Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=1.C.[CH3:16][N:17]([CH3:31])[CH2:18][CH2:19][O:20][C:21]1[C:26]([O:27][CH2:28][CH2:29][OH:30])=[CH:25][CH:24]=[CH:23][N:22]=1.C1COCC1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:31])[CH2:18][CH2:19][O:20][C:21]1[C:26]([O:27][CH2:28][CH2:29][O:30][C:2]2[C:3]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]3[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: CN(C)CCOc1ncccc1OCCO
Reactant: C[C@@H]1CNCCN1c1nccnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H]1CNCCN1c1nccnc1OCCOc1cccnc1OCCN(C)C
Temperature: 100 °C
Reaction time: 0.42 h

Procedure:
(2R)-1-(3-chloro-2-pyrazinyl)-2-methylpiperazine (20 L in toluene solution; see Example 8 for preparation) and active charcoal (201 g) was added to the 328 L-reactor containing 2-{[2-(2-dimethylaminoethoxy)-3-pyridinyl]oxy} ethanol (Example 1C) in toluene solution. The mixture was stirred for 25 minutes before transferred to a through a GAF-filter (containing a Teflon filter bag) to a 250 L-stainless steel reactor. The mixture was heated to 100° C. before the prepared “THF/potassium tert-butoxide-solution” was added to the reactor using a 50 L addition bowl. After 10 L “THF/potassium tert-butoxide-solution” was added, an IP-HPLC was taken to ensure that the title compound had started to form. The total addition of THF/potassium tert-butoxide-solution was made during 2 h and 15 minutes. Water (21 L) and sodium chloride (1 kg) was added to a 198 L-glasslined reactor. The salt was dissolved before the reaction mixture was transferred from the 328 L-reactor and quenched into the 198 L-reactor. Toluene (10 L) was also transferred to make sure that no reaction-mixture was left in the hoses used for the transfer. The mixture was then heated to 70° C. before the mechanical stirrer was turned off. The phases were allowed to separate for 30 minutes before the water phase (25 L) was discharged. The mixture was heated to reflux and toluene (10 L) was distilled off. Water (100 L) was added and the mixture was heated to reflux again and 60 L of water was distilled off. The remaining solution was then cooled to RT. The title compound was never isolated; it was directly used in the next step (Example 3C). IP sample (HPLC) of the toluene mixture confirmed the retention time for the desired product (tret=2.2 minutes).
Reaction SMILES: [C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([NH2:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:3])[CH3:2].[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:1]([N:5]1[CH2:31][CH2:30][CH2:29][CH2:28][C:8]2[C:9]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[C:10]3[C:19]4[CH:18]=[C:17]([NH:20][S:34]([CH3:33])(=[O:36])=[O:35])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1N)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(cc1NS(C)(=O)=O)-c1c(-c3cccs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Temperature: 25 °C

Procedure:
To a solution of 12.5 mg 20b in 2 mL methylene chloride was added 3.2 μL methanesulphonyl chloride and 9.2 μL N,N-diisopropylethylamine. The mixture was stirred at room temperature. After 1 h the mixture was diluted with methylene chloride and was washed with water. The organic phase was dried and concentrated. The crude product was purified by preparative HPLC on a reversed phase C18 column to give 1.8 mg of compound 29a.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCOP(OCC)([CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])=O.[C:29]([O:33][C:34]([N:36]1[C@@H:40]([CH2:41][CH:42]=O)[CH2:39][O:38][C:37]1([CH3:45])[CH3:44])=[O:35])([CH3:32])([CH3:31])[CH3:30]>O1CCCC1>[C:29]([O:33][C:34]([N:36]1[C@@H:40]([CH2:41]/[CH:42]=[C:18](/[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)\[CH3:19])[CH2:39][O:38][C:37]1([CH3:44])[CH3:45])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOP(=O)(OCC)C(C)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC=O)COC1(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C/C(=C\C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N,N-diisopropylamine (1.74 ml) in tetrahydrofuran (8 ml) at −78° C. was added dropwise a solution of n-butyllithium (7.71 ml, 1.6 M in hexane) and the reaction mixture was then warmed to 0° C. for 15 min. After re-cooling to −78° C., a solution of diethyl 1-phenylethyl phosphonate (2.76 ml) in tetrahydrofuran (8 ml) was added dropwise. The mixture was stirred at −78° C. for 30 min and then a solution of (S)-2,2-dimethyl-4-(2-oxo-ethyl)-oxazolidine-3-carboxylic acid tert-butyl ester (2.00 g, CAS 147959-19-1) in tetrahydrofuran (8 ml) was added dropwise over 20 min. The mixture was then allowed to warm to room temperature and stirring continued at room temperature for 48 hours. The mixture was then quenched by addition of aqueous hydrochloric acid (2N) and then made basic by addition of aqueous sodium hydroxide solution (1 N). The mixture was taken up in ethyl acetate and the phases separated. The organic layer was washed sequentially with water and with saturated brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc gradient) to yield a yellow oil, (1.16 g, 44%); MS (ISP): 332.1 ([M+H]+).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]([CH:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=4[F:32])[N:23]=[C:22]([C:33]([F:39])([F:38])[C:34]([F:37])([F:36])[F:35])[CH2:21]3)[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[F:32][C:26]1[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:25]=1[N:24]1[CH:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[CH:15]=2)[CH2:21][C:22]([C:33]([F:38])([F:39])[C:34]([F:36])([F:37])[F:35])=[N:23]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(C3=CCNCC3)c2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.7 %

