Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[S:8][CH:9]=[C:10]([Sn](C)(C)C)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]C1SC=C(Br)N=1.O>N1CCCCC1>[N:1]1([C:7]2[S:8][CH:9]=[C:10]([Br:16])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Brc1csc(Br)n1
Reactant: C[Sn](C)(C)c1csc(N2CCCCC2)n1
Solvent: C1CCNCC1
Solvent: O
Product: Brc1csc(N2CCCCC2)n1
Temperature: 50 °C
Yield: 100 %

Procedure:
Synthesis of 2-Piperidinyl-4-(trimethylstannyl)thiazole 373 as illustrated in FIG. 53. 2,4-Dibromothiazole (358; 1.0 equiv) was dissolved in piperidine (0.5 M) and the reaction was warmed to 50° C. for 8 h, upon which completion of the reaction was indicated by TLC. The mixture was poured into water and extracted with ether (2×). Drying (MgSO4) and evaporation of the solvents gave 2-piperidinyl-4-bromothiazole 372, which was isolated after flash column chromatography (silica gel, 5% EtOAc in hexanes) in 100% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[CH:8]=[O:9].[Si:18]([O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>>[Si:18]([O:25][C:26]1[CH:27]=[CH:28][C:29]([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[C:2]([Cl:1])[CH:3]=2)=[CH:30][CH:31]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(B(O)O)cc1
Reactant: O=Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(C=O)c(Cl)c2)cc1

Procedure:
The title compound was prepared by reacting trifluoro-methanesulfonic acid 3-chloro-4-formyl-phenyl ester (1.78 g, 6.18 mmol) with 4-tert-butyl-dimethylsilyoxyphenylboronic acid (2.03 g, 8.03 mmol) according to Method B to yield 0.92 g (43%) of white solid: mp 38-39° C.; 1H NMR (DMDO-d6); δ 0.23 (6H, s), 0.97 (9H, s), 6.98 (2H, d, J=8.79 Hz), 7.74 (2H, d, J=8.79 Hz), 7.81 (1H, d, J=7.81 Hz), 7.89 (1H, d, J=1.95 Hz), 7.91 (1H, d, J=7.81 Hz), 10.34 (1H, s); MS (ESI) m/z 231/233 (M−H)−(deprotected product ion).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].C([O-])=O.[NH4+]>C(O)C.O.[C].[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCCCC=Cc1ccccn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: O=C(O)CCCCCCc1ccccn1
Yield: 91.4 %

Procedure:
7-(2-Pyridyl)-6-heptenoic acid (0.97 g, 4.7 mmol) was dissolved in ethanol (15 ml), and 10% palladium-carbon (0.16 g) and a solution of ammonium formate (1.7 g, 27.0 mmol) in water (2 ml) were added thereto. The reaction mixture was refluxed for 2 hrs. Palladium-carbon was filtered off. The reaction mixture was combined with water, concentrated under reduced pressure to the half amount and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give the titled compound (0.89 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[C:21]1([C:27]2[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:27]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:28]=[CH:29][C:30]([CH2:31][NH:32][C:14]([C:12]2[S:13][C:9]([S:8][C:7]3[C:6]([Cl:20])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=2)=[O:16])=[CH:33][CH:34]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Reactant: NCc1ccc(-c2ccccc2)cc1
Product: O=C(NCc1ccc(-c2ccccc2)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.28 mmol) and 4-phenyl benzylamine (55 mg, 0.32 mmol). The title compound was obtained as a yellow solid (65 mg, 45% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.41 (1H, m), 8.98 (2H, m), 8.49 (1H, s), 7.63 (4H, m), 7.46 (2H, m), 7.35 (3H, m), 7.38 (1H, m), 4.44 (2H, m). MS m/z: 514.03, 516.08 [M+H]+
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[N:10]([CH2:14][C:15](=[N:17][OH:18])[NH2:16])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[C:19]([O:23][CH2:24][CH3:25])(=O)[CH:20]=[CH2:21].CC[O-].[Na+]>C(O)C>[CH2:24]([O:23][CH2:19][CH2:20][C:21]1[O:18][N:17]=[C:15]([CH2:14][N:10]2[C:11]3[C:12](=[O:13])[N:1]([CH3:2])[C:3](=[O:4])[N:5]([CH3:6])[C:7]=3[N:8]=[CH:9]2)[N:16]=1)[CH3:25]
Reactant: Cn1c(=O)c2c(ncn2CC(N)=NO)n(C)c1=O
Reactant: C=CC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCCc1nc(Cn2cnc3c2c(=O)n(C)c(=O)n3C)no1
Reaction time: 15 h
Yield: 95 %

