Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[H-].[Na+].Cl[C:10]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([N:31]4[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[NH:33][C:32]4=[O:40])[CH2:27][CH2:26]3)=[CH:20][CH:19]=2)[C:15]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:14][C:11]=1[C:12]#[N:13]>CS(C)=O.O>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:5][O:6][C:10]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([N:31]4[C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=5[NH:33][C:32]4=[O:40])[CH2:29][CH2:30]3)=[CH:20][CH:19]=2)[C:15]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: CN(C)CCO
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCOc1nc(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)c(-c2ccccc2)cc1C#N
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a mixture of N,N dimethylaminoethanol in DMSO (1 mL) was added NaH (60% dispersion in mineral oil, 0.019 g, 0.481 mmol). The mixture was heated to 50° C. for 15 min. After cooling, 2-Chloro-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl]-5-phenylnicotinonitrile (2-6, 0.050 g, 0.096 mmol) was added and the reaction was allowed to stir for 16 hr at rt. The resulting mixture was diluted with water (10 mL) and the resulting precipitate was filtered. The filtered cake was purified by reverse phase HPLC. (5% CH3CN: 95% H2O+0.01% TFA to 95% CH3CN: 5% H2O+0.01% TFA). 1H-NMR (500 MHz, d6 DMSO) δ 10.93 (s, 1H), 9.86 (bs, 2H), 8.45 (s, 1H), 7.40-7.55 (m, 4H), 7.25-7.40 (m, 6H), 7.00 (d, J=2.93, 3H), 4.85 (t, J=4.89, 2H), 4.45 -4.55 (m, 1H), 4.34 (s, 2H), 3.64 (bs, 2H), 3.46 (d, J=11.72, 2H), 3.10-3.25 (m, 2H), 2.94 (d, J=4.15, 6H), 2.56-2.69 (m, 2H), 1.93, (d, J=12.00, 2H). HRMS m/z (M+H) Calcd: 573.2973, found: 573.2957.
Reaction SMILES: I[CH2:2][CH:3]1[CH2:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4]1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(#N)C>[O:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[CH2:7][CH:3]1[CH2:2][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: ICC1Cc2ccccc2O1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc2c(c1)CC(CN1CCNCC1)O2
Yield: 53.9 %

Procedure:
To a solution of 2-(iodomethyl)-2,3-dihydro-1-benzofuran (5.3 g, 20.4 mmol) in acetonitrile (70 ml) was added potassium carbonate (5.6 g, 40.5 mmol, 2 eq) and piperazine (8.8 g, 102.2 mmol, 5 eq). The resulting mixture was heated at reflux for 2 hours. The solids were then filtered off and the filtrate was concentrated under vacuum. The crude material was purified by silica gel chromatography using 0.5-2.5% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated under vacuum to afford 1-(2,3-dihydro-1-benzofuran-2-ylmethyl)piperazine as brown oil (2.4 g, 54%); (ES, m/z): [M+H]+ 219; 1H NMR (300 MHz, CDCl3): δ 7.07-7.17 (m, 2H), 6.78-6.85 (m, 2H), 4.92-5.01 (m, 1H), 3.22 (dd, J=9.0 Hz, 15.6 Hz, 1H), 2.91-2.99 (m, 4H), 2.71-2.82 (m, 1H), 2.53-2.71 (m, 6H).
Reaction SMILES: Cl.Cl.NC1CCN(C[C@H]2N3C4N(C(=O)C=CC=4C=CC3=O)C2)CC1.[Cl:25][C:26]1[C:35]([CH:36]=[O:37])=[N:34][C:33]2[NH:32][CH2:31][CH2:30][S:29][C:28]=2[CH:27]=1.[N+](C1C=CC=CN=1)([O-])=O.ClC1C(C=O)=NC2NC(=O)CSC=2C=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[Cl:25][C:26]1[C:35]([CH2:36][OH:37])=[N:34][C:33]2[NH:32][CH2:31][CH2:30][S:29][C:28]=2[CH:27]=1
Reactant: O=Cc1nc2c(cc1Cl)SCCN2
Agent: Cl
Agent: NC1CCN(C[C@@H]2Cn3c(=O)ccc4ccc(=O)n2c43)CC1
Agent: O=Cc1nc2c(cc1Cl)SCC(=O)N2
Product: OCc1nc2c(cc1Cl)SCCN2

