Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[S:23]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24]1.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>[O:13]=[C:12]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:25]3[CH:26]=[CH:27][S:23][CH:24]=3)[CH:3]=2)[CH:8]=[CH:9][C:10]2[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][C:11]1=2
Reactant: OB(O)c1ccsc1
Reactant: CS(=O)(=O)Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
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+]
Product: CS(=O)(=O)Nc1ccc2ccc3ncc(-c4ccsc4)cc3c(=O)c2c1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide (0.100 g, 0.30 mmol), 3-thienylboronic acid (0.077 g, 0.60 mmol), tetrakis(triphenylphosphine)palladium (0) (10 mg, 0.009 mmol) and potassium carbonate (0.124 g, 0.90 mmol) were combined in a dry flask. The flask was purged with argon and 5 mL of dry dioxane was added. Argon was bubbled through the solution for 5 minutes and the solution was stirred and heated to 100° C. After 12 hours, the reaction mixture was poured into 100 mL of ethyl acetate, 100 mL of water, and 25 mL of saturated ammonium chloride. The organic layer was separated, dried with magnesium sulfate, filtered, concentrated, and purified by reverse phase HPLC (30-100% acetonitrile/water gradient, 0.1% trifluoroacetic acid modifier) to afford the title compound. 1H NMR (600 MHz, DMSO-D6) δ 10.40 (s, 1H); 9.34 (d, 1H); 8.70 (d, 1H); 8.28 (s, 1H); 8.00 (d, 1H); 7.78 (m, 2H); 7.73 (m, 1H); 7.58 (dd, 1H); 7.38 (d, 1H); 7.26 (d, 1H); 3.08 (s, 3H). LRMS (APCI) calculated for C19H15N2O3S2 [M+H]+, 383.0; found 383.1.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[C:25]([CH:30]([CH3:32])[CH3:31])[CH:24]=1.N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:21])[C:2]=1[S:29][C:26]1[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][C:25]=1[CH:30]([CH3:32])[CH3:31]
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Reactant: Cc1ccc(S)c(C(C)C)c1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1ccc(SC2=C(O)CC(c3ccccc3)(c3ccccc3)OC2=O)c(C(C)C)c1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 2.1 mmol of 4-methyl-2-isopropylbenzenethiol, and 2.1 mmol of piperidine in 30 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform (m.p. 185°-186° C.). 1H NMR (DMSO-d6) δ 1.17 (d, J=10 Hz, 6 H), 2.15 (s, 3 H), 3.17 (m, 1 H), 3.76 (bs, 2 H), 5.56 (d, 1 H), 6.29 (d, 1 H), 6.94 (s, 1 H), 7.32 -7.47 (m, 10 H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10]C(C)(C)C)=O)[CH2:4][CH:3]1[C:15]1[N:16]=[N:17][N:18]2[C:23]=1[C:22]1[CH:24]=[CH:25][NH:26][C:21]=1[N:20]=[CH:19]2.[C:27]([CH2:29]C(O)=O)#[N:28].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.O>O1CCOCC1.Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:10])[CH2:29][C:27]#[N:28])[CH2:4][CH:3]1[C:15]1[N:16]=[N:17][N:18]2[C:23]=1[C:22]1[CH:24]=[CH:25][NH:26][C:21]=1[N:20]=[CH:19]2
Reactant: CC1CCN(C(=O)OC(C)(C)C)CC1c1nnn2cnc3[nH]ccc3c12
Reactant: N#CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: CC1CCN(C(=O)CC#N)CC1c1nnn2cnc3[nH]ccc3c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 12 %

Procedure:
tert-Butyl 4-methyl-3-(7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidin-1-yl)piperidine-1-carboxylate (5.6 mg, 0.016 mmol) in 4 M hydrogen chloride-1,4-dioxane solution (1.0 mL) was stirred under cooling with ice for 1 hour and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1 mL) and mixed with 2-cyanoacetic acid (2.7 mg, 0.0314 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (11.9 mg, 0.0314 mmol) and then with N,N-diisopylethylamine (0.0082 mL, 0.0471 mmol) and stirred at room temperature for 2 hours. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel thin layer chromatography (NH-PLC05 plate manufactured by Fuji Silysia Chemical Ltd.: chloroform/methanol=15/1 (v/v)) and further purified by silica gel thin layer chromatography (ethyl acetate) to give the title compound as a pale yellow solid (0.62 mg, yield 12%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[C:14]([O:18][C:19]([N:21]1[CH2:24][CH:23]([CH2:25]OS(C)(=O)=O)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH2:24][CH:23]([CH2:25][N:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[N:7]=[CH:8][C:9]2=[O:13])[CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: COc1ccc2ncc(=O)[nH]c2c1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Product: COc1ccc2ncc(=O)n(CC3CN(C(=O)OC(C)(C)C)C3)c2c1
Yield: 35.7 %

