Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([OH:16])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[CH3:23][C:24]1([CH2:28]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:27][O:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[F:22])[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:17][CH3:18])=[C:13]([O:16][CH2:23][C:24]3([CH3:28])[CH2:27][O:26][CH2:25]3)[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1O
Reactant: Cc1ccc(S(=O)(=O)OCC2(C)COC2)cc1
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCC1(C)COC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 24 %

Procedure:
Using an analogous procedure to that described in Example 5 except that the reaction mixture was stirred at ambient temperature for 72 hours, 4-(3'-chloro-4'-fluoroanilino)-6-hydroxy-7-methoxyquinazoline was reacted with 3-methyl-3-(4-toluenesulphonyloxymethyl)-oxetane (Chem. Pharm. Bull., 1985, 33, 1707) to give 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-methyloxetan-3-ylmethoxy)quinazoline in 24% yield, m.p. 226°-227° C. (recrystallised from ethanol); NMR Spectrum: 1.43 (s, 3H), 3.93 (s, 3H), 4.23 (s, 2H), 4.37 (d, 2H), 4.53 (d, 2H), 7.2 (s, 1H), 7.43 (t, 1H), 7.78 (m, 1H), 7.88 (s, 1H), 8.11 (m, 1H), 8.49 (s, 1H), 9.49 (s, 1H); Elemental Analysis: Found C, 59.5; H, 4.7; N, 10.2; C20H19ClFN3O3 requires C, 59.5; H, 4.7; N, 10.4%.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Li+].[Si:11]([O:28][CH2:29][CH2:30][N:31]([CH3:62])[C:32]([C:34]1[CH:35]=[C:36]2[C:41](=[C:42]([CH:44]([NH:46][C:47]3[CH:52]=[C:51]([F:53])[CH:50]=[C:49]([F:54])[CH:48]=3)[CH3:45])[CH:43]=1)[O:40][C:39]([N:55]1[CH2:60][CH2:59][O:58][CH2:57][CH2:56]1)=[CH:38][C:37]2=[O:61])=[O:33])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.S([O:68][CH3:69])(OC)(=O)=O.[NH4+].[Cl-]>C1COCC1>[Si:11]([O:28][CH2:29][CH2:30][N:31]([CH3:62])[C:32]([C:34]1[CH:35]=[C:36]2[C:41](=[C:42]([CH:44]([N:46]([C:47]3[CH:48]=[C:49]([F:54])[CH:50]=[C:51]([F:53])[CH:52]=3)[CH3:1])[CH3:45])[CH:43]=1)[O:40][C:39]([N:55]1[CH2:56][CH2:57][O:58][CH2:59][CH2:60]1)=[CH:38][C:37]2=[O:61])=[O:33])([C:24]([CH3:25])([CH3:27])[CH3:26])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1.[F:53][C:51]1[CH:52]=[C:47]([N:46]([CH3:1])[CH:44]([C:42]2[CH:43]=[C:34]([C:32]([N:31]([CH2:62][CH2:69][OH:68])[CH3:30])=[O:33])[CH:35]=[C:36]3[C:41]=2[O:40][C:39]([N:55]2[CH2:60][CH2:59][O:58][CH2:57][CH2:56]2)=[CH:38][C:37]3=[O:61])[CH3:45])[CH:48]=[C:49]([F:54])[CH:50]=1
Reactant: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)N(C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Reactant: COS(=O)(=O)OC
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(c1cc(C(=O)N(C)CCO)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Product: CC(c1cc(C(=O)N(C)CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc2c(=O)cc(N3CCOCC3)oc12)N(C)c1cc(F)cc(F)c1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 261.7 %

