Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[C:26]2[C:14](=[C:15]([CH3:28])[C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([OH:27])=[CH:22][C:23]=4[C:24]=3[CH:25]=2)[CH:13]=[CH:12][N:11]=1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:9][C:10]1[C:26]2[C:14](=[C:15]([CH3:28])[C:16]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([O:27][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:22][C:23]=4[C:24]=3[CH:25]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Cc1c2ccnc(Cl)c2cc2c1[nH]c1ccc(O)cc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: Cc1c2ccnc(Cl)c2cc2c1[nH]c1ccc(OCc3ccccc3)cc12
Reaction time: 24 h
Yield: 51.2 %

Procedure:
A solution of benzyl bromide (230 μl, 1.9 mMol) in acetone (6 ml) is added at room temperature, over 15 minutes, to a mixture containing 1-chloro-9-hydroxy-5-methyl-6H-pyrido[4,3-b]carbazole (Compound 10) (490 mg, 1.73 mMol), acetone (7 ml), DMF (2 ml) and K2CO3 (400 mg). The assembly is left stirring for 24 h, then the solvents are subsequently evaporated under vacuum. Water is then added (30 ml). The assembly is again left stirring for 24 h. The solid form is recovered by filtration, washed with water, then dried at room temperature for 18 h. An inter-mediate, 1-chloro-9-benzyloxy-5-methyl-6H-pyrido[4,3-b]carbazole (330 mg, 51% yield) is obtained, after chromatography through a silica column using dichloromethane/ethyl acetate (from 99%/1% to 95%/5%) as eluent. The product obtained is identical to that obtained according to the method described in J. Chem. Soc. Perkin Trans. 1, 1979, 1706. The mixture of 1-chloro-9-benzyloxy-5-methyl-6H-pyrido[4,3-b]carbazole obtained above (320 mg, 0.86 mMol), DMF (7 ml) and sodium methoxide (30% solution in methanol, 10 ml) is heated under reflux for 20 h. The reaction mixture is poured into 60 ml of water, then left stirring for 2 h. The solid formed, recovered by filtration, is washed with water then dried. 280 mg (88% yield) of the expected compound 9-benzyloxy-1-methoxy-5-methyl-6H-pyrido[4,3-b]carbazole (Compound 7) are then obtained, after chromatography through a silica column using dichloromethane/ethyl acetate (from 99.5%/0.5% to 99%/1%) as eluent. The proton NMR spectrum of Compound 7 is the following:
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9](Cl)[CH:10]=[CH:11][C:12]=3Cl)[C:7](=[O:19])[C:6]=2[C:5](Cl)=[CH:4][C:3]=1[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([SH:48])=[CH:44][CH:43]=1>O>[NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([S:48][C:45]4[CH:46]=[CH:47][C:42]([CH3:41])=[CH:43][CH:44]=4)[CH:10]=[CH:11][C:12]=3[S:48][C:45]3[CH:46]=[CH:47][C:42]([CH3:41])=[CH:43][CH:44]=3)[C:7](=[O:19])[C:6]=2[C:5]([S:48][C:45]2[CH:46]=[CH:47][C:42]([CH3:41])=[CH:43][CH:44]=2)=[CH:4][C:3]=1[C:21]([O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:22]
Reactant: Nc1c(C(=O)Oc2ccccc2)cc(Cl)c2c1C(=O)c1c(Cl)ccc(Cl)c1C2=O
Reactant: Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Sc2ccc(Sc3ccc(C)cc3)c3c2C(=O)c2c(Sc4ccc(C)cc4)cc(C(=O)Oc4ccccc4)c(N)c2C3=O)cc1
Temperature: 80 °C
Yield: 67.1 %