Procedure:
To a 10 mL round-bottomed flask were added (1R)-1-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-4H,9H-imidazo[1,2,3-ij]-1,8-naphthyridine-4,9-dione dihydrochloride (for a preparation see Example 5A(j)) (75 mg, 0.223 mmol), 7-chloro-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (prepared by (1) reduction of 7-chloro-3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (for a synthesis see WO2003087098 Example 306(e)) with LiAlH4 to give (7-chloro-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazin-6-yl)methanol and then (2) oxidation with MnO2)) (47.8 mg, 0.223 mmol), and NaHCO3 (100 mg, 1.190 mmol) in DCM (4 ml) and methanol (1 ml) to give a brown suspension. Sodium sulfate (200 mg, 1.408 mmol) was added and the reaction was allowed to stir at rt overnight. After 15 h sodium triacetoxyborohydride (94 mg, 0.445 mmol) was added and the reaction was allowed to stir at 25° C. under nitrogen for 4 h. The reaction mixture was adsorbed onto silica and purified using 0-10% MeOH/DCM (1% NH4OH) to give the title compound as a free base (45 mg, 0.090 mmol, 40.5% yield). LCMS & 1H NMR were consistent with the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[C:23]([C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH2:34])=[NH:33])[CH:28]=[CH:29][CH:30]=1)#[N:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:33]=[C:32]([NH:31][C:27]4[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=4)[C:23]#[N:24])[N:34]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: N#Cc1cccc(NC(=N)N)c1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Solvent: O=[N+]([O-])O
Product: N#Cc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(3-cyano-phenyl)-guanidine nitrate were converted to I-90 (58%): MS (AA) Rt=1.79 min, m/z=362 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11]Cl)[O:10][C:6]=2[CH:5]=[C:4]([Cl:13])[CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[O:27][CH2:26]1)[CH2:19][CH2:18]2.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)C>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([CH2:24][C:25]3([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[O:27][CH2:26]3)[CH2:19][CH2:18]4)[O:10][C:6]=2[CH:5]=[C:4]([Cl:13])[CH:3]=1
Reactant: ClCc1cc2c(Cl)cc(Cl)cc2o1
Reactant: CC(C)(C)OC(=O)NC1(CN2CCc3cc(O)ccc32)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC1(CN2CCc3cc(OCc4cc5c(Cl)cc(Cl)cc5o4)ccc32)COC(C)(C)OC1
Yield: 41.2 %

