Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.C(=O)=O.C[Li].C([Li])CCC.CON(C)[C:41](=[O:43])[CH3:42]>O.C1COCC1>[C:41]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][CH:15]=1)[CH2:6][CH2:5]2)(=[O:43])[CH3:42]
Reactant: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1
Reactant: CON(C)C(C)=O
Agent: O=C=O
Agent: [Li]C
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2
Temperature: 25 °C

Procedure:
A mixture of N-((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (1.0 g) and THF (10 ml) was cooled to −78° C. (dry ice bath), and a solution of methyllithium (2.0 ml; 1.6 M in diethyl ether) was added dropwise. One minute after the addition had ended, a solution of butyllithium (1.4 ml; 2.5 M in toluene) was added dropwise. One minute after the addition had ended, N-methoxy-N-methylacetamide (0.24 g) was added. After warming to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phases were dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel (eluent: 1:1 heptane/ethyl acetate). The product was thus obtained with the molecular weight of 393.49 (C24H27NO4); MS (ESI): 394 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-])=O)=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2>C(O)(=O)C.C(O)C.[Fe]>[NH2:12][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2
Reactant: O=[N+]([O-])c1ccc(Br)c2ncccc12
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(Br)c2ncccc12
Reaction time: 0.75 h

Procedure:
At reflux, 10.0 g of 8-bromo-5-nitroquinoline in 68 ml of glacial acetic acid and 34 ml of ethanol were added dropwise to a mixture of 7.75 g of iron powder, 18 ml of glacial acetic acid and 9 ml of ethanol. After stirring for 45 minutes at reflux, the mixture was cooled and filtered through diatomaceous earth. The filtrate was concentrated, taken up in methylene chloride, washed with sodium carbonate solution, dried and concentrated.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)[NH2:5].Br[C:19]1[S:23][CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].N#N>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:19]2[S:23][CH:22]=[N:21][CH:20]=2)[CH:8]=1)[NH2:5]
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Brc1cncs1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(N)cc(-c2cncs2)c1
Temperature: 100 °C