Procedure:
Using the procedure of Example 2, step 2.i, but starting from 7-methoxy-2(1H)-quinoxalinone (1.00 g; prepared according to WO 2006/134378) and 3-[[(methylsulfonyl)oxy]methyl]-1-azetidinecarboxylic acid tert-butyl ester (1.65 g; prepared according to WO 02/066470), the second eluting compound was isolated as a yellow oil (700 mg, 35% yield).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]=[CH:11][CH:12]([C:14]3([CH2:17][CH3:18])[CH2:16][CH2:15]3)O)=[CH:4][C:3]=2[O:2]1.P(Br)(Br)[Br:20].[Br-].[Li+]>[Br-].[Zn+2].[Br-]>[CH2:17]([C:14](=[CH:12][CH:11]=[CH:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)[CH2:15][CH2:16][Br:20])[CH3:18]
Reactant: CCC1(C(O)C=Cc2ccc3c(c2)OCO3)CC1
Reactant: BrP(Br)Br
Agent: [Br-]
Agent: [Li+]
Agent: [Zn+2]
Product: CCC(=CC=Cc1ccc2c(c1)OCO2)CCBr

Procedure:
3-Ethyl-6-(3,4-methylenedioxyphenyl)-3,5-hexadienyl bromide [VIII; Ar is 3,4-methylenedioxyphenyl, R is C2H5 ] was prepared from 3.6 g. of 2-(3,4-methylenedioxyphenyl)vinyl 1-ethylcyclopropyl carbinol (Preparation B9), 3.5 g. of phosphorus tribromide, 4.5 g. of lithium bromide and 3.5 g. of zinc bromide according to the procedure given above in Preparation C1, affording 2 g. of product as an oil.
Reaction SMILES: [N:1]1([C:6]2[CH:28]=[CH:27][C:9]([CH2:10][NH:11][CH2:12][C:13]3[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=3)[O:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C(N(CC)CC)C.[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:37]=1>ClCCl>[N:1]1([C:6]2[CH:28]=[CH:27][C:9]([CH2:10][N:11]([CH2:12][C:13]3[CH:14]=[C:15]([CH:24]=[CH:25][CH:26]=3)[O:16][CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[S:42]([C:38]3[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=3)(=[O:44])=[O:43])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CC(C)OC(=O)COc1cccc(CNCc2ccc(-n3cccn3)cc2)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)COc1cccc(CN(Cc2ccc(-n3cccn3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
A solution of isopropyl [3-({[4-(1H-pyrazol-1-yl)benzyl]amino}methyl)-phenoxy]acetate (0.28 g, 0.75 mmol), triethylamine (0.53 mL, 0.37 mmol) and pyridine-3-sulfonyl chloride (268 mg, 1.50 mmol) in dichloromethane (7 mL) was stirred at room temperature for 15 hours. The mixture was diluted with dichloromethane, and the combined organic layers were washed with water, brine and dried over MgSO4, filtered, and concentrated in vacuo. Purification by column chromatography (0-5% methanol in dichloromethane) afforded the desired product (180 mg, 69% based on the recovered amine starting material) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (d, J=5.56 Hz, 6H) 4.37 (s, 2H) 4.42 (s, 2H) 4.50 (s, 2H) 5.06-5.25 (m, 1H) 6.49 (s, 1H) 6.65-6.75 (m, 2H) 6.77-6.84 (m, 1H) 7.17-7.23 (m, J=8.59 Hz, 3H) 7.46 (dd, J=7.83, 4.80 Hz, 1H) 7.60 (d, J=8.34 Hz, 2H) 7.74 (s, 1H) 7.92 (s, 1H) 8.08 (d, J=7.83 Hz, 1H) 8.83 (d, J=4.29 Hz, 1H) 9.09 (s, 1H). LRMS m/z calcd. for C27H28N4O5S ([M+H]+): 520.2. Found: 521.2.
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:12][CH:13]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])[C:14](Cl)=[O:15]>ClCCl>[C:1]([O:5][C:14](=[O:15])[CH:13]([Cl:12])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[Cl:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)O
Reactant: O=C(Cl)C(Cl)c1ccc(Cl)cc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C(Cl)c1ccc(Cl)cc1Cl
Yield: 82.6 %

