Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=2[N:4]=1.N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>C1(C)C=CC=CC=1>[C:39]([N:25]1[CH2:24][CH2:23][CH:22]([CH2:21][NH:20][C:10]2[N:9]=[C:8]([N:7]3[C:6]4[CH:28]=[CH:29][CH:30]=[CH:31][C:5]=4[N:4]=[C:3]3[CH:2]([F:1])[F:32])[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=2)[CH2:27][CH2:26]1)(=[O:41])[CH3:40]
Reactant: FC(F)c1nc2ccccc2n1-c1nc(NCC2CCNCC2)nc(N2CCOCC2)n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(=O)N1CCC(CNc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-N-(piperidin-4-ylmethyl)-1,3,5-triazin-2-amine (50 mg) and pyridine (2 mL) was added acetic anhydride (14 μL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added toluene, followed by concentrating under reduced pressure. The residue was dissolved in dichloromethane, and silica gel was added thereto, followed by concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate, and subsequently chloroform:methanol) to obtain N-[(1-acetylpiperidin-4-yl)methyl]-4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-amine (44 mg) as a white powder.
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.CCOCC>[OH:1][C@@H:2]([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([O:5][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@@H](O)CC1CCCC1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(OCc1ccccc1)[C@@H](O)CC1CCCC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 287 mg (1.81 mmol) of 2-(S)-hydroxy-3-(cyclopentyl)propanoic acid (from Step F) in 8 mL of DMF was treated with 0.38 mL (2.72 mmol) of TEA and 0.33 mL (2.77 mmol) of benzyl bromide and stirred at rt for 22 h. The reaction was diluted with 200 ml of ether and washed with 200 mL of H2O, 200 mL of 2.0 N HCl, 200 mL of 1.0 N NaHCO3, 200 mL of H2O and 200 mL of sat'd NaCl. The organic layer was dried over MgSO4 and concentrated. Flash chromatography on silica gel using 17:3 v/v hexanes/EtOAc afforded 102 mg (22%, 95.5% ee) of the title compound: RF: 0.40 (4:1 v/v hexanes/EtOAc); 1H NMR (300 MHz): δ 1.04-1.17 (m, 2H), 1.46-1.87 (m, 8H), 1.99 (m, 1H), 2.65 (m, 1H), 4.22 (dd, J=7.8, 4.8, 1H), 5.23 (ABq, J=12.3, 2H), 7.32-7.41 (m, 5H). HPLC: Chirapak AS 4.6×250 mm column, 17:3 v/v hexanes/iPrOH, 0.5 mL/min, 220 nm. Retention times: (S)-Enantiomer, 12.2 min; (R)-enantiomer, 15.3 min.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:5])[CH3:4].[H-].[Na+].CO[C:10]([C:12]1[N:13]([CH:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19](=[O:27])[C:18]2([CH3:29])[CH3:28])[CH:14]=[N:15][CH:16]=1)=O>C1COCC1>[CH3:28][C:18]1([CH3:29])[CH:17]([N:13]2[C:12]([C:10]3[O:1][N:2]=[C:3]([CH3:4])[N:5]=3)=[CH:16][N:15]=[CH:14]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19]1=[O:27]
Reactant: COC(=O)c1cncn1C1c2ccccc2NC(=O)C1(C)C
Reactant: CC(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2cncn2C2c3ccccc3NC(=O)C2(C)C)n1
Reaction time: 0.33 h
Yield: 67.3 %