Procedure:
3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (20.98 g, 90 mmol), 5-bromothiazole (8.85 mL, 99 mmol) and sodium carbonate (90 mL, 180 mmol) were combined in a flask. 2-Methyl-THF (326 mL) was added and the mixture was degassed with N2 for 1.5 h before 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (3.67 g, 4.50 mmol) was added. The reaction was heated to 100° C. overnight and was then cooled to room temperature. The reaction mixture was filtered though a pad of CELITE, washing with ethyl acetate. The layers were separated and the aqueous layer was back-extracted with ethyl acetate, dried over Na2SO4, and concentrated. The residue was purified by chromatography on silica gel (0-40% ethyl acetate in hexanes). 3-Methyl-5-(1,3-thiazol-5-yl)aniline was isolated as a yellowish brown solid. MS ESI: [M+H]+ m/z 191. 1H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 8.02 (s, 1H), 6.80 (s, 1H), 6.71 (s, 1H), 6.50 (s, 1H), 3.71 (s, 2H), 1.79 (s, 3H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:20](Br)[C:21]([O:23]C)=[O:22])[CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1>O1CCOCC1>[CH3:19][O:18][C:16]1[CH:15]=[C:14]([CH:20]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21]([OH:23])=[O:22])[CH:13]=[C:12]([O:11][CH3:10])[CH:17]=1
Reactant: COC(=O)C(Br)c1cc(OC)cc(OC)c1
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(OC)cc(C(Sc2ccccc2)C(=O)O)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of benzenethiol (5.91 g) and potassium hydroxide (3.48 g) in dioxane (200 ml) was heated at 80° C. for one hour under nitrogen. After cooling down to 20° C., a solution of methyl 2-(3,5-dimethoxyphenyl)-2-bromoacetate (15.0 g) in dioxane (100 ml) was added and the mixture was refluxed for two hours. Additionally potassium hydroxide (1.5 g) was added and the reflux continued for further two hours. After cooling to room temperature, the suspension was filtered and the filtrate concentrated to dryness. The residue was partitioned between dichloromethane (300 ml) and aqueous hydrochloric acid (1M, 300 ml). The organic phase was dried and concentrated to dryness, leaving crude 2-(3,5-dimethoxyphenyl)-2-(phenylsulfanyl)acetic acid. Crystallization from diethyl ether gave the pure compound (7.2 g), m.p. 124-126° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:5][OH:6])[CH2:3][OH:4].[Br:7][C:8]1[S:12][C:11]([S:13](Cl)(=[O:15])=[O:14])=[CH:10][CH:9]=1.C(N(CC)CC)C>C1COCC1>[OH:4][CH2:3][CH:2]([NH:1][S:13]([C:11]1[S:12][C:8]([Br:7])=[CH:9][CH:10]=1)(=[O:15])=[O:14])[CH2:5][OH:6]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: NC(CO)CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(NC(CO)CO)c1ccc(Br)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
To a stirred solution of 2-amino-1,3-propanediol (1.26 g, 13.8 mmol) in THF (20 ml) was added at 0° C. (ice water bath) commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) and triethylamine (0.71 ml, 5.07 mmol). The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) to yield the title compound (0.87 g, 72%) as a white solid. MS (ISN) 313.9 [(M−H)−], mp 80° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:15]([O:19][C:20](=[O:30])[CH:21]([CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH:22]([CH3:24])[CH3:23])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>ClCCl>[C:15]([O:19][C:20](=[O:30])[CH:21]([CH2:25][S:26]([N:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:5]=[CH:4][C:3]([Br:2])=[CH:8][CH:7]=2)[CH2:10][CH2:11]1)(=[O:27])=[O:28])[CH:22]([CH3:24])[CH3:23])([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(C)C(CS(=O)(=O)Cl)C(=O)OC(C)(C)C
Reactant: Brc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
A stirred suspension of 4-bromophenylpiperazine hydrochloride (2.84 g) and 2-chlorosulfonylmethyl-3-methyl-butyric acid tert-butyl ester (2.77 g) [preparation described in WO-A-98/05635] in dichloromethane (50 ml), cooled in an ice-bath, was treated with triethylamine (2.99 ml). The reaction was then stirred at room temperature for 2 h. The reaction mixture was then evaporated in vacuo, and the residue was dissolved in ethyl acetate (75 ml) and washed with 1% aqueous citric acid (2×50 ml), water (50 ml), saturated sodium bicarbonate (50 ml), saturated brine (50 ml), dried (MgSO4) and concentrated in vacuo to provide the title compound as a pale yellow gum (3.81 g, 79%).
Reaction SMILES: [CH:1]1(/[CH:7]=[C:8](\[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)/[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:31]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:31][C:14]1[S:13][C:12]([NH:11][C:9](=[O:10])/[C:8](/[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:18]=2)=[CH:7]/[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[N:16][CH:15]=1
Reactant: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)Nc2nccs2)cc1C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)C(=O)Nc2ncc(Br)s2)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
A suspension of (E)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-acrylamide (prepared in Example 12, 150 mg, 3.27 mmol) and N-bromosuccinimide (69 mg, 0.384 mmol) in carbon tetrachloride (2 mL) at 25° C. was treated with benzoyl peroxide (4.65 mg, 0.02 mmol). The resulting reaction mixture was heated to 90° C. where it was stirred overnight at this temperature. The reaction mixture was then allowed to cool to 25° C. and then concentrated in vacuo. The residue was dissolved in ethyl acetate (25 mL). The organic phase was then washed with water (1×30 mL) and a saturated aqueous sodium chloride solution (1×30 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 4/1 hexanes/ethyl acetate) afforded (E)-N-(5-bromo-thiazol-2-yl)-3-cyclohexyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-acrylamide (59 mg, 33%) as an amorphous white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14]C)=[CH:11][CH:12]=2)[N:7]([CH3:16])[CH:6]=1)=[O:4].B(Br)(Br)Br>>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[N:7]([CH3:16])[CH:6]=1)=[O:4]
Reactant: CNC(=O)c1cn(C)c2cc(OC)ccc12
Agent: BrB(Br)Br
Product: CNC(=O)c1cn(C)c2cc(O)ccc12
Yield: 51.1 %

