Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([C:26]#[C:27][CH3:28])[CH2:3][C@:4]1([CH3:25])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:24])[C:8]([CH3:23])=[C:9]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[CH3:14])[O:5]1.CCOCC.[H-].COCCO[Al+]OCCOC.[Na+].[H-].OS(O)(=O)=O>C(Cl)(Cl)Cl>[OH:1][C@@H:2](/[CH:26]=[CH:27]/[CH3:28])[CH2:3][C@:4]1([CH3:25])[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([CH3:24])[C:8]([CH3:23])=[C:9]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[CH3:14])[O:5]1
Reactant: CC#C[C@H](O)C[C@]1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Agent: COCCO[Al+]OCCOC
Agent: O=S(=O)(O)O
Agent: [H-]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: C/C=C/[C@H](O)C[C@]1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1

Procedure:
To a solution of 5.0 g. (13.32 mmol) of 2(S)-[2(R)-hydroxy-3-pentynyl]-2,5,7,8-tetramethyl-6-benzyloxy-chroman in 50 ml. of dry ether was carefully added 4.06 ml. of sodium bis(2-methoxyethoxy)-aluminum hydride (29 mg. - atm. of hydrogen) in 10 ml. of dry ether. The resulting solution was refluxed under argon for 17 hours. The solution was cooled in an ice bath and 10% by volumn aqueous H2SO4 solution (100 ml.) was carefully added. It was filtered, washed with ether and water. The aqueous phase was again extracted with ether (3 × 100 ml.). The combined ether phase was washed with saturated aqueous NaHCO3 solution (3 × 50 ml.) and water (3 × 50 ml.) and dried over MgSO4. Evaporation of ether to dryness at reduced pressure yielded 5.206 g. of crude product which was crystallized from petroleum ether (b.p. 30°-60° C.) to give 4.23 g. of 2(S)-[2(R)-hydroxy-3(E)-pentynyl]-2,5,7,8-tetramethyl-6-benzyloxychroman as white needles, m.p. 68°-70° C. [α]D25 -24.02° (CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:6]([CH2:12]Cl)=[N:7]2.O.[SH:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]2[C:26]=1[NH:27][CH:28]=[N:29]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:22])[N:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[C:6]([CH2:12][S:24][C:25]1[N:33]=[CH:32][N:31]=[C:30]3[C:26]=1[N:27]=[CH:28][NH:29]3)=[N:7]2
Reactant: Sc1ncnc2nc[nH]c12
Reactant: COc1ccccc1-n1c(CCl)nc2cccc(Cl)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1-n1c(CSc2ncnc3[nH]cnc23)nc2cccc(Cl)c2c1=O
Yield: 75.5 %

Procedure:
Prepared according to Procedure C using Intermediate 21 (250 mg, 0.746 mmol), 6-mercaptopurine monohydrate (140 mg, 0.821 mmol), K2CO3 (113 mg, 0.821 mmol), and DMF (4 mL). The crude product was recrystallized from EtOH to provide 254 mg of an off-white solid (76%), mp 237.0° C. (dec; discolors at 154.6° C.). 1H NMR (DMSO-d6) δ: 13.53 (br s, 1H); 8.52 (s, 1H); 8.45 (s, 1H); 7.78 (t, J=7.9 Hz, 1H); 7.64 (d, J=8.0 Hz, 1H); 7.59 (d, J=7.7 Hz, 1H); 7.48 (d, J=7.3 Hz, 1H); 7.42 (t, J=7.7 Hz, 1H); 7.15 (d, J=8.2 Hz, 1H); 7.03 (t, J=7.5 Hz, 1H); 4.45 (s, 2H); 3.76 (s, 3H). 13C NMR (DMSO-d6) ppm: 158.9, 157.1, 154.8, 154.7, 151.5, 149.6, 143.6, 135.1, 133.2, 131.3, 130.4, 130.0, 127.0, 124.8, 121.2, 117.8, 112.7, 56.1, 32.0. MS (ES): m/z 451.0 (M+). Anal. calcd. for C21H15ClN6O2S.0.15C2H6O.0.05KCl: C, 55.43; H, 3.47; Cl, 8.07; N, 18.21; S, 6.95. Found: C, 55.49; H, 3.68; Cl, 7.95; N, 17.82; S, 6.82.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[OH:11][C:12]1[CH:13]=[C:14]([C:18]2([OH:24])[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)[CH:15]=[CH:16][CH:17]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:20]2[CH2:21][CH2:22][CH2:23][C:18]([OH:24])([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([OH:11])[CH:13]=3)[CH2:19]2)=[O:7])=[CH:4][CH:3]=1
Reactant: Oc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: O=C(c1ccc(F)cc1)N1CCCC(O)(c2cccc(O)c2)C1

