Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH3:17])[CH2:12][CH2:11]1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([CH:16]([O:18][Si:19]([C:22]([CH3:23])([CH3:25])[CH3:24])([CH3:21])[CH3:20])[CH3:17])[CH2:14][CH2:15]1
Reactant: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H](COCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(O[Si](C)(C)C(C)(C)C)[C@H]1CC[C@H](CO)CC1

Procedure:
In 50 ml of dry ethanol was dissolved 2.7 g of trans-4-benzyloxymethyl-1-(1-t-butyldimethylsilyloxyethyl)cyclohexane, and 2.0 g of 10% palladium-carbon was added thereto, and the resulting mixture was heated under reflux for 9 hours and 50 minutes while stirring under a hydrogen stream. Further, 2.0 g of 10% palladium-carbon was added to the reaction mixture and the resulting mixture was heated under reflux for 4 hours and 15 minutes while stirring under a hydrogen stream. After completion of the reaction, palladium-carbon was separated by filtration and the solvent was distilled off under reduced pressure to obtain 1.85 g of the desired compound as a colorless oil.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.C1OC2C=CC=CC=2O1.C=O.[ClH:23]>[Cl-].[Zn+2].[Cl-]>[CH2:7]([Cl:23])[C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1
Reactant: Cl
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: C=O
Agent: [Cl-]
Agent: [Zn+2]
Product: ClCc1ccc2c(c1)OCO2
Yield: 70 %

Procedure:
A typical process for preparing piperonal from 1,2-methylenedioxybenzene has been reported by P. P. Shorygin et al. [J. Gen. Chem. (U.S.S.R.), 8,975 (1938)]. This is a two-step process. In the first step, 1,2-methylenedioxybenzene is reacted with formalin in petroleum benzine under the influence of hydrogen chloride gas and zinc chloride to form piperonyl chloride (with a 70-78% yield based on the amount of 1,2-methylenedioxybenzene having reacted). This is followed by the second step in which the piperonyl chloride is reacted with an equimolar amount of hexamine in 60% alcohol to give a 70-80% yield of piperonal. By E. D. Laskina et al. [Chemical Abstracts, 57,9714 (1962)], another process has been described in which 1,2-methelenedioxybenzene is reacted with formalin in the presence of a large excess of the sodium salt of m-nitrobenzenesulfonic acid, hydrogen chloride, and an aluminum catalyst to give a 42.4% yield of piperonal.
Reaction SMILES: Cl.[F:2][C:3]1[C:12]2[O:11][CH2:10][C@H:9]([N:13]([CH:17]([CH3:19])[CH3:18])[CH2:14][CH2:15][CH3:16])[CH2:8][C:7]=2[C:6]([O:20]C)=[CH:5][CH:4]=1.B(Br)(Br)Br.C(Cl)(Cl)Cl>C(Cl)Cl>[F:2][C:3]1[C:12]2[O:11][CH2:10][C@H:9]([N:13]([CH:17]([CH3:19])[CH3:18])[CH2:14][CH2:15][CH3:16])[CH2:8][C:7]=2[C:6]([OH:20])=[CH:5][CH:4]=1
Reactant: CCCN(C(C)C)[C@H]1COc2c(F)ccc(OC)c2C1
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCN(C(C)C)[C@H]1COc2c(F)ccc(O)c2C1
Temperature: -40 °C
Yield: 97 %

Procedure:
(R)-8-Fluoro-3-(N-isopropyl-N-propylamino)-5-methoxy-3,4-dihydro-2H-1-benzopyran hydrochloride (1.03 g, 3.24 mmol) was dissolved in anhydrous CH2Cl2 (30 mL) and cooled to -40° C. To the solution was BBr3 (0.77 mL, 8.1 mmol), dissolved in anhydrous CH2Cl2 (5 mL), added dropwise. The cooling-bath was removed and after 3 h at room temperature the reaction was complete. The reaction was poured out onto an ice/2M NH3 solution and the mixture was extracted, twice, with diethyl ether. The combined ether portions were treated with brine, dried (Na2SO4), filtered, and the solvent removed in vacuo to give the crude residue. Chromatography on silica (eluent: 20% ethyl acetate/hexane) gave 0.84 g (97% yield) of the title compound as a clear oil [α]21D =-94.2° (C=0.1 CHCl3) GC-MS (70 eV) M=267 (26%). The hydrochloride salt was made by dissolving the pure base in diethyl ether and dropping an excess of an ethereal HCl solution. The salt was recrystallized from CHCl3 /diethyl ether/ethyl acetate to give a white solid. Mp: 220°-2° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].Cl[CH:11]([CH3:15])[C:12]([OH:14])=[O:13]>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][CH:11]([C:12]([OH:14])=[O:13])[CH3:15])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CC(Cl)C(=O)O
Product: CC(Nc1cc(F)cc(F)c1)C(=O)O