Procedure:
12.6 g. 2-(theophyllin-7-yl)-acetamidoxime, 10 g. of ethyl acrylate, 220 cm3 of ethanol and 3.4 g. of sodium ethylate are heated under stirring for 15 hours. 16 g. (95% yield) of raw 7-[[5-(2-ethoxy-ethyl)-1,2,4-oxadiazol-3-yl]-methyl]-theophylline are obtained. This product is heated with 20 cm3 diethylamine under stirring for 8 hours on a 110° C. oil bath. The mixture is then evaporated at reduced pressure, washed by trituration with water and salt is formed with 5.8 g. of maleic acid in hot ethanol. 16.2 g. (68% yield) of 7-[{5-(2-diethylamino-ethan-1-yl)-1,2,4-oxadiazol-3-yl}-methyl]-theophilline-maleinate are are obtained. M.p.: 125°-128° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[N+:11]([O-])([O-:13])=[O:12].[K+]>S(=O)(=O)(O)O>[N+:11]([C:8]1[CH:9]=[C:10]2[C:5]([CH2:4][CH2:3][NH:2][CH2:1]2)=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2c(c1)CNCC2
Yield: 50 %

Procedure:
This example shows how to make example compounds of the present invention. More specifically, this example demonstrates how to make four aromatic nitro isomers of 6-position nitro-1,2,3,4-tetrahydroisoquinolinylpurine ribosides NBMPR analogues (compounds 2-5). Several literature methods are employed to synthesize the required nitro-1,2,3,4-tetrahydroisoquinoline (compounds 6-9), which are subsequently reacted with the commercially available 6-chloropurine riboside (10) according to Scheme 1 to obtain the target compounds. The commercially available 5-nitroisoquinoline (11) is reduced using sodium borohydride in ethanol to afford the 5-tetrahydroisoquinoline (6) intermediate in good yield (about 90%). The 7-nitrotetrahydroisoquinoline intermediate (8) is prepared in about 50% yield by nitration of the commercially available 1,2,3,4-tetrahydroisoquinoline using KNO3 in concentrated sulfuric acid according to the method of Ajao et al. (1985) (Scheme 3). The 6- and 8-nitro-1,2,3,4-tetrahydroisoquinoline intermediates 7 and 9, are prepared following reaction Scheme 4 according to the report by Tercel et al. (1996) as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.[NH4+:17].[OH-]>O=S(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:6]([C:7]([NH2:17])=[O:8])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: [NH4+]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: COc1cc(C(N)=O)c([N+](=O)[O-])cc1OC
Temperature: 0 °C