Procedure:
While stirring and with ice cooling, a solution of 17.6 g of t-butanol and 19.2 ml of pyridine in 60 ml of dichloromethane is dripped into a solution, cooled at 5° C., of 62 g of α-chloro-α-(2,4-dichlorophenyl)-acetyl chloride in 60 ml of dichloromethane in such a manner that the temperature of the reaction mixture stays below 10° C. After all the solution has been dripped in, the mixture is stirred overnight at room temperature, is then diluted with 100 ml of dichloromethane and extracted 5 times, each time with 100 ml of water. The organic phase is dried over magnesium sulfate and distilled after the solvent has been evaporated. There is obtained 58 g of α-chloro-α-(2,4-dichlorophenyl)-acetic acid t-butyl ester as a colorless oil; b.p. 98°-103° C./0.13 mbar.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:14]2[C@@H:13]3[CH2:15][C@@H:12]3[CH2:11][C:10]=2[C:9]([C:16]([OH:18])=O)=[N:8]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[Cl-].[C:51]([NH:55][NH3+:56])([CH3:54])([CH3:53])[CH3:52]>C(#N)C>[C:51]([NH:55][NH:56][C:16]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:15][C@H:13]3[C:14]=2[N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[N:8]=1)=[O:18])([CH3:54])([CH3:53])[CH3:52]
Reactant: O=C(O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(C)N[NH3+]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)NNC(=O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a suspension of (1aR,5aR)-2-(pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (1.211 g, 5.0 mmol) and HATU (2.091 g, 5.50 mmol) in acetonitrile (100 mL) was added triethylamine (1.771 g, 17.50 mmol) at room temperature. 2-tert-Butylhydrazinium chloride (0.748 g, 6.00 mmol) was added to the solution and the reaction was stirred for 12 at room temperature. The mixture was concentrated. The residue was diluted with EtOAc (150 mL) and washed with NaHCO3 solution (100 mL). The organic layer was concentrated and purified by silica gel column chromatography to give the title compound (1.42 g) as a glassy solid. LCMS m/z=313.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.49 (dd, J=8.0 and 4.7 Hz, 1H), 1.18 (s, 9H), 1.24-1.29 (m, 1H), 2.29-2.34 (m, 1H), 2.75-2.80 (m, 1H), 2.94 (d, J=16.9 Hz, 1H), 3.03 (dd, J=16.5 and 6.2 Hz, 1H), 4.75 (bs, NH, 1H), 805 (bs, NH, 1H), 8.41 (dd, J=2.5 and 1.5 Hz, 1H), 8.51 (d, J=2.6 Hz, 1H), 9.26 (d, J=1.4 Hz, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([NH2:8])=[S:7])(=[O:3])[CH3:2].Cl[CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=O>CN(C)C=O>[C:1]([O:4][CH2:5][C:6]1[S:7][C:10]2[CH2:14][CH2:13][CH2:12][C:11]=2[N:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(N)=S
Reactant: O=C1CCCC1Cl
Solvent: CN(C)C=O
Product: CC(=O)OCc1nc2c(s1)CCC2
Temperature: 80 °C
Reaction time: 24 h
Yield: 33.8 %

Procedure:
A mixture of 2-acetoxythioacetamide (10 g), 2-chlorocyclopentanone (10.6 g) and dimethylformamide (100 ml) was stirred for 24 hours at 80° C. The reaction mixture was cooled and poured into ice-water (500 ml), followed by extraction twice with ethyl acetate (200 ml). The extract was washed twice with water (100 ml), which was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel chromatography (2.5×50 cm), eluting with ethyl acetate-hexane (3:7). The object fraction was concentrated to give 2-acetoxymethyl-5,6-dihydro-4H-cyclopentathiazole (5 g) as a yellow oily product.
Reaction SMILES: [OH:1][CH:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:21]([NH:23][C:24]2[CH:25]=[C:26]3[C:31](=[CH:32][CH:33]=2)[CH:30]=[N:29][CH:28]=[CH:27]3)=[O:22])[CH2:12][NH:13]C(=O)OC(C)(C)C)=[CH:7][CH:6]=1.[ClH:40]>C(Cl)Cl>[ClH:40].[ClH:40].[NH2:13][CH2:12][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH:2]([OH:1])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:6][CH:7]=1)[C:21]([NH:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[N:29][CH:28]=[CH:27]2)=[O:22]
Reactant: CC(C)(C)OC(=O)NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(OCC(O)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Product: NCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(OCC(O)c2ccccc2)cc1
Reaction time: 8 h

