Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4].Br[C:31]1[CH:32]=[CH:33][C:34]([CH:37]([OH:39])[CH3:38])=[N:35][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O.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>[F:29][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:13]=[CH:14][C:15]([C:31]3[CH:36]=[N:35][C:34]([CH:37]([OH:39])[CH3:38])=[CH:33][CH:32]=3)=[CH:16][CH:17]=2)[O:7][C:6]1([CH3:28])[CH3:27])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: CC(O)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Temperature: 100 °C
Yield: 74.2 %

Procedure:
To a stirred solution of 2,2-Difluoro-1-{(4S,5R)-4-fluoromethyl-2,2-dimethyl-5-[4-(4,4,5,5tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-oxazolidin-3-yl}-ethanone (3 g, 7.26 mmol) and 1-(5-Bromo-pyridin-2-yl)-ethanol (1.46 g, 7.26 mmol) in toluene: ethanol:water (15:15:7 mL) is added Na2CO3 (2.3 g, 21.79 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 30 minutes then Pd(PPh3)4 (0.839 g, 0.726 mmol) is added. The reaction mixture is heated to 100° C. for 16 hours. Solvent is evaporated in vacuo and the crude material is purified by combi-flash using 55% ethyl acetate in hexane as an eluent to afford the title compound (2.2 g). 1H NMR (400 MHz, DMSO-d6) δ: 1.39 (d, J=6.6 Hz, 3H), 1.53 (s, 3H), 1.60 (s, 3H), 4.57-4.58 (m, 0.5H), 4.69-4.70 (m, 1H), 4.75-4.77 (m, 1H), 4.78-7.80 (m, 0.5H), 4.89-4.94 (m, 1H), 5.26 (d, J=3.88 Hz, 1H), 5.41 (d, J=4.6 Hz, 1H), 6.64 (t, J1=52.32 Hz, 1H), 7.57-7.64 (m, 3H), 7.77 (d, J=8.16 Hz, 2H), 8.08 (dd, J1=8.2 Hz, J2=2.32 Hz, 1H), 8.80 (d, J=2.04 Hz, 1H). LC-Ms (m/z): 409 [M+H].
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[N:4]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>CN(C)C=O>[CH3:23][N:14]1[C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]2[CH:10]=[N:9][C:8]([C:5]3[N:4]=[C:3]([CH2:2][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[O:7][N:6]=3)=[C:12]2[CH2:13]1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccccc2C1=O
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CN4CCCC4)n3)ncn2-c2ccccc2C1=O
Yield: 85.4 %

Procedure:
1.5 g (4.5 mmol) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were stirred at 80° for 2 hours in 1.1 ml (14 mmol) of pyrrolidine and 30 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with methylene chloride/methanol 19/1 there were obtained 1.4 g (84%) of 5-methyl-3-[5-(pyrrolidin-1-yl)methyl-1,2,4-oxadiazol-3-yl]-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p 251°-254°.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[O:8].[OH-].[Na+].O.[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CC(C)=O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]([NH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:32]([NH:31][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:33])(=[O:19])=[O:20])=[CH:14][CH:13]=1)=[O:8]
Reactant: NS(=O)(=O)c1ccc(CCNC(=O)N2CCCC2=O)cc1
Reactant: O=C=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NC1CCCCC1)NS(=O)(=O)c1ccc(CCNC(=O)N2CCCC2=O)cc1
Reaction time: 2 h