Procedure:
A suspension of 4,5-dimethoxy-2-nitrobenzoic acid 1 (2 g; 8.8 mmol) in SOCl2 (10 mL) was stirred under reflux for 50 minutes. After cooling, the reaction mixture was poured into a mixture of concentrated NH4OH (50 mL) and ice (30 g). The precipitate were collected by filtration, washed with water, and dried to give 1.85 g crude crystals. After recrystallization from DMF, 1.76 g pure product was obtained (88.5%). 1H NMR(DMSO-d6): δ 7.60(s, 2H, —NH2), 7.57(s, 1H, 6-H), 7.12(s, 1H, 3-H), 3.90, 3.87(s, s, 6H, —OCH3); IR(Kr) υmax: 3454, 2840, 1670, 1512, 1274, 1227 cm−1; GC/MS m/z 226(M+, 10.0), 178(98.5), 163(100.0), 135(51.0).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[C:5]2[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22].C([Sn](CCCC)(CCCC)[CH:29]1[CH:34]=[CH:33][O:32][CH2:31][CH2:30]1)CCC>C1(C)C=CC=CC=1>[O:32]1[CH:31]=[CH:30][CH:29]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:5]3[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])[CH2:34][CH2:33]1
Reactant: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(Br)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)C1C=COCC1
Solvent: Cc1ccccc1
Product: CN(C)CCc1cn(C(=O)c2ccccc2)c2ccc(C3C=COCC3)cc12
Reaction time: 8 h
Yield: 17 %

Procedure:
A solution of 5-bromo-3-[2-(N,N-dimethylamino)ethyl]-1-benzoylindole (Example 5a, 180 mg 0.48 mmol), 4-tributylstannyl-3,4-dihydropyran (180 mg, 0.48 mmol) and tetrakistriphenyphosphine palladium (118 mg, 0.1 mmol) in toluene (3 mL) was stirred at 100-110° C. A second portion of catalyst was added after 1 h and heating was continued overnight. After removal of the solvent in vacuo, flash chromatography on silica gel (2-6% 2M methanolic ammonia in dichloromethane) yielded 5-(3,4-dihydropyran-4-yl)-3-[2-(N,N-dimethylamino)ethyl]-1-benzoylindole (30.5 mg, 17%).
Reaction SMILES: [C:1]1([C:7]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][NH:10][C:9](=[O:19])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29]>>[O:19]=[C:9]1[N:10]([CH:27]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])[C:28]([O:30][CH3:31])=[O:29])[N:11]=[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8]1
Reactant: O=c1cc(-c2ccccc2)c(-c2ccccc2)n[nH]1
Reactant: COC(=O)CCCCCCCBr
Product: CCCCCCC(C(=O)OC)n1nc(-c2ccccc2)c(-c2ccccc2)cc1=O

Procedure:
Reaction of 5,6-diphenyl-3(2H)-pyridazinone and methyl 8-bromooctanoate according to the procedure of Example 1 provided the title compound as an oil.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:37]=[CH:36][C:22]([C:23]([NH:25][CH2:26][C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=O)=[CH:29][CH:28]=4)=[O:24])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:38][NH:39][CH3:40].C(Cl)CCl>ClCCl>[C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([NH:25][CH2:26][C:27]4[CH:35]=[CH:34][C:30]([C:31]([N:39]([CH3:40])[CH3:38])=[O:33])=[CH:29][CH:28]=4)=[O:24])=[CH:36][CH:37]=3)(=[O:17])=[O:18])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccc(CNC(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)cc1
Reactant: CNC
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)C(=O)c1ccc(CNC(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)cc1
Yield: 15.2 %

Procedure:
Combine 4-{[4-(3-Phenyl-indole-1-sulfonyl)-benzoylamino]-methyl}-benzoic acid (0.489 mmole) with dimethylamine (0.587 mmole), and EDC (0.733 mmole) in 5 ml of dichloromethane and stir for 15 hrs. Dilute □eaction and wash with 1 N HCl. Dry organic layer over MgSO4 and concentrate. Purify the residue via column chromatography with a mixture of ethyl acetate and dichloromethane to isolate 0.040 g (15.2%) of the title compound: MSES+ 537.95; MSES− 536.08.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[OH-:16].[Na+]>C(#N)C>[NH2:12][CH2:13][C@@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Br:1])[CH:3]=1)[CH2:10][C:11]([OH:14])=[O:16]
Reactant: O=C1C[C@H](c2ccc(Cl)c(Br)c2)CN1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: NC[C@H](CC(=O)O)c1ccc(Cl)c(Br)c1
Temperature: 95 °C
Yield: 30 %