Procedure:
Lithium bis(trimethylsilyl)amide (0.539 mL, 0.54 mmol) was added to a stirred solution of N-(2-(tert-butyldiphenylsilyloxy)ethyl)-8-(1-(3,5-difluorophenylamino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (230 mg, 0.32 mmol) dissolved in dry THF (3 mL). The solution was stirred over a period of 10 minutes at −20° C. under nitrogen. Dimethyl sulfate (0.051 mL, 0.54 mmol) was added to the mixture and the resulting suspension was left to rise to RT for 1 h30 under nitrogen. A sat. aq. sol. of NH4Cl was added and the reaction mixture was extracted with DCM. The combined organic phases were washed with brine, dried over magnesium sulfate and concentrated. The crude product was diluted with DCM and purified by flash chromatography on silica gel eluting with 4% ethyl alcohol in DCM. The solvent was evaporated to dryness to afford N-(2-(tert-butyldiphenylsilyloxy)ethyl)-8-(1-((3,5-difluorophenyl)(methyl)amino)ethyl)-N-methyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide enantiomer 1 (210 mg, 90%) as a white solid. Mass Spectrum: M+H+ 740.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Cl-].[Ca+2]>CCO.O.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccc(OCc2ccccc2)cc1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1cccnc1Nc1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 73.5 %

Procedure:
A mixture of N-[4-(benzyloxy)phenyl]-3-nitropyridin-2-amine (1.5 g), Fe (2.6 g), and CaCl2 (260 mg) in EtOH (30 mL) and H2O (6.0 mL) was heated at 100° C. for 6 h. After cooling to rt, the precipitate was removed by Celite, and the filtrate was concentrated. The residue was partitioned between AcOEt and sat.NaHCO3aq. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by column chromatography (SiO2, hexane/AcOEt=3/2 to 1/1). The obtained solid was rinsed with iPr2O-hexane to give N2-[4-(benzyloxy)phenyl]pyridine-2,3-diamine (1.0 g) as a pale pink solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:9]=2)[CH:5]=[C:4]([Cl:26])[N:3]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][NH2:36])=[CH:31][CH:30]=1>C(#N)C>[Cl:26][C:4]1[N:3]=[C:2]([NH:36][CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([S:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:18])[CH:9]=2)[CH:5]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(Cl)c2)c2cccnc21
Solvent: CC#N
Product: COc1ccc(CNc2cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)cc(Cl)n2)cc1
Yield: 39.9 %

Procedure:
A mixture of Example 7a (0.500 g, 1.24 mmol) and (4-methoxyphenyl)methanamine (1.018 g, 7.42 mmol) in acetonitrile (7 mL) was heated at 180° C. for 110 minutes The solvent was evaporated. The residue was treated with EtOAc and washed with 20% brine and 5% citric acid. The organic layer was concentrated and purified on a 100 g column using the ISCO Companion flash system eluting with CH2Cl2/EtOAc (98:2 to 95:5) to give 0.250 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][CH2:12][C:13]([OH:15])=[O:14]>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:5]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NCC(=O)O
Product: O=C(O)CNC(=O)c1ccccc1Cl

Procedure:
Commercially available 2-chlorobenzoyl chloride was treated with glycine to give 2-(2-chlorobenzamido)acetic acid 21 in good yield. Then, 21 was reacted with acetic anhydride and benzaldehyde, in the presence of sodium acetate, to lead to the corresponding oxazolone in excellent yield. The resulting (4Z)-4-benzylidene-2-(2-chlorophenyl)oxazol-5(4H)-one 22 was converted via a Friedel-Crafts reaction to 1-(2-chlorophenyl)isoquinoline-3-carboxylic acid 23 in moderate yield2. Finally, the dimeric compounds 24 were easily obtained in good yields by transformation of the acid into acylchloride and further reactions with diamines.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:20]([O:24][C:25](=[O:35])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=1)([CH3:23])([CH3:22])[CH3:21]>C(O)(=O)C.ClCCl>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:33][C:30]4[CH:29]=[CH:28][C:27]([NH:26][C:25](=[O:35])[O:24][C:20]([CH3:22])([CH3:21])[CH3:23])=[CH:32][CH:31]=4)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reaction time: 96 h
Yield: 52.1 %