Procedure:
N-hydroxy-acetamidine (62 mg, 0.84 mmol) is added to a suspension of 3 Å molecular sieves in anhydrous THF (2 mL). After 20 min, NaH (60% in oil, 37 mg, 0.92 mmol) is added. The resulting suspension is stirred for 40 min and a solution of 3-(3,3-Dimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester (100 mg, 0.34 mmol) in THF (dry, 1 mL) is added. The resulting mixture is refluxed for 1 h. The solvent is removed under vacuum and the residue is purified by silca gel chromatography (mobile phase 0 to 40% ethyl acetate-heptane v/v), and gives the title compound (74 mg).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])([O:6]CC)=[O:5])C.Br[Si](C)(C)C>ClCCl>[P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([F:26])([F:27])[C:16]([F:24])([F:25])[C:17]([F:22])([F:23])[C:18]([F:19])([F:20])[F:21])([OH:5])([OH:6])=[O:3]
Reactant: CCOP(=O)(CCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: O=P(O)(O)CCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
To a solution of 18.63 g of 1-(diethylphosphono)-6-(nonafluorobutyl)hexane in 100 mL of dichloromethane was added 16.8 g of bromotrimethylsilane. After 18 hr at room temperature, the solution was concentrated to a nearly colorless liquid, and the intermediate silylphosphonate ester was dissolved in 250 mL of methanol. The resultant solution was stirred at room temperature for 30 min and concentrated to a white solid. Dissolution in methanol and concentration were repeated two times, and two recrystallizations of the crude product from a 99:1 mixture of heptane and 2-propanol gave 12.50 g of 1-phosphono-6-(nonafluorobutyl)hexane (CF3(CF2)3(CH2)6PO3H2) as colorless leaves, m.p. 107-108° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(#N)C>[N:13]1([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[S:9]([NH2:12])(=[O:11])=[O:10])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NS(=O)(=O)c1ccccc1CCl
Reactant: C1CCNC1
Solvent: CC#N
Product: NS(=O)(=O)c1ccccc1CN1CCCC1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
A solution of 2-(chloromethyl)benzenesulfonamide (2.00 g, 10 mmol) in acetonitrile (20 ml) was contacted with pyrrolidine (1.6 ml, 20 mmol). After 1.0 hr at ambient temperature, the volatiles were removed under vacuum and the residue was treated with water (40 ml) and chilled. The resulting solid was pulverized, filtered, and dried to give 2.23 g of white solid, m.p. 110°-112°.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[I-].[Na+].C(#N)C.[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13](=[O:17])[NH:14]3)=[CH:9][CH:8]=2)[CH2:33][CH2:32]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: O=C1CCc2ccc(OCCCCBr)cc2N1
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Yield: 80.8 %

Procedure:
A suspension of 47 g of 7-(4-bromobutoxy)-3,4-dihydrocarbostyril, 35 g of sodium iodide with 600 ml of acetonitrile was refluxed for 30 minutes. To this suspension was added 40 g of 1-(2,3-dichlorophenyl)piperazine and 33 ml of triethylamine and the whole mixture was further refluxed for 3 hours. After the solvent was removed by evaporation, the residue thus obtained was dissolved in chloroform, washed with water then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue thus obtained was recrystallized from ethanol twice, to yield 57.1 g of 7-{4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy}-3,4-dihydrocarbostyril.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19]Br)=[CH:4][CH:3]=1.[NH3:21].CO>O1CCCC1>[NH2:21][CH2:19][C:5]1[C:6]([F:18])=[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])[C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: N
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CBr)c2F)c1
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Reaction time: 16 h
Yield: 21 %

Procedure:
A solution of 3-{[6-bromo-3-(bromomethyl)-2-fluorophenyl]oxy}-5-chlorobenzonitrile (2.5 g, 5.96 mmol) in tetrahydrofuran (THF) (50 mL) was added dropwise to a 7M solution of ammonia in MeOH (42.6 mL, 298 mmol) at RT under nitrogen. The reaction was stirred for 16 h then the reaction mixture was evaporated to dryness. Ethyl acetate and saturated aqueous sodium bicarbonate were added to the residue and the mixture was shaken in a separatory funnel. The organic layer was dried over sodium sulfate and the solvent was evaporated. The residue was purified by chromatography with hexane:ethyl acetate to give the title compound (0.453 g, 21%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.76 (s, 1H), 7.56 (d, 1H), 7.39-7.46 (m, 2H), 7.37 (m, 1H), 3.70 (s, 2H), 1.85 (br. s., 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[OH-].[K+].Br[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1>C1(C)C=CC=CC=1.O.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2ccc3ccccc3c2)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (125 mg, 505 μmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.30 mL, 0.60 mmol) at RT followed by 2-(bromomethyl)naphthalene (123 mg, 556 μmol) and the mixture was stirred at 150° C. for 45 min under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with CH2Cl2 (80 mL). The organic phase was isolated and washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 97:3) gave 57 mg of 6,7-dimethoxy-4-(naphthalen-2-ylmethyl)-1-propylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.42 M HCl solution in MeOH (4.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-(naphthalen-2-ylmethyl)-1-propylisoquinolin-3-ol hydrochloride 20 as a yellow solid (62 mg, 29% yield).
Reaction SMILES: O=S1(=O)N=CC2C=C(C(C)(C)C)C=C(I)C=2O1.[O:18]=[S:19]1(=[O:35])[N:24]=[CH:23][C:22]2[CH:25]=[C:26]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=[C:28]([S:29][CH3:30])[C:21]=2[O:20]1>>[O:35]=[S:19]1(=[O:18])[NH:24][CH2:23][C:22]2[CH:25]=[C:26]([C:31]([CH3:33])([CH3:32])[CH3:34])[CH:27]=[C:28]([S:29][CH3:30])[C:21]=2[O:20]1
Reactant: CSc1cc(C(C)(C)C)cc2c1OS(=O)(=O)N=C2
Agent: CC(C)(C)c1cc(I)c2c(c1)C=NS(=O)(=O)O2
Product: CSc1cc(C(C)(C)C)cc2c1OS(=O)(=O)NC2

