Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:17]([O:21][C:22]([NH:24][CH2:25][C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(Cl)CCl>C(Cl)Cl.C(OCC)(=O)C>[C:17]([O:21][C:22](=[O:23])[NH:24][CH2:25][C:26](=[O:27])[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:15][CH3:16])[C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CCn1c2ccccc2c2cc(NC(=O)CNC(=O)OC(C)(C)C)ccc21
Yield: 65.2 %

Procedure:
To a solution of 3-amino-9-ethylcarbazole (8.1 g, 38 mmol), tert-butoxycarbonylamino-acetic acid (6.7 g, 38 mmol), and N,N-dimethylaminopyridine (5.7 g, 46 mmol) in CH2Cl2 (125 mL) was added EDC (5.5 g, 46 mmol). The resultant solution was stirred at room temperature for 2 days, and then diluted with ethyl acetate (500 mL) and washed with aqueous 1 M HCl (2×100 mL), water (100 mL), saturated aqueous NaHCO3 (100 mL), and then brine (100 mL). The organic layer was then dried (Na2SO4), concentrated under reduced pressure, and then flash chromatographed (silica, 1:39 to 1:19 to 1:9 ethyl acetate/CH2Cl2) to afford [(9-ethyl-9H-carbazol-3-ylcarbamoyl)-methyl]-carbamic acid tert-butyl ester (9.1 g, 65%) as a brown foam. MS m/z @ 368 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[C:15]1[N:20]2[C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=[C:19]2[CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH3:11][S:8]([N:5]1[CH2:6][CH2:7][CH:2]([O:1][C:15]2[N:20]3[C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=[C:19]3[CH:18]=[CH:17][CH:16]=2)[CH2:3][CH2:4]1)(=[O:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2cccc(Cl)n12
Reactant: CS(=O)(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)N1CCC(Oc2cccc3ncc([N+](=O)[O-])n23)CC1
Yield: 54.7 %

Procedure:
To a solution of 4-hydroxy-1-methylsulfonylpiperidine (2.15 g, 12 mmoles) in dimethylformamide (3 ml) was added 60% sodium hydride in oil (0.48 g, 12 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added 5-chloro-3-nitroimidazo[1,2-a]pyridine (1.976 g, 10 mmoles) with stirring under ice-cooling and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The precipitate was filtered off, washed with water and dried to obtain 1.862 g of the desired product (54.7%, yellow solid). The organic layer was washed with water and dried over anhydrous magnesium sulfate. After the solventy was distilled off, the crude crystlals thus obtained were recrystallized from methylene-n-hexane to obtain 460 mg of the desired product (460 mg, tan solid).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:33]3[CH2:38][CH2:37][C@H:36]([NH:39][CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])[CH2:35][CH2:34]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4F)=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12.[O:47]1CCOC[CH2:48]1.[OH-].[K+].CO>O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:33]3[CH2:34][CH2:35][C@H:36]([NH:39][CH2:40][CH2:41][C:42]([OH:44])=[O:43])[CH2:37][CH2:38]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:26])([F:27])[F:28])=[CH:21][C:20]=4[O:47][CH3:48])=[C:13]([O:31][CH3:32])[CH:12]=3)[C:3]=12
Reactant: C1COCCO1
Reactant: CCOC(=O)CCN[C@H]1CC[C@H](n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4F)c(OC)c3)c3c(N)ncnc32)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(-c2nn([C@H]3CC[C@H](NCCC(=O)O)CC3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1OC
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of trans-ethyl 3-({4-[4-amino-3-(4-{[2-fluoro-4-trifluoromethylbenzoyl]amino}-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl}amino)propanoate (0.04 g, 0.06 mmol), p-dioxane (4 mL), potassium hydroxide (0.02 g, 0.31 mmol), a trace amount of methanol and water (0.4 mL) were heated at 80° C. for 1 hour. The mixture was stirred at ambient temperature overnight and at 80° C. for 4 hours. The solvents were evaporated and the residue was purified by preparative HPLC to yield trans-3-({4-[4-amino-3-(3-methoxy-4-{[2-methoxy-4-trifluoromethylbenzoyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]cyclohexyl}amino)propanoic acid (0.04 g, 0.06 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 10.72 (s, 1H), 8.61(d, 1H), 8.28 (d, 1H), 8.24 (s, 1H), 7.61(s, 1H), 7.53 (d, 1H), 7.33 (s, 1H), 7.29 (d, 1H), 4.72 (m, 1H), 4.20 (s, 3H), 4.05 (s, 3H), 1.44-3.61 (m, 13H); RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100A, 250×4.6 mm; 25%-100% acetonitrile—0.05M ammonium acetate over 10 min, 1 mL/min) Rt 6.36 min. MS: MH+ 628.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[C:12]1([CH2:18][CH:19]2[NH:24][CH2:23][CH2:22][NH:21][C:20]2=[O:25])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:5]([O:4][C:2]([N:24]1[CH2:23][CH2:22][NH:21][C:20](=[O:25])[CH:19]1[CH2:18][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1NCCNC1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C1NCCN(C(=O)OCc2ccccc2)C1Cc1ccccc1

