CH:25][C:11]([O:12][CH:13]([C:17]2[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=2)[CH2:14][CH:15]=[CH2:16])=[CH:10][CH:9]=1.C1C[O:30]CC1>CCOCC>[OH:30][CH2:16][CH2:15][CH2:14][CH:13]([C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=1)[O:12][C:11]1[CH:25]=[CH:26][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1
Reactant: C=CCC(Oc1ccc(OC2CCCCO2)cc1)c1ccc(C#N)cc1
Reactant: C1CCOC1
Solvent: CCOCC
Product: N#Cc1ccc(C(CCCO)Oc2ccc(OC3CCCCO3)cc2)cc1
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
4-{1-[4-(Tetrahydro-2H-pyran-2-yloxy)phenoxy]-3-butenyl}benzonitrile (from step (i) above; 4.6 g; 13 mmol) was dissolved in dry THF (50 mL) under argon and cooled to −5° C. Borane-methylsulfide complex (BH3xSMe2) (3.5 mL of a 2 M solution in ether) was added dropwise at 0 to 5° C. The mixture was stirred at that temperature for 1.5 h. After 4 h at rt, tlc showed that the reaction was complete. The reaction mixture was quenched with 14 mL of H2O and 5 g of NaBO3. The mixture was stirred overnight, the solvent decanted off, and the residue treated with ether and decanted. The combined organic fractions were washed with brine, dried (Na2SO4), and evaporated. The crude product was purified by chromatography on silica (iso-propanol:ethyl acetate:heptane; 5:20:70). Yield: 2.44 g (58%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]4=3)[C:14]3[C:9]2=[CH:10][C:11]([O:25][CH3:26])=[CH:12][CH:13]=3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl.Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>[Cl-].[Na+].O>[CH3:26][O:25][C:11]1[CH:10]=[C:9]2[C:14]([C:15]3[C:20]([CH:8]2[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH2:40][CH2:41][N:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:7][CH:6]=2)=[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]2=[CH:17][CH:16]=3)=[CH:13][CH:12]=1
Reactant: COc1ccc2c(c1)C(c1ccc(O)cc1)c1c-2ccc2ccccc12
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1)C(c1ccc(OCCN3CCCCC3)cc1)c1c-2ccc2ccccc12

Procedure:
Five g of the compound of Example 1 was combined with 10.9 g of potassium carbonate, 50 ml of dimethylformamide, and 2.9 g of 1-(2-chloroethyl)piperdine hydrochloride. The mixture was stirred under reflux for 1 hour under nitrogen, and it was then cooled and poured into 1500 ml of iced brine. The aqueous mixture was extracted 3 times with 200 ml portions of ethyl acetate, and the organic extract was washed 3 times with 25 ml portions of brine, dried and evaporated under vacuum to obtain 6.6 g of tan crystals. The impure product was purified by high performance liquid chromatography over silica gel, using 2% triethylamine and diethyl ether. The product-containing fractions were concentrated under vacuum to obtain 5.43 g of white crystals, which were recrystallized from 60 ml of acetone to obtain 3.95 g of pure product, m.p. 147°-148° C.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].COCCO[AlH2-]OCCOC.[Na+].[CH3:27][O:28][C:29]1[C:42]2[CH2:41][CH2:40][C:39]3[N:38]([CH3:43])[C:37](=O)[CH2:36][CH2:35][C:34]=3[C:33]=2[CH:32]=[CH:31][CH:30]=1.[OH-].[K+]>C1(C)C=CC=CC=1.O>[CH3:27][O:28][C:29]1[C:42]2[CH2:41][CH2:40][C:39]3[N:38]([CH3:43])[CH2:37][CH2:36][CH2:35][C:34]=3[C:33]=2[CH:32]=[CH:31][CH:30]=1
Reactant: COc1cccc2c1CCC1=C2CCC(=O)N1C
Agent: COCCO[Al+]OCCOC
Agent: COCCO[AlH2-]OCCOC
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1CCC1=C2CCCN1C
Yield: 58.2 %

