Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=O.O1CCCC1.Cl.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][NH2:28])[CH:20]=1>O>[NH2:11][C:4]1[CH:3]=[C:2]([Cl:1])[CH:10]=[CH:9][C:5]=1[C:6]([NH:28][CH2:27][CH2:26][CH2:25][C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)=[O:8]
Reactant: NCCCc1cccnc1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(Cl)ccc1C(=O)NCCCc1cccnc1
Reaction time: 3 h

Procedure:
A mixture of 3.43 g of 4-chloroanthranilic acid, 3.24 g of N,N'-carbonyldiimidazole and 50 ml of tetrahydrofuran was stirred at 5°-25° C. for 3 hours and 4.18 g of 3-(3-pyridinyl)propylamine dihydrochloride was added. The reaction mixture was stirred at room temperature for 18 hours, heated at reflux temperature for one hour and then with 10 ml of water for 30 minutes. The mixture was concentrated and treated with 100 ml. of methylene chloride and 10 ml of 1N sodium hydroxide. The layers were separated and the organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate and the desired product, mp 145°-147° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[CH:44][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][P:21](=[O:28])([O:25]CC)[O:22]CC)=[CH:18][C:12]=3[N:11]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([N:38]4[CH2:42][CH:41]=[CH:40][CH2:39]4)=[O:37])=[CH:32][CH:31]=3)[C:10](=[O:43])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C[Si](Br)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][P:21](=[O:22])([OH:25])[OH:28])=[CH:18][C:12]=3[N:11]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([C:36]([N:38]4[CH2:42][CH:41]=[CH:40][CH2:39]4)=[O:37])=[CH:32][CH:31]=3)[C:10](=[O:43])[CH2:9]2)=[O:7])=[CH:44][CH:45]=1
Reactant: CCOP(=O)(CCc1ccc2c(c1)N(Cc1ccc(C(=O)N3CC=CC3)cc1)C(=O)CN(C(=O)c1ccc(Cl)cc1)C2)OCC
Agent: C[Si](C)(C)Br
Solvent: CC#N
Product: O=C(c1ccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccc(CCP(=O)(O)O)cc32)cc1)N1CC=CC1
Reaction time: 8 h

Procedure:
40 mg (0.051 mmol) of diethyl [2-(4-(4-chlorobenzoyl)-2-oxo-1-[4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)-benzyl]-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-8-yl)ethyl]phosphonate was dissolved in 10 ml of acetonitrile. 0.15 ml of trimethylsilyl bromide was added to the obtained solution, and they were stirred overnight. The solvent was evaporated, and the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:40]1([CH3:49])[CH:45]=[CH:44][CH:43]=[C:42](B(O)O)[CH:41]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([C:42]3[CH:41]=[C:40]([CH3:49])[CH:45]=[CH:44][CH:43]=3)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: Cc1cccc(B(O)O)c1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(-c3cccc(C)c3)nc(-c3ccccc3)n2)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 86, step 86.1, 4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester replacing 2-chloro-6-methyl-pyrimidine-4-carboxylic acid methyl ester and 3-tolylboronic acid replacing phenylboronic acid.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:39]=[N:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=2)[CH2:26][CH2:25]1>>[C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH2:20][N:24]4[CH2:25][CH2:26][CH:27]([C:30]5[CH:39]=[N:38][C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[N:31]=5)[CH2:28][CH2:29]4)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([CH:13]=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-c2nc3nccn3cc2-c2ccccc2)cc1
Reactant: c1ccc2nc(C3CCNCC3)cnc2c1
Product: c1ccc(-c2cn3ccnc3nc2-c2ccc(CN3CCC(c4cnc5ccccc5n4)CC3)cc2)cc1
Yield: 33.2 %

