Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.Cl.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][C:34]=1[O:35][CH3:36])[CH2:31][NH:30][CH2:29][CH2:28]2>O>[Cl:8][C:6]1[N:5]=[C:4]([N:30]2[CH2:29][CH2:28][C:27]3[C:32](=[CH:33][C:34]([O:35][CH3:36])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH2:31]2)[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: Nc1nc(Cl)nc(Cl)n1
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc2c(cc1OC)CN(c1nc(N)nc(Cl)n1)CC2
Reaction time: 1 h

Procedure:
2-amino-4,6-dichloro-1,3,5-triazine (9.7 g, 58.8 mM) was dispersed in water (50 mL), sodium carbonate solution (2N, 60 mL) and dioxane 15 mL) at 0° C. 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (13.9 g, 58.8 mM) was added and the mixture was stirred vigorously for 1 hr. The product was filtered, rinsed with water, dried and recrystallized from methanol; 14.3 g (75%), mp=196°-197° C.
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[C:10]([OH:21])(=[O:20])[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=1.O1COCO[CH2:23]1.C(O)(=O)C>O>[C:15]([C:14]1[CH:18]=[C:19]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:21])[O:20][CH2:23]2)([OH:17])=[O:16]
Reactant: C1OCOCO1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc2c(c1)COC2=O
Temperature: 131.5 °C

Procedure:
In a 3000-l glass lined reactor, 550 Kg of oleum containing 25% of SO3 are charged under vacuum and good aspiration, then, consecutively, under stirring, 56 Kg of terephthalic acid at 20-23° C. and 26 Kg of 1,3,5-trioxane at 15-20° C. are added thereinto. The reactor is heated at 130-133° C. for 4 hours, then the mixture is cooled to 20-23° C. and 118 Kg of glacial acetic acid are couled portionwise thereinto at a temperature not higher than 25° C. At the end of this operation, 1000 Kg of water are added portionwise, whereby the temperature is maintained not higher than 43-45° C. by circulation of water in the jacket. The mixture is stirred for about 1 hour at 20-23° C., then the product is centrifugated, squeezed and abundantly washed with water in order to remove the larger amount of sulfuric acid from the mother liquors and to obtain 100-105 Kg of 5-carboxyphthalide as a well squeezed, wet raw-product. In a 3000-l stainless steel reactor the product thus obtained is suspended in 680 Kg of deionized water and a solution of 60 Kg of sodium bicarbonate in 540 Kg of deionized water is then slowly added to said suspension to a pH of 7.0-7.2. To the solution thus obtained, lightly cloudy, 10 Kg of Celite® are added, the solid is filtered off and the solution, at a temperature of 22-25° C., is brought to pH=3 with 32% hydrochloric acid, then stirred at 20-22° C. and centrifugated. The product is well squeezed, abundantly washed with deionized water and dried under vacuum to give 41-43.7 Kg of 5-carboxyphthalide.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([OH:22])=[N:17][N:16]=[C:15]3Cl)=[O:11])[CH:6]=[CH:7][CH:8]=1>[Pd].CO>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[C:18]([OH:22])=[N:17][N:16]=[CH:15]3)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(O)nnc(Cl)c2c1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc2c(O)nncc2c1
Reaction time: 16 h
Yield: 34.5 %

Procedure:
A mixture of 4-chloro-1-hydroxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (64 mg, 0.174 mmol) (example 25), MeOH (3 mL) and 10% wet Pd/C (catalytic) was evacuated and flushed (3×) with hydrogen. The mixture was stirred under hydrogen for 16 h. The mixture was filtered through celite, rinsed with MeOH and concentrated under vacuum. Chromatography (Hex/EtOAc) was used to obtain 1-hydroxy-phthalazine-6-carboxylic acid (3-trifluoromethyl-phenyl)-amide (20 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ: 7.35 (d, 1H), 7.45 (t, 1H), 8.03 (s, 1H), 8.08 (d, 1H), 8.19 (s, 1H), 8.30-8.37 (m, 2H), 8.44 (d, 1H), 10.05 (s, 1H), 11.26 (s, 1H) ppm. m/z 334.10.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH2:23])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCCBr
Reactant: CC(C)(C)OC(=O)NCc1cccc(Oc2cc(Cl)ccc2N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCNc1ccc(Cl)cc1Oc1cccc(CNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 96 h
Yield: 60.4 %