Procedure:
Benzyl chloroformate (8.5 g.) is added to a stirred mixture of 3-(phenylmethyl)piperazinone (XXIX, Example 62, 6.8 g.), chloroform (75 ml.), and saturated sodium bicarbonate solution (20 ml.). After 30 minutes the chloroform phase is separated, washed twice with water, and concentrated. The residual oil is crystallized from ethyl acetate-SSB and then ethyl acetate again to give the title compound, m.p. 125°-127.5°.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[SH:28].O[CH:30]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[S:28][CH:30]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:36])[CH3:37]
Reactant: CC(C)(C)OC(=O)NCC(O)c1ccccc1
Reactant: Sc1cc(Cl)ccc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(Sc1cc(Cl)ccc1Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 25 %

Procedure:
To a solution of triphenylphosphine (1.97 g), 2,5-dichlorothiophenol (0.90 g) and the product from step (a) (1.48 g) in THF (30 ml) under nitrogen at 0° C. was added diethylazodicarboxylate (1.18 ml) dropwise and the mixture was stirred at 0° C. for 45 minutes, then at room temperature for 72 h. The mixture was concentrated and the residue purified by chromatography (silica, 10% ethyl acetate/isohexane as eluent) to give the sub-title compound as a clear oil (500 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][NH:12]C(OCC2C=CC=CC=2)=O)=[O:10])[CH:6]=[CH:5][C:4]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1>CO.C1COCC1.[C].[Pd]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][NH2:12])=[O:10])[CH:6]=[CH:5][C:4]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: COc1nc(C(=O)NNC(=O)OCc2ccccc2)ccc1-n1cnc(C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc(C(=O)NN)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.2 %

Procedure:
Under a nitrogen atmosphere, to a mixture of benzyl 2-{[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]carbonyl}hydrazinecarboxylate (14.6 g) in methanol (150 mL) and THF (100 mL) was added 5% palladium-carbon (1.5 g) at room temperature, and the mixture was stirred at room temperature for 6 hr under a hydrogen atmosphere. Under a nitrogen atmosphere, the catalyst was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. To a mixture of the residue in ethanol (200 mL) and THF (400 ml) was added 5% palladium-carbon (1.5 g) at room temperature, and the mixture was stirred at room temperature overnight under a hydrogen atmosphere. Under a nitrogen atmosphere, the catalyst was filtered off, and the solvent in the filtrate was evaporated under reduced pressure. The residue was collected by filtration, washed with ethyl acetate and dried to give the title compound (3.9 g). The solvent in the mother liquor was evaporated under reduced pressure, and the residue was collected by filtration, washed with ethyl acetate and dried to give the title compound (2.6 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[SH:15])[NH:11][C:10](=[O:16])[C:9](=[O:17])[NH:8]2)([CH3:4])([CH3:3])[CH3:2].[S:18](Br)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].N1C=CC=CC=1>CCOC(C)=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12]([NH:11][C:10](=[O:16])[C:9](=[O:17])[NH:8]2)=[CH:13][C:14]=1[S:15][S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2[nH]c(=O)c(=O)[nH]c2cc1S
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Sc2cc3[nH]c(=O)c(=O)[nH]c3cc2C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the General Method 15 using 6-tert-butyl-7-mercapto-1,4-dihydro-quinoxaline-2,3-dione (prepared in Example DDD, 9.1 mmol), tosyl bromide (2.1 g, 9.1 mmol), pyridine (2 mL), EtOAc (50 mL). The crude product was purified by flash silica gel chromatography (5%-10% MeOH in CH2Cl2) as eluents. MS(APCI): 405 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1.[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[N:19]1C(=O)O[C:22](=[O:23])[C:21]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:20]12>>[CH3:11][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:19][C:20]1[CH:30]=[CH:29][CH:28]=[CH:27][C:21]=1[C:22]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([OH:10])=[N:2]1)=[O:23]
Reactant: Oc1n[nH]c2ccccc12
Reactant: Cc1cccc(-n2c(=O)oc(=O)c3ccccc32)c1C
Product: Cc1cccc(Nc2ccccc2C(=O)n2nc(O)c3ccccc32)c1C
Yield: 42.5 %