Procedure:
5-[3-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-phenyl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (800.0 mg, 1.32 mmol) prepared in Example 60 and trifluoroacetic acid (1011.0 uL, 13.21 mmol) were added at 0° C. to dichloromethane (6.6 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure to give 820.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([OH:40])=O)([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:58]1([S:61]([NH2:64])(=[O:63])=[O:62])[CH2:60][CH2:59]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[CH:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([NH:64][S:61]([CH:58]6[CH2:60][CH2:59]6)(=[O:63])=[O:62])=[O:40])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3cccc(C)n3)nc2c1C
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)C4C3)cc(-c3cccc(C)n3)nc2c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.6 %

Procedure:
A mixture of the acid 17-[2-(6-methyl-2-pyridyl)-7-methoxy-8-methylquinolin-4-yl-oxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (102, 28 mg, 0.046 mmol) and CDI (15 mg, 0.092 mmol) in dry THF (3 mL) was heated at reflux for 2 h under nitrogen. The activation was monitored by LC-MS. The reaction mixture was cooled at room temperature and cyclopropylsulfonamide (17 mg, 0.137 mmol) was added. Then, DBU (16 μL, 0.105 mmol) was added and the reaction was heated at 55° C. After 24 h, the pH of the reaction mixture was adjusted to 3 with citric acid (5%). Then, the solvent was evaporated, and the residue partitioned between AcOEt and water. The crude material was purified by preparative HPLC to give 17 mg (52%) of the target compound 103: m/z=716 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([F:28])[CH:19]=2)([NH:14][C:15]([NH2:17])=[S:16])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.Cl[CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C:31]1=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:18]2[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[C:20]([F:28])[CH:19]=2)([NH:14][C:15]2[S:16][C:30]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=3[N:17]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1
Reactant: COC(=O)C[C@](NC(N)=S)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Reactant: O=C1CCCCC1Cl
Solvent: CO
Product: COC(=O)C[C@](Nc1nc2c(s1)CCCC2)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Yield: 11 %

Procedure:
A solution of (S)-methyl 3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-thioureidopropanoate (100 mg, 0.23 mmol) and 2-chloro cyclohexanone (36 mg, 0.28 mmol) in MeOH (5.0 mL) was heated at 70° C. for 18 h. The concentrated reaction mixture was purified by silica gel ISCO chromatography (12 g column) using hexanes/EtOAc (0-30% over 15 min). (S)-methyl 3-(5-chloropyridin-2-yl)-3-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-ylamino)propanoate was isolated as a clear oil, (13 mg, 11% yield). LCMS: 1.70 min [M+1] 514.3 (2 min gradient, MeOH/H2O 0.1% TFA); HPLC: 3.65 min (4 min gradient, MeOH/H2O 0.2% PPA); Purity 96%; NMR: 400 MHz 1H (CDCl3) 8.43 ppm, 1H, d, J=2.20 Hz; 7.55 ppm, 1H, dd, J=8.57, 2.42 Hz; 7.49 ppm, 1H, s; 7.29 ppm, 2H, m; 7.14 ppm, 1H, d, J=7.91 Hz; 3.98 ppm, 1H, d, J=15.82 Hz; 3.70 ppm, 1H, d, J=15.82 Hz; 3.60 ppm, 1H, s; 3.47 ppm, 3H, s; 2.40 ppm, 4H, m; 1.68 ppm, 4H, m.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=2)=[O:12])[C:4](=[O:28])[CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:39])=[C:34](B(O)O)[CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:39])=[C:32]([C:2]2[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:27])[C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=3)=[O:12])[C:4](=[O:28])[CH:3]=2)[CH:31]=1
Reactant: Cc1ccc(Cl)cc1B(O)O
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C
Reaction time: 8 h