Procedure:
160 mg (0.53 mmol) 4-(6-phenylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde and 182 mg (0.64 mmol) 2-piperidine-4-yl-quinoxaline were reacted for two days at room temperature and purified as described in example 6.0. 87.3 mg of the desired compound were obtained.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH:4]=1.[CH2:17]([CH2:19][NH2:20])[OH:18].CCN(C(C)C)C(C)C>CCCCO>[Cl:16][C:12]1[CH:11]=[C:10]([NH:9][C:5]2[N:6]=[CH:7][N:8]=[C:3]([NH:20][CH2:19][CH2:17][OH:18])[CH:4]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: NCCO
Reactant: Clc1cccc(Nc2cc(Cl)ncn2)c1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OCCNc1cc(Nc2cccc(Cl)c2)ncn1
Temperature: 200 °C
Yield: 68 %

Procedure:
75 mg of 6-chloro-N-(3-chlorophenyl)pyrimidin-4-amine hydrochloride, 24 mg of ethanolamine and 87 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc: MeOH 10:1. 2-(6-(3-Chlorophenylamino)pyrimidin-4-ylamino)ethan-1-ol in the form of a colorless solid was obtained.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH2:8][CH2:7]2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([CH2:28]Cl)=[N:26][CH:27]=2)=[CH:18][CH:17]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=3)=[CH:27][N:26]=1)[CH2:8][CH2:7]2
Reactant: Fc1ccc(-c2ccc(CCl)nc2)cc1
Reactant: O=C1NCCc2cc(Br)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccc(Br)cc2CCN1Cc1ccc(-c2ccc(F)cc2)cn1
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) suspension of NaH (0.084 g. 3.5 mmol) and Kl (0.1 g, 0.6 mmol) in DMF (10 mL) is added dropwise a solution of 6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline (0.65 g, 2.9 mmol) in DMF (10 mL). After 15 minutes, a solution of 5-(4-fluorophenyl)-2-(chloromethyl)pyridine (1.27 g, 5.8 mmol) in DMF (10 mL) is added dropwise and the resulting solution stirred for 12 hours. The reaction mixture is then partitioned between water (200 mL) and EtOAc (200 mL). The aqueous layer is extracted with EtOAc (1×200 mL). The combined organic extracts are then washed with H2O (4×200 mL), saturated NaCl solution (2×200 mL), and dried over MgSO4 and concentrated in vacuo. The resulting material is chromatographed (silica gel. 1:4 EtOAc-hexanes) to afford 6-bromo-2-{[5-(4-fluorophenyl)-2-pyridyl]methyl}-1-oxo-1,2,3,4 -tetrahydroisoquinoline as pale yellow oil.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.[CH2:12](I)[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:12]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH2:13][CH2:14][CH3:15]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOc1cc(C=O)ccc1OC
Temperature: 25 °C

Procedure:
Isovanillin (6.00 g, 39.4 mM), butyl iodide (5.7 ml, 49.3 mM), and anhydrous potassium carbonate (6.8 g, 49.3 mM) were dissolved in dried dimethylformamide (50 ml) and stirred at room temperature for one night, then the solution was diluted with ethyl acetate (300 ml) and washed with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to obtain a residue as a light yellow oil. The residue was purified by flash chromatography (SiO2: eluted by 20% ethyl acetate/hexane solution). The solvent was removed in vacuo and the resultant product was dried to obtain 3-butoxy-4-methoxy-3-benzaldehyde 8.09 g (yield 99.0%) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:32]2=[CH:33][CH:34]=[N:35][CH:36]=[C:31]2[C:5]2[C:6]([OH:30])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:11])=[CH:9][C:4]=2[O:3]1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>N1C=CC=CC=1>[C:38]([O:30][C:6]1[C:5]2[C:31]3[C:32]([C:2]([CH3:1])([CH3:37])[O:3][C:4]=2[CH:9]=[C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:11])[CH:7]=1)=[CH:33][CH:34]=[N:35][CH:36]=3)(=[O:40])[CH3:39]
Reactant: CCCCCCCCCCCCCCCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCC(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
10-Acetoxy-5,5-dimethyl-8-(2-eicosyl)-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-(2-eicosyl)-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=2)[CH:3]=1.O=[C:23]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH:5]=[C:4]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([NH:20][CH3:21])[N:15]=3)[CH:3]=[C:2]2[NH:1][CH:27]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:26]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: CNc1nccc(-c2cc(N)c3cc(OC)ccc3c2)n1
Product: CNc1nccc(-c2cc(NC3CCN(C(=O)OC(C)(C)C)C3)c3cc(OC)ccc3c2)n1