Procedure:
A mixture of tert-butyl[3-(2-amino-5-chlorophenoxy)benzyl]carbamate (10.5 g. 30 mmols), ethyl 5-bromovalerate (10.2 ml, 60 mmols), potassium carbonate (4.2 g, 30 mmols) and N,N-dimethylformamide (100 ml) was stirred at 60° C. for 96 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 5-[2-[3-(tert-butoxycarbonylaminomethyl)phenoxy]-4-chlorophenyl]aminovalerate (8.65 g, 60.4%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:31])[NH:12][C@H:13]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[CH:7][C:6]=1[N+:32]([O-])=O)(=[O:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:31])[NH:12][C@H:13]([C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=2)=[CH:7][C:6]=1[NH2:32])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(C(=O)N[C@@H](c2ccc(C(F)(F)F)cc2)c2ncccc2F)cc1N
Reaction time: 5 h

Procedure:
To a round bottom flask purged with N2 was added 10% Pd/C (20.29 mg, 0.019 mmol) and under a N2 atmosphere (S)-4-(((3-fluoropyridin-2-yl)(4-(trifluoromethyl)phenyl)methyl)carbamoyl)-2-nitrophenyl acetate (91 mg, 0.191 mmol) in EtOAc (10 mL) was added. The solution was purged for a further 2 min, then capped with a balloon of H2. After 5 h, the reaction was filtered through a pad of Celite® brand filter agent and the Celite® brand filter agent rinsed with EtOAc. The filtrate was concentrated in vacuo and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (4 g), eluting with 0 to 75% EtOAc in hexane, to provide the title compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 9.85 (s, 1H), 8.35-8.54 (m, 2H), 8.19 (s, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.59 (dd, J=8.5, 2.0 Hz, 1H), 7.55 (s, 4H), 7.38-7.47 (m, 1H), 7.32 (dt, J=8.4, 4.3 Hz, 1H), 7.04 (d, J=8.3 Hz, 1H), 6.62 (dd, J=6.9, 2.0 Hz, 1H), 2.20 (s, 3H). MS (ESI pos. ion) m/z: 448.1 (M+H).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:11])(=[O:10])[CH:7]([CH3:9])[OH:8].O.[C:13](O)(=[O:15])[CH3:14]>>[C:13]([O:8][CH:7]([CH3:9])[C:6]([OH:11])=[O:10])(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: CC(O)C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)OC(C)C(=O)O
Temperature: 114 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
In a distillation reactor at atmospheric pressure, an acid solution formed by combining 30 ml of glacial acetic acid with 0.5 ml concentrated sulfuric acid was maintained at approximately 114° C. A reactant solution was prepared by combining 5.0 ml of an 85% lactic acid solution, by weight (15% water) with 20 ml of glacial acetic acid, and was added dropwise to the distillation reactor. The resulting distillate was collected and analyzed by NMR. After 1 hour, the 2-acetoxy propionic acid product yield was greater than about 90%. A small amount of dimer or polymer was also detected.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([Br:27])=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2[O:28][CH3:29])[C:12]2[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=2[NH:10][CH2:9]1)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH2:7][C@@H:8]1[C:14](=[O:15])[N:13]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([Br:27])=[CH:24][CH:25]=3)[CH:20]=[CH:19][C:18]=2[O:28][CH3:29])[C:12]2[CH:30]=[CH:31][CH:32]=[CH:33][C:11]=2[NH:10][CH2:9]1
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](N)CNc2ccccc21
Yield: 70.58 %

Procedure:
To a stirred solution of [(S)-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl]-carbamic acid tert-butyl ester (Intermediate 4)(100 mg, 0.19 mmol) in DCM (2 mL) at 0° C. was added 50% TFA in DCM (4 mL) dropwise. After 2 h the mixture was evaporated and the residue was washed with ether to afford (S)-3-amino-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-1,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2-one trifluoroacetate (72 mg, 70.58%). LC-MS: 426 (M+H).
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([OH:5])=O.[C:14]1([OH:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([C:17]1[CH:18]=[CH:19][C:14]([OH:20])=[CH:15][CH:16]=1)=[O:5]
Reactant: Oc1ccccc1
Reactant: CCCCCCCCC(C)C(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCCCCC(C)C(=O)c1ccc(O)cc1
Yield: 40 %