Procedure:
Under argon (in a flask dried by heating), 92 mg (0.20 mmol) of tert-butyl 4-{[2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoyl]amino}benzoate (racemate), 41 mg (0.24 mmol, 1.2 eq.) of 5-chloro-2-methylphenylboronic acid, 84 mg (0.61 mmol, 3.0 eq.) of potassium carbonate and 16 mg (0.02 mmol, 0.1 eq.) of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were suspended in 5.0 ml of dioxane and stirred overnight in an oil bath already preheated to 110° C. The reaction mixture was filtered through Celite and the residue was washed with dioxane. The combined filtrates were concentrated under reduced pressure. The residue was triturated with water, filtered off, washed with water and dried under reduced pressure. Yield: 105 mg (purity 91%, 95% of theory)
Reaction SMILES: [OH:1][C:2]1[C:12]([OH:13])=[CH:11][CH:10]=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].[Br:14]Br>C(O)(=O)C>[Br:14][C:11]1[CH:10]=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]2=[C:2]([OH:1])[C:12]=1[OH:13])=[O:6]
Reactant: BrBr
Reactant: O=C1NC(=O)c2c1ccc(O)c2O
Solvent: CC(=O)O
Product: O=C1NC(=O)c2c1cc(Br)c(O)c2O

Procedure:
3,4-Dihydroxyphthalimide (Example 4e) was heated with bromine in acetic acid for about 6 hours to give 5-bromo-3,4-dihydroxyphthalimide which was subsequently treated in a manner similar to Example 1f)-h).
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[NH:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24].O.N>C(O)CCC>[CH3:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[N:12]1[CH2:13][CH2:14][CH2:15][N:16]([C:17]2[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:24])[C:2]1=[NH:1]
Reactant: Cc1cccc(C)c1NCCCNc1c(C)cccc1C
Reactant: N#CBr
Agent: N
Solvent: CCCCO
Solvent: O
Product: Cc1cccc(C)c1N1CCCN(c2c(C)cccc2C)C1=N
Reaction time: 2 h
Yield: 36.7 %

Procedure:
A solution of 0.75 g (7.1 mmoles) of cyanogen bromide in 10 ml of n-butanol is added dropwise, within about 0.5 hours, to a stirred solution of 2.0 g (7.1 mmole) of 1,3-bis(2',6'-dimethylphenyl-amino)-propane in 20 ml of n-butanol at 110° to 115° C. After the addition the mixture is stirred for further 2 hours at the same temperature. Thereafter the mixture is cooled, shaken five times with 10 ml of water each, the aqueous solutions are combined, and the pH of the mixture is adjusted to 8.0 to 8.5 with concentrated aqueous ammonia. The separated unreacted starting substance (0.4 g, m.p.: 68°-71° C.) is filtered off, the aqueous filtrate is rendered alkaline with 2 n aqueous sodium hydroxide solution, and the aqueous-alkaline phase is extracted thrice with 30 ml of chloroform each. The organic phases are combined, washed with water, dried over potassium carbonate, and the solvent is distilled off. 0.8 g (36.7%) of 1,3-bis(2',6'-dimethylphenyl)-2-imino-hexahydro-pyrimidine are obtained; m.p.: 181°-183° C. (after recrystallization from aqueous isopropenol).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH:17]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[CH:8][C:7]([CH2:15][CH2:16][CH2:17][N:30]2[CH2:29][CH2:28][N:27]([CH:26]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[CH2:32][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1cccs1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1-c1cccs1

