Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:18]([CH2:20][C:21]([N:23]1[CH2:30][CH2:29][CH2:28][C@H:24]1[C:25]([OH:27])=[O:26])=[O:22])[CH3:19])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].O[N:32]1[C:36](=[O:37])[CH2:35][CH2:34][C:33]1=[O:38].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.O1CCCC1>[C:33]1(=[O:38])[N:32]([O:26][C:25](=[O:27])[C@@H:24]2[CH2:28][CH2:29][CH2:30][N:23]2[C:21](=[O:22])[CH2:20][N:18]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH3:19])[C:36](=[O:37])[CH2:35][CH2:34]1
Reactant: O=C1CCC(=O)N1O
Reactant: CN(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(CC(=O)N1CCC[C@H]1C(=O)ON1C(=O)CCC1=O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
4.5 g of CBZ-sarcosine is dissolved in 100 ml tetrahydrofuran and 2.4 ml of n-methylmorpholine is added. The reaction mixture is cooled to -10° C. and stirred while 2.6 ml of isobutylchloroformate is added. After 5 minutes of additional stirring at -10° C. 4.15 g L-proline-t-butylester hydrochloride in 100 ml of tetrahydrofuran and 3.0 ml of n-methylmorpholine are added to the reaction mixture. The reaction mixture is stirred overnight and slowly warmed to room temperature. The solvent is evaporated under reduced pressure at 30° C. and the residue is dissolved in 600 ml ethylacetate. The ethylacetate layer is washed with (3×150 ml), lN sodium hydroxide, water (1×200 ml) 10% citric acid (3×150 ml), and water (3×150 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to provide carbobenzoxysarcosyl-proline-t-butyl ester (CBZ-Sar-L-Pro-O-t-But). 6.5 g of this material is dissolved in 15 ml of methylene chloride and 25 ml of trifluoroacetic acid is then added. The reaction mixture is kept at room temperature for 45 minutes and then the solvent is evaporated under reduced pressure at 30° C. The residue is triturated with hexane (3×50 ml) and the hexane removed by decantation. The residue is evaporated from (2×50 ml) of benzene to provide an oily residue which is carbobenzoxysarcosyl-L-proline (CBZ-Sar-L-Pro). 5.4 g of this material and 3.45 g of N-hydroxysuccinimide are dissolved in 100 ml of tetrahydrofuran and cooled to 0° C. To this cooled reaction mixture is added 4.12 g of dicyclohexylcarbodiimide. The reaction mixture is stirred overnight at 4° C. and the solvent is evaporated under reduced pressure. The residue is dissolved in 400 ml of ethylacetate and the dicyclohexyl urea is filtered off. The filtrate is washed with lN-hydrochloric acid (3×100 ml), water (1×100 ml), saturated sodium bicarbonate solution (2×100 ml) and water (2×100 ml). The organic layer is dried over anhydrous magnesium sulfate, filtered and the solvent is evaporated under reduced pressure to provide carbobenzoxy-sarcosyl-L-proline-succinimidyl ester.
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[CH:6]([N:9]1[C:13]([C:14]2[N:23]=[C:22]3[N:16]([CH2:17][CH2:18][O:19][C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=43)[CH:15]=2)=[N:12][CH:11]=[N:10]1)([CH3:8])[CH3:7].[OH-].[Na+:29]>O>[CH:6]([N:9]1[C:13]([C:14]2[N:23]=[C:22]3[N:16]([CH2:17][CH2:18][O:19][C:20]4[CH:27]=[CH:26][C:25]([S:2]([O-:5])(=[O:4])=[O:3])=[CH:24][C:21]=43)[CH:15]=2)=[N:12][CH:11]=[N:10]1)([CH3:8])[CH3:7].[Na+:29]
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccccc1OCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)[O-])ccc1OCC2
Reaction time: 0.08 h