Procedure:
To (4R)-4-(3-bromo-4-chlorophenyl)pyrrolidin-2-one (0.2 g, 0.73 mmol) was added 0.2 mL acetonitrile and 1 mL 6N HCl aqueous solution. The mixture was heated overnight at 95° C. The reaction mixture was then cooled to room temperature and neutralized with a 4N NaOH aqueous solution. The mixture was purified by reversed phase LC/MS to provide (3R)-4-amino-3-(3-bromo-4-chlorophenyl)butanoic acid (43 mg, 30% yield), which was then converted to the title compound as the hydrochloride salt by lyophilization from a 1N HCl aqueous solution. 1H-NMR (400 MHz, CD3OD): δ 7.68-7.69 d, J=2.00 Hz, 1H), 7.51-7.53 (d, J=8.44 Hz, 1H), 7.30-7.33 (dd, J=8.4, 2.44 Hz, 1H), 3.32-3.40 (m, 2H), 3.15-3.21 (m, 1H), 2.77-2.83 (dd, J=16.8, 6.4, 4 Hz, 1H), 2.63-2.69 (dd, J=16.4, 7.66 Hz, 1H); MS (ESI) m/z 293.89 (M+H)+.
Reaction SMILES: OO.[CH3:3][O:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:26])[CH2:9][CH2:10][NH:11][C:12]1[N:13]=[N+:14]([O-:25])[C:15]2[CH:24]=[C:23]3[C:19]([CH2:20][CH2:21][CH2:22]3)=[CH:18][C:16]=2[N:17]=1.C(O)(C(F)(F)F)=[O:28]>C(Cl)Cl.N>[O-:25][N+:14]1[C:15]2[CH:24]=[C:23]3[C:19](=[CH:18][C:16]=2[N+:17]([O-:28])=[C:12]([NH:11][CH2:10][CH2:9][N:8]([CH2:7][CH2:6][CH2:5][O:4][CH3:3])[CH3:26])[N:13]=1)[CH2:20][CH2:21][CH2:22]3
Reactant: COCCCN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: O=C(O)C(F)(F)F
Agent: N
Agent: OO
Solvent: ClCCl
Product: COCCCN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 35.7 %

Procedure:
H2O2 (70%, 2.5 mL, ca. 50 mmol) was added dropwise to a stirred solution of TFM (7.1 mL, 50 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 32 (1.7 g, 5.0 mmol) and TFA (1.9 mL, 25 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4×125 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 33 (620 mg, 35%) as a red solid: mp 129-131° C.; 1H NMR δ 8.13 (s, 1H, H-9), 8.10 (s, 1H, H-5), 7.39 (br s, 1H, NH), 3.57-3.66 (m, 2H, NCH2), 3.46 (t, J=6.3 Hz, 2H, OCH2), 3.33 (s, 3H, OCH3), 3.11 (dt, J=7.4, 0.9 Hz, 2H, H-8), 3.06 (dt, J=7.4, 1.1 Hz, 2H, H-6), 2.68 (t, J=6.0 Hz, 2H, NCH2), 2.52 (t, J=7.2 Hz, 2H, NCH2), 2.28 (s, 3H, NCH3), 2.20 (p, J=7.4 Hz, 2H, H-7), 1.77 (tt, J=7.2, 6.4 Hz, 2H, CH2); 13C NMR δ 155.6, 149.5, 145.7, 138.0, 129.7, 115.8, 111.6, 70.7, 58.6, 55.8, 54.3, 41.7, 38.8, 33.4, 32.4, 27.4, 25.6; MS (APCI) m/z 348 (MH+, 100%). Anal. calcd for C17H25N5O3: C, 58.8; H, 7.3; N, 20.2. Found: C, 58.8; H, 7.0; N, 20.0%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[Cl:25])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[N:17]([CH3:18])[C:15]([C:13]1[S:12][C:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:26][C:6]=3[O:7][CH2:8][CH2:9][C:10]=2[CH:14]=1)=[O:16]
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccccc1Cl
Reactant: OB(O)c1ccccc1
Product: CN(C(=O)c1cc2c(s1)-c1ccc(-c3ccccc3)cc1OCC2)c1ccccc1Cl