Procedure:
4.5 g of phenyl 1-amino-4,5,8-trichloroanthraquinone-2-carboxylate and 2 g of anhydrous potassium carbonate are introduced into 100 cc of dimethylformamide, 4 g of 4-methylthiophenol are added, and the mixture is then heated to 80° C. under a gentle stream of nitrogen and is kept at this temperature until the reaction is complete. The reaction mixture is then diluted at 40° C. with 40 cc of water, is allowed to cool completely and is filtered with suction, and the product is washed with a mixture of dimethylformamide and water and then with water. After drying at 60° C., 4.8 g of phenyl 1-amino-4,5,8-tri-(4-methylphenylmercapto)-anthraquinone-2-carboxylate are obtained, corresponding to a yield of 67% of theory.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=1>[Ni].C1COCC1>[NH2:16][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cc(F)ccc1N
Temperature: 50 °C
Yield: 85.2 %

Procedure:
A slurry of Raney nickel (W.R. Grace 2800, 30.6 g calc. dry weight) was added to a 2-gallon Parr stirred pressure reactor containing THF (3 L). tert-Butyl 5-fluoro-2-nitrophenylcarbamate (102 g) was added. The vessel was sealed, purged, and pressurized to about 30 psig with hydrogen. The mixture was vigorously stirred at ambient temperature (20° C.) while hydrogen was supplied on-demand at 30 psig. After stirring for 16 h, the vessel was vented and purged with nitrogen. The product mixture was filtered to remove the catalyst using THF (1 L) to rinse the reactor and catalyst cake. The solvent was removed under vacuum. Heptane (510 mL) was added and the mixture was heated to 50° C. for 1 h, then cooled slowly to 0° C. The solids were filtered and washed with cold heptanes (100 mL) and dried under vacuum at 50° C. (76.7 g of product isolated, 87% pure, 73% yield).
Reaction SMILES: [OH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([O:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)c1cc(O)n(C)n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)n(C)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of methyl 5-hydroxy-1-methyl-1H-pyrazole-3-carboxylate (10.0 g, 64.0 mmol), benzyl bromide (12.0 g, 70 mmol) and potassium carbonate (13.8 g, 100 mmol) in N,N-dimethylformamide (150 mL) was stirred at 50° C. for 16 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to purify the residue by NH-silica gel column chromatography (hexane/ethyl acetate 90:10 to 50:50). Solvent was removed to obtain a solid (15.8 g, quant.).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:34])[CH:17]([NH:21][CH:22]2[CH2:31][CH2:30][C:29]3[C:24](=[C:25]([F:33])[CH:26]=[C:27]([F:32])[CH:28]=3)[CH2:23]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.C=O.[C:37]([BH3-])#N.[Na+]>CO>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:34])[CH:17]([N:21]([CH:22]2[CH2:31][CH2:30][C:29]3[C:24](=[C:25]([F:33])[CH:26]=[C:27]([F:32])[CH:28]=3)[CH2:23]2)[CH3:37])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: [BH3-]C#N
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CCCC(C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1)N(C)C1CCc2cc(F)cc(F)c2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide (1 equiv) is dissolved in methanol and to the reaction is added formalin (4 equiv) and sodium cyanoborohydride (2.0 equiv). The reaction is stirred at rt for 3 h, quenched with water, and extracted with methylene chloride. The solvent is dried, concentrated and the residue purified by silica gel chromatography to provide the title compound: Diagnostic C13 NMR (100 MHz, CDCl3) 55.9, 57.0, 57.1, 56.0, 65.1, 67.2, 101.0, 104.5, 110.5, 110.7, 131.1; MS m/z 488.4 (M+1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:23][C:22]3[C:17](=[CH:18][C:19]([F:24])=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:25])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(OCC)C>C(O)C.[Pd]>[F:24][C:19]1[CH:18]=[C:17]2[C:22]([CH2:23][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[C:15](=[O:25])[NH:16]2)=[CH:21][CH:20]=1
Reactant: O=C1Nc2cc(F)ccc2CN1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CCOCC
Product: O=C1Nc2cc(F)ccc2CN1C1CCNCC1
Reaction time: 96 h
Yield: 86.8 %