Procedure:
The compound of Example 55 was prepared according to the general preparation protocol A from 4-fluorobenzoyl chloride and 3-(3-hydroxyphenyl)-piperidine-3-ol.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:10](OC)(OC)([O:12][CH3:13])[CH3:11].C(OC(=O)C)(=O)C>>[C:3]([C:2](=[C:10]([O:12][CH3:13])[CH3:11])[C:1]([O:8][CH3:9])=[O:7])([O:5][CH3:6])=[O:4]
Reactant: COC(=O)CC(=O)OC
Reactant: COC(C)(OC)OC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(C(=O)OC)=C(C)OC
Temperature: 130 °C
Yield: 77.5 %

Procedure:
264 g (2 mol) of dimethyl malonate, 961 g (8 mol) of trimethyl orthoacetate and 1 g of catalyst from Example 1 were put into the pressure apparatus described in Example 2. The mixture was heated to 130° C., whereupon an internal pressure of 1.5 bar developed. 100 g of acetic anhydride were then metered in over the course of 12 hours, the low-boiling component was distilled off at a head temperature of 82° to 87° C. and the reaction temperature was gradually increased to 160° C. After complete distillation of the low-boiling component, the mixture was cooled, the excess trimethyl orthoacetate distilled off at reduced pressure and the crude product was fractionated through a short column at a head temperature of 110° C. under a high vacuum of 0.3 mbar. In this way methyl 2-carbomethoxy-3-methoxy-2-butenoate was obtained in a yield of 77.5% and methyl 2-carbomethoxy-3,3-dimethoxy-butanoate was obtained in a yield of 11% of the theoretical yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[CH:9][S:8][C:7]=1[NH:18][C:19](=[O:23])[CH2:20][C:21]#[N:22])=[O:5])[CH3:2].S(Cl)([Cl:27])(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=2)=[C:9]([Cl:27])[S:8][C:7]=1[NH:18][C:19](=[O:23])[CH2:20][C:21]#[N:22])=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)csc1NC(=O)CC#N
Solvent: ClCCl
Product: CCOC(=O)c1c(NC(=O)CC#N)sc(Cl)c1-c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a cold (0° C.) solution of 4-(4-bromophenyl)-2-(2-cyano-acetylamino)-thiophene-3-carboxylic acid ethyl ester (4.0 g, 10.18 mmol) in methylene chloride (34 mL) was added sulfuryl chloride (0.82 mL, 10.2 mmol). The cold bath was removed, and the reaction was stirred at room temperature for 4 h. Saturated aqueous sodium bicarbonate solution was then added (30 mL) to the reaction. The layers were separated, and the aqueous was extracted with additional methylene chloride (3×15 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the titled compound as a solid. MS (DCI/NH3) m/e 446 (M+NH3)+, NMR (300 MHz, CDCl3): δ ppm 12.1 (br s, 1H), 7.53 d, 2H), 7.09 (d, 2H), 4.08 (q, 2H), 3.67 (s, 2H), and 0.91 (t, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([CH2:9]O)=[N:5][CH:6]=[CH:7][CH:8]=1.Cl.[NH2:12][CH2:13][CH2:14][SH:15].[BrH:16]>>[BrH:16].[BrH:16].[NH2:2][C:3]1[C:4]([CH2:9][S:15][CH2:14][CH2:13][NH2:12])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCCS
Reactant: Nc1cccnc1CO
Agent: Br
Agent: Cl
Product: NCCSCc1ncccc1N