Procedure:
To chlorosulfonic acid (4 mL) at 0° C. was added 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (400 mg, 1.35 mmol) portion wise and the resulting mixture stirred for 5 min then added drop wise to ice. NaOH (7.2 g) in H2O (20 mL) was added to the mixture and stirred for 1 h at RT then concentrated in vacuo. The resulting residue was purified by column chromatography (C18, gradient 0.5-1% MeOH in H2O) then extracted into hot MeOH. Upon cooling the mixture was filtered and the filtrate concentrated in vacuo affording Sodium 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonate (1.32 g) contaminated with inorganic salts. LCMS: RT 2.14 min [M+H]+ 376.1
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[NH:8][C:7](=[O:16])[C:6]=2[CH:17]=1.[BrH:18].C1(S[C:26]([C:28]2[S:29][CH:30]=[CH:31][CH:32]=2)=[NH:27])C=CC=CC=1>CO>[BrH:18].[O:16]=[C:7]1[C:6]2[CH:17]=[C:2]([NH:1][C:26]([C:28]3[S:29][CH:30]=[CH:31][CH:32]=3)=[NH:27])[CH:3]=[CH:4][C:5]=2[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[NH:8]1
Reactant: Nc1ccc2c(c1)C(=O)Nc1ccccc1O2
Reactant: N=C(Sc1ccccc1)c1cccs1
Agent: Br
Solvent: CO
Product: N=C(Nc1ccc2c(c1)C(=O)Nc1ccccc1O2)c1cccs1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.3 %

Procedure:
To a solution of 2-amino-10H-dibenzo[b,f][1,4]oxazepin-11-one (Example 4, 100 mg, 0.44 mmol) in methanol was added thiophene-2-carboximidothioic acid phenyl ester hydrobromide (146 mg, 0.48 mmol). The mixture was stirred at room temperature for 24 hr. The solvent was evaporated to give a yellow solid that was recrystalized from a mixture of ethanol and diethyl ether to give a yellow solid (yield 50 mg, 43%). H1 NMR (DMSO d6) δ: 11.38 (bs, 1H), 10.67 (s, 1H), 9.77 (bs, 1H), 8.95 (bs, 1H), 8.19-8.18 (m, 1H), 8.10 (s, 1H), 7.85 (s, 1H), 7.71-7.68 (m, 1H), 7.55-7.53 (m, 1H), 7.40-7.43 (m, 2H), 7.21-7.18 (m, 3H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][CH3:5].O[CH:8]([CH3:12])[C:9](=O)[CH3:10]>C(O)CCCCC>[CH3:1][N:2]1[C:9]([CH3:10])=[C:8]([CH3:12])[N:4]([CH3:5])[C:3]1=[S:6]
Reactant: CC(=O)C(C)O
Reactant: CNC(=S)NC
Solvent: CCCCCCO
Product: Cc1c(C)n(C)c(=S)n1C
Temperature: 155 °C
Reaction time: 24 h

Procedure:
1,3-dimethyl-4,5-dimethylimidazole-2-thione was synthesized according to a method obtained by modifying a method suggested by N. Kuhn, et al. (N. Kuhn and T. Kratz, Synthesis, June 1993, p.561), and a procedure of synthesizing the same is described below. 100 mmol of dimethylthiourea and 100 mmol of 3-hydroxyl-2-butanone were added to 250 ml of 1-hexanol in order, and then subjected to a reflux reaction for about 12 hours while increasing a reaction temperature to 150 to 160° C. At this time, white solid reactants were dissolved in 1-hexanol to be partly converted into yellow solid reactants according to an increase in the reaction temperature. After a completion of the reflux reaction, the resulting solution was left in a freezer at about −30° C. for about one day to separate into a white solid component and a yellow liquid component. The yellow liquid component was removed by use of a syringe, and the remaining white solid component was rinsed with water and ether and dried to produce 1,3-dimethyl-4,5-dimethylimidazole-2-thione. 1,3-dimethyl-4,5-dimethylimidazole-2-thione thus produced was analyzed by a 1H-NMR analyzer and the results are as follows:
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH:3]1[CH2:6][N:5]([C:7]2[C:8]([F:28])=[CH:9][C:10]3[C:11]([CH:27]=2)=[N:12][C:13]2[N:14]([CH3:26])[CH:15]=[C:16]([C:21]([O:23]CC)=[O:22])[C:17](=[O:20])[C:18]=2[CH:19]=3)[CH2:4]1.CS(O)(=O)=O>C(O)C.[OH-].[K+]>[CH3:1][N:2]([CH3:29])[CH:3]1[CH2:4][N:5]([C:7]2[C:8]([F:28])=[CH:9][C:10]3[C:11]([CH:27]=2)=[N:12][C:13]2[N:14]([CH3:26])[CH:15]=[C:16]([C:21]([OH:23])=[O:22])[C:17](=[O:20])[C:18]=2[CH:19]=3)[CH2:6]1
Reactant: CCOC(=O)c1cn(C)c2nc3cc(N4CC(N(C)C)C4)c(F)cc3cc2c1=O
Agent: CS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)C1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C)C1
Temperature: 80 °C
Reaction time: 5 h
Yield: 79.3 %