Procedure:
3-(1-Benzylpiperidin-4-yl)-7-fluoro-3,4-dihydroquinazolin-2(1H)-one (1.32 g, 3.89 mmol) was dissolved in ethanol (100 mL) at room temperature. To this was added palladium (10% on charcoal, 130 mg). The resulting mixture was stirred under a hydrogen balloon for 4 d. The reaction was filtered through a pad of celite, eluting with ethanol (50 mL), and concentrated in vacuo to afford a yellow residue. Upon addition of diethyl ether (20 mL), a solid precipitated from solution. Trituration and filtration with diethyl ether (2×5 mL) gave the title compound as a yellow solid (0.842 g, 87% yield). 1H-NMR (CD3OD, 400 MHz) δ 6.94-6.88 (m, 2H), 6.78 (dd, J=6.2, 4.0, 1H), 4.42 (s, 2H), 4.41-4.35 (m, 1H), 3.53-3.47 (m, 2H), 3.21-3.13 (m, 2H), 2.25-2.14 (m, 2H), 1.98-1.92 (m, 2H). Mass spec.: 250.10 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]2[N:7]=[C:8]([N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]2=[N:4][N:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[N:15]1([C:8]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=3[C:5]3=[N:4][N:3]=[C:2]([NH:1][C:28](=[O:31])[CH2:29][CH3:30])[N:6]3[N:7]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Nc1nnc2c3c(c(N4CCCCC4)nn12)CCCC3
Reactant: CCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)Nc1nnc2c3c(c(N4CCCCC4)nn12)CCCC3

Procedure:
An 8.17 gm (0.030 mole) quantity of the compound of Example 9 was added to 3.54 gm (0.035 mole) of triethylamine, 300 mg of 4-dimethylaminopyridine, 3.24 gm (0.035 mole) of propionyl chloride and 50 ml of methylene chloride. This mixture was refluxed for 61/2 hours. The solvent was evaporated. The residue was patitioned between CH2Cl2 and water. The organic layer was washed with water, dried, and evaporated, resulting in a gummy residue. This residue was triturated with ether and hexane, producing a white solid. The solid was filtered and washed with ethane, then treated with benzene and hexane producing crystalline N-(7,8,9,10-tetrahydro-6-(1-piperidinyl)-1,2,4-triazolo [3,4-a]phthalazin-3yl)propanamide; mp 173-174° C. (benzene-hexane).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:15]=2)[C:10]([OH:12])=O)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O.[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][NH2:53])=[CH:48][CH:47]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl.CCOC(C)=O>[F:45][C:46]1[CH:51]=[CH:50][C:49]([CH2:52][NH:53][C:10]([C:9]2[CH:13]=[C:14]([CH:15]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=3)[CH:8]=2)[C:16]([O:18][CH3:19])=[O:17])=[O:12])=[CH:48][CH:47]=1
Reactant: COC(=O)c1cc(Oc2ccc(F)cc2)cc(C(=O)O)c1
Reactant: NCc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Oc2ccc(F)cc2)cc(C(=O)NCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To a solution of 3-(4-fluorophenoxy)-5-(methoxycarbonyl)benzoic acid (2.2 g, 7.58 mmol) in DMF/CH2Cl2 at rt was added EDCI.HCl (1.889 g, 9.85 mmol) followed by HOBt.H2O (1.024 g, 7.58 mmol) with stirring. After one minute (4-fluorophenyl)methanamine (0.949 g, 7.58 mmol) was added to the mixture and it was stirred at rt for 4 h. EtOAc and aq NaHCO3 were added to the mixture. The EtOAc layer was separated, washed with water, dried over MgSO4 and concentrated in vacuo to obtain a crude product (2.7 g, 6.79 mmol, 90% yield) as a light yellow solid. The crude product was used in the next step without further purification. MS (ESI): (M+H)+=382.21.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[CH3:19][C:20]1[CH:21]=[N:22][C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=2[CH:29]=1.C[Si]([N:34]=[C:35]=[S:36])(C)C>C1C=CC=CC=1.O>[CH3:19][C:20]1[CH:21]=[N:22][C:23]2[CH:24]([C:35](=[S:36])[NH2:34])[CH2:25][CH2:26][CH2:27][C:28]=2[CH:29]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: C[Si](C)(C)N=C=S
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CC(C)NC(C)C
Product: Cc1cnc2c(c1)CCCC2C(N)=S