Procedure:
This material was prepared from 6-methoxy-1-methyl-1H-indole-3-carboxylic acid methylamide 21a (453 mg, 2.1 mmol) by treatment with BBr3 in a manner as previously described for example 1d to give 219 mg (51%) of a pale orange solid. 1H NMR (CD3OD) δ7.75 (1H, d, J=8.5 Hz), 7.47 (1H, s), 6.61-6.66 (2H, m), 3.62 (3H, s), 3.24 (1H, s), 2.79 (3H, s). ESIMS (MH+): 205.10.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[C:14]([O:15][C@@H:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:29].[CH3:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(Cl)Cl.N1C=CC=CC=1>[N:18]1([CH2:17][C@H:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:15][C:14]2[CH:13]=[CH:12][C:11]3[C:10](=[O:29])[CH2:9][CH2:8][CH2:7][C:6]=3[C:5]=2[CH2:4][NH:3][S:38]([C:35]2[CH:34]=[CH:33][C:32]([O:31][CH3:30])=[CH:37][CH:36]=2)(=[O:40])=[O:39])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: NCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)NCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)cc1
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 5-aminomethyl-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one bis-hydrochloride (40 mg, 0.092 mmole) in CH2Cl2 (1 mL) and pyridine (1 mL) was added 4-methoxybenzenesulfonyl chloride (0.75 mL, 0.4 M solution in trifluorotoluene, 3 equiv). The reaction was shaken overnight. A polyamine resin was added to quench the excess sulfonyl chloride. The mixture was filtered and concentrated. The residue was dissolved in EtOAc and washed with 1 M NaOH and brine, dried over Na2SO4 and concentrated to give a light brown oil. Purification by chromatography (5% MeOH/CH2Cl2 with 1% NH4OH) gave the title compound as an off-white foam (32 mg, 0.060 mmol, 66%). The structure was confirmed by NMR and mass spectrometry. MS m/z 532 (M++H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17](=[O:19])[NH2:18])[CH2:12]1)[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH2:30]([O:37][C:38](Cl)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:30]([O:37][C:38]([N:14]1[CH2:15][CH2:16][CH:11]([C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])[CH2:9][CH3:10])[CH2:12][CH:13]1[C:17](=[O:19])[NH2:18])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C1CCNC(C(N)=O)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](NC(=O)OC(C)(C)C)C1CCN(C(=O)OCc2ccccc2)C(C(N)=O)C1
Reaction time: 1 h

Procedure:
To a chilled (0° C.) solution of [(S)-1-(2-carbamoyl-piperidin-4-yl)-propyl]-carbamic acid tert-butyl ester (780 mg, 2.73 mmol) in methylene chloride (25 mL) was added DIPEA (0.41 mL, 2.9 mmol) followed by benzylchloroformate (723 μL, 4.1 mmol). After 1 hour, the reaction was diluted with dichloromethane (200 mL), washed with saturated ammonium chloride, brine, dried over sodium sulfate, filtered and concentrated to afford 4-((S)-1-tert-butoxycarbonylamino-propyl)-2-carbamoyl-piperidine-1-carboxylic acid benzyl ester.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[N:24]1C(=O)C(=CC2C=CC=CC=2)S[C:25]1=[S:37])(=O)C.[CH2:38]([NH2:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CO>[C@@H:6]1([NH:24][C:25]([NH:45][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[S:37])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NCc1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](N2C(=O)C(=Cc3ccccc3)SC2=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CO
Product: OC[C@H]1O[C@@H](NC(=S)NCc2ccccc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 23 h

Procedure:
N-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-5-benzylidenerhodanine (2.204 g., 0.004 mole) was added to a solution of benzylamine (2.58 g., 0.024 mole) in 50 ml. of methanol in a pressure bottle. The reaction mixture was stirred at room temperature for 23 hours in the pressure bottle with the stopper well closed. The mixture was filtered, and the filtrate was evaporated to a sticky syrup below 30° in vacuo. The residual syrup was dissolved in the minimum ammount of acetone, and anhydrous ether was added to the solution to give a yellow sticky solid. The supernatant was decanted, and the residual sticky solid was dissolved in the minimum amount of acetone. Benzene was added to the solution to give a precipitate. The precipitate was filtered, partially dissolved in ethyl acetate, and then chromatographed on a column of silica gel (1×20 cm) using ethyl acetate as the first solvent and acetone as the second solvent. Fifty ml. of ethyl acetate effluent was collected in the first Erlenmeyer flask and 75 ml. of acetone effluent was collected in the second Erlenmeyer flask. The volume of the acetone effluent was reduced ca. 25 ml. and was set aside at 5° for 16 hours. The white precipitate was filtered, washed with acetone, and dried at room temperature in vacuo, yielding 0.99 g. (64.2%); m.p. 97°-100° (dec.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[CH3:15][C@H:16]1[CH2:24][C:23]2[C:18](=[CH:19][C:20]([CH3:25])=[CH:21][CH:22]=2)[C@@H:17]1[NH2:26].C(N(CC)CC)C>CN(C)C(=O)C>[Cl:1][C:2]1[C:3]([C:12]([NH2:14])=[O:13])=[N:4][C:5]([NH:26][C@H:17]2[C:18]3[C:23](=[CH:22][CH:21]=[C:20]([CH3:25])[CH:19]=3)[CH2:24][C@@H:16]2[CH3:15])=[N:6][CH:7]=1
Reactant: Cc1ccc2c(c1)[C@H](N)[C@@H](C)C2
Reactant: CS(=O)(=O)c1ncc(Cl)c(C(N)=O)n1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: Cc1ccc2c(c1)[C@H](Nc1ncc(Cl)c(C(N)=O)n1)[C@@H](C)C2
Yield: 17.4 %