Procedure:
1H-Indazol-3-ol was reacted with N-(2,3-dimethylphenyl)isatoic anhydride according to the general procedure A above and afforded the desired amine as a yellow solid in 42.5% yield; m.p. 182°-184° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCCCCCCCCCC>C1(C)C=CC=CC=1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(Br)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCC
Product: Cc1ccc(-c2ccccc2)c([N+](=O)[O-])c1
Yield: 100.5 %

Procedure:
To a solution of commercially available 1-bromo-4-methyl-2-nitro-benzene (0.107 g, 0.49 mmol) in anhydrous toluene (3 mL) was added CsCO3 (0.305 g, 0.94 mmol) followed by phenylboronic acid (0.062 g, 0.49 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3.]undecane as a 0.1M solution in toluene (0.200 mL, 4 mole %). Nitrogen was bubbled through the resulting suspension for three minutes then palladium acetate (0.0043 g, 4 mole %) was added, the reaction vessel sealed and immersed in an 80° C. oil bath and heated for 22 hours. Subsequent filtration through celite and removal of volatiles under vacuum gave the crude product (0.105 g, 100%), which was sufficiently pure for use as isolated.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[S:16][CH:17]=[C:18]([C:20](=[O:22])[NH2:21])[N:19]=2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[C:20]([C:18]1[N:19]=[C:15]([N:12]2[CH2:11][CH2:10][CH:9]([OH:8])[CH2:14][CH2:13]2)[S:16][CH:17]=1)(=[O:22])[NH2:21]
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(c2nc(C(N)=O)cs2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NC(=O)c1csc(N2CCC(O)CC2)n1
Yield: 100.5 %

Procedure:
To a solution of 4-t-butyidimethylsilyloxy-1-(4-carbamoyl-1,3-thiazol-2-yl)piperidine (1.226 g, 3.59 mmol) (obtained as described in Reference Example 15(1)) in anhydrous tetrahydrofuran (30 ml) were added acetic acid (1.85 ml) and a solution of 1.0M tetra-n-butylammonium fluoride in tetrahydrofuran (32.3 ml, 32.3 mmol) in an ice bath, and the mixture was stirred for 24 hours. After checking the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column to afford 1-(4-carbamoyl-1,3-thiazol-2-yl)-4-hydroxypiperidine (0.82 g, yield 100%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[C:7]2[N:10]3[C@@:14]([O:21][CH3:22])([C@H:15]([CH2:16][O:17][C:18]([NH2:20])=[O:19])[C:6]=2[C:4](=[O:5])[C:3]=1[O:24][CH3:25])[C@H:13]1[NH:23][C@H:12]1[CH2:11]3.[OH-].[K+].C(=O)=O.[CH2:31]([O:33][CH2:34][CH2:35][O:36][CH2:37]CO)[CH3:32]>C(Cl)(Cl)Cl.CO>[C:18](=[O:17])([OH:19])[NH2:20].[OH:17][CH2:16][CH:15]1[C:6]2[C:4](=[O:5])[C:3]([O:24][CH2:25][CH2:37][O:36][CH2:35][CH2:34][O:33][CH2:31][CH3:32])=[C:2]([CH3:1])[C:8](=[O:9])[C:7]=2[N:10]2[CH2:11][CH:12]3[NH:23][CH:13]3[C:14]12[O:21][CH3:22]
Reactant: COC1=C(C)C(=O)C2=C(C1=O)[C@@H](COC(N)=O)[C@@]1(OC)[C@H]3N[C@H]3CN21
Reactant: CCOCCOCCO
Agent: O=C=O
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOCCOCCOC1=C(C)C(=O)C2=C(C1=O)C(CO)C1(OC)C3NC3CN21
Product: NC(=O)O
Yield: 62 %