Procedure:
Then, the same procedure as in Example 1 was repeated except that the above (+)-2-methyl decanoic acid was used instead of (+)-2-methyl butanoic acid to convert this compound into an acid chloride, which was reacted with phenol through aluminum chloride in methylene chloride to obtain (+)-4-(2-methyldecanoyl) phenol having the aforementioned physical and chemical properties at a yield of 40%.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][C:9](=O)[CH:8]([CH3:13])[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>C1C=CC=CC=1>[CH2:4]([O:3][C:1]([N:6]1[CH2:11][CH:10]=[C:9]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:8]([CH3:13])[CH2:7]1)=[O:2])[CH3:5]
Reactant: C1CCNC1
Reactant: CCOC(=O)N1CCC(=O)C(C)C1
Solvent: c1ccccc1
Product: CCOC(=O)N1CC=C(N2CCCC2)C(C)C1

Procedure:
A mixture of 92.2 g of 1-carbethoxy-3-methyl-4-piperidone and 53.5 g of pyrrolidine in 1.0 liter of benzene is heated to the boil at reflux for 2 hours and the resulting water is continuously removed azeotropically. The reaction mixture is concentrated and the crude 1,2,3,6-tetrahydro-3-methyl-4-pyrrolidinylpyridine-1-carboxylic acid ethyl ester, obtained as an oil, is used as such for the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C([SiH](CC)CC)C>>[CH2:14]([C:12]1[S:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:10][CH:11]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc(-c2ccc(C(O)c3ccccc3)s2)cc1
Agent: CC[SiH](CC)CC
Product: COc1ccc(-c2ccc(Cc3ccccc3)s2)cc1
Yield: 99 %

Procedure:
The title compound was prepared from the product of step 2 (0.6 g, 2.0 mmol) and triethylsilane (2.4 g, 20.2 mmol) using the procedure of Example 159, step 3 with 99% yield (0.55 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18](F)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][NH:37][CH2:36][CH2:35][NH:34]2)=[CH:29][CH:28]=1>CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:24])[C:8]2[CH:9]=[C:10]3[CH:20]=[C:19]([F:21])[C:18]([N:37]4[CH2:36][CH2:35][NH:34][CH:33]([C:30]5[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=5)[CH2:38]4)=[C:17]([F:23])[C:11]3=[N:12][C:13]=2[N:14]([CH3:16])[CH:15]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(C2CNCCN2)cc1
Reactant: CCOC(=O)c1cn(C)c2nc3c(F)c(F)c(F)cc3cc2c1=O
Solvent: CS(C)=O
Product: CCOC(=O)c1cn(C)c2nc3c(F)c(N4CCNC(c5ccc(OC)cc5)C4)c(F)cc3cc2c1=O
Temperature: 95 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
A suspension of 3-ethoxycarbonyl-7,8,9-trifluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (2.5 g) and (RS)-2-(4-methoxyphenyl)piperazine (3.5 g) in dimethyl sulphoxide (40 cc) is heated with stirring to a temperature in the region of 95° C. for 2 hours. After treatment of the reaction mixture according to the conditions described in Example 39, (RS)-3-ethoxycarbonyl-7,9-difluoro-8-[3-(4-methoxyphenyl)-1-piperazinyl]-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine (2.8 g) is obtained in the form of a yellow solid, m.p. 209° C., which is used without further purification for the subsequent steps.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CC(C)=O>[CH2:21]([O:12][C:3]1[C:4]([N+:9]([O-:11])=[O:10])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[Br:1])[CH:20]=[CH2:19]
Reactant: Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1c(Br)cc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.2 %

Procedure:
To a mixture of 2-bromo-4-methyl-6-nitrophenol (7.00 g, 30.2 mmol), K2CO3 (6.26 g, 45.3 mmol) in acetone (105 mL) was added allyl bromide (3.80 ml, 45.3 mmol). The reaction mixture was stirred at room temperature overnight. It was then heated at 40° C. for 5 hrs. Inorganic salts were filtered and washed with acetone. The filtrate was concentrated to give 7.74 g (94%) of the desired product. MS (DCI/NH3) m/z: 289.0 (M+NH4)+; 1H NMR (300 MHz, CD3OD) δ ppm 2.37 (s, 3 H) 4.61 (d, J=6.10 Hz, 2 H) 5.26 (dd, J=10.51, 1.80 Hz, 1 H) 5.39 (dd, J=17.29, 1.80 Hz, 1 H) 6.09 (m, 1 H) 7.63 (s, 1 H) 7.74 (s, 1 H).
Reaction SMILES: C1(C2SC=[C:10]([C:12]([C:14]3[CH:19]=[C:18](OC)[C:17](OC)=[C:16](OC)[CH:15]=3)=O)[N:11]=2)C=CC=CC=1.[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35]1[S:36][CH2:37][CH:38]([C:40]([OH:42])=O)[N:39]=1.N[C@H](C(O)=O)CS>>[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[C:27]1[C:35]1[S:36][CH:37]=[C:38]([C:40]([C:10]2[NH:11][C:19]3[C:14]([CH:12]=2)=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:42])[N:39]=1
Reactant: COc1cc(C(=O)c2csc(-c3ccccc3)n2)cc(OC)c1OC
Reactant: O=C(O)C1CSC(c2cc3ccccc3[nH]2)=N1
Agent: N[C@@H](CS)C(=O)O
Product: O=C(c1csc(-c2cc3ccccc3[nH]2)n1)c1cc2ccccc2[nH]1