Procedure:
5 g of 4-[2-(oxo-pyrrolidine-1-carboxamido)-ethyl]-benzenesulfonamide are dissolved in 100 ml of acetone with 0.65 g of NaOH and water. 2.3 g of cyclohexyl-isocyanate are added dropwise with agitation and ice cooling, and agitation is continued for 2 hours at room temperature. Subsequently, the substantial amount of acetone is distilled off under reduced pressure, the aqueous solution is acidified and the product is reprecipitated from dilute ammonia. The N-(4-[2-(2-oxo-pyrrolidine-1-carboxamido)-ethyl]-benzenesulfonyl)-N'-cyclohexyl urea is recrystallized from dilute ethanol, and has a melting point of 189°-190° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][Cl:12])[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:13]([P:17]([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16]>CN(C)C=O.C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl-:12].[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH2:11][P+:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: ClCc1nc2cc(Br)cnc2[nH]1
Reactant: CCCCP(CCCC)CCCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCC[P+](CCCC)(CCCC)Cc1nc2cc(Br)cnc2[nH]1
Product: [Cl-]
Temperature: 90 °C

Procedure:
Alternatively, 4.0 g of 6-bromo-2-chloromethyl-3H-imidazo[4,5-b]pyridine (compound J1) are suspended in 17 ml of N,N-dimethylformamide and 54 ml of acetonitrile. 4.8 ml of tributylphosphine and 600 mg of tetrabutylammonium iodide are added sequentially at 40° C. Subsequently, the mixture is heated to 90° C. for 18 hours. The mixture is concentrated to dryness to give 8.94 g of the crude title compound as an oil, which is purified by chromatography on flash silica gel (eluent gradient: dichloromethane/5-20 vol. % 2-propanol). The remaining residue is re-dissolved in 150 ml of ethyl acetate. Upon standing at room temperature, a precipitate of the title compound is formed, which is collected by filtration and dried under high vacuum to yield 4.52 g of (6-bromo-3H-imidazo[4,5-b]pyridin-2-ylmethyl)-tributyl-phosphonium chloride as an amorphous solid of m.p. 180° C. ESI-MS: 412.5, 414.4 (M+, 100%:98%). TLC: Rf=0.45-0.55 (dichloromethane/methanol 10:1 parts by volume).
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][S:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[SH-:20].[Na+].[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][CH2:28][CH2:29]Cl>CN(C=O)C>[S:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][CH2:28][CH2:29][S:20][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][S:4][N:3]=1
Reactant: Clc1nsnc1-c1cccnc1
Reactant: [SH-]
Reactant: ClCCCc1cccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cncc(-c2nsnc2SCCCc2cccs2)c1
Reaction time: 1 h
Yield: 31 %

Procedure:
A solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (2.0 g, 10.1 mmol) in DMF (10 ml) was cooled to 5° C. whereupon potassium carbonate (2.8 g, 20.2 mmol) and sodium hydrosulfide monohydrate (1.5 g, 20.2 mmol ) were added to the reaction. Stirred for 1 h then potassium carbonate (1.4 g, 10.1 mmol) and a solution of 3-(2-thienyl)-1-chloro-propane (1.8 g, 11.2 mmol) in DMF (5 ml) were added to the reaction and stirred for 1 h at room temperature. The reaction was quenched with water then extracted with methylene chloride (3×75 ml). The organic phase was dried over NaCl/Na2SO4 then evaporated. The residue was purified by flash chromatography eluting with 1:1 ethyl acetate/hexanes to yield 1.0 g of 3-(3-(3-(2-thienyl)-1-propylthio)-1,2,5-thiadiazol-4-yl)pyridine. Quaternization and reduction was done as described in example 9. (Compound 66). M.p. 98°-100° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]([C:53]([NH:55][C@H:56]([CH2:67][OH:68])[C:57]([O:59]CC2C=CC=CC=2)=[O:58])=[O:54])=[N:18][C:19]([NH:38][CH2:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH3:52])=[C:20]([C:22]([NH:24][C@H:25]([CH2:36][OH:37])[C:26](=[O:35])[O:27]CC2C=CC=CC=2)=[O:23])[N:21]=1>C(O)C.O.O.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]1[C:17]([C:53]([NH:55][C@@H:56]([C:57]([OH:59])=[O:58])[CH2:67][OH:68])=[O:54])=[N:18][C:19]([NH:38][CH2:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH3:52])=[C:20]([C:22]([NH:24][C@@H:25]([C:26]([OH:35])=[O:27])[CH2:36][OH:37])=[O:23])[N:21]=1
Reactant: COCCOCCOCCOCCCNc1nc(C(=O)N[C@H](CO)C(=O)OCc2ccccc2)c(NCCCOCCOCCOCCOC)nc1C(=O)N[C@H](CO)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COCCOCCOCCOCCCNc1nc(C(=O)N[C@H](CO)C(=O)O)c(NCCCOCCOCCOCCOC)nc1C(=O)N[C@H](CO)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
A 50 mL round-bottom flask equipped with magnetic stir bar was charged with bis-benzyl ester 12 (0.501 g, 0.521 mmol), dissolved in EtOH—H2O (20 mL; 3:1, v/v), and 10% Pd—C (100 mg) was added as slurry in water (1-2 mL). The reaction mixture was purged thoroughly with argon and then with H2 and stirred at room temperature for 2 h in an atmosphere of H2. The catalyst was removed by filtration, solvents were removed in vacuo, and the crude product subjected to purification by preparative RP-HPLC to give 11 (0.108 g, 26%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=[C:11]([C:19]([NH:21][C@H:22]3[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]3[OH:28])=[O:20])[CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C>C(OCC)(=O)C.CO.[Pd]>[OH:28][C@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@@H:22]1[NH:21][C:19]([C:11]1[CH:10]=[C:9]([CH2:8][C:5]2[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)=[O:20]
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2ccc(Cl)nc2)c2ccccc2n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Cc2cccnc2)c2ccccc2n1
Reaction time: 18 h

