Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:5]([O:7][CH3:8])=[O:6])[CH2:3]I.[C:16]1(=O)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]1>CN(C=O)C.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].II.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>[C:12]([O:11][C:9]([NH:1][C@@H:2]([CH2:3][C:16]1[CH2:20][CH2:19][C:18](=[O:21])[CH:17]=1)[C:5]([O:7][CH3:8])=[O:6])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)[C@H](CI)NC(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)C1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: II
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CC1=CC(=O)CC1)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
Boc-β-Iodo-Ala-OMe (1.0 g, 3 mmol) was added to a slurry of zinc dust (0.596 g, 9 mmol) and I2 (0.2 mg) in 3 ml DMF under N2. The mixture was stirred for 1 h then Pd2 dba3 (0.070 g, 0.076 mmol), SPhos ligand (0.062 g, 0.15 mmol), and 1,3-cyclopentanedione (0.63 g, 3.9 mmol) were added. The reaction mixture was stirred over night. Purification by flash chromatography (0-100% EtOAc in iso-hexane) gave compound the title compound (0.468 g) in 70% yield. [M+H]+: 284.
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=1)=[O:5].O1C=CN=C1[Cl:25]>CN(C)C=O.ClCCl>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:25])=[O:12])=[CH:9][N:8]=1)=[O:5]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)O)cn1
Reactant: Clc1ncco1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 6-(2-methylbenzoylamino)nicotinic acid (0.3 g) in dimethylformamide (0.5 ml) and dichloromethane (2.5 ml) is added dropwise oxazolyl chloride (0.2 ml), and the mixture is stirred at room temperature for 2 hours. The mixture is evaporated under reduced pressure to remove the solvent to give 6-(2-methylbenzoylamino)nicotinoyl chloride.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].[F:4][C:5]([F:15])([F:14])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O>C(O)C>[F:4][C:5]([F:15])([F:14])[C:6](=[N:3][OH:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [NH3+]O
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: [Cl-]
Solvent: CCO
Product: ON=C(c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.5 %

Procedure:
A mixture of hydroxylammonium chloride (13.9 g, 200 mmol) and 2,2,2-trifluoroacetophenone (17.4 g, 92 mmol) in absolute ethanol (150 ml) was heated at reflux for 1 h and then stirred at ambient temperature for 16 h. The solvent was evaporated in vacuo, the residue suspended in water (100 ml), filtered and washed with water (20 ml), n-heptane (20 ml) and dried to give 14.0 g 2,2,2-trifluoroacetophenone oxime.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].[N+:30]([C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)([O-:32])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1C=CC=CC=1>[N+:30]([C:33]1[CH:34]=[CH:35][C:36]([C:37]([O:27][C@H:19]2[CH2:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:18]2[NH:17][C:12]2[C:11]([CH2:28][CH3:29])=[N:10][C:9]([C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])=[C:14]([CH2:15][CH3:16])[N:13]=2)=[O:38])=[CH:40][CH:41]=1)([O-:32])=[O:31]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@H]1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A solution of (1S,2R)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol (321 mg, 0.75 mmol), 4-nitrobenzoic acid (552 mg, 3.3 mmol), and triphenylphosphine (964 mg, 3.7 mmol) in benzene (19 mL) was purged with nitrogen and cooled to 0° C. The resulting yellow suspension was treated with diethylazodicarboxylate (0.58 mL, 3.7 mmol) becoming lighter in color with gradual warming to RT. After 18 hours, the volatiles were removed under reduced pressure with the resulting crude residue being absorbed on 6 g silica gel and purified by Biotage MPLC (40 g column, 15% ethyl acetate/heptane) to afford the title compound as a light yellow solid. IR (diffuse reflectance) 1725, 1568, 1550, 1527, 1498, 1467, 1392, 1372, 1349, 1320, 1273, 1119, 1103, 836, 719 cm−1; OAMS supporting ions at: ESI+ 576.8; MS (CI) m/z 577 (MH+); HRMS (FAB) calcd for C30H26CL2N4O4 +H1 577.1409, found 577.1417.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[N:10]([CH2:11][CH2:12][CH3:13])[C:9](=[O:14])[N:8]2[C:4]([N:5](C(NCCC)=O)[C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=32)=[N:3]1.[OH-].[Na+]>C1COCC1>[CH3:25][C:2]1([CH3:1])[N:10]([CH2:11][CH2:12][CH3:13])[C:9](=[O:14])[N:8]2[C:4](=[N:5][C:6]3[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=32)[NH:3]1
Reactant: CCCNC(=O)N1C2=NC(C)(C)N(CCC)C(=O)N2c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCN1C(=O)n2c(nc3ccccc32)NC1(C)C