Procedure:
A solution of di-isopropylamine [11.11 g., 0.11 mol.) in benzene (50 ml.) was cooled to 0° C and treated portionwise with a 9% w/v solution of butyl lithium in hexane (79 ml., 0.11 mol.). After 45 minutes at 0° C the solution was treated dropwise with 3-methyl-5,6,7,8-tetrahydroquinoline (14.7 g., 0.10 mol.) with rapid stirring and under an atmosphere of nitrogen. After 11/2 hours at 0° C the red suspension was treated portionwise over 2 minutes with trimethylsilylisothiocyanate (14.7 ml., 0.11 mol.) and the reaction mixture stirred at 0° C for 1/2 hour and at room temperature for 1 hour. The solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-lithio-N-trimethylsilyl)thiocarboxamide was diluted with water (25 ml.), causing hydrolysis to 3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-trimethylsilyl)thiocarboxamide and subsequent hydrolysis to the title compound and the pH adjusted to 2.0 with 2N HCl. The mixture was extracted with ethylacetate (3 × 25 ml.) and the combined extracts discarded. The aqueous solution was adjusted to pH 10.0 with sodium carbonate and extracted with chloroform (3 × 50 ml.). The combined extracts were washed with saturated brine (1 × 50 ml.), dried (MgSO4) and the solvent removed in vacuo. The residual oily solid was triturated with n-hexane (100 ml.) and the solid filtered and recrystallised from isopropanol to give the title compound as pale yellow needles (8.9 g., 43%) m.p. 153° C identical in all respects to authentic material. The filtrate was analysed by g.l.c. (10% SE30, T=160° C and identified as a mixture of 8-cyano-3-methyl-5,6,7,8-tetrahydroquinoline (1 g., 6% yield based on starting material) and recovered 3-methyl-5,6,7,8-tetrahydroquinoline (7.17 g., 48% yield based on starting material)
Reaction SMILES: Br[C:2]1[C:3]([O:32][CH3:33])=[CH:4][C:5]2[CH2:6][CH2:7][N:8]3[C:14]4[C:15](=[O:26])[N:16]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:13]=4[C:12]([C:27]4[S:31][CH:30]=[N:29][CH:28]=4)=[C:9]3[C:10]=2[CH:11]=1.[N:34]1[CH:39]=[CH:38][CH:37]=[C:36](B(O)O)[CH:35]=1.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+].Cl>C(Cl)Cl.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(COC)OC>[N:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:2]2[C:3]([O:32][CH3:33])=[CH:4][C:5]3[CH2:6][CH2:7][N:8]4[C:14]5[C:15](=[O:26])[N:16]([C:22]([CH3:24])([CH3:23])[CH3:25])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:13]=5[C:12]([C:27]5[S:31][CH:30]=[N:29][CH:28]=5)=[C:9]4[C:10]=3[CH:11]=2)[CH:35]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1cc2c(cc1Br)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCCC3
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCOCC
Product: COc1cc2c(cc1-c1cccnc1)-c1c(-c3cncs3)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCCC3
Yield: 100.3 %