Procedure:
A mixture of the product of Step F (0.05 g; 0.21 mmol) and the product of Step C (0.08 g; 0.21 mmol) and Cs2CO3 (0.07 g; 0.21 mmol) in anhydrous DMF (1 ml) was stirred overnight at room temperature under N2. This was diluted to 10 ml with diethyl ether, washed with H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2; hexane/EtOAc 7:3), to give the title compound (0.05 g; 41%) as a brownish syrup. 1H-NMR (CDCl3) 1.44 (m, 15H); 2.95 (tr, 2H, J=8.5 Hz); 3.41 (tr, 2H, J=8.5 Hz); 3.45 (5, 2H); 3.87-4.01 (m, 4H); 4.69 (broad s, 1H); 5.03 (s, 2H); 6.49 (d, 1H, J=8.5 Hz); 6.69 (dd, 1H, J=2.5, 8.5 Hz); 6.79 (s, 2H); 7.23 (s, 1H, J=2.5 Hz); 7.39 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:19](I)=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:1][C:2]1[C:19]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])=[CH:18][C:5]([C:6]([N:8]=[S@@:9]([CH3:17])(=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: C[S@@](=O)(=NC(=O)c1cnc(N)c(I)c1)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1cc(C(=O)N=[S@@](C)(=O)c2ccccc2)cnc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a degassed solution containing (S)-6-amino-5-iodo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (345 mg, 0.86 mmol) in 6.0 mL DMF at room temperature was added triethylamine (0.36 mL, 2.6 mmol), trimethylsilylacetylene (0.24 mL, 1.7 mmol), dichlorobis(triphenylphosphine)palladium(II) (60 mg, 0.09 mmol), and copper(I)iodide (16 mg, 0.09 mmol). After stirring at room temperature for 1 hour, the reaction was partitioned between EtOAc and H2O. The EtOAc layer was washed with saturated NaHCO3, brine, dried with anhydrous Na2SO4 and rotary evaporated. Then added 30 mL ethyl ether to the dark oil, filtered to remove the dark precipitate. The organic extracts were concentrated and the residue was purified by chromatography (silica gel, ethyl ether/EtOAc) to the title compound as a tan foam (317 mg, 99%).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:6]=2[N:7]=1.O1CCOCC1.C1C=C[NH+]=CC=1.[Br:25][Br-]Br>CCOC(C)=O>[Br:25][C:11]1[C:5]2[S:4][C:3]([S:2][CH3:1])=[N:7][C:6]=2[CH:8]=[CH:9][C:10]=1[NH2:12]
Reactant: CSc1nc2ccc(N)cc2s1
Agent: c1cc[nH+]cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CSc1nc2ccc(N)c(Br)c2s1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a round bottom flask was added 2-(methylthio)-1,3-benzothiazol-6-amine (0.301 g, 1.533 mmol), Dioxane (10 mL), and pyridinium bromide perbromide (0.589 g, 1.840 mmol). The reaction mixture was then stirred at room temperature for ˜5 minutes, then suspended in EtOAc, washed with sat'd Na2S2O3, then with sat'd NaHCO3, then water, then brine. Organics were then dried over Na2SO4 filtered & concentrated. The resulting residue was purified using silica gel chromatography (0-45% ethyl acetate/hexanes) to give 7-bromo-2-(methylthio)-1,3-benzothiazol-6-amine (13-1) as a tan solid. HRMS (M+H)+: observed=274.9307, calculated=274.9307.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:19][CH:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>>[CH3:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:22][CH2:21]1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: CC1CCC(N)CC1
Product: C[C@H]1CC[C@H](Nc2ncc(C#Cc3ccccc3)cn2)CC1

Procedure:
The title compound, white solid, MS: m/e=292.2 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and 4-methyl-cyclohexylamine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[F:31][C:32]([F:44])([F:43])[C:33]1[CH:34]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[CH2:18][N:19]([S:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([C:32]([F:31])([F:43])[F:44])[CH:34]=3)(=[O:41])=[O:40])[C:20](=[O:28])[N:21]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4cccc(C(F)(F)F)c4)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 3-trifluoromethylbenzenesulphonyl chloride to give the title compound as a colorless solid. MS: 586.8 ([M+H]+)
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=2)([OH:18])[CH:11]([N:13]2[N:17]=[N:16][CH:15]=[N:14]2)[CH3:12])=[CH:6][CH:5]=1.[H-].[Na+].[CH3:34]I>CN(C)C=O.O>[F:29][C:26]([F:27])([F:28])[O:25][C:22]1[CH:23]=[CH:24][C:19]([C:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:30])[F:31])=[CH:5][CH:6]=2)([O:18][CH3:34])[CH:11]([N:13]2[N:17]=[N:16][CH:15]=[N:14]2)[CH3:12])=[CH:20][CH:21]=1
Reactant: CI
Reactant: CC(n1ncnn1)C(O)(c1ccc(OC(F)(F)F)cc1)c1ccc(OC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C(C)n1ncnn1
Reaction time: 20 h