Procedure:
A solution of 3-amino-2-hydroxymethylpyridine hydrochloride (3.4 g.) and cysteamine hydrochloride (2.38 g.) in aqueous hydrobromic acid (50 ml. 48%) was heated under reflux for 12 hours. Concentration under reduced pressure followed by re-evaporation of the residue with ethanol gave a yellow solid (7.5 g.) which was recrystallised from methanol-ether to afford 3-amino-2-[(2-aminoethyl)thiomethyl]pyridine dihydrobromide (5.8 g.) m.p. 195°-196°.
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([S:11][CH2:12][CH3:13])[CH:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CC(C)([O-])C.[Na+].CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:12]([S:11][C:4]1[CH:3]=[C:2]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:9]=[C:8]([CH3:10])[C:5]=1[C:6]#[N:7])[CH3:13]
Reactant: CCSc1cc(Cl)cc(C)c1C#N
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: CCSc1cc(N2CCOCC2)cc(C)c1C#N
Temperature: 100 °C
Reaction time: 16 h
Yield: 26.8 %

Procedure:
To a solution of 4-chloro-2-ethylsulfanyl-6-methyl-benzonitrile (0.9 g, 4.26 mmol) in dioxane (90 ml) are added morpholine (0.56 g, 6.39 mmol) and sodium tert-butoxide (1.2 g, 12.8 mmol). The reaction mixture is degassed and flushed with Argon for 30 min and then (2-biphenyl)di-tert-butylphosphine (0.25 g, 0.85 mmol) and bis(dibenzylideneacetone)-palladium(0) (0.5 g, 0.85 mmol) are added. The reaction mixture is stirred at 100° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture is filtered through a pad of celite pad. The filtrate is concentrated to get the crude product, which is purified by column chromatography (silica gel, 5% acetone/hexane) to yield 2-ethylsulfanyl-6-methyl-4-morpholin-4-yl-benzonitrile (0.30 g, 1.14 mmol, 27%).
Reaction SMILES: ClC1C=C(C=CC=1Cl)[C:5]([NH:7][CH:8]1[C:14](=[O:15])[NH:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9]1)=[O:6].[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=C=O)=[CH:33][CH:32]=1.C(N(CC)CC)C>C1COCC1>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:5]([NH:7][CH:8]2[C:14](=[O:15])[NH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:9]2)=[O:6])=[CH:33][CH:32]=1
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)NC1N=C(c2ccccc2)c2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of Intermediate 3 (30 mg) and 4-chloro-1-isocyanato-benzene (0.01 ml) in dry THF (4 ml) was treated with triethylamine (0.05 ml). The mixture was stirred at room temperature for 18 h, and was then partitioned between water and dichloromethane. The organic layer was passed through a hydrophobic frit, and was then evaporated. The residue was triturated with petroleum ether giving the title compound as a beige solid (34 mg).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH2:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(OC(C)C)(C)C.C(O)C>C1(C)C=CC=CC=1>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH:18][S:29]([CH3:28])(=[O:31])=[O:30])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)C1CCc2cccc(OCCN)c2C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CCCN(CCC)C1CCc2cccc(OCCNS(C)(=O)=O)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.45 g (5 mmol) of 2-dipropylamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthalene and 1.38 g (10 mmol) of potassium carbonate were initially introduced into 20 ml of toluene. 0.63 g (5.5 mmol) of methanesulphonyl chloride was then added dropwise, and the mixture was subsequently stirred for 3 h at room temperature. The mixture was then filtered and evaporated. The residue obtained was stirred with petroleum ether and filtered off under suction. The product, obtained by chromatography over silica gel 60, 40-63 μm, using diisopropyl ether/ethanol, 3:2, was recrystallized from petroleum ether with activated charcoal.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11](=[O:36])[NH:12][CH:13]2[CH2:17][S:16][C:15]3[CH:18]=[C:19]([C:22]4[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([F:29])[C:23]=4[C:30]4[N:31]=[N:32][N:33]([CH3:35])[N:34]=4)[CH:20]=[CH:21][C:14]2=3)[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>>[Cl:28][C:26]1[CH:25]=[C:24]([F:29])[C:23]([C:30]2[N:31]=[N:32][N:33]([CH3:35])[N:34]=2)=[C:22]([C:19]2[CH:20]=[CH:21][C:14]3[CH:13]([NH:12][C:11]([C:8]4([NH2:7])[CH2:10][CH2:9]4)=[O:36])[CH2:17][S:16][C:15]=3[CH:18]=2)[CH:27]=1
Reactant: Cn1nnc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)SCC3NC(=O)C2(NC(=O)OC(C)(C)C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Product: Cn1nnc(-c2c(F)cc(Cl)cc2-c2ccc3c(c2)SCC3NC(=O)C2(N)CC2)n1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-11 [C], (1-{(rac)-6-[5-chloro-3-fluoro-2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-2,3-dihydro-benzo[b]thiophen-3-ylcarbamoyl}-cyclopropyl)-carbamic acid tert-butyl ester (example 60) has been treated with trifluoroacetic acid (90%) to give the title compound as light yellow amorphous solid. MS: 445.1 (MH+, 1Cl).
Reaction SMILES: [OH-].[Na+].[CH2:3]([SH:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[C:11]1[C:12]([C:18]([OH:20])=[O:19])=[N:13][C:14](Cl)=[CH:15][CH:16]=1.Cl>CS(C)=O.O>[CH2:3]([S:9][C:11]1[C:12]([C:18]([OH:20])=[O:19])=[N:13][C:14]([S:9][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:15][CH:16]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCS
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCSc1ccc(SCCCCCC)c(C(=O)O)n1
Temperature: 135 °C
Yield: 75.4 %