Procedure:
A solution of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (0.079 g, 0.29 mmol) in a mixture of acetic acid and dichloromethane (1:9; 3 mL) was added to a mixture of (polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 0.097 g, 0.4 mmol) and N-(4-formylphenyl)carbamic acid tert-butyl ester (0.088.4 g, 0.4 mmol). The reaction mixture was shaken for 4 days and then filtered. The filtrate was evaporated and the and the involatile residue was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 21 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give tert-butyl 4-((4-(3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperazin-1-yl)methyl)phenylcarbamate (0.0722 g, 52%) as a white solid, which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[CH:7][CH:6]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1B(O)O.[F-].[Cs+]>C(COC)OC>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:22]2[CH:21]=[CH:20][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: COC(=O)Cc1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 65.9 %

Procedure:
Tetrakis triphenyphosphine palladium (65 mg, 7.4 mol %) was added to a dimethoxy ethane (5.4 mL) solution of (4-Trifluoromethanesulfonyloxy-phenyl)-acetic acid methyl ester (447 mg, 1.5 mmol), 2-naphthaleneboronic acid (286 mg, 1.67 mmol) and cesium fluoride (505 mg, 3.33 mmol). The reaction was flushed with nitrogen and heated in an oil bath to 100° C. while stirring for 3 hours. The reaction was then diluted with ethyl acetate and extracted with water, 1M sodium hydroxide, water and brine. The organic portion was dried over magnesium sulfate and concentrated in vacuo. The resulting residue was chromatographed on a Biotage Flash 40S column eluting with 5% ethyl acetate in hexanes to give the title compound as a clear oil (273 mg, 66%). 1H NMR (400 MHz, CDCl3) δ8.01-7.38 (m, 11H), 3.72 (s, 3H), 3.69 (2H)
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH:11]([O:12][CH3:13])[CH2:10][C:9]2[C:8](=[NH:14])[NH:7][C:6](=N)[C:5]=2[CH2:4]1.Cl.[C:17]1([CH2:23][CH2:24][CH2:25][NH:26][C:27]2[S:28][CH2:29][C:30](=[NH:32])[N:31]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N=C1C2CCCCC=2C(=N)N1.Cl.N=C1NC(=N)CS1>>[NH:14]=[C:8]1[C:9]2[CH2:10][CH:11]([O:12][CH3:13])[CH:3]([O:2][CH3:1])[CH2:4][C:5]=2[C:6](=[C:29]2[S:28][C:27]([NH:26][CH2:25][CH2:24][CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:31][C:30]2=[NH:32])[NH:7]1
Reactant: N=C1CSC(NCCCc2ccccc2)=N1
Reactant: COC1CC2=C(CC1OC)C(=N)NC2=N
Agent: Cl
Agent: N=C1CSC(=N)N1
Agent: N=C1NC(=N)C2=C1CCCC2
Product: COC1CC2=C(CC1OC)C(=C1SC(NCCCc3ccccc3)=NC1=N)NC2=N

Procedure:
When equivalent amounts of 5,6-dimethoxy-4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2-(3-phenylpropylamino)-4-imino-2-thiazoline hydrochloride are substituted for the 4,5,6,7-tetrahydro-1,3-diiminoisoindoline and 2,4-diiminothiazolidine hydrochloride respectively, in the procedure described in Example 10, part A above, there is obtained as the product 1-imino-5,6-di-methoxy-4,5,6,7-tetrahydro-3-[2-(3-phenylpropylamino)-4-imino-2-thiazolin-5-ylidene]isoindoline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:48])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:36]([C:38]2[S:42][C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[C:39]=2[Cl:47])=[O:37])[CH2:16][C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([C:30](=[O:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CCO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:48])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:36]([C:38]2[S:42][C:41]3[CH:43]=[CH:44][CH:45]=[CH:46][C:40]=3[C:39]=2[Cl:47])=[O:37])[CH2:16][C:17]2[CH:18]=[C:19]([C:24]3[CH:25]=[CH:26][C:27]([CH:30]([OH:35])[C:31]([F:33])([F:32])[F:34])=[CH:28][CH:29]=3)[CH:20]=[CH:21][C:22]=2[F:23])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)C1CCC(N(Cc2cc(-c3ccc(C(=O)C(F)(F)F)cc3)ccc2F)C(=O)c2sc3ccccc3c2Cl)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CN(C(=O)OC(C)(C)C)C1CCC(N(Cc2cc(-c3ccc(C(O)C(F)(F)F)cc3)ccc2F)C(=O)c2sc3ccccc3c2Cl)CC1
Temperature: 25 °C