Procedure:
1,1-bis(4-trifluoromethoxyphenyl)-2-(2H-tetrazol-2-yl)propanol (220 g) was added to a stirred suspension of sodium hydride (24 mg of a 50% dispension in oil) in dry dimethylformamide (6.0 cm3) at the ambient temperature under a nitrogen atmosphere, and the mixture stirred for a further 2 hours after which methyl iodide (71 mg) was added and the resultant mixtures stirred for a further 20 hours. After diluting with water the mixture was extracted with diethyl ether (3×15 cm3), the extracts were combined, dried over anhydrous magnesium sulphate and concentrated by evaporation of the solvent under reduced pressure. The residual yellow oil was subjected to h.p.l.c using a silica gel column eluted with a mixture of n-hexane and ethyl acetate (5:1 by volume) to yield 1,1-bis(4-trifluoromethoxyphenyl)-1-methoxy-2-(2H-tetrazol-2-yl)propane.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.N12CCN(CC1)CC2.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:23][CH2:22]1>C(O)(C)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:35][C:32]2[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)=[CH:34][CH:33]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: CN1CCC(COc2ccc(N)cc2)CC1
Agent: C1CN2CCN1CC2
Solvent: CC(C)O
Product: CN1CCC(COc2ccc(Nc3ncc(Br)n4ccnc34)cc2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 5,8-dibromo-imidazo[1,2-a]pyrazine (0.100 g, 0.36 mmol) in isopropanol (5 mL) are added 1,4-diazabicyclo[2,2,2]octane (DABCO) (0.036 mL, 0.36 mmol) and 4-(1-methyl-piperidin-4-ylmethoxy)-phenylamine (79.6 mg, 0.36 mmol). The reaction mixture is stirred at 90° C. overnight. The solvent is evaporated and the residue chromatographed on silica gel column eluting with 97:3 followed by 94:6 and 90:10 DCM:MeOH. The title compound is obtained as a solid (20 mg, 13%). LCMS: Rt 2.30 min (94%), m/z (APCI) 417.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][N:7]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:12]=2[N:13]=1>N1C=CC=CC=1>[CH3:6][N:7]([CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:25][CH:26]=1)[CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([NH:18][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][C:12]=2[N:13]=1
Reactant: CN(CCc1ccc(N)cc1)Cc1nc2cc(N)ccc2o1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CN(CCc1ccc(NS(C)(=O)=O)cc1)Cc1nc2cc(NS(C)(=O)=O)ccc2o1

Procedure:
Methanesulphonyl chloride (0.38 g, 3.3 mmole) and N-methyl-N-(5-aminobenzoxazol-2-ylmethyl)-4-aminophenethylamine (see Preparation 1C--0.45 g, 1.5 mmole) in pyridine (20 ml) when reacted together under conditions similar to those of Example 2 gave the title compound, yield from ethanol 0.25 g, m.p. 174°-176°.
Reaction SMILES: [N:1]([CH2:4][C:5]1([CH3:24])[O:22][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH:6]1[CH3:23])[NH:13][C:12](=[O:18])[C:11]([CH:19]([CH3:21])[CH3:20])=[CH:10]3)=[N+]=[N-].[H][H].[ClH:27].CO>CN(C)C=O.CO.[Pd]>[NH2:1][CH2:4][C:5]1([CH3:24])[O:22][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH:6]1[CH3:23])[NH:13][C:12](=[O:18])[C:11]([CH:19]([CH3:20])[CH3:21])=[CH:10]3.[ClH:27]
Reactant: [H][H]
Reactant: Cc1cc2c(c3cc(C(C)C)c(=O)[nH]c13)OC(C)(CN=[N+]=[N-])C2C
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2c(c3cc(C(C)C)c(=O)[nH]c13)OC(C)(CN)C2C
Yield: 83.7 %

Procedure:
2-Azidomethyl-8-isopropyl-2,3,5-trimethyl-6,7-dihydrofuro[2,3-f]quinoline-7-one (1.25 g, 3.83 mmol) was dissolved in dimethylformamide (200 ml). To the solution, 10% palladium-on-carbon (1.45 g) was added, followed by stirring at room temperature for 90 minutes in the atmosphere of hydrogen. The reaction mixture was filtered, and the filtrate was condensed under reduced pressure. The resultant residue was suspended in methanol (50 ml), and the suspension was dissolved with 1.37 N HCl-methanol (4 ml, 5.31 mmol). The reaction mixture was condensed under reduced pressure, and the residue was recrystallized from methanol-ether to obtain 1.08 g of the title compound as colorless powdery crystals (83.7%).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[Br:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>>[Br:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=3[C:12]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[N:13]2)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: BrCc1ccc(Br)cc1
Product: Clc1ccc(-c2nn(Cc3ccc(Br)cc3)c3c2CCNCC3)cc1
Yield: 25.6 %