Procedure:
This compound is prepared by essentially the same method as described in Example 8 except that the 2,2-dioxo-6-(1,1-dimethylethyl)-8-iodo-1,2,3-benzoxathiazine is replaced by 2,2-dioxo-6-(1,1-dimethylethyl)-8-methylthio-1,2,3-benzoxathiazine. Thereby is obtained 2,2-dioxo-3,4-dihydro-6-(1,1-dimethylethyl)-8-methylthio-1,2,3-benzoxathiazine.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:16]2[CH:20]=[C:19]([CH:21]([OH:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:18]=[N:17]2)=[N:13][C:12]=1[CH3:29])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:21]([C:19]1[N:18]=[N:17][N:16]([C:14]2[S:15][C:11]([C:9]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[C:12]([CH3:29])[N:13]=2)[CH:20]=1)(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1nc(-n2cc(C(O)c3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: Cc1nc(-n2cc(C(=O)c3ccccc3)nn2)sc1C(=O)NCc1ccccc1
Yield: 53 %

Procedure:
A solution of N-benzyl-2-(4-(hydroxy(phenyl)methyl)-1H-1,2,3-triazol-1-yl)-4-methylthiazole-5-carboxamide (0.18 g, 0.44 mmol) and Dess-Martin periodinane (0.28 g, 0.67 mmol) in dichloromethane (20 mL) was stirred at ambient temperature for 3 hours and washed with 10% aqueous solution of sodium thiosulfate (20 mL) and saturated aqueous sodium bicarbonate (20 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by column chromatography to yield the title compound as a white solid in 53% yield: mp 176-178° C. (dichloromethane/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 9.48 (s, 1H), 9.06 (t, J=6.0 Hz, 1H), 8.22 (d, J=6.0 Hz, 2H), 7.77-7.75 (m, 1H), 7.62 (t, J=6.0 Hz, 2H), 7.39-7.25 (m, 5H), 4.47 (d, J=6.0 Hz, 2H), 2.65 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 184.5, 160.0, 154.0, 152.6, 146.9, 138.9, 136.1, 133.7, 129.9, 128.7, 128.3, 127.3, 126.9, 126.8, 125.7, 42.8, 17.1; MS (ES+) m/z 404.3 (M+1).
Reaction SMILES: CCCCCCCCCCCC.I[C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2.[C@@H]1(N)CCCC[C@H]1N.[CH3:32][O:33][C:34]([C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)=[O:35].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:32][O:33][C:34]([C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]([C:14]2[N:15]=[CH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:37]=1)=[O:35]
Reactant: Ic1cc2ccccc2cn1
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: CCCCCCCCCCCC
Solvent: C1COCCO1
Product: COC(=O)c1cn(-c2cc3ccccc3cn2)c2ccccc12
Temperature: 100 °C
Reaction time: 17 h
Yield: 156.9 %