Procedure:
To a solution of 4-[(6-chloropyridin-3-yl)methyl]-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (A) (0.15 g, 0.38 mmol) in 3.5 mL ethyl acetate and a few drops of methanol to increase solubility was added triethylamine (0.053 mL, 0.38 mmol) and palladium on carbon (10 mol %). The reaction mixture was placed under a H2 (g) atmosphere with a balloon for 18 h. The reaction mixture was filtered through Celite, washed with excess methanol, and concentrated. The resulting residue was subjected to purification via reverse phase HPLC to afford the title compound that gave a mass ion (ES+) of 362.1866 for M+H+. 1H NMR (400 MHz, CDCl3) δ 8.58 (s, 1H), 8.49 (dd, J=1.3, 4.8 Hz, 1H), 8.27 (d, J=7.7 Hz, 1H), 8.17 (s, 1H), 8.15 (dd J=0.7, 8.6 Hz, 1H), 8.01 (d, J=7.9 Hz, 1H), 7.78-7.74 (m, 1H), 7.63-7.52 (m, 1H), 7.44-7.42 (m, 1H), 7.19 (dd, J=4.9, 7.9 Hz, HA 4.51 (s, 2H), 3.93-3.84 (m, 1H), 3.62-3.54 (m, 1H), 3.36 (d, J=4.2, 1H), 2.17-2.12 (m, 2H) 1.82-1.79 (m, 2H), 1.52-1.34 (m, 4H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:28]B1OB(C)OB(C)O1.C([O-])([O-])=O.[K+].[K+]>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.O1CCOCC1>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([CH3:28])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccc(F)cc3)ccc2c1O
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCCCOC(=O)c1nc(C)c2cc(Oc3ccc(F)cc3)ccc2c1O
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of 1-Bromo-7-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester (434 mg, 1 mmol), Pd(PPh3)4 (116 mg, 0.1 mmol), trimethylboroxine (140 μl, 1 mmol), K2CO3 (414 mg, 3 mmol), and 1,4-dioxane (8 ml) was refluxed with stirring for 2 h. Subsequently, the mixture was concentrated in vacuo. To the residue was added water (10 ml). The mixture was acidified by the addition of aqueous 6N HCl and then extracted with EtOAc (40 ml). The organic phase was dried over MgSO4 and evaporated in vacuo. Purification of the residue by flash column chromatography on silica gel using hexanes:EtOAc=94:6 as the eluent gave the title compound as white solid (229 mg); MS-(+)-ion M+1=370.1.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=4)[N:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].[CH:27]1(B(O)O)[CH2:29][CH2:28]1.C(N(CC)CC)C.N1C=CC=CC=1>O1CCCC1>[CH:27]1([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([C:12]4[N:16]([C:17]5[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=5)[N:15]=[CH:14][CH:13]=4)[CH:7]=3)[C:3]([CH2:1][CH3:2])=[N:4]2)[CH2:29][CH2:28]1
Reactant: OB(O)C1CC1
Reactant: CCc1n[nH]c2cc(-c3ccnn3-c3ccc(S(C)(=O)=O)cc3)ccc12
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1nn(C2CC2)c2cc(-c3ccnn3-c3ccc(S(C)(=O)=O)cc3)ccc12
Reaction time: 0.17 h
Yield: 100.2 %