Procedure:
tert-butyl 3-((7-methoxy-3-(2-(methylamino)pyrimidin-4-yl)naphthalen-1-yl)amino)pyrrolidine-1-carboxylate 147 was synthesized according to General Procedure E utilizing compound 33 and replacing tert-butyl 4-oxopiperidine-1-carboxylate with tert-butyl 3-oxopyrrolidine-1-carboxylate. LCMS: 450 [M+H].
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[C:13]([CH3:14])=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[CH3:15])(=[O:5])[CH3:4].C(OCC)C.[Cl-].[NH4+]>O1CCOCC1>[CH3:14][C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([CH3:15])[C:6]=1[C:3](=[O:5])[CH2:4][Br:1])[C:10]#[N:11]
Reactant: CC(=O)c1c(C)cc(C#N)cc1C
Reactant: BrBr
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cc(C#N)cc(C)c1C(=O)CBr
Yield: 82.4 %

Procedure:
4.6 g of bromine are introduced slowly at about -5° C. into a solution of 4 g of 4-acetyl 3,5-dimethyl benzonitrile, prepared according to the method described in J. Chem. Soc. Perkin Trans. II, p. 943-949 (1988),in 10 ml of diethyl ether and 5 ml of dioxane. The mixture is allowed to attain room temperature, and after it has been stirred for 1 hour 15 ml of a saturated solution of ammonium chloride are added to it. The organic phase is separated and the solvent is removed under reduced pressure to give 4.8 g of the desired product. M.p.=76° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH2:1]([NH:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(NCc4ccccc4)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C#Cc2ccc(C3(NCc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.1 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-benzylamino-cyclopropyl)-phenylethynyl]-benzoate (Compound 111, 75.0 mg, 0.19 mmol) in ethanol (4 mL) and tetrahydrofuran (4 mL) was treated with NaOH (80.0 mg, 2.0 mmols, 2.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 35.0 mg (50%) of the title compound as a colorless solid.
Reaction SMILES: C1(C2C=CC=CC=2)C(C(N2CC(=O)CCC2C(OC)=O)=O)=CC=CC=1.[C:26]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:27]([C:32]([N:34]2[CH2:39][C:38]([O:42][CH3:43])([O:40][CH3:41])[CH2:37][CH2:36][CH:35]2[C:44](OC)=[O:45])=[O:33])=[CH:28][CH:29]=[CH:30][CH:31]=1.[Li+].[BH4-]>C1COCC1>[C:26]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]([N:34]1[CH2:39][C:38]([O:40][CH3:41])([O:42][CH3:43])[CH2:37][CH2:36][CH:35]1[CH2:44][OH:45])=[O:33]
Reactant: COC(=O)C1CCC(OC)(OC)CN1C(=O)c1ccccc1-c1ccccc1
Agent: COC(=O)C1CCC(=O)CN1C(=O)c1ccccc1-c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1(OC)CCC(CO)N(C(=O)c2ccccc2-c2ccccc2)C1
Temperature: 25 °C