Procedure:
25 cm3 of 1,4-dioxane, 0.256 cm3 of n-dodecane, 1.25 g (4.9 mmol) of 3-iodoisoquinoline and 0.582 cm3 (4.85 mmol) of trans-1,2-cyclohexanediamine are added at a temperature in the region of 22° C. under an argon atmosphere to 0.850 g (4.85 mmol) of 3-methoxycarbonyl-1H-indole, 2.2 g (10.36 mmol) of potassium orthophosphate and 0.085 g (0.45 mmol) of copper iodide. After stirring at a temperature in the region of 100° C. for 17 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is diluted with 100 cm3 of dichloromethane, the suspension obtained is filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give 2.3 g of a brown oil which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (85/15 by volume)]. After concentrating the fractions under reduced pressure, 1.1 g of 3-methoxycarbonyl-1-(isoquinol-3-yl)-1H-indole are obtained in the form of a white solid. Mass spectrum (EI): El: m/e 302 (M+·), m/e 271.
Reaction SMILES: [ClH:1].Cl.[CH3:3][C:4]1[CH:5]=[CH:6][C:7](OS(C2C=CC=CC=2S(N(C)CC2C=NC=CC=2)(=O)=O)(=O)=O)=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16].CC1C=CC([O:54][S:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[S:64]([N:67]([CH3:75])[CH2:68][C:69]2[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=2)(=[O:66])=[O:65])(=[O:57])=[O:56])=C(C=1)OCCCON.C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[ClH:1].[ClH:1].[CH3:3][C:4]1[CH:5]=[C:6]([O:54][S:55]([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=2[S:64]([N:67]([CH3:75])[CH2:68][C:69]2[CH:70]=[N:71][CH:72]=[CH:73][CH:74]=2)(=[O:65])=[O:66])(=[O:57])=[O:56])[CH:7]=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16]
Reactant: Cc1ccc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)Cc2cccnc2)c(OCCCONC(=N)N)c1
Reactant: Cc1ccc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)Cc2cccnc2)c(OCCCON)c1
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N(C)Cc2cccnc2)c1
Yield: 76 %

Procedure:
3-[5-Methyl-3-[(2-(N-methyl-N-(3-pyridylmethyl)aminosulfonyl)phenylsulfonyloxy]phenoxy]propoxy guanidine dihydrochloride: The title compound was prepared in 76% yield from 3-[5-methyl-3-[(2-(N-methyl-N-(3-pyridylmethyl)aminosulfonyl) phenylsulfonyloxy]phenoxy]propoxyamine, as prepared in the preceding step, in a manner analogous to step f of Example 1. 1H-NMR (300 MHz, DMSO-d6) δ 8.78 (t, J=5.2 Hz, 2H), 8.23 (m, 3H), 8.06 (t, J=7.7 Hz, 1H), 7.94 (t, J=7.7 Hz, 1H), 7.88 (t, J=7.9 Hz, 1H), 7.71 (br s, 4H), 6.75 (s, 1H), 6.55 (s, 1H), 6.51 (s, 1H), 4.72 (s, 2H), 3.99 (t, J=6.3 Hz, 2H), 3.90 (t, J=6.4 Hz, 2H), 2.88 (s, 3H), 2.22 (s, 3H), 2.01 (pentet, J=6.4 Hz, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C24H29N5O7S2: 564.2 (M+H), 586.1 (M+Na). Found: 564.1, 586.2.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:13][C:14]([CH3:28])([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]1)=[O:18])[CH3:15]>>[CH3:15][C:14]([CH3:28])([O:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([CH2:25][CH2:26][O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH2:1])[CH2:23][CH2:24]1)=[O:18])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCN(CCO)CC1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(C)(C)OC(=O)N1CCN(CCOC(=O)[C@@H](N)Cc2ccccc2)CC1
Yield: 78 %