Procedure:
To 300 ml of DMSO was added 84.5 g of powdered NaOH with vigorous stirring followed by the addition of 150 g of n-hexyl mercaptan. The anion of the mercaptan was allowed to form and then 111 g of 3,6-dichloro-2-pyridinecarboxylic acid in 110 ml of DMSO was added through a dropping funnel. the temperature was increased during addition to 135° C. and maintained at that temperature for 21/2 hours. Upon cooling the brown solution was poured into three volumes of water. The resulting solution was acidified with HCl and extracted with 1,1,1-trichloroethane. The organic layer was dried over MgSO4 and the solvent removed on a rotary evaporator. The reaction yielded 155 g (68% yield) of 3,6-bis(n-hexylthio)-2-pyridinecarboxylic acid as a dark oil which solidified on standing; m.p. 40°-42° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:14]([O-])=O)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.C([O-])=O.[NH4+]>CO.O1CCCC1.[Pd]>[NH2:14][C:4]1[CH:5]=[CH:6][C:7]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:2]([F:1])[CH:3]=1
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2F)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cn(-c2ccc(N)cc2F)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.5 %

Procedure:
3-Fluoro-4-(4-methylimidazol-1-yl)nitrobenzene (64.7 g, 0.293 M) was dissolved in a mixture of methanol (200 ml) and tetrahydrofuran (800 ml), cooled to 0° under nitrogen, and treated with ammonium formate (99.3 g, 1.46 M) followed by palladium on charcoal (10%, 2.5 g). The mixture was stirred at ambient temperature for 48 hours, filtered through celite, celite washed with methanol (200 ml), and filtrate evaporated to dryness. The residue was partitioned between ethyl acetate (800 ml) and 10% aqueous sodium bicarbonate (250 ml). The organic layer was separated, washed with brine (250 ml), dried (magnesium sulfate) and evaporated to give title compound (50.6 g).
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[C:4]([C:13]([C:15]2[CH:16]=[C:17]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[C:18]#[N:19])=[O:14])=[N:5][C:6]([O:11]C)=[N:7][C:8]=1[O:9]C>C(Br)(=O)C>[CH3:1][N:2]([CH3:24])[C:3]1[C:8](=[O:9])[NH:7][C:6](=[O:11])[NH:5][C:4]=1[C:13]([C:15]1[CH:16]=[C:17]([CH:20]=[C:21]([CH3:23])[CH:22]=1)[C:18]#[N:19])=[O:14]
Reactant: COc1nc(OC)c(N(C)C)c(C(=O)c2cc(C)cc(C#N)c2)n1
Agent: CC(=O)Br
Product: Cc1cc(C#N)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2N(C)C)c1