Procedure:
Methyl 1-(biphenylcarbonyl)-5-oxopiperidine-2-carboxylate was converted to methyl 1-(biphenylcarbonyl)-5,5-dimethoxypiperidine-2-carboxylate (4.3 mmol, 1.65 g) following the general protocol described in Part I above. To a solution of this ketal in anhydrous THF was added LiBH4 (2M in THF) (9.4 mmol, 4.7 mL) at 0° C. under argon. The resulting mixture was stirred at rt and the reaction was tracked by analytical HPLC. The reaction was carefully quenched with saturated NH4Cl and extracted with EtOAc. The organic layer was separated, dried with MgSO4, and concentrated in vacuo to give desired biphenyl-2-yl(2-(hydroxymethyl)-5,5-dimethoxypiperidin-1-yl)methanone in quantitative yield which was used for next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[C:12]3[N:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].O.C([O-])(O)=O.[Na+]>CS(C)=O.C(OC(=O)C)(=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:16][CH2:15][CH2:14][C:13](=[O:17])[C:12]3[N:18]=[CH:19][CH:20]=[CH:21][C:11]2=3)=[O:9])=[CH:22][CH:23]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCCC(O)c2ncccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2cccnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 0.5 g of 5-(4-nitrobenzoyl)-9-hydroxy-6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepine in 5 ml of dimethyl sulfoxide and 1 ml of acetic anhydride is stirred at room temperature 16 hours. To the mixture is added 10 ml of water and 1N NaHCO3. The mixture is extracted with ethyl acetate and the extract washed with water, 1N NaHC3, brine and dried. The solvent is removed to give a solid. chromatography on silica gel with ethyl acetate as solvent gives the product as a solid, m.p. 188°-190° C.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[CH3:20][N:21]1[CH2:30][CH2:29][CH:28]2[CH:23]([CH2:24][CH2:25][CH2:26][NH:27]2)[CH2:22]1.C(N(CC)CC)C>O1CCCC1>[CH3:20][N:21]1[CH2:30][CH2:29][C@@H:28]2[C@H:23]([CH2:24][CH2:25][CH2:26][N:27]2[C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:22]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CN1CCC2NCCCC2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1CC[C@@H]2[C@H](CCCN2C(=O)N2c3ccccc3C(=O)Nc3cccnc32)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1.64 g (5.0 mmoles) of 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 0.8 g (5.2 mmoles) of 8-methyl-2,8-diazabicyclo[4.4.0]decane and 0.85 ml (6.0 mmoles) of triethylamine in 20 ml of tetrahydrofuran was stirred for 3 hours at ambient temperature. The reaction mixture was concentrated in vacuo and the residue was divided between ethyl acetate and dilute aqueous potassium carbonate solution. The organic phase was separated off, dried and concentrated in vacuo. Chromatographic purification took place on silica gel (30-60 μm) using the solvent mixture ethyl acetate/methanol/concentrated ammonia 70/30/1, v/v/v. The two main fractions were concentrated, ground with acetonitrile and the resulting precipitate was filtered off. 100 mg (5% of theory) of crystals of m.p. 230°-233° C., which were identified as trans compound using spectroscopic methods, were obtained from the main fraction eluted initially. The subsequent main fraction contained 200 mg (10% of theory) of the crystalline cis compound of m.p. 160°-161° C.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11]([N:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:29])[CH2:26][C:27]#[N:28])[C@H:21]([CH3:30])[CH2:20]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl[C:32]1[S:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1>C1COCC1>[C:11]([N:19]1[CH2:24][CH2:23][N:22]([C:25](=[O:29])[CH:26]([C:32]2[S:33][C:34]3[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=3[N:36]=2)[C:27]#[N:28])[C@H:21]([CH3:30])[CH2:20]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)CC#N
Reactant: Clc1nc2ccccc2s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(C(=O)c2ccccc2)CCN1C(=O)C(C#N)c1nc2ccccc2s1
Reaction time: 10 h
Yield: 6.5 %

Procedure:
NaHMDS (1.48 ml, 1M in THF) was added into a solution of (R)-N-benzoyl-3-methyl-N′-(2-cyano-acetyl)piperazine (190 mg) and 2-chlorobenzothiazole (100 mg) in THF (10 ml). After the reaction was stirred for 10 hours, 4 ml of solution was separated and quenched with MeOH. After solvents were removed under vaccum, the residue was purified using Shimadzu automated preparative HPLC System to give (R)-N-(benzoyl)-3-methyl-N′-[(benzothiazol-2-yl)-2-cyanoacetyl]-piperazine (15.4 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](O)([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([Cl:23])=[C:16]([F:24])[CH:15]=2)[CH:10]([CH3:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCC(OC(=O)C(C)=O)(C2C3OC=CC=3C(Cl)=C(F)C=2)C(C)C1)C1C=CC=CC=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[C:22]3[O:21][CH:20]=[CH:19][C:18]=3[C:17]([Cl:23])=[C:16]([F:24])[CH:15]=2)[C@H:10]([CH3:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CCC1(O)c1cc(F)c(Cl)c2ccoc12
Agent: CC(=O)C(=O)OC1(c2cc(F)c(Cl)c3ccoc23)CCN(Cc2ccccc2)CC1C
Product: C[C@@H]1CN(Cc2ccccc2)CC[C@@H]1c1cc(F)c(Cl)c2ccoc12