Procedure:
Using the procedure set forth in U.S. Pat. No. 3,598,859 (or Example A above), N-(3,5-difluorophenyl)-D,L-alanine was prepared using 3,5-difluoroaniline (Aldrich) and 2-chloropropionic acid (Aldrich).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([C:14]2[N:19]=[CH:18][C:17]([C:20]3[N:24]4[N:25]=[CH:26][CH:27]=[C:28]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[C:23]4=[N:22][C:21]=3[CH2:35][S:36][C:37]3[CH:46]=[CH:45][C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[N:38]=3)=[CH:16][CH:15]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.[C:56]([O:60][C:61]([N-:63][S:64](N1C=CC(=[N+](C)C)C=C1)(=[O:66])=[O:65])=[O:62])([CH3:59])([CH3:58])[CH3:57]>C(Cl)Cl>[O:32]1[CH2:33][CH2:34][N:29]([C:28]2[C:23]3[N:24]([C:20]([C:17]4[CH:16]=[CH:15][C:14]([N:8]5[CH2:9][CH2:10][N:11]([S:64]([NH:63][C:61](=[O:62])[O:60][C:56]([CH3:58])([CH3:57])[CH3:59])(=[O:65])=[O:66])[CH2:12][CH2:13]5)=[N:19][CH:18]=4)=[C:21]([CH2:35][S:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[N:22]=3)[N:25]=[CH:26][CH:27]=2)[CH2:30][CH2:31]1
Reactant: C[N+](C)=c1ccn(S(=O)(=O)[N-]C(=O)OC(C)(C)C)cc1
Reactant: c1ccc2nc(SCc3nc4c(N5CCOCC5)ccnn4c3-c3ccc(N4CCNCC4)nc3)ccc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)NS(=O)(=O)N1CCN(c2ccc(-c3c(CSc4ccc5ccccc5n4)nc4c(N5CCOCC5)ccnn34)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compound 6 (137 mg, 0.612 mmol) was placed in an 8 mL vial equipped with a stir bar and then DCM (1 mL) and DIEA (68.2 μL, 0.486 mmol) were added. (tert-Butoxycarbonyl)((4-(dimethyliminio)pyridin-1(4H)-yl)sulfonyl)amide (48.8 mg, 0.162 mmol) was added as a solid and the reaction was stirred at rt for 3 h and then the solvent was removed under reduced pressure. The crude product was chromatographed on a 12 g SiO2 pre-packed column eluting with 0-100% EtOAc/heptane. The resulting product was chromatographed on a 12 g SiO2 pre-packed column eluting with 0-80% EtOAc/heptane to afford the title compound 31a. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.55 (d, J=2.2 Hz, 1H), 7.96 (d, J=5.6 Hz, 1H), 7.80-7.92 (m, 3H), 7.71 (d, J=8.1 Hz, 1H), 7.58-7.66 (m, 1H), 7.29-7.48 (m, 2H), 7.24 (d, J=8.8 Hz, 1H), 6.70 (d, J=8.8 Hz, 1H), 6.04 (d, J=5.9 Hz, 1H), 4.85 (s, 2H), 3.89-4.00 (m, 4H), 3.80-3.89 (m, 4H), 3.62-3.73 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8].C([O-])(=O)C.[Mn+2:17].C([O-])(=O)C>>[C:1]([O-:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:8])([CH3:9])[CH3:10].[Mn+2:17].[C:1]([O-:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)CCCCCC(=O)O
Agent: [Mn+2]
Agent: CC(=O)[O-]
Product: CC(C)(C)CCCCCC(=O)[O-]
Temperature: 140 °C
Reaction time: 2 h