Procedure:
The title compound was prepared by hydrolysis of the precursor compound of Example 3 in the presence of 10% aqueous sodium hydroxide and THF employing the method of paragraph 2, Example 1. The product was crystallized from acetone to give colorless prisms, mp 170° C. (dec). The confirmatory elemental analysis is shown in Table III.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][NH:8][C:7]2=O)([O-])=O.ClC1C=C(NC2C3C(=CC=C(N)C=3)N=CN=2)C=CC=1OCC1C=CC=C(F)C=1.[CH3:43][C:44]1[CH:45]=[C:46]([NH2:58])[CH:47]=[CH:48][C:49]=1[O:50][C:51]1[CH:52]=[N:53][C:54]([CH3:57])=[CH:55][CH:56]=1>>[CH3:43][C:44]1[CH:45]=[C:46]([NH:58][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([NH2:1])[CH:5]=3)[N:10]=[CH:9][N:8]=2)[CH:47]=[CH:48][C:49]=1[O:50][C:51]1[CH:52]=[N:53][C:54]([CH3:57])=[CH:55][CH:56]=1
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: O=c1[nH]cnc2ccc([N+](=O)[O-])cc12
Agent: Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4ccc(N)cc34)cc2C)cn1
Yield: 56 %

Procedure:
The procedures of (1-1) to (1-4) of Example 1 were repeated except for using 3-methyl-4-(6-methyl-pyridin-3-yloxy)-phenylamine instead of 3-chloro-4-(3-fluoro-benzyloxy)-phenylamine to obtain the title compound (0.38 g, 56%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([N:13]=[N+]=[N-])[CH2:10][CH:9]1[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OC(=O)C)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([NH2:13])[CH2:10][CH:9]1[CH3:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CC(N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Product: CC1CC(N)CN1C(=O)OC(C)(C)C
Reaction time: 12 h

Procedure:
The 4-azido-2-methyl-pyrrolidine-1-carboxylic acid t-butyl ester (93.41 mg, 0.41 mmol) was taken up in ethyl-acetate in a Paar vessel. The solution was flushed with argon and Pd/C (100.00 mg) was added to the vessel. The argon atmosphere was replaced by hydrogen at 50 psi. The vessel was shaken for 12 h. The hydrogen atmosphere was replaced by argon and the solution was filtered through a celite pad. The pad was washed twice with ethyl acetate. The solvent was removed under reduced pressure. The product was used without further purification. Yield 79.65 mg.C10H20N2O2 MS m/e=200.2 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH3:13])([CH3:14])[C:6]=2[CH:15]=1
Reactant: CN1C(=O)OC(C)(C)c2cc(N)ccc21
Reactant: OB(O)c1ccccc1Cl
Product: CN1C(=O)OC(C)(C)c2cc(Nc3ccccc3Cl)ccc21

Procedure:
Prepared from 6-amino-1,4,4-trimethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 2-chlorophenyl boronic acid according to the coupling procedure described in example 1. MS (ESI) m/z [M+H]+(317/319); MS (ESI) m/z [M−H]−(315/317); Anal. calcd for C17H17ClN2O2: C, 64.46; H, 5.41; N, 8.84. Found: C, 64.42; H, 5.29; N, 8.76.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].CO.C([O-])(=O)C.[Na+].[F:17][C:18]([F:25])([F:24])[C:19]([F:23])([F:22])[C:20]#[N:21]>O>[C:3]([C:2](=[C:20]([NH2:21])[C:19]([F:23])([F:22])[C:18]([F:25])([F:24])[F:17])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: N#CC(F)(F)C(F)(F)F
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)C(C(C)=O)=C(N)C(F)(F)C(F)(F)F
Yield: 29.1 %