Procedure:
N-(2-Chloro-6-methylbenzoyl)-4-[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine 2-[4-[(1,1-dimethylethoxy)carbonyl]-1-piperazinyl]ethyl ester was prepared in 78% yield from N-(2-chloro-6-methylbenzoyl)4-[(2,6-dichlorophenyl)carbonyl]amino]-L-phenylalanine and 2-[4-[(1,1-dimethylethoxy)carbonyl]-1-piperazinyl]ethanol using the procedure described in example 129. HR MS: Obs. mass, 717.1995. Calcd. mass, 717.2013 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:33][O:34][C:35]1[CH:41]=[CH:40][CH:39]=[C:37]([OH:38])[CH:36]=1.CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:38][C:37]3[CH:39]=[CH:40][CH:41]=[C:35]([O:34][CH3:33])[CH:36]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(O)c1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(OC(=O)c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 1.59 g (11.5 mmol) of powdered potassium carbonate, 1.43 g (11.5 mmol) of resorcinol monomethyl ether and 20 ml of dry dimethylformamide is stirred at room temperature for 2 days, then poured into 60 ml of water and extracted three times with methylene chloride. The organic extracts are washed once with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The residue obtained is chromatographed on silica gel while eluting with ethyl acetate/n-hexane (3:1) and subsequently crystallized from ethyl acetate. There is obtained m-methoxyphenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 184°-185°.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:14]=1[C:15]#[N:16].O.[OH-].[Li+]>CS(C)=O>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:12][C:13]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][C:14]=2[C:15]#[N:16])[CH:7]=1
Reactant: N#Cc1cc(C(F)(F)F)ccc1N
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc(C(F)(F)F)ccc1Nc1cc(F)ccc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Combine 2,4-difluoro-1-nitro-benzene (5.36 g, 33.69 mmol), 2-amino-5-trifluoromethyl-benzonitrile (5.701 g, 30.63 mmol) and lithium hydroxide monohydrate (2.57 g, 61.25 mmol) in methyl sulfoxide (DMSO, 70 ml). Heat the resulting mixture to 55° C. for 16 hours. Cool the reaction mixture to ambient temperature, then pour into approximately 250 ml of ice water and stir for one hour. Filter the resulting mixture, wash with a large amount of water and collect the precipitate to obtain 9.53 g of the title compound (29.30 mmol, 96% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 324(M−1).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[Si:28]([O:35][CH:36]([CH3:50])[C:37]([CH3:49])([CH3:48])[O:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Si:28]([O:35][CH:36]([CH3:50])[C:37]([CH3:49])([CH3:48])[O:38][C:39]1[CH:40]=[CH:41][C:42]([N:4]2[C:5](=[O:27])[C:6]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]2[CH2:1][CH3:2])=[CH:43][CH:44]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(O[Si](C)(C)C(C)(C)C)C(C)(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)C(C)O[Si](C)(C)C(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 85.4 %

Procedure:
To a suspension of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.56 g), [4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylpropoxy)phenyl]boronic acid (1.1 g), triethylamine (1.1 mL), pyridine (0.63 mL) and molecular sieves 4 A (1.1 g) in dichloromethane (10 mL) was added copper(II) acetate (0.56 g) and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.87 g, 87%).
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)#[CH:2].[C:10](OC(=O)C)(=[O:12])[CH3:11]>ClCCl>[C:10]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:1]#[CH:2])=[CH:4][CH:5]=1)(=[O:12])[CH3:11]
Reactant: C#Cc1ccc(N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: C#Cc1ccc(NC(C)=O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1.0 g of 4-ethynylaniline and 2.4 mL of acetic anhydride in 5.0 mL of dichloromethane was stirred at room temperature for 18 hours. The solution was evaporated in vacuo at 40° C. The resulting semi solid mixture was suspended in hexanes and filtered. The hexanes filtrate was washed twice with water and dried over sodium sulfate. After filtering it was combined with the hexanes insoluble residue, dissolved in dichloromethane and purified by column chromatography in the same solvent to yield 0.96 g of 1-acetamido-4-ethynylbenzene.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([CH2:10][C:11](=[O:13])[CH3:12])[CH:7]=[CH:6][C:5]=1[S:14]([NH2:17])(=[O:16])=[O:15]>O1CCOCC1>[Br:1][CH:10]([C:8]1[CH:7]=[CH:6][C:5]([S:14]([NH2:17])(=[O:16])=[O:15])=[C:4]([Cl:3])[CH:9]=1)[C:11](=[O:13])[CH3:12]
Reactant: BrBr
Reactant: CC(=O)Cc1ccc(S(N)(=O)=O)c(Cl)c1
Solvent: C1COCCO1
Product: CC(=O)C(Br)c1ccc(S(N)(=O)=O)c(Cl)c1
Yield: 145.8 %

Procedure:
Bromine 0.022 ml, 0.42 mmol) is added to a stirred solution of ketone (23c) (0.15 g, 6.1 mmol) in dioxan (15 ml). After 30 minutes the solvent is removed to give a brown oil (0.2 g).