Procedure:
A solution of 3-(5-dimethylamino-2,6-dimethoxy-pyrimidine-4-carbonyl)-5-methyl-benzonitrile (0.0834 g, 0.255 mmol) in acetyl bromide (3.0 mL) was heated at 70° C. for 12 h. Reaction mixture was concentrated and purified by reverse phase HPLC (Phenomenex Synergi® column, 5 to 100% acetonitrile/H2O) to give an orange solid after lyophilization (0.030 g, 39%). 1H NMR (300 MHz, CDCl3): δ 9.55 (br s, 1H), 9.32 (br s, 1H), 7.85 (s, 1H), 7.79 (s, 1H), 7.64 (s, 1H), 2.45 (s, 9H). Mass spectrum: 299.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]=[S:17](Cl)([CH3:19])=[O:18])(=[O:15])=[O:14])=[CH:9][CH:8]=1>ClCCl.Cl>[CH3:19][S:17](=[N:16][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=1)(=[O:15])=[O:14])([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:18]
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)N=S(C)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N=S(C)(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Pyrrolidine (1.53 mL) is added drop wise to N-(4-methylbenzenesulfonyl)methylsulfonimidoyl chloride (5.00 g) in dichloromethane (10 mL) at 0° C. and the resulting mixture is allowed to warm to room temperature overnight. The reaction mixture is diluted with dichloromethane, hydrochloric acid (1 N; 10 mL) is added, and the mixture is stirred for 0.5 h at room temperature. The organic phase is separated, washed with aqueous NaHCO3 solution and water, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (ethyl acetate/methanol 100: 080:20) to give the title compound. LC (method 1): tR=0.88 min; Mass spectrum (ESI+): m/z=303 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:27][CH:26]=2)[CH2:16][CH2:15][CH2:14]1)[CH2:3][CH2:4][CH2:5][O:6][CH:7]1[CH2:12]CCC[O:8]1.C(Cl)(=O)C>C(O)(=O)C>[CH3:1][N:2]([CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:41])[C:25]2[CH:26]=[CH:27][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:29][CH:30]=2)[CH2:16][CH2:15][CH2:14]1)[CH2:3][CH2:4][CH2:5][O:6][C:7](=[O:8])[CH3:12]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CCCOC3CCCCO3)c3ccccc32)cc1
Solvent: CC(=O)Cl
Solvent: CC(=O)O
Product: CC(=O)OCCCN(C)C1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)cc2)c2ccccc21
Reaction time: 8 h
Yield: 16.2 %

Procedure:
To 5-{N-methyl-N-[3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propyl]amino}-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.4 g) is added a mixture of acetyl chloride (0.5 ml) and acetic acid (5 ml) at room temperature, and the mixture is stirred overnight. The reaction solution is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30:1), and further purified again by silica gel column chromatography (eluent; n-hexane:ethyl acetate=1:2) to give 5-[N-methyl-N-(3-acetyloxypropyl)amino]-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.06 g) as colorless amorphous.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][C:14]([CH3:23])([CH3:22])[C:13]=34)[O:6][N:5]=2)[CH2:3][CH2:2]1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]2[CH:11]=[N:10][C:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:8]=3)=[C:13]2[C:14]1([CH3:23])[CH3:22])(=[O:26])[CH3:25]
Reactant: CC1(C)Nc2ccccc2-n2cnc(-c3nc(C4CC4)no3)c21
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1c2ccccc2-n2cnc(-c3nc(C4CC4)no3)c2C1(C)C
Reaction time: 72 h