Procedure:
To a stirred mixture of 65 g (0.4995 mole) of ethyl acetoacetate, 200 ml. of methanol and 100 ml. of saturated sodium acetate at 50° C. was introduced 100 g (0.769 mole) of pentafluoropropionitrile in 3 hours. The reaction mixture was poured into 1200 ml. of water. An oil separated from the reaction mixture. The aqueous solution was extracted with ether. The ether solution was combined with the oil, dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 40 g (37%) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate. A mixture of 21.8 g (0.0790 mole) of ethyl 2-acetyl-3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 75 ml. of 58% ammonium hydroxide was stirred for 66 hours. The reaction mixture was extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 16.3 g (88%) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate, nD25 =1.4011. A well stirred mixture of 54 g (0.23 mole) of ethyl 3-amino-4,4,5,5,5-pentafluoro-2-pentenoate and 31 g (0.237 mole) of chlorocarbonylsulfenyl chloride was held at 100° C. for 1 hour. The reaction mixture was cooled and triturated with hexane. The solid precipitate was washed with water and recrystallized from hexane-ether to give 31 g (46%) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, m.p. 95°-97° C. A mixture of 10 g (0.0344 mole) of ethyl 2,3-dihydro-2-oxo-4-pentafluoroethyl-5-thiazolecarboxylate, 4 g (0.0506 mole) of pyridine and 150 ml. of phosphorus oxychloride was held at reflux for 18 hours. Excess phosphorus oxychloride was removed under reduced pressure. The residue was treated with water and extracted with ether. The ether solution was dried (MgSO4) and concentrated under reduced pressure. The residue was distilled to give 7.5 g (71%) of ethyl 2-chloro-4-pentafluoroethyl-5-thiazolecarboxylate, nD25 =1.4460.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C:18]4[S:19][C:20]5[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=5[N:22]=4)=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:29]I>CN(C=O)C>[CH3:29][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][C:18]3[S:19][C:20]4[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:12]=2)[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:9]1
Reactant: CI
Reactant: c1ccc2sc(Oc3ccc4c(CN5CCOCC5)c[nH]c4c3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(CN2CCOCC2)c2ccc(Oc3nc4ccccc4s3)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 43.1 %

Procedure:
To a cooled (0° C.) solution of 2-(3-morpholin-4-ylmethyl-1H-indol-6-yloxy)-benzothiazole (280 mg, 0.77 mmol) in DMF (4 mL) was added NaH (95%, 29 mg, 1.15 mmol) and the resulting suspension was stirred (0° C., 15 min) then warmed (rt, 30 min). The reaction mixture was cooled (0° C.) and treated with methyliodide (72 μL, 163 mg, 1.15 mmol) and then warmed (rt, 30 min). The reaction mixture was partitioned with EtOAc and brine (20 mL each). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using MeOH:DCM (0-20%) to provide the title compound as a clear oil (126 mg, 43%). MS (ESI): mass calcd. for C21H21N3O2S, 379.4; m/z found, 380.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.79 (d, J=8.6, 1H), 7.76 (d, J=7.7, 1H), 7.66 (d, J=8.0, 1H), 7.41-7.38 (m, 1H), 7.29 (d, J=2.1, 1H), 7.29-7.25 (m, 1H), 7.12 (dd, J=8.6, 2.1, 1H), 3.77 (5, 3H), 3.74 (t, J=4.6, 4H), 3.71 (5, 2H), 2.53 (br s, 4H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([I:27])[C:25]=1[OH:26])[C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:6]>C(O)(=O)C.Cl>[I:27][C:24]1[CH:23]=[C:4]([CH:3]=[C:2]([I:1])[C:25]=1[OH:26])[C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[O:9][C:8]=1[CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[O:6]
Reactant: CCOC(=O)CCc1oc2ccccc2c1C(=O)c1cc(I)c(O)c(I)c1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CCc1oc2ccccc2c1C(=O)c1cc(I)c(O)c(I)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
300 g of compound 5 are dissolved in 200 ml of acetic acid and 300 ml of 12N HCl. Stir at 90° C. for 2 hours and distill at least 400 ml of solvent. Cool to room temperature and add 1 L of water. Stir well for 2 hours and filter. Wash with water. Dry.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:8].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[CH2:29]([O:28][C:26]([CH2:25][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:18][CH2:19][C:20]([F:23])([F:21])[F:22])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:8])=[O:27])[CH3:30]
Reactant: CCOC(=O)CBr
Reactant: O=C(NCc1ccccn1)c1cc(O)ccc1OCC(F)(F)F
Product: CCOC(=O)COc1ccc(OCC(F)(F)F)c(C(=O)NCc2ccccn2)c1