Procedure:
A suspension of 1.9 g of 8-(3-dimethylamino-1-azetidinyl)-3-ethoxycarbonyl-7-fluoro-1-methyl-4-oxo1,4-dihydrobenzo[b][1,8]naphthyridine in 20 cm3 of ethanol and 19 cm3 of 0.5N aqueous potassium hydroxide is heated with stirring to a temperature in the region of 80° C. for 5 hours. After cooling to approximately 5° C., the reaction mixture is treated with 9.5 cm3 of N aqueous methane sulphonic acid solution. The insoluble matter is drained, washed with twice 10 cm3 of water and 3 times 25 cm3 of ethanol and recrystallized in 125 cm3 of dimethylformamide. 1.4 g of 8-(3-dimethylamino-1-azetidinyl)-7-fluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 312° C.
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[C:13](=[O:26])[N:12]([CH3:27])[C:11]=2[N:10]=[CH:9]1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[CH3:27][N:12]1[C:11]2[N:10]=[CH:9][NH:8][C:16]=2[C:15](=[O:17])[N:14]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[C:13]1=[O:26]
Reactant: Cn1c(=O)n(COC(=O)C(C)(C)C)c(=O)c2c1ncn2Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: Cn1c(=O)n(COC(=O)C(C)(C)C)c(=O)c2[nH]cnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
2,2-Dimethylpropionic acid 7-benzyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydropurin-1-ylmethyl ester (4.26 g) was dissolved in acetic acid (100 ml), and 10% palladium on carbon (1.5 g) was added thereto. The reaction mixture was stirred under hydrogen atmosphere at room temperature overnight, filtered through Celite, and the filtrate was concentrated to give 2.98 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([O-:11])([OH:10])=[O:9].[N:12]#[C:13][NH2:14]>C(O)C>[N+:8]([O-:11])([OH:10])=[O:9].[C:2]1([NH:1][C:13]([NH2:14])=[NH:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: N#CN
Solvent: CCO
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1ccccc1
Temperature: 0 °C

Procedure:
Phenyl guanidine nitrate is prepared from a mixture of 12.8 g (0.1 mole) of aniline, 9.0 g of concentrated nitric acid (equivalent to 0.1 mole of HNO3), 12.6 g of a 50 percent aqueous cyanamide solution (equivalent to 0.15 mole of cyanamide) and 100 ml of ethyl alcohol which is heated under reflux for 20 hours. The reaction mixture is then cooled to 0°C for 5 hours and the precipitated product is collected on a filter. The product is purified by recrystallization from ethyl alcohol. The purified white crystalline solid melts at 125°-7°C. The infrared spectrum was consistent with the assigned structure.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH2:9])[CH:5]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([Cl:18])=[CH:13][N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.CCOC(C)=O>[Cl:10][C:11]1[N:16]=[C:15]([NH:9][C:6]2[CH:5]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[NH:8][N:7]=2)[C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 40 °C

Procedure:
A mixture of 5-cyclopropyl-1H-pyrazol-3-amine (246 mg, 2.00 mmol), 2,4,5-trichloropyrimidine (367 mg, 2.00 mmol, 1 equiv.) and Na2CO3 (233 mg, 2.20 mmol, 1.1 equiv.) in EtOH (10 mL) is heated at 40° C. for 16 h. The crude reaction mixture is diluted with EtOAc and sequentially washed with: water (3×) and saturated aqueous NaCl (1×). The resulting EtOAc layer is dried over Na2SO4 and then concentrated in vacuo, providing 2,5-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine; ESMS m/z 270.0 (M+H+).
Reaction SMILES: C(Br)C.[Mg].[CH3:5][CH:6]([CH3:11])[CH2:7][CH2:8][C:9]#[CH:10].[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:15])[CH:13]=[O:14].[Cl-].[NH4+]>CCOCC>[OH:14][CH:13]([C:10]#[C:9][CH2:8][CH2:7][CH:6]([CH3:11])[CH3:5])[C:12]([O:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:15]
Reactant: C#CCCC(C)C
Reactant: CCCCOC(=O)C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCBr
Product: CCCCOC(=O)C(O)C#CCCC(C)C
Temperature: 25 °C
Yield: 45.5 %