Procedure:
A solution of sodium bis-(2-methoxyethoxy)aluminium hydride in toluene (Red-Al, 65% wt, 37.2 ml, 124 mmol) was added to a stirred solution of 7-methoxy-4-methyl-1,4,5,6-tetrahydro-2H-benzo[f]quinoline-3-one (10 g, 41.2 mmol) in toluene (200 ml). The mixture was heated at reflux, under argon for 6 h and allowed to cool. Water (7 ml) was added dropwise with ice cooling and the aluminium salts dissolved by addition of 50% KOH (37 ml). The organic phase was separated, washed with water (2×100 ml), dried (Na2SO4) and concentrated in vacuo to afford an oil which was chromatographed on silica gel, with 10-15% ethyl acetate-pentane gradient elution to give the title compound as a yellow oil (5.5 g, 58%)
Reaction SMILES: I[CH2:2][CH3:3].[CH2:4]([NH:11][C:12](=[O:34])[N:13]([C:15]1[CH:16]=[C:17]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][C:22]=2[OH:33])[CH:18]=[CH:19][CH:20]=1)[CH3:14])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:2]([O:33][C:22]1[CH:23]=[C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:25]=[CH:26][C:21]=1[C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N:13]([CH3:14])[C:12]([NH:11][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:34])[CH:16]=1)[CH3:3]
Reactant: CCI
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCC)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 200 μL (2.46 mmol, 3 eq) of 1-iodoethane and 350 mg (0.82 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 6 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 4.4 eq) of potassium carbonate at 80° C. for 5 hours, methyl 3-[2-ethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH:4]1([C:7]2[C:8](=[O:32])[NH:9][C:10](/[C:13](/[C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:23](F)[CH:22]=3)=[CH:14]/[C@H:15]3[CH2:19][CH2:18][C:17](=[O:20])[NH:16]3)=[CH:11][CH:12]=2)[CH2:6][CH2:5]1.O>CO>[CH:4]1([C:7]2[C:8](=[O:32])[NH:9][C:10](/[C:13](/[C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:23]([O:2][CH3:1])[CH:22]=3)=[CH:14]/[C@H:15]3[CH2:19][CH2:18][C:17](=[O:20])[NH:16]3)=[CH:11][CH:12]=2)[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(/C(=C\[C@H]2CCC(=O)N2)c2ccc(C3CC3)c(=O)[nH]2)cc1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cc(/C(=C\[C@H]2CCC(=O)N2)c2ccc(C3CC3)c(=O)[nH]2)ccc1S(C)(=O)=O
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
A 28% solution of sodium methoxide in methanol (14 μL) was added to a solution of 3-cyclopropyl-6-{(E)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-one obtained in Example 4-386 (10 mg) in methanol (0.5 mL), after which the mixture was stirred at 70° C. for 30 minutes. The reaction solution was left to cool to room temperature. 3-Cyclopropyl-6-{(E)-1-[3-fluoro-4-(methylsulfonyl)phenyl]-2-[(2R)-5-oxopyrrolidin-2-yl]ethenyl}pyridin-2(1H)-one (50 mg), methanol (3 mL) and a 28% solution of sodium methoxide in methanol (80 μL) were then added, after which the mixture was stirred at 70° C. for two hours. The reaction solution was left to cool to room temperature and a 28% solution of sodium methoxide in methanol (1 mL) was then added, after which the mixture was stirred at 70° C. for one hour. The reaction solution was left to cool to room temperature, and water was then added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography (methanol:ethyl acetate=1:10) to give the title compound as a pale yellow solid (40 mg, 65%).
Reaction SMILES: [F:1][C:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][C@H:5]1[C:9](=[O:10])[O:8][C@H:7]([C@@H:11]([NH:19][C:20]([C:22]2[CH:31]=[N:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=2)=[O:21])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:6]1.C(O)(=O)C.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCOCC1.O>[CH2:12]([C@H:11]([NH:19][C:20]([C:22]1[CH:31]=[N:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1)=[O:21])[C@@H:7]([OH:8])[CH2:6][C@H:5]([C:9](=[O:10])[NH:45][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:4][CH2:3][C:2]([F:1])([CH3:32])[CH3:33])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(F)CC[C@@H]1C[C@@H]([C@H](Cc2ccccc2)NC(=O)c2cnc3ccccc3n2)OC1=O
Solvent: O
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(C)(F)CC[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution of the product from Method E (0.10 g, 0.22 mmol) in dioxane (2 mL) was added glacial acetic acid (0.038 mL, 0.66 mmol) and benzylamine (approx. 1 mL, excess). The resulting solution was warmed to reflux for 1 hour, cooled to ambient temperature and diluted with water. The solution was extracted with ethyl acetate and the combined organics were dried over magnesium sulfate (MgSO4), filtered and concentrated. Chromatography on silica gel, followed by recrystallization from methylene chloride/hexanes gave the title compound (0.068 g, 56%). m.p. 183-184° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[CH3:13][S-:14].[Na+]>CN(C=O)C.O>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([S:14][CH3:13])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: C[S-]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(SC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.2 %