Procedure:
Using the general method of Example I Part A, 10.4 g (0.032 mole) of 5-hydroxy-N-(2-pyridylmethyl)-2-(2,2,2- trifluoroethoxy)benzamide was reacted with 7.45 g (0.045 mole) of ethyl bromoacetate to give 5.0 g of ivory powdery 5-(ethoxycarbonylmethoxy)-N-(2-pyridylmethyl)-2-(2,2,2- trifluoroethoxy)benzamide, m.p. 73°-76° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)([CH:10]2[CH2:15][CH2:14][N:13](S(C3C=CC=CC=3)(=O)=O)[CH2:12][CH2:11]2)O)=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.[BrH:39]>>[BrH:39].[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:26][CH:27]=1
Reactant: O=S(=O)(c1ccccc1)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: Br
Solvent: Oc1ccccc1
Product: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
A mixture of 164 g (0.342 mole) of α,α-bis(4-fluorophenyl)-1-(phenylsulfonyl)-4-piperidinemethanol and 80 g (80 g) of phenol in 700 ml of 48% hydrobromic acid was heated at reflux for 7 hr and then was stirred at room temperature for 9 hr. The hydrobromic acid solution was decanted from a gum in the bottom of the reaction flask. The gum was triturated with ~1 liter of ether, and a tan solid formed. The solid was washed with several portions of ether and was dried under high vacuum to give 9.13 g (73%) of slightly impure title product, m.p. 211°-215° C. A small sample of this solid was recrystallized from methanol to give an analytically pure sample as a crystalline solid; m.p. 216°-218° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]2[C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:27]([N:30]1[CH2:35][CH2:34][CH:33]([C:36](O)=[O:37])[CH2:32][CH2:31]1)(=[O:29])[CH3:28].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(#N)C.O.C(N(CC)CC)C>[C:27]([N:30]1[CH2:31][CH2:32][CH:33]([C:36]([N:14]2[CH2:15][CH2:16][C@@H:11]([N:9]([CH3:10])[C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:26][CH:25]=3)[C@H:12]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=3)[CH2:13]2)=[O:37])[CH2:34][CH2:35]1)(=[O:29])[CH3:28]
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCNC[C@H]1c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N1CCC(C(=O)N2CC[C@@H](N(C)C(=O)c3ccc(Cl)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 44.5 %

Procedure:
To a solution of 4-chloro-N-[(3R,4R)-3-(3,4-dichlorophenyl)piperidin-4-yl]-N-methylbenzamide monohydrochloride (200 mg) obtained in Example 137a, 1-acetylpiperidine-4-carboxylic acid (118 mg) and triethylamine (127 μL) in acetonitrile (5 mL) were added WSC.HCl (176 mg) and HOBt (140 mg), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH Chromatorex) (solvent gradient; 15→100% ethyl acetate/hexane) to give the title compound (113 mg, 44%) as a white powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(NC(C)C)(C)C.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[NH2:11])=[CH:22][CH:21]=1
Reactant: COc1ccc(NN)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 72 %

Procedure:
To a suspension of 4-methoxyphenylhydrazine hydrochloride (41 g, 230 mmol) in methylene chloride (1000 ml) under nitrogen were added diisopropylamine (79.8 g, 612 mmol), 4-chlorobenzylchloride (40.25 g, 250 mmol) and tetrabutylammonium bromide (22.8 g, 70 mmol). The resulting mixture was stirred at ambient temperature for 48 hours. The reaction mixture was then washed with water, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 2.5% methanol in methylene chloride) followed by washing of the solid with 10% ethyl ether in hexane and drying in vacuo to provide 43.5 g of 1-(4-chlorobenzyl)-1-(4methoxyphenyl)hydrazine, mp. 55° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([SH:15])=[N:6][C:5]=2[N:16]=1.Cl[CH2:18][C:19]1[N:20]=[C:21]([NH:24][C:25](=[O:27])[CH3:26])[S:22][CH:23]=1>>[NH2:1][C:2]1[S:3][C:4]2[C:9]([NH:10][C@H:11]([CH3:14])[CH2:12][OH:13])=[N:8][C:7]([S:15][CH2:18][C:19]3[N:20]=[C:21]([NH:24][C:25](=[O:27])[CH3:26])[S:22][CH:23]=3)=[N:6][C:5]=2[N:16]=1
Reactant: CC(=O)Nc1nc(CCl)cs1
Reactant: C[C@H](CO)Nc1nc(S)nc2nc(N)sc12
Product: CC(=O)Nc1nc(CSc2nc(N[C@H](C)CO)c3sc(N)nc3n2)cs1