Procedure:
Neodecanoic acid (300 grams) and manganese (II) acetate (106 grams) were both placed into a reaction vessel equipped with a condenser, Dean-stark trap, thermometer, thermocouple, and a gas inlet. Nitrogen gas was bubbled into the reactants. The reactants were heated to 140° C. and stirred for two hours. Overheads and condensate from the reaction were collected in the trap. A subatmospheric pressure was applied to the reaction vessel and the reactants were stirred for an additional two hours at 140° C. until the reaction was complete. Analysis of the product indicated that the product had a kinematic viscosity of 54.8 cSt at 100° C. and a manganese content of 8.1 percent by weight.
Reaction SMILES: Cl([O-])=O.[Na+].P([O-])(O)(O)=[O:6].[Na+].[C:11]([O:15][C:16]([N:18]1[CH:24]([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][N:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH:35]=[O:36])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>O.O1CCOCC1>[C:11]([O:15][C:16]([N:18]1[CH:24]([C:25]([F:28])([F:27])[F:26])[CH2:23][CH2:22][N:21]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]([OH:6])=[O:36])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: O=P([O-])(O)O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CCC1C(F)(F)F
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2C(=O)O)CCC1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A solution of sodium chlorite (214 mg; 2.36 mmol; 5.5 eq.) and sodium dihydrogenphosphate (186 mg; 1.55 mmol; 3.6 eq.) in water (2 mL) was added dropwise to a mixture of 4-(2-formyl-phenyl)-7-trifluoromethyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester (160 mg; 0.43 mmol; 1 eq.) in 1,4-dioxane (2 mL). The reaction mixture was stirred at room temperature for 1 hour and the 1,4-dioxane concentrated in vacuo. The aqueous solution was diluted with water, the pH made acidic with 0.1M HCl and extracted with EA (2×). The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (140 mg, 84%) as a yellow solid. UPLC/MS: (MS+) 389.2 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][CH2:11][CH2:12][C:5]2=[N:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1nc2n(c(=O)c1O)CCCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: COC(=O)c1nc2n(c(=O)c1O)CCC=C2
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-hydroxy-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-2-carboxylate in 1,4,-dioxane was added dichloro-dicyano benzoquinone (1.1 eqs.). The mixture was stirred and heated to 60° C. for 1 hour. TEA (5 eqs.) was added and stirring was continued for 4 hours. The solution was cooled to room temperature and the product was purified by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluants (column: C18). The product was obtained after lyophilization of the pooled product fractions as a fluffy white material.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:24][CH2:23][C:17]2([O:21][C:20](=O)[NH:19][CH2:18]2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>O1CCCC1>[CH2:7]([N:14]1[CH2:24][CH2:23][C:17]([OH:21])([CH2:18][NH:19][CH3:20])[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1NCC2(CCN(Cc3ccccc3)CC2)O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNCC1(O)CCN(Cc2ccccc2)CC1
Yield: 98.3 %

Procedure:
To a stirred mixture of 7 g lithium aluminum hydride and 150 ml tetrahydrofuran under argon is added dropwise over 20 minutes a solution of 24.6 g 8-benzyl-1-oxa-3,8-diazaspiro[4.5]decan-2-one in 150 ml tetrahydrofuran. The mixture is heated at reflux for two hours. The stirred mixture is treated with sequential dropwise additions of 7 ml water, 7 ml 15% sodium hydroxide and 21 ml water. The mixture is filtered and the filter cake is washed with three 200 ml portions of dichloromethane. Evaporation of the combined filtrates affords 23 g of 1-benzyl-4-hydroxy-4-methylaminomethylpiperidine, an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:14]=[O:15])=[C:5]([CH3:13])[C:6]=1[CH2:7][CH2:8][C:9]([O:11]C)=[O:10].Cl>[OH-].[Na+]>[C:9]([CH2:8][CH2:7][C:6]1[C:5]([CH3:13])=[C:4]([CH:14]=[O:15])[NH:3][C:2]=1[CH3:1])([OH:11])=[O:10]
Reactant: COC(=O)CCc1c(C)[nH]c(C=O)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Temperature: 25 °C
Yield: 98.2 %