Procedure:
Following Examples 44 and 60, 8-bromo-N-(2-chlorophenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide 150 and phenyl boronic acid were reacted to give 135. MS: (ESI+) 446.1
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][O:23][CH3:24])[CH2:17]2)[CH2:10][C@H:9]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([NH:33][C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[CH:27]=1)=[O:7].[H-].[Na+].[CH3:51]I>O1CCCC1.[Cl-].[Na+].O>[F:48][C:2]([F:1])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:45])([F:46])[F:44])[CH:42]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][C@H:18]([CH2:22][O:23][CH3:24])[CH2:17]2)[CH2:10][C@H:9]1[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[C:28]([N:33]([CH3:51])[C:34](=[O:39])[C:35]([F:38])([F:37])[F:36])[CH:27]=1)=[O:7]
Reactant: CI
Reactant: COC[C@@H]1CN(CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(NC(=O)C(F)(F)F)c3)C2)CCO1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC[C@@H]1CN(CCN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(C)c(N(C)C(=O)C(F)(F)F)c3)C2)CCO1
Reaction time: 0.33 h
Yield: 23.2 %

Procedure:
To a solution of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-2-[4-methyl-3-(trifluoroacetylamino)benzyl]-4-[2-[(2S)-2-(methoxymethyl)morpholino]ethyl]piperazine (131 mg) in tetrahydrofuran (2 ml) was added sodium hydride (10 mg) and the resulting mixture was stirred for 20 minutes. Methyl iodide (28 mg) was added to the mixture and the whole was stirred at room temperature overnight. Brine was added to the mixture and the organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by HPLC to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[4-methyl-3-(N-methyl-N-trifluoroacetylamino)benzyl]-4-[2-[(2S)-2-(methoxymethyl)-morpholino]ethyl]piperazine (31 mg) as an oil. The obtained compound was converted to its dihydrochloride in a conventional manner.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][S:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27](=[O:47])[CH2:28][C:29]1([C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)[CH3:25]>>[CH2:24]([O:26][C:27](=[O:47])[CH2:28][C:29]1([C:32]2[CH:37]=[CH:36][C:35]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH2:14][S:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:34][CH:33]=2)[CH2:31][CH2:30]1)[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4CSCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-4-phenethylsulfanylmethyl-isoxazole and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:6]2[CH2:5][CH2:4]1.Cl[C:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][N:15]=1.N12CCCN=C1CCCCC2>N1C(C)=CC=CC=1C>[O:16]1[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:14]([N:10]2[CH2:9][CH2:8][N:7]3[CH2:12][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5][CH:6]3[CH2:11]2)=[N:15]1
Reactant: Clc1noc2ccccc12
Reactant: OCC1CCC2CNCCN2C1
Solvent: Cc1cccc(C)n1
Solvent: C1CCC2=NCCCN2CC1
Product: OCC1CCC2CN(c3noc4ccccc34)CCN2C1
Temperature: 145 °C
Yield: 41.6 %