Procedure:
The titled compound was prepared from the product of example 4, step (b), and N-[4-(chloromethyl)-2-thiazolyl]-acetamide, using the method of example 4, step (c)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[C:20]5[CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26][C:21]=5[N:22]([CH3:25])[C:23]=4[CH:24]=3)[C:12](=[O:37])[CH:11]=2)=[N:6][CH:7]=1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:50].Cl>>[ClH:50].[ClH:50].[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]([C:16]3[CH:17]=[CH:18][C:19]4[C:20]5[CH2:29][NH:28][CH2:27][CH2:26][C:21]=5[N:22]([CH3:25])[C:23]=4[CH:24]=3)[C:12](=[O:37])[CH:11]=2)=[N:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccc(F)cn5)cc4=O)cc31)CNCC2
Yield: 84 %

Procedure:
tert-Butyl 7-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (415 mg, 0.823 mmol) was deprotected and converted to the dihydrochloride according to procedure of Example 30 (steps e and g) to provide the title compound (328 mg, 84%) as a white solid: mp 174-180° C.; 1H NMR (500 MHz, CD3OD) δ 8.70 (s, 1H), 8.00 (dt, J=8.4, 2.8 Hz, 1H), 7.91-7.88 (m, 2H), 7.63 (d, J=8.4 Hz, 1H), 7.55 (s, 1H), 7.11 (dd, J=8.3, 1.7 Hz, 1H), 6.69 (dd, J=7.5, 2.7 Hz, 1H), 6.45 (d, J=2.6 Hz, 1H), 5.46 (s, 2H), 4.49 (s, 2H), 3.75 (s, 3H), 3.68 (t, J=6.1 Hz, 2H), 3.22 (t, J=6.1 Hz, 2H); ESI MS m/z 405 [M+H]+; HPLC (Method B) 95.5% (AUC), tR=10.9 min.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH2:23][OH:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[C:12](=O)[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2].Cl.[NH2:26][OH:27]>C(O)C>[CH2:1]([N:3]([CH2:22][CH2:23][OH:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[C:12](=[N:26][OH:27])[CH:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: NO
Reactant: CCN(CCO)c1ccc(C2=CC(=O)C(=O)c3ccccc32)cc1
Agent: Cl
Solvent: CCO
Product: CCN(CCO)c1ccc(C2=CC(=NO)C(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 4-(4-(ethyl(2-hydroxyethyl)amino)phenyl)naphthalene-1,2-dione (8.5 g, 26.48 mmol) in absolute ethanol (150 ml) was treated in one portion with hydroxylamine hydrochloride (3.68 g, 52.96 mmol) recrystallised from 75:25 EtOH:H2O and stirred at RT for 2 hrs. The mixture was then evaporated in vacuo and the residue suspended in H2O (500 ml). The aqueous phase was then basified to pH 10 with ammonium hydroxide solution and extracted into EtOAc (×4). The combined organics were then dried (Na2SO4) and evaporated in vacuo to afford the product, 4-(4-(ethyl(2-hydroxyethyl)amino)phenyl)-2-(hydroxyimino)naphthalen-1(2H)-one, as a dark red solid (9.1 g, 100%). Analysis of the product by 1H NMR gave a spectrum consistent with the structure.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([CH2:46][C:47]([NH2:49])=[O:48])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][C:47]([NH2:49])=[O:48])[CH2:41][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)CN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(N)=O)CC1

Procedure:
In a manner analogous to the method described in examples 8, rac-(4S*,5R*)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 7) was coupled with 2-piperazin-1-yl-acetamide dihydrochloride (Matrix Scientific) to give the title compound as a racemic mixture. HR-MS (ES, m/z) calculated for C35H43N6O3Cl2 [(M+H)+] 665.2768, observed 665.2767.