Procedure:
2,4-Dimethyl-5-formyl-3-(2-methoxycarbonylethyl)pyrrole (0.23 g, 1.2 mmol) in 6N sodium hydroxide (10 mL) was heated at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, acidified with 6 N hydrochloric acid and extracted three times with 10 mL of ethyl acetate. The combined organic layers were washed with 10 mL of water and 5 mL of brine, dried over anhydrous sodium sulfate and evaporated to dryness to give 230 mg (106% yield) of crude 4-carboxyethyl-3,5-dimethyl-2-formylpyrrole as a brown oil.
Reaction SMILES: [CH3:1][C:2](/[CH:4]=[N:5]/[OH:6])=O.Cl.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1>C(OCC)C.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[N:16]=[C:2]([CH3:1])[CH:4]=[N+:5]2[O-:6])=[CH:11][CH:10]=1
Reactant: CC(=O)/C=N/O
Reactant: NNc1ccc(F)cc1
Agent: [Cu+2]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCOCC
Product: Cc1c[n+]([O-])n(-c2ccc(F)cc2)n1
Temperature: 23 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a stirred solution of anti-pyruvic aldehyde 1-oxime (3.4 g, 39 mmol) in diethyl ether (75 mL) was added 4-fluorophenylhydrazine hydrochloride (5.85 g, 36 mmol). The reaction mixture was stirred at 23° C. for 16 h, and then concentrated under reduced pressure. The crude residue was dissolved in pyridine (120 mL). A solution of copper(II) sulfate pentahydrate (18 g, 72 mmol) in water (55 mL) was added dropwise over 4 min. The resulting mixture was stirred at reflux for 2 h. The mixture was concentrated under reduced pressure to remove excess pyridine. To the mixture was added 1.0 M aqueous hydrochloric acid. The mixture was extracted with ethyl acetate and the organic layer was separated and washed with 1.0 M aqueous hydrochloric acid until a clear amber organic layer was obtained. The organic layer was dried (MgSO4), filtered, and evaporated under reduced pressure to afford the title compound (6.6 g) as a colorless solid. The title compound was used directly in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:20]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)[CH:21]=4)[CH2:26]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: c1cc2c(cc1N1CCOCC1)CCNC2
Product: O=C(c1cc2ncc(Cl)cn2n1)N1CCc2cc(N3CCOCC3)ccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C(OC(=O)C(CCOC)C[C:12]1([C:17]([OH:19])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1)C1C=CC=CC=1.Br[CH2:26][C:27](=[CH2:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>O1CCCC1.[Cl-].[Zn+2].[Cl-]>[C:31]([O:30][C:28](=[O:29])[C:27](=[CH2:35])[CH2:26][C:12]1([C:17]([OH:19])=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:34])([CH3:33])[CH3:32]
Reactant: COCCC(CC1(C(=O)O)CCCC1)C(=O)OCc1ccccc1
Reactant: C=C(CBr)C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: C=C(CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Yield: 259.9 %