Procedure:
A Grignard reagent was prepared under dry nitrogen by the addition, over a 1 hour period, of a solution comprising 10.9 grams (g) (0.10 mole) of ethyl bromide is 15 milliliters (ml) of anhydrous ether to a stirred suspension of 2.4 g (0.10 g atom) of clean magnesium metal turnings in 70 ml of dry ether. Stirring at 25° C. was continued for an additional hour and then a solution of 9.6 g (0.10 mole) of 5-methyl-1-hexyne in 15 ml of dry ether was added during 30 minutes with stirring. The resulting greyish solution was then heated at reflux for 2 hours and cooled to room temperature. The solution was transferred under dry nitrogen to a 200 ml addition funnel, followed by flushing with two 15 ml portions of dry ether. This solution was then added over a 45 minute period to a stirred solution of 13.0 g (0.10 mole) of n-butyl glyoxalate in 70 ml of dry ether cooled to -20° C. The mixture was stirred at -20° C. for 2 hours and allowed to warm to room temperature overnight. The resulting yellow-orange solution was cautiously treated with 75 ml of saturated ammonium chloride solution and after stirring for 5 minutes, the two phases which formed were separated. The aqueous phase was extracted twice with 60 ml portions of ether and the combined organic phases were washed with three 75 ml portions of brine and dried over MgSO4. After filtration and concentration at the stripper, the residual reddish-orange oil (18.0 g.), was fractionated through a 15 cm Vigreux column to afford, after a small forerun, a single volatile fraction, boiling point (b.p.) 107.0°-117.0° C./0.20 millimeter (mm). Redistillation of this cut provided 10.3 g (41% yield) of n-butyl 2-hydroxy-7-methyl-3-octynoate as a light yellow, sweet smelling, mobile oil, b.p. 112.0°-115.0° C./0.20 mm.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][C:8]([OH:10])=[O:9]>CO.[Pd]>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)CCc1ccco1
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCC1CCCO1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(furan-2-yl)propanoic acid (11.0 g, 80.0 mmol) and Pd/C (1.1 g, 10%) in MeOH (110 mL) was stirred at 60° C. under 30 bar of H2 overnight. The mixture was then filtered and the filtrate was concentrated in vacuo to give the title compound, which was used for next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(Cl)c2)n1
Reactant: O=C(Cl)Oc1ccccc1
Product: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccc(Cl)c2)n1
Yield: 18.8 %

Procedure:
The title compound was prepared from 3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-amine (1.42 g, 5.69 mmol) and phenyl chloroformate (2.2 mL, 17.1 mmol) using the procedure in Example 118A to give phenyl 3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-ylcarbamate (394 mg, 1.07 mmol, 19%). 1H NMR (300 MHz, DMSO-d6) δ 10.17 (br s, 1H), 7.62-7.58 (m, 3H), 7.48-7.39 (m, 3H), 7.25 (t, 1H), 7.09 (br s, 2H), 6.40 (s, 1H), 1.28 (s, 9H); LC-MS (ESI) m/z 370 (M+H)+.
Reaction SMILES: C(Cl)Cl.[C:4]([CH:7]1[CH2:11][CH2:10][CH2:9][O:8]1)(=[O:6])[CH3:5].OS(C(F)(F)F)(=O)=O.C[SiH](C)C.[Br:24]N1C(=O)CCC1=O>C(N(CC)CC)C>[Br:24][CH2:5][C:4]([CH:7]1[CH2:11][CH2:10][CH2:9][O:8]1)=[O:6]
Reactant: CC(=O)C1CCCO1
Reactant: O=C1CCC(=O)N1Br
Agent: C[SiH](C)C
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)C1CCCO1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
To a 20-liter glass vessel was added methylene chloride (10.0 liters) followed by acetyltetrahydrofuran (838.0 g, 7.34 moles). The solution was then cooled back to −10° C. and triethylamine was added (854.0 g, 8.44 moles). The vessel was purged with nitrogen and trimethylsilane triflate (1713.0 g, 7.71 moles) was added dropwise at a maximum temperature of −8° C. Addition was typically complete in 45 minutes. After 15 minutes stirring, a sample was removed for TLC and GC analysis, which showed that the reaction was completed. N-bromosuccinimide (1340 g. 7.53 moles) was added to the solution at a maximum temperature of −5° C. over a period of approximately 45 minutes in six portions. After a 30 minute stirring, the solution was sampled for GC and TLC analysis, which showed that the reaction was completed. The solution was then transferred to a 50-liter separating vessel, and 5% sodium bicarbonate (5 liters) was added with caution. The solution was stirred and separated. The upper aqueous phase was discarded, and the methylene chloride phase was washed with water, dried over sodium sulphate, filtered and stored in a freezer before use in the next step.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]=1[CH:15]([CH3:17])[CH3:16])=[O:4].Cl.[N:19]1([C:25]2[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[S:27][N:26]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[S:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:25]([N:19]2[CH2:20][CH2:21][N:22]([CH2:2][C:3]([C:5]3[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:6]=3[CH:15]([CH3:17])[CH3:16])=[O:4])[CH2:23][CH2:24]2)=[N:26]1
Reactant: CC(=O)Nc1ccc(C(=O)CCl)c(C(C)C)c1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Product: CC(=O)Nc1ccc(C(=O)CN2CCN(c3nsc4ccccc34)CC2)c(C(C)C)c1
Yield: 66.7 %