Procedure:
To tert-butyl 2-(4-(2-hydroxy-2-phenylethoxy)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropylcarbamate (E276) in CH2Cl2 was added HCl (4 N, dioxane) and the solution was stirred overnight. The solvents were evaporated to give 3-amino-2-(4-(2-hydroxy-2-phenylethoxy)phenyl)-N-(isoquinolin-6-yl)propanamide dihydrochloride (E278).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1([C:36]2[C:37]([O:42][CH2:43][CH3:44])=[N:38][CH:39]=[CH:40][CH:41]=2)[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([Cl:21])[CH:19]=2)[N:14]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=2[O:33][CH3:34])(=[O:24])=[O:23])[C:13]1=[O:35]>ClCCl.N1C=CC=CC=1>[Cl:21][C:18]1[CH:19]=[C:20]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=1[O:33][CH3:34])(=[O:23])=[O:24])[C:13](=[O:35])[C:12]2([NH:11][C:2](=[O:3])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:36]1[C:37]([O:42][CH2:43][CH3:44])=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCOc1ncccc1C1(N)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(Cl)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1ncccc1C1(NC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
0.83 ml (6.6 mmol) of phenyl chloroformate was slowly added dropwise to a solution, cooled to 0° C., of 2.57 g (5.1 mmol) of 3-amino-5-chloro-1-(2,4-dimethoxyphenylsulfonyl)-3-(2-ethoxypyridin-3-yl)-1,3-dihydroindol-2-one in 10 ml of dichloromethane and 4.1 ml of pyridine. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and extracted with water. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in a little dichloromethane, and six times the volume of diisopropyl ether were added. The resulting precipitate was filtered off, washed with diisopropyl ether and dried in vacuo. 3.01 g of the title compound were obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[Cl:21][C:22]1[CH:23]=[C:24]([CH2:29][C:30](OC)=O)[CH:25]=[CH:26][C:27]=1[Cl:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:29][C:30]1[NH:20][C:18](=[O:19])[C:3]2[N:4]=[N:5][N:6]([CH:7]([CH3:17])[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[N:1]=1
Reactant: CC(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Product: CC(CCCc1ccccc1)n1nnc2c(=O)[nH]c(Cc3ccc(Cl)c(Cl)c3)nc21

Procedure:
Analogously to the procedure of Example 5, the title compound is prepared from 1.0 g (3.8 mmol) of 5-amino-1-(1-methyl-4-phenyl-butyl)-1H-[1,2,3]triazole-4-carboxamide and 2.5 g (11.4 mmol) of methyl 3,4-dichlorophenylacetate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[Na+].[Cl-].[OH2:22]>>[OH:1][CH2:2][CH2:3][NH:4][CH2:8][CH2:7][NH:6][C:5](=[O:22])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O
Reactant: CCCCCCCCCCCC1=NCCN1CCO
Agent: [Cl-]
Agent: [Na+]
Product: CCCCCCCCCCCC(=O)NCCNCCO

Procedure:
22 g of 1-(2-hydroxyethyl)-2-undecyl-2-imidazoline and 300 ml of water was stirred at 40°-50° C. for 24 hours. The resulting soapy solution was salted with 50 g of NaCl and then extracted with 500 ml ethyl acetate. The organic layer was dried, filtered and concentrated to give 23 g of solid. This material was dissolved in hexane by heating at 50 C. for 2 hrs., then cooled to room temperature and filtered to afford 18.8 g of pure product, m.p. 92°-94° C.
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([SH:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].C1CCN2C(=NCCC2)CC1>C(O)C>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([S:20][C:2]2[NH:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CCO
Solvent: C1CCC2=NCCCN2CC1
Product: O=[N+]([O-])c1ccc(Sc2nc3ccccc3[nH]2)cc1
Yield: 15.3 %

Procedure:
2-Chlorobenzimidazole (0.033 moles, 5.0 g), 4-nitrothiophenol (0.033 moles, 4.14 g), and DBU (0.033 moles, 5.0 g) in 200 ml ethanol were heated at 55° C. for 3 hr. The reaction was concentrated, ethyl acetate added, washed with water, dried over sodium sulfate and the solvent removed. The solid was slurred in hexane to yield 2-(4-nitrophenylthio)benzimidazole 1.37 g, 15%. Mass Spec (FD) 271. Calculated for C13H8N3O2S: C, 57.55; H, 3.34; N, 15.49. Found: C, 57.50; H, 5.54; N, 15.23.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([NH:17][CH3:18])[C:9]2=O.Cl>[Pd].C(O)C>[ClH:1].[CH3:2][O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([NH:17][CH3:18])[CH2:9]2
Reactant: CNC1CCc2c(ccc(OC)c2OC)C1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CNC1CCc2c(ccc(OC)c2OC)C1
Reaction time: 24 h