Procedure:
A mixture of 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-4,4-dimethylimidazo-[1,5-a]quinoxaline (XXXIII, EXAMPLE 99, 0.19 g) and acetic anhydride (3 ml) is stirred at 100° for 3 days. Excess acetic anhydride is then removed under reduced pressure and the residue is partitioned between dichloromethane and aqueous sodium bicarbonate. The phases are separated and the organic phase is filtered through sodium sulfate and concentrated. The crude product is chromatographed on silica gel (200 ml) eluting with ethyl acetate/dichloromethane (20/80). The appropriate fractions are pooled and concentrated to give the title compound, mp 169°-171°; MS (m/z) at 349; IR (mineral oil) 1666, 1613, 1327, 1281 and 1504 cm-1 ; NMR (CDCl3) 1.12, 1.94, 2.16, 2.18, 7.20, 7.33, 7.52 and 8.14 δ.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[Br:14]Br>C(Cl)Cl>[Br:14][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)=[O:10]
Reactant: CC(=O)c1ccc(C)c([N+](=O)[O-])c1
Reactant: BrBr
Solvent: ClCCl
Product: Cc1ccc(C(=O)CBr)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 99.9 %

Procedure:
A solution of 1-(4-methyl-3-nitro-phenyl)ethanone (Sigma-Aldrich, 25.08 g, 0.14 mol) in CH2Cl2 (269 mL) is cooled to 0° C. To this is added bromine (7.17 mL, 0.14 mol) at 0° C. with stirring. The reaction mixture is allowed to warm slowly to rt over a total of 90 minutes. Ice water (500 mL) is added, organics are collected and aqueous layer is extracted with CH2Cl2 (2×250 mL). The organic layers are combined, washed with water, dried with Na2SO4 and concentrated to give the title compound (36.1 g, 99% yield). LCMS m/z=258.3, 260.2 [M+H]+, tR=2.39 min.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])C.Cl>[OH-].[Na+].[Na+].[Cl-]>[CH3:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)CCCOCCOCCOCCOC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: COCCOCCOCCOCCCC(=O)O
Reaction time: 2 h
Yield: 94.4 %

Procedure:
4-{2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethoxy}-butyric acid ethyl ester (1.07 g, 4.0 mmol) was dissolved in 1M NaOH (10 mL) and the reaction was stirred for 2 h. Crude reaction was diluted with sat. NaCl (40 mL), acidified to pH ˜2 with conc. HCl, washed CH2Cl2 (2×50 mL), dried MgSO4, and evaporated to dryness to afford 3 a clear oil (0.945 g, 94% yield).
Reaction SMILES: C([S:4][CH2:5][CH:6]([S:8]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])[CH3:7])(=O)C.C(SCCS(N1CCC[C@H]1C(O)=O)(=O)=O)(=O)C.N1CCC[C@H]1C(O)=O>>[SH:4][CH2:5][CH:6]([S:8]([N:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])(=[O:10])=[O:9])[CH3:7]
Reactant: CC(=O)SCC(C)S(=O)(=O)N1CCC[C@H]1C(=O)O
Agent: CC(=O)SCCS(=O)(=O)N1CCC[C@H]1C(=O)O
Agent: O=C(O)[C@@H]1CCCN1
Product: CC(CS)S(=O)(=O)N1CCC[C@H]1C(=O)O

Procedure:
By substituting 1-[[2-(Acetylthio)-1-methylethyl]-sulfonyl]-L-proline for the 1-[[2-(acetylthio)ethyl]sulfonyl]-L-proline in the procedure of Example 2, 1-[2-mercapto-1-methylethyl)sulfonyl]-L-proline is obtained.