Procedure:
0.30 g (1.27 mmol) of 5-chloro-2-(methylsulfonyl)pyrimidine-4-carboxamide, 0.25 g (1.53 mmol) of (1R,2S)-2,6-dimethyl-2,3-dihydro-1H-indene-1-amine and 0.28 g (2.54 mmol) of triethylamine in 1.5 ml of N,N-dimethylacetamide are heated in a closed cuvette in the microwave at 120° C. for 45 minutes (Biotage Initiator, http://www.biotage.com/DynPage.aspx?id=22001). The crude mixture obtained in this manner is applied to silica gel and purified by column chromatography using the mobile phase heptane/ethyl acetate. Concentration gives initially 0.07 g of 5-chloro-2-{[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}pyrimidine-4-carboxamide (wax-like) and then 0.252 g of 5-{[(1R,2S)-2,6-dimethyl-2,3-dihydro-1H-inden-1-yl]amino}-2-(methylsulfonyl)pyrimidine-4-carboxamide (yield 52% at a purity of 95%).
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH3:19])[C:4]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.C1N2CN3CN(C2)C[N:21]1C3.[Br-].[NH4+].C(O)(C)C>O>[Cl:18][C:15]1[CH:16]=[CH:17][C:4]2[N:3]([CH3:19])[CH2:2][CH2:1][N:21]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5]=2[CH:14]=1
Reactant: CCN(C)c1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: [Br-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CN1CCN=C(c2ccccc2)c2cc(Cl)ccc21

Procedure:
Reflux 0.005 moles of 2-(2-ethyl-methylamino)-5-chlorobenzophenone, 0.020 moles of hexamethylenetetramine and 0.020 moles of ammonium bromide together for 2 hours in 14 ml. of 85% (v/v) aqueous isopropyl alcohol. Pour the reaction mixture into water and extract the product with benzene. Wash the benzene solution with water, dry over anhydrous sodium sulfate, filter and evaporate to dryness. After recrystallization, 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine is obtained. The material gives a single spot by thin layer chromatography, and after drying under vacuum at 110° C., shows no depression on mixed melting point with an authentic sample.
Reaction SMILES: S1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]2[C:16]([CH2:17][N:18]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:3][CH2:2]1.O[O:32][S:33]([O-:35])=O.[K+]>CO.O.C([O-])([O-])=O.[Na+].[Na+]>[O:32]=[S:33]1(=[O:35])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]2[C:16]([CH2:17][N:18]([C:25]3[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:3][CH2:2]1
Reactant: O=S([O-])OO
Reactant: c1cncc(N(Cc2cccnc2N2CCSc3ccccc32)c2cccnc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S1(=O)CCN(c2ncccc2CN(c2cccnc2)c2cccnc2)c2ccccc21
Reaction time: 2 h

Procedure:
To a solution of: N-{[2-(2,3-dihydro-4H-1,4-benzothiazin-4-yl)pyridine-3-yl]methyl}-N-pyridin-3-ylpyridin-3-amine (52 mg, 0.126 mmol) in methanol (1.5 mL) and water (1 mL) was added Oxone™ (97 mg, 0.157 mmol). The reaction progress was monitored by LC/MS and after 2 hours the reaction was diluted with water and Na2CO3 solution and the product was extracted into ethyl acetate, the solution dried, filtered, and the solvent evaporated. The residue was purified by chromatography on silica gel eluting with a 20-100% acetone/hexane gradient to give the title compound as a coloress glass. 1H-NMR (500 MHz, CDCl3): δ 8.51 (1H, d, J=3.6 Hz), 8.29 (2H, s), 8.26 (2H, d, J=3.9 Hz), 7.88 (2H, t, J=9.0 Hz), 7.26-7.31 (4H, m), 7.18-7.21 (2H, m), 7.00 (1H, t, J=7.3 Hz), 6.22 (1H, d, J=8.3 Hz), 4.76 (2H, s), 4.38 (2H, br s), 3.57 (2H, t, J=5.8 Hz). m/e (m+1): 444.2.
Reaction SMILES: CO.[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([O:19]CCC)=[O:18])=[CH:11][C:6]=2[CH:5]=[CH:4]1.[OH-].[K+]>O>[S:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][C:6]=2[CH:5]=[CH:4]1
Reactant: CCCOC(=O)CCOCCc1ccc2sccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCOCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 86.7 %