Procedure:
A solution of 12 mg of 16m, 6 mg of pyridine-3-boronic acid, 10 mg of K2CO3, 1.5 ml of degassed dimethoxyethane, 100 μl of water and 5 mg of Pd(PPh3)4 was heated at 90° C. for 4 hr under a N2 atmosphere. The mixture was cooled and poured into 10 ml of 2N NaOH and extracted with ethyl acetate. The extract was washed once with water, dried and chromatographed using a gradient of heptane/acetone as eluent. The material thus isolated was taken up in 200 μl of CH2Cl2 and treated with 0.2N HCl in diethyl ether, to pH slight acidic, to provide 12 mg of 16n as a yellowish HCl salt, MS-ESI:
Reaction SMILES: B(F)(F)F.CCOCC.C(O[CH:13](OCC)[CH2:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)C>C(Cl)Cl>[CH3:23][O:22][C:18]1[CH:19]=[CH:20][C:21]2[CH:13]=[CH:14][S:15][C:16]=2[CH:17]=1
Reactant: CCOC(CSc1cccc(OC)c1)OCC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc2ccsc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.3 %

Procedure:
To a solution of boron trifluoride etherate (14.45 mL, 115 mmol) in 2000 mL of methylene chloride stirring in a cold water bath 20° C. was added dropwise 1-(2,2-Diethoxy-ethylsulfanyl)-3-methoxy-benzene (28.2 gm, 110 mmol) dissolved in 500 mL of methylene chloride. The addition was complete in 3 hrs. and then the reaction was warmed to room temperature for a further 1.5 hrs. The reaction mixture was then quenched with saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer was back extracted several times with methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was chromatographed on silica gel (using a gravity column) using hexanes as the eluant to yield 10.9 gm of the title compound.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]([CH2:15][CH:16]1[CH2:18][O:17]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7].S(=O)(=O)(O)[OH:20].[Cl-].[Na+]>O1CCCC1>[OH:17][CH2:18][C@H:16]1[O:20][C@@H:2]([CH2:3][OH:1])[CH2:4][N:5]([S:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:7])=[O:8])[CH2:15]1
Reactant: O=S(=O)(c1ccccc1)N(CC1CO1)CC1CO1
Reactant: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1C[C@@H](CO)O[C@@H](CO)C1
Reaction time: 72 h
Yield: 25 %

Procedure:
Tetrahydrofuran (60 mL) was added to chirally-enriched N,N-bis(2-oxiranylmethyl)benzenesulfonamide (from step (i) above; 14.8 g, 55 mmol), followed by dilute sulfuric acid (15 mL of 1 M), and the mixture stirred for 3 days. Solid sodium chloride (11 g) was added and the mixture stirred for 1 hour. The organic phase was separated and concentrated under reduced pressure to give crude product (22.4 g). The material was purified by column chromatography over silica, eluting with dichloromethane:ethanol (19:1), to give the title compound (4 g, 25%) and an impure fraction that was a 2:1 mixture of cis- and trans-isomers (8 g, 75%).
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH2:11][CH2:12][S:13][C:14]([F:17])([F:16])[F:15])(=[O:9])=[O:8])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[C:1]1([CH3:18])[CH:2]=[CH:3][C:4]([S:7]([O:10][CH2:11][CH2:12][S:13]([C:14]([F:16])([F:17])[F:15])=[O:27])(=[O:8])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OCCSC(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCS(=O)C(F)(F)F)cc1
Reaction time: 12 h
Yield: 100 %