Procedure:
A mixture consisting of racemic (7S*,9aS*)-7-(hydroxymethyl)perhydro-1H-pyrido[1,2-a]pyrazine (see Example 27; 500 mg, 2.93 mmol), 3-chloro-1,2-benzisoxazole (890 mg, 5.86 mmol) and 1,8-diazabicyclo[5.4.0]-undec-7-ene (DBU, 446 mg, 0.438 ml, 2.93 mmol) in 2,6-lutidine (0.5 ml) was stirred and heated at 145° C. for 18 hours. The solvent was removed in vacuo, and the tarry residue was thoroughly extracted with methylene chloride (150 ml). Insolubles were filtered and the solvent was removed in vacuo to afford a dark brown residue. Flash chromatography of the entire sample (20 g silica gel, 32-63 mesh; eluting with ethyl acetate/methanol=95:5 in volume) afforded 350 mg (41.7%) of the title compound (in which the 7- and 9a-hydrogen substituents remain cis) as a colorless amorphous solid. HRMS m/z 287.1639 (M, C16H21N3O2). 13CNMR (CDCl3) delta 164.0, 161.0, 129.5, 122.3, 122.1, 116.1, 110.5, 67.5, 60.2, 58.2, 54.2, 53.7, 48.3, 34.4, 26.9, 26.3.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([OH:6])(=[O:5])=[O:4].[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[N:18]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])[C:19]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1O)=[O:20]>N1C=CC=CC=1>[CH2:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]1[N:18]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[F:39])[C:19]([C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[O:4][S:3]([C:2]([F:8])([F:7])[F:1])(=[O:6])=[O:5])=[O:20]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: O=C(c1c(O)ccc2ccccc12)N(Cc1ccccc1F)C1Cc2ccccc2C1
Solvent: c1ccncc1
Product: O=C(c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12)N(Cc1ccccc1F)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoromethanesulfonic acid anhydrous (0.27 mL, 1.6 mmol) is added dropwise in 10 minutes to a solution of 2-hydroxy-naphthalene-1-Carboxylic acid indan-2-yl-(2-fluoro-benzyl)-amide (17) (323 mg, 0.8 mmol) in anhydrous pyridine (5 mL) at 0° C. under nitrogen. The mixture is stirred at room temperature overnight and concentrated under reduced pressure. The residue (18) is dried in vacuo and used for the next step without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=2)[C:10]2[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CCc1cc2c(NCc3ccc(OC)c(OC)c3)nc(Cl)nc2s1
Reactant: c1nc[nH]n1
Product: CCc1cc2c(NCc3ccc(OC)c(OC)c3)nc(-n3cncn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-ethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-ethyl-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C(N(CC)CC)C.[C:8]([CH:11]([N:13]1[CH:16]([S:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][C:14]1=[O:37])O)([OH:10])=[O:9].S(Cl)([Cl:40])=O>C(Cl)Cl>[C:8]([CH:11]([N:13]1[CH:16]([S:17][C:18]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][C:14]1=[O:37])[Cl:40])([OH:10])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C(O)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C(Cl)N1C(=O)CC1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A cooled (ice bath) solution of the triethylamine salt of 1-(1'-carboxy-1'-hydroxymethyl)-4-tritylthio-2-azetidinone (1.04 g, 2.0 mmol) in methylene chloride (5 ml) was treated dropwise, under N2, with thionyl chloride (0.16 ml, 2.2 mmol) in methylene chloride (2 ml). The solution was stirred at room temperature for 20 min and concentrated. The residue was diluted with benzene and filtered over a Celite/charcoal bed. The filtrate was evaporated in vacuo to give 870 mg (quantitative) of the title compound as an amorphous solid. It was used in the next step without further purification. ir νmax : 1775 cm-1 ; 1Hmr (CDCl3) δ: 9.22 (1H, bs), 7.27 (15H, m), 5.3 and 5.2 (1H, 2d, J=2 Hz), 4.6 (1H, m) and 2.8 ppm (2H, m).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=O)[NH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14].P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:13]([O:15][CH3:16])=[O:14])[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1[nH]c(=O)c2ccccc2c1O
Product: COC(=O)c1nc(Cl)c2ccccc2c1O
Temperature: 0 °C

Procedure:
2.84 g (13 mmol) of methyl 4-hydroxy-1 (2H)-isoquinolone-3-carboxylate (prepared as in M. Suzuki, SYNTHESIS, 461 (1978)) was stirred at 70° C. for 3 h in 25 ml of phosphorus oxychloride. After cooling, the mixture was added to 500 ml of ice water, the precipitate was filtered off with suction next morning and dried at 70° C. under an IR Lamp. 2.96 g of product were obtained; m.p. 168° C.