Procedure:
3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole (20 mg, 0.054 mmol), cyclopropylboronic acid (14 mg, 0.16 mmol), cupric acetate (20 mg, 0.11 mmol), triethylamine (0.038 mL, 0.27 mmol), pyridine (0.035 mL, 0.44 mmol), and tetrahydrofuran (2.0 mL) were added to a 10 mL sealed tube. The mixture was subjected to microwave radiation (300 watts, 140° C.) for 10 minutes. The solvent was removed and the residue was extracted with ethyl acetate (10 mL). The ex-tract was washed with saturated sodium bicarbonate solution (2×50 mL). Concentration afforded 22 mg (40%) of 1-cyclopropyl-3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole. LC/MS (EI) tR 4.15 (Method A), m/z 407.1 (M++1). 1H NMR (CDCl3) δ 1.1 (m, 4H); 1.4 (t, 3H); 2.9 (m, 2H); 3.1 (s, 3H); 3.5 (m, 1H): 6.5 (s, 1H); 6.9 (d, 1H); 7.4 (s, 1H); 7.5 (d, 1H); 7.6 (d, 2H); 7.8 (s, 1H); 7.9 (d, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[CH2:16][C:17]([OH:19])=[O:18])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:29][C:30]([NH2:32])=[NH:31])=[N:4][CH:3]=1.[H-].[Na+].[C:35]([O:39][C:40](=O)[CH2:41]N(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)CC1C=CC(OC)=CC=1)([CH3:38])([CH3:37])[CH3:36].O>COCCOC>[O:39]([CH:35]([CH3:37])[CH3:38])[CH:40]([CH3:41])[CH3:2].[C:35]([O:18][C:17](=[O:19])[CH2:16][N:15]([S:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([Cl:1])=[CH:3][N:4]=[C:5]2[NH:29][C:30]([NH2:32])=[NH:31])=[CH:10][CH:9]=1)(=[O:13])=[O:14])[CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: COc1ccc(CN(CC(=O)OC(C)(C)C)S(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)cc1
Reactant: COc1ccc(CN(CC(=O)O)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)OC(C)C
Product: COc1ccc(CN(CC(=O)OC(C)(C)C)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)cc1
Temperature: 60 °C
Yield: 96.8 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(4-methoxybenzyl)glycine ##STR24## Guanidine hydrochloride (118 mg, 1.24 mmol) was added in one portion to a stirred suspension of NaH (23 mg, 80% dispersion by wt in mineral oil, 0.78 mmol) in DME (10 mL) and the mixture was heated at 60° C. under N2 for 30 min. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-N-(4-methoxybenzyl)glycine t-butyl ester (155 mg, 0.31 mmol) was added and the mixture heated at 90° C. for 1 h. The cooled mixture was poured into water and extracted with EtOAc (×3). The combined organic extracts were then washed with water, brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using hexane-EtOAc (80:20), and then CH2Cl2 -MeOH-0.880NH3 (95:5:0.5 to 90:10:1) as eluant to give a yellow gum. Trituration with i-Pr2O gave N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(4-methoxybenzyl)glycine t-butyl ester (80 mg, 0.15 mmol) as a sticky yellow solid. A small sample (10-15 mg) was dissolved in EtOAc, a solution of HCl in Et2O was added and the solvents were evaporated in vacuo, to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(4-methoxybenzyl)glycine t-butyl ester hydrochloride (18 mg) as a solid. (All characterisation data is for the HCl salt).
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[CH2:3][C:4]([O:6]CC)=O.[CH2:13]([NH:16][C:17]([NH2:19])=[O:18])[CH2:14][CH3:15].Cl>O.C(O)C>[CH2:13]([N:16]1[C:2](=[O:10])[CH2:3][C:4](=[O:6])[NH:19][C:17]1=[O:18])[CH2:14][CH3:15]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCCNC(N)=O
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCCN1C(=O)CC(=O)NC1=O