Procedure:
Trifluoroacetophenone (265) (90 mg, 0.13 mmol) was dissolved in EtOH (0.9 mL) with a little DCM. Sodium borohydride (8 mg, 0.21 mmol) was added portionwise and the reaction stirred at RT until complete. H2O (5 mL) was added and the product extracted with EtOAc (2×5 mL). Drying (MgSO4), filtration, reduction in vacuo and chromatography with EtOAc/heptanes gave the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].Cl.[NH2:8][C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[N:11]([OH:26])[C:10]1=[O:27]>N1C=CC=CC=1>[NH2:8][C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[N:11]([O:26][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[C:10]1=[O:27]
Reactant: CN(C)C(=O)Cl
Reactant: N[C@H]1Cc2cc(Oc3ccccc3)ccc2N(O)C1=O
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)ON1C(=O)[C@@H](N)Cc2cc(Oc3ccccc3)ccc21
Temperature: 25 °C
Yield: 63.9 %

Procedure:
Dimethylcarbamyl chloride (37 μL, 0.39 mmol) was added to a solution of (3S)-3-amino-1-hydroxy-6-phenoxy-3,4-dihydroquinolin-2(1H)-one, hydrochloride salt (93, Example 71) (100 mg, 0.33 mmol) in pyridine (2 mL). The reaction mixture was maintained at RT for 1.5 h, then concentrated in vacuo; the resulting residue was diluted with EtOAc (20 mL) and water (10 mL). The separated organic phase was washed with water (10 mL), dried over Mg2SO4, filtered, and concentrated in vacuo to provide the title compound as an oil (72 mg, 65%). LCMS m/z 253.0 [(M-dimethyl carbamic acid)+1]. 1H NMR (400 MHz, CD3OD) δ 2.94-3.02 (m, 1H), 3.02 (br s, 3H), 3.08 (dd, half of ABX pattern, J=15.5, 6.4 Hz, 1H), 3.17 (br s, 3H), 3.78 (dd, J=13.3, 6.3 Hz, 1H), 6.90-7.00 (m, 5H), 7.11 (ddt, J=7.7, 7.1, 1.1 Hz, 1H), 7.32-7.37 (m, 2H).
Reaction SMILES: N[CH2:2][C:3]1([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:22])=[O:21])=[CH:18][CH:17]=1.[N:25]1C=CC=CC=1>>[ClH:22].[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:25][CH:8]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2([CH3:2])[N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)=[O:21])=[CH:18][CH:17]=1
Reactant: NCC1(N2CCCCC2)CCCCC1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: c1ccncc1
Product: CC1(N2CCCCC2)CCCCC1NC(=O)c1ccc(F)cc1
Product: Cl
Reaction time: 1 h

Procedure:
A mixture of 1-(1-aminomethylcyclohexyl) piperidine (1.5 g.), 4-fluorobenzoyl chloride (2 ml) and pyridine (10 ml) was allowed to stand at room temperature for 1 hr. The crystalline material produced was filtered (2.35 g. 86.6%) and afforded pale lemon rosettes of 1-(4-fluorobenzamido-methylcyclohexyl)piperidine, hydrochloride m.p. 243°-5° (Decomp.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][OH:27])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](Cl)=[O:42])=[CH:39][CH:38]=1.O>ClCCl>[CH3:35][O:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([O:27][CH2:26][CH2:25][N:22]2[CH2:23][CH2:24][CH:19]([NH:18][C:10]3[N:9]([CH2:8][C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[N:11]=3)[CH2:20][CH2:21]2)=[O:42])=[CH:39][CH:38]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)OCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cc1
Reaction time: 8 h
Yield: 43.5 %