Procedure:
(2-(1H-Indol-2-yl)thiazol-4-yl)(1H-indol-2-yl)methanone (8) was prepared using the similar method as used of compound 1h from 2-(1H-indol-2-yl)-4,5-dihydrothiazole-4-carboxylic acid and cysteine. NMR (500 MHz, CDCl3) δ 9.39 (s, 1H), 8.54 (s, 1H), 8.46 (s, 1H), 8.06 (s, 1H), 8.03 (dd, 1H), 7.66 (d, 1H), 7.51 (d, 1H), 7.41 (d, 1H), 7.33 (t, 1H), 7.29 (d, 1H), 7.15 (t, 1H), 7.09 (d, 1H), 6.72 (s, 1H). MS (ESI) m/z 366.1 (M+Na)+, 341.9 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.CCCCCC.C([Li])CCC.[CH3:19][S:20]SC>C(OCC)C.O>[CH3:19][S:20][C:4]1[S:5][CH:6]=[CH:7][C:3]=1[O:2][CH3:1]
Reactant: CSSC
Reactant: COc1ccsc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Solvent: O
Product: COc1ccsc1SC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 21 g of 3-methoxythiophene in diethyl ether at -40° C. was added 115 ml of a 1.6 molar hexane solution of n-butyllithium. The mixture was warmed slowly over 10 minutes to 0° C., then refluxed for 1 hour, was cooled to -78° C. and a solution containing 21.4 g of dimethyldisulphide in 100 ml of diethyl ether was added. The reaction mixture was warmed to room temperature and stirred for 30 minutes, was poured into water and the organic layer washed with water, with brine, and was then dried over magnesium sulphate and evaporated to dryness.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:8][C@H:9]([C:14]([O:16]CC2C=CC(OC)=CC=2)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])=[N:4][N:5]([CH3:7])[CH:6]=1.[Li+].[OH-].Cl>CO>[Br:1][C:2]1[C:3]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH:11]([CH3:12])[CH3:13])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: COc1ccc(COC(=O)[C@H](CC(C)C)Nc2nn(C)cc2Br)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)C[C@H](Nc1nn(C)cc1Br)C(=O)O
Reaction time: 0.5 h

Procedure:
To 4-methoxybenzyl N-(4-bromo-1-methyl-1H-pyrazol-3-yl)leucinate (1.19 g, 2.89 mmol) in MeOH (60 mL) was added dropwise an aqueous LiOH solution (1.0 M, 14.5 mL, 14.5 mmol) and the reaction was stirred for ½ hour. The reaction was acidified (pH=4–5) with aqueous 10% HCl and the product extracted with EtOAc (3×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (Hex/EtOAc/AcOH, 70/29/1, then 50/49/1) to afford N-(4-bromo-1-methyl-1H-pyrazol-3-yl)leucine.
Reaction SMILES: [C:1]([O-:8])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[NH4+:9].[NH4+].[S:11]([O-:15])([O-:14])(=[O:13])=[O:12]>>[S:11]([O-:15])([O-:14])(=[O:13])=[O:12].[NH4+:9].[NH4+:9].[C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C([O-])CCC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: O=C(O)CCC(=O)O

Procedure:
After the diammonium succinate is formed, it is reacted with sulfate ions from a sulfate ion source to form ammonium sulfate and pure succinic acid. This can be accomplished by the addition of sulfuric acid, as the reaction is advantageously performed at a pH of less than 2, preferably between 1.5 and 1.8 to form crystalline succinic acid. Succinic acid has extremely low solubility in aqueous solutions with a pH below 2, particularly in the range of 1.5 to 1.8. In a preferred method, ammonium bisulfate is combined with the ammonium succinate to yield free succinic and ammonium sulfate. The succinic acid can be filtered from the product stream including the ammonium sulfate and further purified by the addition of methanol. Any remaining sulfates will be insoluble in methanol, whereas the succinic acid will be substantially dissolved in the methanol. After methanol is evaporated, substantially pure crystalline succinic acid remains. The evaporated methanol can be condensed and reused.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10](Br)[CH2:11][CH2:12]Cl)=[O:9])=[CH:4][CH:3]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.[OH-].[Na+]>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)C(Br)CCCl)cc1
Reactant: c1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)C2(n3ccnc3)CC2)cc1
Temperature: 0 °C