Procedure:
Cyclopentane carboxylic acid dilithio dianion (prepared from cyclopentane carboxylic acid (2.58 g) as described in Example 15) in tetrahydrofuran (100 ml) was treated with zinc chloride (1.85 g) at room temperature for 30 minutes, followed by t-butyl 2-bromomethylpropenoate (5.0 g) at -78° C. The reaction mixture was worked-up and the product purified as previously described to give 3-(1-carboxycyclopentyl)-2-methylenepropanoic acid t-butyl ester as an oil (5.1 g, 89%). Found: C,66.16; H,8.89. C14H22O4 requires C,66.11; H,8.72%.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:28])[Cl:27])[CH:20]=[C:19]([Cl:29])[C:3]=1[O:4][CH2:5][C:6](=[CH2:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][CH:10]=1.Cl.[CH3:31][O:32][NH2:33].CO.C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[CH3:31][O:32][N:33]=[C:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]([CH2:5][O:4][C:3]2[C:2]([Cl:1])=[CH:22][C:21]([O:23][CH2:24][CH:25]=[C:26]([Cl:27])[Cl:28])=[CH:20][C:19]=2[Cl:29])=[CH2:18])=[CH:14][CH:13]=1)[CH3:16]
Reactant: C=C(COc1ccc(C(C)=O)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=C(COc1ccc(C(C)=NOC)cc1)COc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
286 mg of 1-(4-{2-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxymethyl]-allyloxy}-phenyl)-ethanone and 56 mg of O-methyl-hydroxylamine hydrochloride are introduced into 4 ml of methanol. 55 mg of sodium acetate are then added and the mixture is stirred for 24 hours at 25° C. The reaction mixture is diluted with 12 ml of ethyl acetate and washed twice with water. After concentration of the organic phase and purification over silica gel, the title compound is obtained.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[CH:6][C:7]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:18])[CH2:12]2)=[N:8][C:9]=1[NH2:10].[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH:31]=O)(=[O:27])=[O:26].[S].C(N(CC)CC)C>CN(C)C=O.C(#N)C>[CH3:24][S:25]([C:28]1[CH:29]=[C:30]([C:31]2[NH:10][C:9]3=[N:8][C:7]([N:11]4[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([N:19]5[CH2:23][CH2:22][CH2:21][CH2:20]5)=[O:18])[CH2:12]4)=[CH:6][CH:5]=[C:4]3[N:3]=2)[CH:33]=[CH:34][CH:35]=1)(=[O:26])=[O:27]
Reactant: CS(=O)(=O)c1cccc(C=O)c1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Agent: Cl
Agent: [S]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cccc(-c2nc3ccc(N4CCC[C@@H](C(=O)N5CCCC5)C4)nc3[nH]2)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (125 mg, 0.3 mmol) in anhydrous N,N-dimethylformamide (2.5 mL) was added 3-(methylsulfonyl)benzaldehyde (76 mg, 0.4 mmol). The solution was stirred at 80° C. for 1 h. Sulfur was added (25 mg, 0.8 mmol) followed by triethylamine (140 μL, 1.0 mmol). The mixture was stirred at 85° C. for 24 h followed by stirring at room temperature for another 24 h. The mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane and water. The aqueous layer was extracted with dichloromethane and the combined extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified via flash chromatography (20-100% ethyl acetate in heptanes gradient followed by 0-10% methanol in dichloromethane). The residue was repurified via flash chromatography (0-10% methanol in dichloromethane) to afford a yellow solid that was stirred in acetonitrile (3 mL) at 40° C. for 2.5 h. The solid was filtered, washed with cold acetonitrile and dried under high vacuum at 40° C. to afford the title compound. 1H NMR (500 MHz, CD3OD) δ 1.60-1.74 (m, 1H) 1.77-1.89 (m, 2H) 1.89-2.11 (m, 4H) 2.81 (br s, 1H) 2.97-3.09 (m, 2H) 3.17-3.26 (m, 3H) 3.41-3.52 (m, 2H) 3.52-3.63 (m, 1H) 3.74 (br s, 1H) 4.37 (br s, 1H) 4.64 (d, 1H) 6.91 (br s, 1H) 7.74-7.89 (m, 2H) 8.05 (d, 1H) 8.35 (br s, 1H) 8.65 (br s, 1H).
Reaction SMILES: OC[C@@H](N)CC(C)C.COC(=O)[C@H](CC(C)C)N.OCCN.[CH3:23][CH:24]([CH3:34])[CH2:25][C@H:26]([NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:27]O.[Cl-].C([NH3+])C(C)C.[CH3:41][C:42]1[CH:47]=[C:46]([N+:48]([O-:50])=[O:49])[CH:45]=[CH:44][C:43]=1[N:51]=[C:52]=[S:53]>>[CH3:41][C:42]1[CH:47]=[C:46]([N+:48]([O-:50])=[O:49])[CH:45]=[CH:44][C:43]=1[N:51]=[C:52]1[N:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[C@@H:26]([CH2:25][CH:24]([CH3:34])[CH3:23])[CH2:27][S:53]1
Reactant: CC(C)CN[C@H](CO)CC(C)C
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Agent: CC(C)C[C@H](N)CO
Agent: CC(C)C[NH3+]
Agent: COC(=O)[C@@H](N)CC(C)C
Solvent: NCCO
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SC[C@H](CC(C)C)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (2S)-4-methyl-2-(isobutylamino)pentan-1-ol as described in Method B4c. The resulting 2-hydroxyethylamine was converted to N-(1S)-1-(chloromethyl)-3-methylbutyl)-N-(isobutyl)ammonium chloride according to Method B7c. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with N-(1S)-1-(chloromethyl)-3-methylbutyl)-N-(isobutyl)ammonium chloride to Method C1b to afford (4S)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:13][C:14]1[CH:15]=[C:16]([CH:26]([NH:28][C:29]([C:31]2[N:32]=[C:33](Cl)[O:34][CH:35]=2)=[O:30])[CH3:27])[CH:17]=[C:18]([F:25])[C:19]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22].C([O-])([O-])=O.[K+].[K+]>>[F:25][C:18]1[CH:17]=[C:16]([CH:26]([NH:28][C:29]([C:31]2[N:32]=[C:33]([O:12][C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:7]=3)[O:34][CH:35]=2)=[O:30])[CH3:27])[CH:15]=[C:14]([F:13])[C:19]=1[NH:20][S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: Oc1cccc(C2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(NC(=O)c1coc(Oc2cccc(C3CCCC3)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 71.9 %