Procedure:
To 600 mg (2.0 mmol) of trifluoromethylthioethyl p-toluenesulfonate in 10 mL of dichloromethane at 20 to 25° C. was added 493 mg (2.2 mmol of peracid) of 77% m-chloroperbenzoic acid. After stirring for about 12 hours, the mixture was washed with aqueous sodium sulfite, aqueous sodium bicarbonate, and the organic layer was dried using phase separating paper. Removal of solvent by rotoevaporation gave 630 mg (2.0 mmol, 100% yield) of trifluoromethylsulfinylethyl p-toluenesulfonate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=2)[C:12]#[N:13])=[CH:4][CH:3]=1.[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>CS(C)=O>[CH3:17][N:18]1[CH2:24][CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:9][C:10](=[O:16])[C:11](=[CH:14][CH:15]=3)[C:12]#[N:13])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1
Reactant: N#Cc1ccc(-c2ccc(F)cc2)[nH]c1=O
Reactant: CN1CCCNCC1
Solvent: CS(C)=O
Product: CN1CCCN(c2ccc(-c3ccc(C#N)c(=O)[nH]3)cc2)CC1

Procedure:
From 12.9 g. of 6-(p-fluorophenyl)-1,2-dihydro-2-oxonicotinonitrile and 13.8 g. of N-methylhomopiperazine in 180 ml. of dimethyl sulfoxide, there is obtained 6-[p-(hexahydro-4-methyl-1H-1,4-diazepin-1-yl)phenyl]-1,2-dihydro-2-oxonicotinonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]2[C:3]=1[C:4](=O)[C:5](=[O:13])[NH:6]2.[C:15]1([CH3:26])[CH:20]=[CH:19][C:18]([S:21]([NH:24][NH2:25])(=[O:23])=[O:22])=[CH:17][CH:16]=1>CO>[C:15]1([CH3:26])[CH:16]=[CH:17][C:18]([S:21]([NH:24][N:25]=[C:4]2[C:3]3[C:7](=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:2]=3[Cl:1])[NH:6][C:5]2=[O:13])(=[O:22])=[O:23])=[CH:19][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: COc1ccc(Cl)c2c1NC(=O)C2=O
Solvent: CO
Product: COc1ccc(Cl)c2c1NC(=O)C2=NNS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
25.0 g (0.118 mole) of 4-chloro-7-methoxyisatin is taken up in 500 ml CH3OH at 60° and treated portionwise with 23.8 g of 97% p-toluenesulfonylhydrazine (≅ 23.1 g or 1.05 equivalents). The mixture is kept at ~60° for 15 minutes and then stirred at room temperature for 20 hours.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[S:7][CH:8]=1.[O:17]1[CH2:21][CH2:20][CH2:19][C@@H:18]1[C:22]([OH:24])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[C:12]([O:11][C:10](=[O:16])[NH:9][C:6]1[S:7][CH:8]=[C:4]([CH2:3][N:2]([CH3:1])[C:22]([C@H:18]2[CH2:19][CH2:20][CH2:21][O:17]2)=[O:24])[N:5]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CNCc1csc(NC(=O)OC(C)(C)C)n1
Reactant: O=C(O)[C@H]1CCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CN(Cc1csc(NC(=O)OC(C)(C)C)n1)C(=O)[C@H]1CCCO1

Procedure:
tert-Butyl 4-((methylamino)methyl)thiazol-2-ylcarbamate (Intermediate 17) was coupled with (R)-2-tetrahydrofuroic acid using TBTU (Method 2) to afford (4-{[methyl-((R)-tetrahydro-furan-2-carbonyl)-amino]-methyl}-thiazol-2-yl)-carbamic acid tert-butyl ester.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[CH:7]=[C:8]([C:14]#[N:15])[C:9]([C:12]#[N:13])=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.Br[CH:17]([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>>[CH:1]1([CH2:4][N:5]([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[C:8]([C:14]#[N:15])[CH:7]=2)[C@H:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH3:25])[CH2:2][CH2:3]1
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(NCC2CC2)cc1C#N
Product: C[C@@H](C(=O)OC(C)(C)C)N(CC1CC1)c1ccc(C#N)c(C#N)c1

Procedure:
Synthesized in a manner similar to example 1B using 4-[(cyclopropylmethyl)amino]-1,2-benzenedicarbonitrile and 1,1-dimethylethyl 2-bromopropanoate: MS (ES) m/z 326 (M+1).