Procedure:
Starting with N-[4-(2-chloro-acetyl)-3-isopropyl-phenyl]-acetamide (0.876 g, 3.453 mmol), and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (0.883 g, 3.453 mmol) and following the procedure as outlined in Example 517, N-{4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-acetyl]-3-isopropyl-phenyl}-acetamide (0.1.0 g, 2.302 mmol) was obtained as its hydrochloride salt from treatment with dioxane/HCl(gas). Yield=67%. 100% purity at 254 nM. 1H NMR (400 MHz, DMSO-d6) δ 10.44–10.29 (bm, 2H), 8.13 (d, J=8.49 Hz, 1H), 8.09 (d, J=8.49 Hz, 1H), 7.81 (d, J=9.12 Hz, 1H), 7.73–7.68 (m, 2H), 7.57 (t, J=7.49 Hz, 1H), 7.45 (t, J=7.49 Hz, 1H), 5.04 (s, 2H), 4.13–4.02 (m, 2H), 3.76–3.45 (m, 18H, H2O), 2.06 (s, 3H), 1.18 (d, J=6.85 Hz, 6H).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:25][C:26]1[CH:31]=[C:30]([C:32](OCC)=[O:33])[CH:29]=[CH:28][N:27]=1)[CH2:6][C:7](=[O:24])[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[CH2:11][CH2:10]1)=O.[BH4-].[Na+]>>[OH:33][CH2:32][C:30]1[CH:29]=[CH:28][N:27]=[C:26]([CH2:25][NH:5][CH2:6][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[CH2:11][CH2:10]2)=[O:24])[CH:31]=1
Reactant: CCOC(=O)c1ccnc(CN(CC(=O)NC2CCN(Cc3ccccc3OC)CC2)C(=O)C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccccc1CN1CCC(NC(=O)CNCc2cc(CO)ccn2)CC1

Procedure:
By General Procedure U from ethyl 2-({2,2,2-trifluoro-N-[({1-[(2-methoxyphenyl)methyl]piperidin-4-yl}carbamoyl)methyl]acetamido}methyl)pyridine-4-carboxylate using 5 equiv. of NaBH4. Purification by column chromatography using 1% MeOH/DCM to 28% MeOH/DCM/1% NH4OH as elutent to get the product as an off white solid. 1H-NMR (300 MHz, CDCl3): δ 8.42 (d, 1H), 7.42 (d, 1H), 7.35 (d, 1H), 7.25 (m, 2H), 7.15 (m, 1H), 6.99-6.85 (m, 2H), 4.65 (s, 2H), 3.80 (m, 4H), 3.60 (s, 2H), 3.45 (s, 2H), 3.25 (s, 2H), 2.90 (m, 2H), 2.22 (m, 2H), 1.90 (m, 2H), 1.60 (m, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[N:7][CH:8]=1.Br[CH2:17][CH:18]1[CH2:20][CH2:19]1>>[CH:18]1([CH2:17][O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])=[N:7][CH:8]=2)[CH2:20][CH2:19]1
Reactant: BrCC1CC1
Reactant: CC(C)(C)C(=O)Nc1ccc(CO)cn1
Product: CC(C)(C)C(=O)Nc1ccc(COCC2CC2)cn1