Procedure:
A solution of mitomycin A (100 mg or 0.286 mmole) in 4 ml of diethylene glycol monoethyl ether was stirred at room temperature and under nitrogen for 45 minutes with 480 mg of a 1.6% solution of KOH in diethylene glycol monoethyl ether. The reaction mixture was decomposed with excess dry ice while immersing the flask into a water bath at room temperature. It was then isolated on a silica gel column using CHCl3 -MeOH 9:1 as solvent. Final purification was achieved by preparative thin layer chromatography on silica gel with a mixture of CHCl3 -MeOH 9:1. This procedure resulted in 80 mg (62%) of the title compound, having a melting point of 140°-143° C. (decomposition) and providing the following analysis:
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH2:6].[C:8]12([C:18]([Cl:20])=[O:19])[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>C1C=CC=CC=1>[ClH:20].[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][NH:6][C:18]([C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:19]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CN(C)CCCN
Solvent: c1ccccc1
Product: CN(C)CCCNC(=O)C12CC3CC(CC(C3)C1)C2
Product: Cl
Yield: 67.9 %

Procedure:
2.5 grams of N,N-dimethyl-1,3-propane diamine was added to a cold solution of 5 grams 1-adamantane carboxylic acid chloride in 15 cc benzene. An immediate precipitate formed. The mixture was stirred and permitted to sit for thirty minutes. The precipitate was washed with benzene several times, centrifuged, and dried in vacuum, yielding 5 grams of N-(3-dimethylaminopropyl)adamantane-1- carboxamide hydrochloride having a melting point of 154°-157° C. This product was dissolved in 150 cc acetone, placed in a refrigerator for crystal growth and 4.8 gms of the product was recovered.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C@@H:3]([N:5]1[CH2:10][CH2:9][C@:8]([CH2:18][CH2:19][C:20](O)=[O:21])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[O:7][C:6]1=[O:23])[CH3:4].CC[N:28]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][C:2]([CH3:25])([CH3:24])[C@@H:3]([N:5]1[CH2:10][CH2:9][C@:8]([CH2:18][CH2:19][C:20]([NH2:28])=[O:21])([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[O:7][C:6]1=[O:23])[CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: C[C@H](N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](N1CC[C@](CCC(N)=O)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Reaction time: 8 h
Yield: 29.7 %

Procedure:
3-((R)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanoic acid (50 mg, 0.144 mmol), EDCI (55 mg, 0.28 mmol), HOBt (38 mg, 0.28 mmol), and DIEA (90 mg, 0.07 mmol) were dissolved in CH2Cl2 (10 mL) under ice bath. The mixture was stirred under an NH3 atmosphere overnight. The reaction mixture was concentrated to give the crude product, which was purified by preparative TLC to give 3-((R)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanamide (15 mg, 30%). LC-MS Method 1 tR=2.027, min, m/z=351.1; 1H NMR (CDCl3) 0.73 (s, 9H), 1.12 (d, 3H), 1.89-1.98 (m, 1H), 2.01-2.12 (m, 1H), 2.22-2.38 (m, 3H), 2.48-2.52 (m, 1H), 2.71 (m, 1H), 3.18 (m, 1H), 4.46 (m, 1H), 5.29 (s, 1H), 5.53 (s, 1H), 7.07 (m, 2H), 7.29 (m, 2H)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([CH2:9]O)=[CH:4][N:3]=1.S(Cl)([Cl:13])=O>ClCCl>[Cl:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([CH2:9][Cl:13])=[CH:4][N:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cnc(Cl)c(Br)c1
Solvent: ClCCl
Product: ClCc1cnc(Cl)c(Br)c1
Reaction time: 5 h
Yield: 62.7 %