Procedure:
3-Cyclopentylphenol (40 mg, 0.25 mmol) and 2-chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (40 mg, 0.11 mmol) was reacted using K2CO3 (50 mg, 0.36 mmol) as described above to give the title compound (40 mg, 75%) after purification by flash chromatography on silica gel (hexane: EtOAc=1:1).
Reaction SMILES: [C:1]([OH:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+:14]>>[C:1]([O-:12])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Na+:14]
Reactant: CCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCC(=O)[O-]

Procedure:
Sodium decanoate was prepared by thoroughly mixing decanoic acid with 2% aqueous NaOH at about 70° C. until the pH passed 10.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1.N1C2C(=CC=CC=2)C=[C:15]1C(OCC)=O>>[CH3:15][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([O:12][CH3:13])=[O:11])[CH:3]=[CH:2]1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: COC(=O)c1cccc2cc[nH]c12
Product: COC(=O)c1cccc2ccn(C)c12
Yield: 90 %

Procedure:
According to the procedure of Preparation 9 (a), except substituting methyl indole-7-carboxylate for the ethyl indole-2-carboxylate, the title compound (2.4 g, 90%) was obtained as an oil: MS (ES) m/e 190.2 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].[F:14][C:15]([Si](C)(C)C)([F:17])[F:16]>CN(C)C=O>[F:14][C:15]([F:17])([F:16])[CH:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[OH:7]
Reactant: O=Cc1nccs1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(c1nccs1)C(F)(F)F
Yield: 73.6 %

Procedure:
According to Reference Example 8-2, by use of thiazole-2-carbaldehyde (300 mg, 2.65 mmol) dissolved in N,N-dimethylformamide (4.5 mL), potassium carbonate (73 mg, 0.53 mmol) and (trifluoromethyl)trimethylsilane (0.470 mL, 3.18 mmol), the mixture was stirred and reacted at room temperature for 1.2 hours. Then, purification by preparative thin-layer chromatography (chloroform/methanol=15/1) was performed to give 2,2,2-trifluoro-1-(thiazol-2-yl)ethanol (Compound DM) (357 mg, yield: 74%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].[I-].[Na+]>>[CH2:24]([N:26]([CH2:2][C:3]1[N:7]2[C:8]3[CH:23]=[CH:22][CH:21]=[CH:20][C:9]=3[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N:11][CH2:12][C:6]2=[N:5][N:4]=1)[CH2:27][CH3:28])[CH3:25]
Reactant: ClCc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2
Reactant: CCNCC
Agent: [I-]
Agent: [Na+]
Product: CCN(CC)Cc1nnc2n1-c1ccccc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, 1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine was reacted with diethylamine in the presence of sodium iodide to give 1-[(diethylamino)methyl]-6-(o-chlorophenyl)4H-s-triazolo[4,3-a][1,4]benzodiazepine.