Procedure:
To methanol (12 mL) solution of 12.0 g of propyl 3-(2-(1-benzothiophen-5-yl)ethoxy)propionate was added water (12 mL) solution of 2.76 g of potassium hydroxide, which was then stirred at room temperature for 1.5 hours. This reaction mixture was distilled off under reduced pressure, to which were added 36 mL of toluene and 36 mL of water. The pH was adjusted to 1.9 with 8 mL of 6 mol/L hydrochloric acid. The organic layer was separated, followed by distilling off the solvent under reduced pressure. Thereto were added 12 mL of toluene and 24 mL of cyclohexane. The precipitate was collected by filtration to provide 8.91 g of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid as white solid form.
Reaction SMILES: [CH:1]([C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1)=[O:2].Cl.[CH3:15][C:16]1([CH3:23])[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][NH2:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH3:15][C:16]1([CH3:23])[CH2:20][CH2:19][CH2:18][CH:17]1[CH2:21][NH:22][C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([CH:1]=[O:2])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: CC1(C)CCCC1CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC1(C)CCCC1CNC(=O)C=Cc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cold (0° C.) solution of 4-formylcinnamic acid (345 mg, 1.96 mmol) and 2,2-dimethylcyclopentylmethylamine, hydrochloride (321 mg, 1.96 mmol; title B compound of Example 1) in DMF (5 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (954 mg, 2.16 mmol) and N-methylmorpholine (0.47 mL, 4.31 mmol). The cooling bath was removed and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and washed with 1 N HCl and saturated NaHCO3 solution. The organic layer was dried (MgSO4) and concentrated in vacuo to yield a light amber gum. MS: (ESI), (M+H)+ 286.
Reaction SMILES: [CH2:1]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]=1/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH2:2][CH2:3][CH3:4].[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:20][C:19](=[O:21])/[CH:18]=[CH:17]/[C:6]2[CH2:7][CH2:8][C:9]3[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=3)[C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: CCCCC1=C(/C=C/C(=O)O)CCc2cc(OC)ccc21
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCC1=C(/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)CCc2cc(OC)ccc21

Procedure:
As in Example 113, (E)-3-(1-butyl-3,4-dihydro-6-methoxy-2-naphthalenyl)-2-propenoic acid (1.8 g) was reacted with 4-nitrophenol (0.97 g) in dichloromethane (30 mL) in the presence of 1,3-dicyclohexylcarbodiimide (1.3 g) overnight at room temperature. The normal work up yielded 1.5 g of crude ester. Crystallization from diethyl ether-2-propanol furnished (E)-3-(1-butyl-3,4-dihydro-6-methoxy-2-naphthalenyl)-2-propenoic acid 4-nitrophenyl ester, mp 94°-95° C. Anal. Calcd for C24H25NO5 : C, 70.74; H, 6.18; N, 3.44 Found: C, 70.42; H, 6.04; N, 3.29
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][CH2:7][CH:8]([OH:19])[CH2:9][CH2:10][CH2:11][CH:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:13])[CH:3]=[CH2:4].[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C1C=CC=CC=1.CCOCC.[O-2].[O-2].[Mn+4]>[CH2:20]([N:22]([CH2:23][CH3:24])[CH2:4][CH2:3][C:2]1([OH:1])[CH2:5][CH2:6][CH2:7][CH:8]([CH2:9][CH2:10][CH2:11][CH:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:13])[O:19]1)[CH3:21]
Reactant: C=CC(O)CCCC(O)CCCC(C)OC(C)(C)C
Reactant: CCNCC
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCN(CC)CCC1(O)CCCC(CCCC(C)OC(C)(C)C)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
41.3 G. of 3,7-dihydroxy-11-tertiarybutoxy-dodec-1ene produced in Example 121 was dissolved in benzene solution and added to a slurry of 320 g. of activated manganese dioxide in 1600 ml. of benzene containing 120 ml. of diethylamine. The reaction mixture was stirred at room temperature for 20 hours and filtered free of solids. Removal of the solvents in vacuo gave a pale brown oil. The oil was dissolved in ether and extracted with aqueous 1N hydrochloric acid. Sodium hydroxide was added to the acid extract. Extraction into ether and evaporation of the solvent affords 2-[2'-diethylaminoethyl]-6-[4-t-butoxypentyl]-2-tetrahydropyranol.