Procedure:
A mixture of 4-fluoro-2-methoxy-1-nitrobenzene (1.38 g, 8.06 mmol) and sodium methyl mercaptide (0.622 g, 8.87 mmol) in DMF (25 mL) was stirred at room temperature for 18 hours. The reaction was the diluted with water and extracted with EtOAc. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to give (3-methoxy-4-nitrophenyl)(methyl)sulfane (0.95 g, 59%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.C(O)(=O)CCCCC(O)=O.[H][H]>[Ni].O>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:4]=1[NH2:1]
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Agent: O=C(O)CCCCC(=O)O
Solvent: O
Product: Nc1ccc(N)c(N)c1

Procedure:
91 Parts of finely ground 2,4-dinitro-aniline together with 73 parts of adipic acid, 10 parts of a commercial-type nickel catalyst and 400 parts by volume of water were charged into a hydrogenation autoclave. After the autoclave had been sealed, hydrogenation was effected in the usual manner at a temperature ranging from 60 to 100° C., while keeping the hydrogen pressure constant for about half an hour after the end of hydrogenation. For evidencing 1,2,4-triamino-benzene obtained, residual hydrogen was released, and the mixture was freed from the catalyst by filtration through a pressure filter under 20 atmsg. nitrogen and the filtrate passed into another flask flushed with nitrogen. The urea compound was prepared as described in Example 1. 62 Grams of a compound having a melting point higher than 335° C. were obtained. The following table shows accordance of the analytical data with the calculated values of the formula
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([CH:15]([CH3:17])[CH3:16])[C:9]=2[O:8][CH2:7][C:6]1=[O:18].C([O-])([O-])=O.[K+].[K+].[Na+].[I-].[CH2:27]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH2:28][CH2:29][CH3:30]>C(Cl)Cl.CO>[CH2:27]([CH:31]1[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][N:5]2[C:10]3[CH:11]=[CH:12][CH:13]=[C:14]([CH:15]([CH3:17])[CH3:16])[C:9]=3[O:8][CH2:7][C:6]2=[O:18])[CH2:33][CH2:32]1)[CH2:28][CH2:29][CH3:30]
Reactant: CCCCC1CCNCC1
Reactant: CC(C)c1cccc2c1OCC(=O)N2CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: CCCCC1CCN(CCCN2C(=O)COc3c(C(C)C)cccc32)CC1
Yield: 38.3 %

Procedure:
4-(3-Chloropropyl)-8-isopropyl-4H-benzo[1,4]oxazin-3-one (95MF98) (0.112 g, 0.42 mmol), K2CO3 (0.115 g, 0.84 mmol), NaI (0.125 g, 0.84 mmol) and 4-butylpiperidine (0.062 g, 0.44 mmol) were mixed according to GP13. Prep TLC (SiO2; CH2Cl2/MeOH 10:1) gave the title compound (111MF02) (0.06 g, 39%). 1H NMR (CDCl3) δ 6.99-6.91 (m, 3H), 4.55 (s, 2H), 3.96 (t, J=7.4 Hz, 2H), 3.27 (m, 1H), 2.89 (d, J=11.2 Hz, 2H), 2.40 (t, J=7.2 Hz, 2H), 1.93-1.83 (m, 4H), 1.66 (d, J=9.6 Hz, 2H); 1.27-1.20 (m, 15H), 0.88 (t, J=6.8 Hz, 3H); 13C NMR (CDCl3) δ 164.7, 142.9, 137.5, 128.7, 122.6, 121.1, 112.9, 67.7, 56.0, 54.2, 39.9, 36.4, 35.9, 32.5, 29.1, 27.2, 24.9, 23.0, 22.7, 14.2.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8](O)=[O:9])[S:6][CH:7]=1.C1N=C[N:15](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8]([NH2:15])=[O:9])[S:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1nc(C(F)(F)F)cs1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1nc(C(F)(F)F)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a solution of 4-trifluoromethyl-thiazole-2-carboxylic acid (50 g, 1 eq.) in anhydrous THF (480 mL) was added carbodiimidazole (45.2 g, 1.1 eq.) portionwise under nitrogen in an ice/water bath (about 5° C.). The reaction mixture was stirred at room temperature for 16 hrs. NH4OH (25% in H2O; 1.930 mL) was added. The solution was stirred for 4 hrs, and then partitioned in DCM (500 mL) and H2O (500 mL). Aqueous layer was further extracted with DCM (500 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to yield compound 285a as an orange solid in 72% yield. MS (ESI, EI+): m/z=197 (MH+).