Procedure:
82.6 g=0.3 mol of 1-bromo-3-chloropropyl 4-methylphenyl ketone were added in portions at 0°-5° C. with stirring and cooling to a solution of 102 g=1.5 mol of imidazole in 150 ml of dimethylformamide, and the mixture was stirred for 15 hours at room temperature. For work-up, the mixture was poured into 1.5 liters of ice water and extracted twice with 150 ml of methylene chloride in each case, and the organic phase was washed twice with 100 ml of 2N NaOH in each case, dried over sodium sulfate and filtered. The solution thus prepared of the corresponding compound of the formula VII was added dropwise at 20° C. with vigorous stirring and cooling to a mixture of 70 ml of 50% strength sodium hydroxide solution and 1.6 g of tetrabutylammonium bromide, and the mixture was stirred for 8 hours at 20° C. and worked up as specified in Example 1. The oily residue (66.5 g, 98% of theory) crystallized. A sample of this had the melting point: 88°-90° C. from methyl tert.butyl ether.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[N:11]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:14])=[O:13]
Reactant: COC(=O)c1cccc(Cl)c1NS(=O)(=O)c1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cl)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 39 %

Procedure:
To a solution of 0.90 g (2.532 mmol) of the product of Example 2 in 10 mL of DMF was added 0.127 g (3.165 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 min at room temperatue and then 0.38 mL (3.165 mmol) of benzyl bromide was added. This reaction mixture was stirred overnight at room temperature, poured into water and then extracted with ether. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to provide a white solid which was recrystallized from EtOAc/liexanes to provide 0.44 g (39%) of the desired product as white crystals. CI Mass Spec: 446 (M+H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH2:10][C@H:9]1[C:14]([CH3:22])([CH3:21])[O:15][SiH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])C1C=CC=CC=1>C(O)C>[C:17]([SiH2:16][O:15][C:14]([CH3:22])([CH3:21])[C@@H:9]1[CH2:10][O:11][CH2:12][CH2:13][NH:8]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1COCCN1Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1COCCN1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A solution of 1.54 g (4.79 mmol) (S)-4-benzyl-3-(tert-butyl-dimethyl-silanyloxymethyl)-morpholine in 24 ml ethanol was deoxygenated by three cycles of evacuation and flushing with argon. After addition of 0.5 g palladium on charcoal (10%) the reaction vessel was evacuated and filled with hydrogen gas. The reaction mixture was stirred at room temperature under an atmosphere of hydrogen over night. Filtration over decalite and evaporation of the solvent in vacuo gave 1.08 g (97.4%) of the crude title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1>>[NH2:29][CH:26]1[CH2:27][CH2:28][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=3[NH:12][C:13](=[O:21])[CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:3]=2)[CH2:24][CH2:25]1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: NC1CCNCC1
Product: NC1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)CC1

Procedure:
Prepared according to the method of example 30, using N-(2,6-dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (0.113 g) and 4-piperidinamine (0.152 mL) to afford the title compound (0.109 g).
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14](/[CH:17]=[C:18]2\[C:19](=[O:39])[NH:20][C:21]3[C:26]\2=[CH:25][C:24]([S:27]([CH2:30][C:31]2[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=2[Cl:38])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[NH:13][C:12]=1[CH3:40])=O.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[Cl:38][C:32]1[CH:33]=[CH:34][C:35]([Cl:37])=[CH:36][C:31]=1[CH2:30][S:27]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[NH:20][C:19](=[O:39])/[C:18]/2=[CH:17]\[C:14]1[NH:13][C:12]([CH3:40])=[C:11]([C:9]([N:45]2[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]2)=[O:8])[C:15]=1[CH3:16])(=[O:28])=[O:29]
Reactant: CN1CCNCC1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)ON1C(=O)CCC1=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cc(Cl)ccc4Cl)cc32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
5-[5-(2,5-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester was condensed with 1-methyl-piperazine to give the titled compound.