Procedure:
92 mg (84%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(thiophene-2-yl)-1H-pyrazol-3-yl)propanal (50 mg, 0.191 mmol), 1-(bis(4-fluorophenyl)methyl)piperazine (55 mg, 0.191 mmol), DIPEA (0.050 mL, 0.287 mmol) and NaBH(OAc)3 (121 mg, 0.573 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:14])[C:5](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[C:6]([OH:8])=[O:7].[OH-].[CH2:16]([N+](CCCC)(CCCC)CCCC)CCC.S(OC)(OC)(=O)=O>ClCCl>[CH3:16][O:7][C:6](=[O:8])[C:5]1[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12])[NH2:14]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: Nc1cc(Cl)cc([N+](=O)[O-])c1C(=O)O
Agent: [OH-]
Solvent: ClCCl
Solvent: COS(=O)(=O)OC
Product: COC(=O)c1c(N)cc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.3 %

Procedure:
3.25 g (15 mmol) of 4-chloro-6-nitro-anthranilic acid and 9.73 ml of a 40% aqueous solution of tetrabutylammonium hydroxide are placed in 65 ml of dichloromethane. Then 1.43 ml (15 mmol) of dimethyl sulfate are added dropwise thereto and the mixture is stirred for 1 hour at room temperature and washed in succession with a small amount of water and saturated sodium chloride solution. The aqueous phases are extracted by shaking with dichloromethane and the combined organic phases are dried over sodium sulfate, filtered and concentrated. The residue is stirred with a small amount of ethyl acetate. The product is precipitated with hexane and dried. 1.67 g (48.3% of theory) of 4-chloro-6-nitro-anthranilic acid methyl ester having a melting point of 114°-116° are obtained.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])=[N:7][N:8]=1.[CH:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)([CH3:21])[CH3:20].C(N1C=CN=C1)(N1C=CN=C1)=O>O1CCCC1>[CH:19]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:3][C:4]2[S:5][C:6]([S:9][CH2:10][CH2:11][N:12]([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:14])[CH3:15])=[N:7][N:8]=2)=[O:27])=[CH:29][CH:30]=1)([CH3:21])[CH3:20]
Reactant: CC(C)N(CCSc1nnc(N)s1)C(C)C
Reactant: CC(C)c1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)c1ccc(C(=O)Nc2nnc(SCCN(C(C)C)C(C)C)s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.1 %

Procedure:
Sodium hydride (0.6 g) and 2-amino-5-diisopropylaminoethylthio-1,3,4-thiadiazole (2.6 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes while being cooled with ice. 4-Isopropylbenzoic acid (1.6 g) and carbonyldiimidazole (1.8 g) were stirred in tetrahydrofuran (30 ml) for 30 minutes at room temperature and the mixture was added to the former reaction mixture. The mixture was stirred for 4 hours at room temperature, and then concentrated under a vacuum. The residue, with water added thereto, was extracted with ethyl acetate. The extract was dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=15:1). The resulting solid was recrystallized from n-hexane/ethanol, thereby yielding 2.3 g of the aimed compound.
Reaction SMILES: C(O[C:5]1([CH3:16])[CH:9]=[CH:8][C:7](=[O:10])[CH:6]1[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=O)C.C1(C)C=CC=CC=1.[C:24]([O-:27])(=[O:26])[CH3:25].[Na+]>C(O)(=O)C>[C:24]([O:27][CH:9]1[CH2:8][C:7](=[O:10])[C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:5]1[CH3:16])(=[O:26])[CH3:25]
Reactant: CC(=O)[O-]
Reactant: CCCCCC1C(=O)C=CC1(C)OC(C)=O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCCCCC1=C(C)C(OC(C)=O)CC1=O
Yield: 170.1 %