Procedure:
The title compound (0.032 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.3 mmol) using 4-bromobenzyl bromide (0.3 mmol) in place of 2-chloromethyl-thiophene. MS (ESI): exact mass calculated for C20H19BrClN3, 415.05; found, m/z 418.0 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.48-7.40 (m, 6H), 6.92 (d, J=8.4 Hz, 2H), 5.28 (s, 2H), 3.32-3.30 (br m, 4H), 3.03-3.01 (br m, 4H).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].C(=O)([O-])[O-].[Ca+2].ClCCl.[CH2:13]([C:15]1[CH:21]=[C:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[C:18]([CH2:29][CH3:30])[C:16]=1[NH2:17])[CH3:14]>ClC(Cl)C.O>[CH2:13]([C:15]1[CH:21]=[C:20]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[C:18]([CH2:29][CH3:30])[C:16]=1[N:17]=[C:1]=[S:2])[CH3:14]
Reactant: CCc1cc(Cc2ccccc2)cc(CC)c1N
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCc1cc(Cc2ccccc2)cc(CC)c1N=C=S
Reaction time: 2 h

Procedure:
34.0 g of thiophosgene, 54.8 g of calcium carbonate and 460 ml of dichloromethane are stirred with 230 ml of water. A solution of 59.3 g of 2,6-diethyl-4-benzylaniline in 200 ml of dichloroethane is stirred dropwise into this mixture at room temperature. The reaction mixture is stirred for 2 hours under reflux and, after cooling, is filtered over diatomaceous earth. The organic phase is separated from the filtrate, dried over sodium sulfate and freed of the solvent to give the title compound of formula ##STR14## in the form of a yellow oil which is used without further purification for the next reaction.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([OH:28])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si](OCC1N=CC2N=CN(C3SC(C(OC)=O)=C(O)C=3)C=2C=1)(C(C)(C)C)(C)C.C([O-])([O-])=O.[K+].[K+].Br[CH:64]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=1[C:72]([F:75])([F:74])[F:73])[CH3:65]>CN(C)C=O>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26][CH3:27])=[O:25])=[C:21]([O:28][CH:64]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][C:67]=4[C:72]([F:73])([F:74])[F:75])[CH3:65])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1O
Reactant: CC(Br)c1ccccc1C(F)(F)F
Agent: COC(=O)c1sc(-n2cnc3cnc(CO[Si](C)(C)C(C)(C)C)cc32)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1OC(C)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example B3, 8.0 g of an isomeric mixture of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-hydroxythiophene-2-carboxylate and methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1H-imidazo[4,5-c]pyridin-1-yl]-3-hydroxythiophene-2-carboxylate (example C3) and 3.15 g of K2CO3 and 5.95 g of 1-(1-bromoethyl)-2-(trifluoromethyl)benzene in 240 ml anhydrous N,N-dimethylformamide yield compound B25a and compound B25b.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](OC(=O)C(F)(F)F)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[CH3:51][C:52]1[CH:53]=[CH:54][C:55]([Sn](CCCC)(CCCC)CCCC)=[N:56][CH:57]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:16])([CH3:17])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:30]=[CH:31][C:32]([C:55]2[CH:54]=[CH:53][C:52]([CH3:51])=[CH:57][N:56]=2)=[CH:33][CH:34]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC(=O)C(F)(F)F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)nc1
Yield: 41.8 %

Procedure:
A solution containing the product from Example 23I (0.114 g, 0.162 mmol) in DMF (1.6 mL) was treated with LiCl (0.068 g, 1.60 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.034 g, 0.048 mmol), and the product from Example 74A (0.367 g, 0.961 mmol), heated at 100° C. for 16 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-15% ethyl acetate in dichloromethane. The product was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA) to give the title compound (0.044 g, 42% yield).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:20]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([CH3:14])=[CH:16][CH:17]=1)[CH2:11]2
Reactant: Cc1ccc(CN)cc1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1ccc(CN2Cc3cccc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.245 g, 0.7 mmol), 4-methyl-benzylamine (0.102 mL, 0.8 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(4-methyl-benzyl)-2,3-dihydro-isoindol-1-one (0.080 g, 31%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.35 (s, 3H), 4.14 (s, 2H), 4.76 (s, 2H), 7.11-7.38 (m, 6H), 7.91 (d, 1H). GC-MS: m/z 363 (M)+.