Procedure:
Metallic sodium (2.6 g, 113 mmol) is added to ethanol (60 ml). The mixture is stirred until the sodium has completely finished reacting. Diethyl malonate (116 ml, 105 mmol) and n-propylurea (10 g, 98 mmol) are then added and the mixture is stirred under reflux for 5 h. After conc. HCl (5 ml) and hot water (45 ml) have been added, the mixture is filtered and the filtrate is concentrated in vacuo. Ethanol is added to the residue and the mixture is stirred. The solid is filtered off with suction and dried.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][N:6]1[CH2:11][CH2:10][C:9]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:12][CH:8]2[CH2:7]1.O1CCOCC1>O>[CH3:5][N:6]1[CH2:11][CH2:10][C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([N:1]=[N+:2]=[N-:3])[CH:8]([OH:12])[CH2:7]1
Reactant: [N-]=[N+]=[N-]
Reactant: CN1CCC2(c3ccccc3)OC2C1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CCC(N=[N+]=[N-])(c2ccccc2)C(O)C1

Procedure:
1.4 G. of sodium azide (NaN3) in 6 ml. of water was added to a solution of 3.6 g. of 1-methyl-4-phenyl-3,4-epoxypiperidine in 20 ml. of dioxane and the resulting combined solution refluxed for two hours. A further portion of 1.4 g. of NaN3 in 6 ml. of water was then added and the reaction mixture refluxed overnight. Upon cooling 3.2 g. of crystals of the dresired 1-methyl-4-phenyl-4-azido-3-hydroxypiperidine were obtained, which had a melting point of 170°-71° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:11]1(B2OC(C)(C)C(C)(C)O2)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.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>[C:11]1([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1C1=CCCCC1
Temperature: 80 °C
Yield: 38.6 %

Procedure:
A solution of 1.00 g (6.31 mmol) of 2-chloro-3-nitro-pyridine in toluene (50 mL) and EtOH (25 mL) was treated with 1.58 g (7.57 mmol) of 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 25.2 mL (50.4 mmol) of 2.0 M aqueous Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 729 mg (0.631 mmol) of Pd(PPh3)4, and heated to 80° C. for 16 h. The mixture was diluted with EtOAc (100 mL) and washed with water (1×75 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with CH2Cl2 afforded 497 mg (39%) of the title compound as a yellow solid: 1H-NMR (CD3OD; 400 MHz): δ 8.70 (dd, 1H, J=5.2, 1.6 Hz), 8.20 (dd, 1H, J=8.4, 1.6 Hz), 7.51-7.46 (m, 1H), 5.81 (sept, 1H, J=2.4 Hz), 2.44-2.37 (m, 2H), 2.19-2.12 (m, 2H), 1.84-1.76 (m, 2H), 1.74-1.66 (m, 2H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:13][CH2:14][CH2:15][C:16]#[N:17]>C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:13][CH2:14][CH2:15][C:16]#[N:17]
Reactant: N#CCCCBr
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COCCNCCCC#N