Procedure:
To a stirred mixture of 4.5 parts of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidineethanol, 2 parts of N,N-diethylethanamine and 195 parts of dichloromethane is added dropwise a solution of 1.7 parts of 4-methoxybenzoyl chloride in dichloromethane. Upon completion, stirring is continued overnight at room temperature. Water is added and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (98:2 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is converted into the hydrochloride salt in 2-propanone. The salt is filtered off and dried, yielding 2.5 parts (43.5%) of [2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl] 4-methoxybenzoate; dihydrochloride. hemihydrate; mp. 189.2° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[C:7]([C:10]([OH:12])=[O:11])=[CH:8][CH2:9][CH:3]1[CH2:4][CH2:5]2.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:20]CN(CC)CC>C(Cl)(Cl)Cl>[CH3:20][O:11][C:10]([C@@H:7]1[C@H:8]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][C@H:3]2[N:2]([CH3:1])[C@@H:6]1[CH2:5][CH2:4]2)=[O:12]
Reactant: CCN(CC)CC
Reactant: Sc1ccccc1
Reactant: CN1C2CC=C(C(=O)O)C1CC2
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1[C@H]2CC[C@@H](C[C@H]1Sc1ccccc1)N2C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A nitrogen purged 0° C. solution of methylester of anhydroecgonine (2.008 g, 11.08 mmol) and thiophenol (2.9 mL, 3.05 g, 27.7 mmol) in chloroform (100 mL) was treated with Et3N (0.55 mL) and stirred at room temperature for 24 h. The mixture was then concentrated on a rotary evaporator, diluted with Et2O (50 mL) and washed twice with 0.1N NaOH (3×20 mL). The organic layer was dried (Na2SO4), decanted and concentrated on a rotary evaporator. The residue was purified by flash chromatography (20% Et3N/Et2O) to afford 3α(phenylthio)tropane-2a-carboxylic acid methyl ester as a very pale yellow oil (319 mg, 10%) contaminated with the starting material (5% of 319 mg).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].Br[C:7]1[S:8][C:9]([C:13]2[C:14]([CH3:28])=[N:15][N:16]3[C:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:20][C:19]([CH3:27])=[N:18][C:17]=23)=[C:10]([Br:12])[N:11]=1.ICCCC.[Cl-].N>C1COCC1>[Br:12][C:10]1[N:11]=[C:7]([CH2:1][CH2:2][CH2:3][CH3:4])[S:8][C:9]=1[C:13]1[C:14]([CH3:28])=[N:15][N:16]2[C:21]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:20][C:19]([CH3:27])=[N:18][C:17]=12
Reactant: [Li]CCCC
Reactant: CCC(CC)c1cc(C)nc2c(-c3sc(Br)nc3Br)c(C)nn12
Agent: N
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCCCI
Product: CCCCc1nc(Br)c(-c2c(C)nn3c(C(CC)CC)cc(C)nc23)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.8 %

Procedure:
Under a nitrogen atmosphere, add n-butyl lithium (2.5 M in hexane, 0.2 mL, 0.5 mmol) to a solution of 3-(2,4-dibromo-thiazol-5-yl)-7-(1-ethyl-propyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (230 mg, 0.5 mmol) in THF (3 mL) at −78° C. After 30 min, add 1-iodobutane (138 mg, 0.75 mmol) and continue stirring for 1 hour. Warm up to room temperature and stir for one hour. Quench the reaction by adding saturated ammonia chloride solution and extract with ethyl acetate. Dry the organic portion over sodium sulfate, filter, and concentrate to a residue. Purify the crude material by flash chromatography, eluting with hexanes/ethyl acetate (10/1.5) to give the title compound as orange foam (78 mg). ES/MS m/z (81Br) 437.4 (M+1)+.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[C:20]([Br:28])=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10]1)=O)(C)(C)C.BrC1C2C(S([Cl:43])(=O)=O)=CC=CC=2C=NC=1.C(OC(NC1CCCNC1)=O)(C)(C)C>>[NH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([C:18]2[C:19]3[C:20]([Br:28])=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:10]1.[ClH:43]
Reactant: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Reactant: CC(C)(C)OC(=O)NC1CCCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: CC(C)(C)OC(=O)NC1CCCNC1
Product: Cl
Product: NC1CCCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1