Procedure:
To a solution of 2-chloro-3-bromo-5-hydroxymethylpyridine (1.0 g, 4.5 mmol) in dichloromethane (20 mL) at 25° C. was added thionyl chloride (361 μL, 4.9 mmol) dropwise. The solution was stirred for 5 h, after which the reaction was quenched with saturated aqueous NaHCO3 and the layers separated. The aqueous phase further extracted with EtOAc (3×) and the combined organic phases dried over MgSO4 and concentrated to furnish 2-chloro-3-bromo-5-chloromethylpyridine as a yellow solid (0.68 g, 63%). GC-MS: Exact mass calcd for C6H5BrCl2N [M+H]+, 241. Found 241.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:18][C:9]2=[N:10][C:11]([Br:17])=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2].CC(C)([O-])C.[K+].[C:25]([O:29][C:30]([N:32]1[CH2:36][C@H:35]([CH3:37])OS1(=O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>>[CH2:1]([O:3][C:4]([C:6]1[N:18]([C@H:35]([CH3:37])[CH2:36][NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[C:9]2=[N:10][C:11]([Br:17])=[C:12]([O:14][CH2:15][CH3:16])[CH:13]=[C:8]2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCC)c(Br)nc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)c1cc2cc(OCC)c(Br)nc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
This compound was prepared in analogy to example 3, intermediate j) from 6-bromo-5-ethoxy-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester, potassium tert-butoxide and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3].[CH2:9](O)[CH2:10]/[CH:11]=[CH:12]\[CH2:13]C.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCCCCCC)CCCCCCC.C([O-])(=O)CCCCCCCCCCC>C1(C)C=CC=CC=1>[C:1]([O:7][CH2:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH3:13])(=[O:6])/[C:2](=[CH:4]\[CH3:5])/[CH3:3]
Reactant: CC/C=C\CCO
Reactant: C/C=C(/C)C(=O)OC
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCCCCCC[Sn+2]CCCCCCCC
Solvent: Cc1ccccc1
Product: C/C=C(/C)C(=O)OCC/C=C\CC

Procedure:
A mixture of 20.0 g. of methyl angelate, 26.34 g. of (Z)-3-hexenyl alcohol, 100 ml. of toluene and 1.2 g. of dioctyltin laurate was placed in a 300 ml. glass flask, which was equipped with a Soxhlet extractor filled on the top with molecular sieve 4A and a reflux cooler.
Reaction SMILES: C([S:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][S:33]C(=O)C)[CH2:20][C:21](OC)=[O:22])[CH2:14][C:15](OC)=[O:16])(=O)C.C1COCC1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[SH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([CH:19]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][SH:33])[CH2:20][CH2:21][OH:22])[CH2:14][CH2:15][OH:16]
Reactant: COC(=O)CC(CCCCCCCCSC(C)=O)C(CCCCCCCCSC(C)=O)CC(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCCC(CCCCCCCCS)C(CCO)CCCCCCCCS
Temperature: 25 °C
Reaction time: 3 h
Yield: 29.6 %