Procedure:
To a stirred mixture of 2-methoxyethylamine (20.3 g, 270 mmol) and potassium carbonate (11.2 g, 81.1 mmol) was added 4-bromobutyronitrile (10.0 g, 67.6 mmol) over 20 minutes. This mixture was heated at reflux temperature for 1 h, mixed with ethyl acetate (100 mL) and filtered. The filtrate was concentrated and distilled at 109°-115° C. (0.1 mmHg) to give a clear liquid (9.78 g, quantitative).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]([F:13])[F:12])[CH:7]=[C:6]([F:14])[C:3]=1[CH2:4][OH:5].[C:15]([OH:22])(=[O:21])/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19].[CH2:23]([C@@H:25]1[CH2:30][NH:29][CH2:28][CH2:27][N:26]1[C:31](OCC1C=CC(OC(F)F)=CC=1)=[O:32])C>>[C:15]([OH:22])(=[O:21])/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19].[CH3:23][C@@H:25]1[CH2:30][NH:29][CH2:28][CH2:27][N:26]1[C:31]([O:5][CH2:4][C:3]1[C:2]([F:1])=[CH:9][C:8]([O:10][CH:11]([F:12])[F:13])=[CH:7][C:6]=1[F:14])=[O:32]
Reactant: CC[C@@H]1CNCCN1C(=O)OCc1ccc(OC(F)F)cc1
Reactant: OCc1c(F)cc(OC(F)F)cc1F
Agent: O=C(O)/C=C/C(=O)O
Product: C[C@@H]1CNCCN1C(=O)OCc1c(F)cc(OC(F)F)cc1F

Procedure:
(R)-2,6-Difluoro-4-difluoromethoxybenzyl 2-methylpiperazine-1-carboxylate fumarate was prepared from 2,6-difluoro-4-difluoromethoxybenzyl alcohol and (R) 1-chlorocarbonyl-2-methyl-4-tert-butoxycarbonylpiperazine according to the methods described for Examples 54 to give the product as a white solid (2.9%); HPLC (XTERRA, 50/80, 220 nm) 86.0% (1.55 min); NMR δH (400 MHz, DMSO-d6) 1.154(3H, d, J 7.0 Hz), 2.639(1H, bm), 2.863(2H, bm), 3.007(2H, bm), 3.714(1H, bd), 4.122(1H, bs), 5.106(2H, q), 6.590(2H, s), 7.108(2H, d, J 8.5 Hz) and 7.360(1H, t, J 73 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=O.[C:12]1([S:18]([CH2:21][C:22]#[N:23])(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:21]([S:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:19])=[O:20])[C:22]#[N:23])[CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10]
Reactant: N#CCS(=O)(=O)c1ccccc1
Reactant: Cc1cc(C=O)cc(C)c1O
Product: Cc1cc(C=C(C#N)S(=O)(=O)c2ccccc2)cc(C)c1O

Procedure:
M31 was prepared with 3,5-dimethyl-4-hydroxybenzaldehyde and phenylsulfonly acetonitrile under similar conditions as decribed for M26.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[Cl:19]C(OCC)=O.[CH2:25]([NH2:28])[CH2:26][NH2:27]>C(Cl)(Cl)Cl.CN(C)C=O>[ClH:19].[NH2:27][CH2:26][CH2:25][NH:28][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cl
Reactant: NCCN
Reactant: N#Cc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cl
Product: N#Cc1ccc(C(=O)NCCN)cc1

Procedure:
In a manner analogous to that described in Example 7, 11.8 g (0.08 mol) of 4-cyanobenzoic acid are reacted with triethylamine and ethyl chloroformate and worked-up and then added dropwise to a solution of 21.4 ml of ethylenediamine in 350 ml of chloroform. After adding 45 ml of dimethylformamide, the mixture is heated to 60° for a further 1 hour. After filtration, the filtrate is concentrated, and the residue is treated in the same manner as described in Example 7. There are obtained 3.5 g of N-(2-aminoethyl)-4-cyanobenzamide hydrochloride, m.p. 212°-215° (decomposition). The free base melts at 124°-126°.