Procedure:
14.0 g of 5,6-dimethoxy-2-methylamino-1-tetralone hydrochloride (0.051 mole), 400 ml of absolute ethanol, 10 ml of 1M methanolic HCl and 4.0 g of 5% Pd/C are placed into an autoclave (50% humidity), then the mixture is hydrogenated (P about 7 atm., T=80° C.) with stirring for 24 hours. The mixture is filtered, washing thoroughly the filtration cake with hot methanol, then the alcoholic solution is evaporated to dryness. The resulting solid is taken up into 150 ml of acetone, then the precipitate is filtered and dried under vacuum at 60° C. Yield: 10.8 g, 82% (moles), 77% (weight); M.p.=219-220° C.
Reaction SMILES: F[C:2](F)(F)[C:3]1[CH:8]=CN=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:4]=1.Cl[C:20]1N=C(C(F)(F)F)C=C[N:21]=1>>[CH3:2][C:3]1[N:4]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[CH:20]=[N:21][CH:8]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: FC(F)(F)c1ccnc(N2C[C@@H]3CCNC[C@@H]32)n1
Product: Cc1cncc(N2C[C@@H]3CCNC[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 27, substituting 2-bromo-6-methylpyrazine for 2-chloro-4-(trifluoromethyl)pyrimidine.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[S:8][C:4]=2[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI>O1CCCC1>[I:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([S:9][CH3:12])[S:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Sc1nc2ccc(I)cc2s1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1nc2ccc(I)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred, room temperature mixture of 6-iodobenzo[d]thiazole-2-thiol (Reference Example 6a, 1.5 g, 5.1 mmol) and potassium carbonate (0.707 g, 5.1 mmol) in tetrahydrofuran (30 mL) was added methyl iodide (0.35 mL, 5.6 mmol). The reaction mixture was stirred at room temperature overnight, then volatiles were removed under reduced pressure to give a solid. The solid was partitioned between saturated aqueous sodium carbonate and chloroform. The chloroform layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to provide 6-iodo-2-(methylthio)benzo[d]thiazole. 1H NMR (300 MHz, CDCl3) δ ppm 2.78 (s, 3H), 7.58 (d, J=9 Hz, 1H), 7.69 (dd, J=2, 9 Hz, 1H), 8.07 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 308 (M+H)+.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:51]=[C:50]([CH3:52])[C:45]4[NH:46][C:47](=[O:49])[O:48][C:44]=4[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([O:38]CC)=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:53]=[CH:54][CH:55]=[CH:56][C:6]=2[NH:5]1.Cl>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:41][C:42]3[CH:51]=[C:50]([CH3:52])[C:45]4[NH:46][C:47](=[O:49])[O:48][C:44]=4[CH:43]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([CH:29]4[CH2:34][CH2:33][N:32]([CH2:35][C:36]([OH:38])=[O:37])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:53]=[CH:54][CH:55]=[CH:56][C:6]=2[NH:5]1
Reactant: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(C)c4[nH]c(=O)oc4c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(C3CCN(CC(=O)O)CC3)CC2)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 39 mg (1.61 mmol) LiOH in 5 mL water was added to a solution of 240 mg (0.32 mmol) (R)-2-(1′-ethoxycarbonylmethyl-4,4′-bipiperidinyl-1-yl)-1-(4-methyl-2-oxo-2,3-dihydrobenzoxazol-6-ylmethyl)-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 10 mL THF and the reaction solution was stirred for 1 h at RT. 1.61 mL of 1 M HCl was added and the mixture was evaporated down i.vac. The residue was combined with a little water, stirred, the water was decanted off and the residue was dried in the air.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=2)=[CH:4][CH:3]=1
Reactant: OCc1ccc(Br)cc1
Reactant: Cc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCc2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of (4-bromo-phenyl)-methanol (4.54 g, 24.3 mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride (999 mg, 25 mmol, 60% in oil) under nitrogen atmosphere on an ice bath (0° C.), which was stirred for 30 minutes at room temperature. 2-Fluoro-6-methylpyridine (1.8 g, 16.2 mmol) was then added to the reaction mixture on an ice bath (0° C.), and stirred for 5 hours at room temperature. The reaction mixture was partitioned into water and ethyl acetate on the ice bath (0° C.). The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:15) to obtain the title compound (3.65 g, 81%).