Procedure:
This material was prepared in analogy to example 86 step A] from N-(5-hydroxymethyl-pyridin-2-yl)-2,2-dimethyl-propionamide (1.04 g) and bromomethyl cyclopropane (0.813 g) as a light yellow oil (0.87 g). MS (ESI): 263.1. (MH+).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[NH2:14][C:15]([NH2:17])=[S:16]>O>[SH:16][C:15]1[N:17]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:3][N:14]=1
Reactant: CN(C)C=CC(=O)c1ccccc1
Reactant: NC(N)=S
Solvent: O
Product: Sc1nccc(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
A mixture of 17.5 g. of 3-dimethylaminoacrylophenone and 30.44 g. of thiourea is intimately mixed and fused at 180°-190° C. for one hour. The mixture is cooled and water is added and the desired compound is recovered by filtration, m.p. 203°-205° C.
Reaction SMILES: [CH3:1][C:2]1[CH:23]=[C:22]([C:24](=O)[CH2:25][CH3:26])[C:21]([CH3:28])=[CH:20][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[C:12](=[CH:17]\[O:18][CH3:19])/[C:13]([O:15][CH3:16])=[O:14].[Cl-].[NH2:30][OH:31]>CO>[OH:31]/[N:30]=[C:24](/[C:22]1[C:21]([CH3:28])=[CH:20][C:3]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2/[C:12](=[CH:17]\[O:18][CH3:19])/[C:13]([O:15][CH3:16])=[O:14])=[C:2]([CH3:1])[CH:23]=1)\[CH2:25][CH3:26]
Reactant: CCC(=O)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Reactant: NO
Agent: [Cl-]
Solvent: CO
Product: CC/C(=N\O)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.9 %

Procedure:
To a solution of 0.17 g (0.44 mmol) of (E)-methyl 2-(2-((2,5-dimethyl-4-propionylphenoxy)methyl)phenyl)-3-methoxyacrylate obtained in Step 3 and 0.06 g (0.88 mmol) of hydroxylamine chloride in 10 mL of methanol was added 0.8 g of a molecular sieve for dehydration. The reaction mixture was stirred at room temperature for 3 hours and filtered through celite and the filtrate was concentrated in a vacuum. The concentrate was stirred in water (10 mL) and extracted twice with 10 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified through silica gel chromatography to produce (E)-methyl 2-(2-((4-((E)-1-(hydroxyimino)propyl)-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate as a white solid (0.11 g, yield: 67%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1.[CH3:18][C:19]1([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)[CH2:21][O:20]1>CCCCCC.CN(C=O)C>[CH3:3][N:4]1[CH2:17][CH2:16][C:7]2[N:8]([CH2:18][C:19]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][N:23]=3)([OH:20])[CH3:21])[C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=3[C:6]=2[CH2:5]1
Reactant: CC1(c2ccncn2)CO1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccncn2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
Sodium hydride (200 mg, 8.33 mmol) was washed with hexane and dried under vacuum. DMF (4 mL) was added, resulting in a suspension. 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (400 mg, 2 mmol) in 2 mL DMF was added dropwise and stirred for 30 min at RT. 4-(2-Methyl-oxiranyl)-pyrimidine (490 mg, 3.60 mmol) in 2 mL DMF was added dropwise and the reaction mixture was stirred overnight at RT. After the completion of reaction, the reaction mixture was quenched with ice-cold water and extracted three times with EtOAc. The combined organic layers were washed with water several times followed by brine, and then dried over sodium sulfate. The solvent was evaporated and the residue washed with hexane and crystallized from ether-DCM and hexane to obtain 350 mg of desired product. 1HNMR (CD3OD, Oxalate salt) d (ppm): 9.10 (s, 1H), 8.50 (d, 1H), 7.50 (d, 1H), 7.10 (s, 1H), 6.95 (d, 1H), 6.80 (d, 1H), 4.40 (m, 4H), 3.60 (m, 2H), 3.40 (m, 1H), 3.20 (m, 1H), 3.0 (s, 3H), 2.50 (s, 3H), 1.60 (s, 3H).