Procedure:
In the same apparatus as in Example 1, 3-acetoxy-2-n-pentyl-3-methyl-4-cyclopentenone (22.4 g), toluene (60 ml), acetic acid (10 ml) and sodium acetate (4 g) were charged and heated for 10 hours with agitation. After the completion of the reaction, acetic acid was evaporated off under reduced pressure. The residue was extracted with toluene (70 ml) and water (50 ml) and treated as in Example 1 to obtain 4-acetoxy-2-n-pentyl-3-methyl-2-cyclopentenone (18.6 g). Yield, 83%, B.P., 125°-135° C./0.2-0.5 mmHg.
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[CH2:65]([SH:72])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:65]([S:72][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([C:6]([Cl:13])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: SCc1ccccc1
Reactant: Cc1c(Br)ccc2c(Cl)ccnc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(SCc2ccccc2)ccc2c(Cl)ccnc12
Temperature: 110 °C
Yield: 99.2 %

Procedure:
To a vial charged with 7-bromo-4-chloro-8-methylquinoline (0.950 g, 3.70 mmol) was added Dioxane (14.81 ml), DIEA (1.294 ml, 7.41 mmol), xantphos (0.429 g, 0.741 mmol), Pd2(dba)3 (0.339 g, 0.370 mmol) and benzyl mercaptan (0.438 ml, 3.70 mmol). The vessel was sealed and heated to 110° C. for 3 hr affording complete conversion according to LC-MS. The mixture was filtered through Celite and dried under reduced pressure and purified with a 25 g Interchim column ramping EtOAc in heptane (0-50%, 10% DCM throughout) affording product as a yellow oil as a mixture of mono and bis substituted product according to MS as one LC peak, 7-(benzylthio)-4-chloro-8-methylquinoline (1.100 g, 3.67 mmol, 99% yield). m/z (ESI) 300.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1([CH3:27])[NH:22][C:21]([CH2:24][CH3:25])([CH3:23])[CH2:20][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6]2=[O:19])[CH:4]1[CH3:26])[CH3:2].[CH2:28]1[O:30][CH2:29]1>CO.Cl>[CH2:1]([C:3]1([CH3:27])[N:22]([CH2:28][CH2:29][OH:30])[C:21]([CH2:24][CH3:25])([CH3:23])[CH2:20][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6]2=[O:19])[CH:4]1[CH3:26])[CH3:2]
Reactant: C1CO1
Reactant: CCCCCCCCN1C(=O)NC2(CC(C)(CC)NC(C)(CC)C2C)C1=O
Agent: Cl
Solvent: CO
Product: CCCCCCCCN1C(=O)NC2(CC(C)(CC)N(CCO)C(C)(CC)C2C)C1=O
Temperature: 110 °C
Yield: 97.1 %

Procedure:
To a solution of 6.0 g of 7,9-diethyl-6,7,9-trimethyl-3-octyl-1,3,8-triazaspiro[4.5]decane-2,4-dione (Compound 5) obtained as described in Example 4, in 40 ml of methanol were added 3 drops of concentrated hydrochloric acid and 3.5 g of ethylene oxide. The mixture was heated at 110° C for 24 hours in a sealed tube and then concentrated to give 6.5 g of Compound 118 as an oil. This product had an Rf value of 0.33 on thin layer chromatography on a 0.25 mm thick layer of silica gel (Kieselgel 60F 254, available from Merck & Co.; eluent, benzene containing 5% of triethylamine).
Reaction SMILES: [OH:1][N:2]([CH:5]([C:26]1[CH:31]=[CH:30][C:29]([O:32]COC)=[CH:28][CH:27]=1)[CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:9])=[O:8])[CH:3]=[O:4].O>ClCCl>[OH:1][N:2]([CH:5]([C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1)[CH2:6][S:7]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)(=[O:9])=[O:8])[CH:3]=[O:4]
Reactant: COCOc1ccc(C(CS(=O)(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)N(O)C=O)cc1
Solvent: O
Solvent: ClCCl
Product: O=CN(O)C(CS(=O)(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 26.4 %

Procedure:
A suspension of Example 129 (186 mg, 0.366 mmol) in dichloromethane (20 mL) at −78° C. was treated with boranetrifluoride diethyl etherate (55.6 mL, 0.439 mmol), stirred at 0° C. for 3 hours and left at room temperature overnight, treated with water, extracted with ethyl acetate, dried (Na2SO4), filtered, concentrated and purified on silica gel with 80% ethyl acetate/hexanes to provide 45 mg (26%) of the title compound as an orange solid.