Procedure:
To a flame-dried 20 mL vial fitted with a screw-top septa cap was charged with dimethyl 3,4-bis(8-(acetylthio)octyl)hexanedioate (1 equiv, 0.34 mmol, 187 mg, mixture of stereoisomers) and THF (4.5 mL). DIBAl-H (12 equiv, 4.1 mmol, 2.7 mL of a nominally 1.5 M solution in toluene) was added dropwise. The reaction was stirred for 3 h at rt, quenched by careful addition of 2 N HCl (5 mL), diluted with 10 mL sat. aq. NH4Cl (10 mL), and extracted with Et2O (3×15 mL). The combined organic layers were washed with brine (1×15 mL), dried with Na2SO4, concentrated in vacuo, and purified by flash column chromatography (35% EtOAc/Hex) to afford rac-3,4-Bis(8-mercaptooctyl)hexane-1,6-diol (41 mg, 30%) and meso-3,4-Bis(8-mercaptooctyl)hexane-1,6-diol (49 mg, 49%). TLC rac-Rf=0.57 (50% EtOAc/Hex), meso-Rf=0.38 (50% EtOAc/Hex); rac: 1HNMR (400 MHz): δ 3.60-3.79 (4H), 2.54 (q, 4H, J=7.3 Hz), 1.14-1.68 (38H); 13CNMR (100 MHz): δ 61.6, 35.8, 34.0, 33.7, 30.7, 30.0, 29.5, 29.1, 28.3, 28.0, 24.6; FTIR: 3323, 2922, 2852, 1463, 1051, 722 cm−1; HRMS-ESI: calc. for C22H46NaO2S2 (M+Na)+: 429.2837. found: 429.2825; meso: 1HNMR (400 MHz): δ 3.59-3.76 (4H), 2.54 (q, 4H, J=7.3 Hz), 1.87 (bs, 2H), 1.08-1.68 (36H); 13CNMR (100 MHz): δ 61.9, 36.7, 34.0, 33.8, 30.7, 30.0, 29.5, 29.1, 28.4, 28.0, 24.7; FTIR: 3329, 2922, 2852, 1463, 1051, 721 cm−1; HRMS-ESI: calc. for C22H46NaO2S2 (M+Na)+: 429.2837. found: 429.2829.
Reaction SMILES: [CH:1]1[C:6]([N+:7]([O-])=O)=[CH:5][CH:4]=[C:3]([OH:10])[CH:2]=1.[CH3:11][C:12]([CH3:14])=O.[H][H]>[Pt]=O>[CH:12]([NH:7][C:6]1[CH:5]=[CH:4][C:3]([OH:10])=[CH:2][CH:1]=1)([CH3:14])[CH3:11]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(C)=O
Reactant: [H][H]
Agent: O=[Pt]
Product: CC(C)Nc1ccc(O)cc1
Yield: 40.4 %

Procedure:
Twenty-five g (0.18 moles) of p-nitrophenol and 58 g (1 mole) of acetone were mixed together and catalytically reduced using hydrogen and platinum oxide until hydrogen was no longer taken up. The work-up followed the procedure of Majors (J. Amer. Chem. Soc. 31:1901-1908 (1931), giving 11 g (41%) of N-isopropyl-p-hydroxyaniline, m.p. 143° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=2)[CH2:11][N:12]([CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=1.[NH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1>>[OH:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][CH2:28][NH:27][C:2]2[N:7]=[C:6]([C:8]3[CH:9]=[C:10]([CH:24]=[CH:25][CH:26]=3)[CH2:11][N:12]([CH2:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[S:13]([CH3:16])(=[O:15])=[O:14])[CH:5]=[CH:4][N:3]=2)=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)N(Cc1cccnc1)Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: NCCc1ccc(O)cc1
Product: CS(=O)(=O)N(Cc1cccnc1)Cc1cccc(-c2ccnc(NCCc3ccc(O)cc3)n2)c1

Procedure:
Intermediate 13 was coupled with tyramine following procedure F. LC-MS showed the product had the expected M+H+ of 490. 1H NMR (Varian 300 MHz, CDCl3, shifts relative to the solvent peak at 7.24 ppm) δ 8.5 (d, 2H) 8.4 (s, 1H) 8.3 (d, 1H) 7.9 (m, 4H) 7.4 (d, 2H) 7.3 (m, 1H) 7.1 (d, 2H) 6.9 (d, 1H) 6.7 (d, 1H) 5.6 (m, 1H) 4.4 (d, 4H) 3.7 (m, 2H) 2.9 (m, 5H).