Procedure:
(R/S)-3-(tert-Butoxycarbonylamino)-1-(4-bromo-5-isoquinolinesulfonyl)piperidine (Intermediate 2) can be prepared from 4-bromo-5-isoquinolinesulfonyl chloride and 3-(tert-butoxycarbonylamino)piperidine (AstaTech) according to the method described in Example 1-1, Step A, and then used in the method of Example 1-1, Step B in a similar manner to obtain the title compound as hydrochloride.
Reaction SMILES: N1C=CC=C(C[NH:8][CH2:9][CH2:10][NH2:11])C=1.[N+:12]([CH:15]=[C:16](SC)SC)([O-:14])=[O:13]>C1C=CC=CC=1>[N+:12]([CH:15]=[C:16]1[NH:11][CH2:10][CH2:9][NH:8]1)([O-:14])=[O:13]
Reactant: NCCNCc1cccnc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: c1ccccc1
Product: O=[N+]([O-])C=C1NCCN1
Temperature: 25 °C
Yield: 131.8 %

Procedure:
A mixture of N-(3-pyridylmethyl)ethylenediamine (15.1 g), 1-nitro-2,2-bis(methylthio)ethylene (18.2 g) and benzene (150 ml) was refluxed for 4 hours with stirring. The qenerated gas was collected by an alkali trap. The reaction mixture was cooled to room temperature, and filtered to collect crystals. Recrystallization from methanol gave 1-(3-pyridylmethyl)-2-(nitromethylene imidazolidine (17 g) of the following formula as pale yellow crystals. mp. 169°-171° C. ##STR15##
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].[S:11](Cl)([Cl:14])(=[O:13])=[O:12]>C(#N)C>[CH3:2][O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][S:11]([Cl:14])(=[O:13])=[O:12]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=S(=O)(Cl)Cl
Agent: Cl
Solvent: CC#N
Product: COC(=O)[C@@H](NS(=O)(=O)Cl)C(C)C

Procedure:
A suspension of 15.3 g (90 mmol) of L-valine methyl ester hydrochloride in 45 ml of acetonitrile was treated with 22 ml (270 mmol) of sulfuryl chloride and heated at reflux for 16 h. The resulting light yellow solution was allowed to cool and concentrated in vacuo to a viscous oil. The oil was treated two times with acetonitrile followed each time by concentration in vacuo. The crude desired product was thus obtained as a viscous oil.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[C:21](=[O:28])[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1>C1(C)C(C)=CC=CC=1>[Cl:27][C:24]1[CH:23]=[CH:22][C:21](=[O:28])[C:20]([NH:19][C:15]([C:3]2[N:4]([CH3:14])[S:5](=[O:12])(=[O:13])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:2]=2[OH:1])=[O:17])=[CH:26][CH:25]=1
Reactant: Nc1ccc(Cl)ccc1=O
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2ccc(Cl)ccc2=O)=C(O)c2ccccc2S1(=O)=O
Temperature: 25 °C
Yield: 40.7 %

Procedure:
A mixture of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (1.5 g) and 2-amino-5-chloro-2,4,6-cycloheptatrien-1-one (0.87 g) in xylene (37 ml) was refluxed for 24 hours. The reaction mixture was cooled to room temperature. The crystals were collected by filtration and recrystallized from N,N-dimethylformamide to give N-(5-chloro-1-oxo-2,4,6-cycloheptatrien-2-yl)-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (0.89 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=[O:7])[CH2:3][CH:2]=1.[N+:8]([O-])([OH:10])=[O:9].S(=O)(=O)(O)O>>[OH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: O=C1C=CN=CC1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cnccc1O
Temperature: 100 °C

Procedure:
4-Hydroxy-3-nitropyridine was prepared by addition of 4-pyridone (50 g, 0.532M) to a mixture of fuming nitric acid and sulfuric acid. The resulting solution was heated for 1 hour at 100° C. The solution was cooled and poured into 500 mL of ice water and the desired product was obtained as a solid. (mp. 280° C.)