Procedure:
Beginning with 0.56 gm (1.49 mMol) 1-benzyl-3-methyl-4-hydroxy-4-(4-chloro-5-fluorobenzofur-7-yl)piperidine, 1-benzyl-3-methyl-4-(methyl oxoacetoxy)-4-(4-chloro-5-fluorobenzofur-7-yl)piperidine was recovered essentially as described in EXAMPLE 16. This material was treated with tri(n-butyl)tin hydride essentially as described in EXAMPLE 16 to provide the desired compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:40])[C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[C:19]([O:29]COC)=[C:18]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=3)[CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1COCC1.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([C:16]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[CH:23]=3)[C:19]([OH:29])=[C:18]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=3)[CH:17]=2)=[O:40])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCOc1c(-c2cccc(C)c2)cc(C(=O)NCCCCCCCc2ccccc2)cc1-c1cccc(C)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2cc(C(=O)NCCCCCCCc3ccccc3)cc(-c3cccc(C)c3)c2O)c1
Yield: 76.5 %

Procedure:
To a solution of N-7-phenylheptyl-3,5-bis-(3-methylphenyl)-4-methoxymethoxybenzamide (1.04 g, 1.94 mmol) in 3.5 mL THF was added 2N HCl (1.1 mL, 2.2 mmol) at room temperature and the reaction mixture was refluxed for 2 hours before a catalytic amount of camphorsulfonic acid was added. The reaction was refluxed overnight and the resulting goo was dissolved in EtOAc and washed with water. The organic layer was dried over Na2SO4 and the solvent was removed in vacuo. This yielded an oil that was passed through a pad of silica gel using 20% EtOAc: 80% Hexanes. There yielded 730 mg, 81% of a light yellow viscous oil. 1H NMR (CDCl3) δ 1.33–1.39 (m, 6H); 1.59–1.63 (m, 6H); 2.42 (s, 6H); 2.58 (t, J=7.69 Hz, 2H); 3.44 (quartet, J=7.03 Hz, 2H); 6.06 (t, J=7.50 Hz, 1H); 7.14–7.18 (m, 3H); 7.22–7.28 (m, 4H); 7.34–7.40 (m, 6H); 7.68 (s, 2H); IR 3525, 3025, 2925, 2850, 1630, 1600, 1530, 1460, 1325, 1230, and 700 cm−1; mass spectrum [(+)ESI], m/z 492 [M+H]+; Anal Calcd. For C34H37NO2: C, 83.06; H, 7.59; N, 2.85. Found: C, 83.80; H, 7.62; N, 2.93.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[CH:13]=[O:14].B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[CH:13]=[O:14]
Reactant: COc1ccc2c(c1)c(C=O)cn2C
Agent: BrB(Br)Br
Product: Cn1cc(C=O)c2cc(O)ccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-Methoxy-1-methyl-1H-indole-3-carbaldehyde (4.5 g, 23.8 mmol, in 150 ml DCM) was added BBr3 solution (2 M in DCM, 60 ml, 5 eq) at −10° C. with stirring for 5 min. The cooling bath was removed and the reaction mixture was slowly warmed up to r.t. The reaction was monitored by TLC (2% MeOH in DCM) and LCMS (after 3.5 h, no starting material remained). The reaction mixture was then cooled to −10° C., and 16 ml of MeOH were slowly added. The pH of mixture was adjusted to 8 by adding sat. NaHCO3 and/or 4 N NaOH. The organic solvents were removed under reduced pressure and the remaining aqueous mixture was extracted with ethyl acetate (30 ml×5). The organic layers were combined, washed with brine (10 ml×1), dried over Mg2SO4, filtered and dried under reduced pressure to give the title compound as 4.06 g purple powder (yield: 97%) that was used without further purification. LCMS (2-85% ACN/H2O in 7 min): 176.1 (40%). Rf 0.11 (2% MeOH in DCM).