Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[S:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH:9](O)[CH2:10][C:4]=2[CH:3]=1.[Cl-:18].[Ca+2].[Cl-].Cl>C1C=CC=CC=1>[Cl:18][CH:9]1[C:8]2[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=2[S:6][C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=2[CH2:10]1
Reactant: OC1Cc2cc(F)ccc2Sc2ccccc21
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: Fc1ccc2c(c1)CC(Cl)c1ccccc1S2

Procedure:
21.2 g of 2-fluoro-10,11-dihydro-dibenzo[b,f]thiepin-10-ol, 110 ml of benzene and 7.9 g of finely powdered calcium chloride are saturated with hydrochloric acid gas at 15° C (2 hours). The precipitate is filtered off and washed with benzene. The filtrate is evaporated under reduced pressure. There is obtained 10-chloro-2-fluoro-10,11-dihydro-dibenzo[b,f]thiepin as pink crystals which melt at 90°-92° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][C@H:15]3[C@H:17]([NH2:20])[CH2:18][CH2:19][C@H:14]3[CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH:23](=O)[C:24]([CH3:27])([CH3:26])[CH3:25].C(O)(=O)C.C([BH3-])#N>ClCCl>[CH2:23]([NH:20][C@H:17]1[C@H:15]2[C@H:14]([CH2:13][N:12]([S:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=3)(=[O:10])=[O:11])[CH2:16]2)[CH2:19][CH2:18]1)[C:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Reactant: CC(C)(C)C=O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)(C)CN[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(3aS,4R,6aR)-2-(3-(Trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine (100 mg, 0.299 mmol) from Step A of Example 254 and pivalaldehyde (0.043 mL, 0.389 mmol) were combined in dichloromethane (1 mL). Acetic acid (0.3 mL) was added. The reaction was stirred at room temperature for 20 minutes, then PS-cyanoborohydride (147 mg, 0.359 mmol) was added. The reaction was stirred at room temperature for 72 hours, then filtered. The reaction mixture was washed with 1 N NaHCO3 and concentrate in vacuo. The crude material was purified using a 12 g silica gel cartridge with a gradient of 0-4% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.40-8.41 (bs, 1H), 8.22-8.25 (m, 1H), 7.92-7.95 (m, 1H), 7.75 (t, J=7.8 Hz, 1H), 3.42 (dd, J=9.8, 3.1 Hz, 1H), 3.17 (dd, J=9.6, 3.1 Hz, 1H), 3.06-3.10 (m, 1H), 2.96 (dd, J=9.6, 7.7 Hz, 1H), 2.74-2.77 (m, 1H), 2.48-2.53 (m, 1H), 2.30 (d, J=11.3 Hz, 1H), 2.22-2.27 (m, 1H), 2.22 (d, J=7.9 Hz, 1H), 1.78-1.92 (m, 2H), 1.18-1.31 (m, 3H), 0.90 (s, 9H); MS (ESI+) m/z 405 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[CH:28][C:27]=1B(O)O>>[Cl:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[CH:28][C:27]=1[C:5]1[C:4]([C:3]([OH:24])=[O:2])=[CH:9][C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)=[CH:7][CH:6]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1Cl
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: O=C(O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1cc(Cl)cc(Cl)c1Cl
Yield: 1.9 %

Procedure:
Using the conditions of General Procedure A for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 111 mg, 0.25 mmol) was reacted with 2,3,5-trichlorophenylboronic acid (available from Alfa Aesar; 113 mg, 0.5 mmol). The resulting ester was hydrolyzed and the acid was purified to give 2′,3′,5′-trichloro-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (2.5 mg, 2%). 1H NMR (300 MHz, DMSO-d6) δ 13.27 (br s, 1H), 8.58 (d, J=1.9 Hz, 1H), 8.50 (s, 1H), 8.34 (d, J=2.1 Hz, 1H), 8.30 (d, J=7.9 Hz, 1H), 8.10 (dd, J=8.4, 2.0 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.88 (d, J=2.4 Hz, 1H), 7.77 (d, J=8.5 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.47-7.53 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:9])([CH2:10][N:19]2[CH:23]=[N:22][CH:21]=[N:20]2)[CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2(COC3CCCCO3)CO2)cc1
Reactant: c1nc[nH]n1
Solvent: CN(C)C=O
Product: OC(COC1CCCCO1)(Cn1cncn1)c1ccc(Cl)cc1
Yield: 71.9 %

Procedure:
37 g (0.138 mol) of 2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-2-yl-oxymethyl)-oxirane are added to a mixture of 22.4 g (0.32 mol) of 1,2,4-triazole, 5 g (0.04 mol) of potassium tert.-butylate and 300 ml of dimethylformamide at room temperature, while stirring. After the addition has ended, the reaction mixture is stirred at 80° C. for 12 hours and is then concentrated by stripping off the solvent under reduced pressure. Water is added to the residue which remains, the resulting mixture is extracted three times with methylene chloride and the combined organic phases are dried over magnesium sulphate and concentrated by stripping off the solvent under reduced pressure. The product thus obtained is purified chromatographically on silica gel with methylene chloride/ethyl acetate =4:1 as the mobile phase. 33.5 g (72% of theory) of 2-(4-chlorophenyl)-1-[(tetrahydro-2H-pyran-2-yl)-oxy]-3-(1,2,4-triazol-1-yl)-propan-2-ol are obtained in this manner in the form of pale yellow crystals of melting point 70° C.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[C:7]([CH3:17])[C:6]=2[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=1.[Cl:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[F:30]>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[C:7]([CH3:17])[C:6]=3[CH:5]=[C:4]([C:18]#[N:19])[CH:3]=2)=[CH:23][C:22]=1[F:30]
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCCNC2=O
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: Cc1c2n(c3c(-c4ccc(Cl)c(F)c4)cc(C#N)cc13)CCCNC2=O

Procedure:
The title compound, off-white solid (85 mg, 92%), MS (ISP) m/z=368.4 [(M+H)+], mp 247.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-11-methyl-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 17) (79.5 mg, 0.25 mmol) and commercially available 4-chloro-3-fluoro-phenylboronic acid (56.7 mg, 0.325 mmol).
Reaction SMILES: S([O:7][CH2:8][CH3:9])(OCC)(=O)=O.[CH3:10][N:11]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]1[CH2:17][C:18](O)=[O:19].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:10][N:11]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]1[CH2:17][C:18]([O:7][CH2:8][CH3:9])=[O:19]
Reactant: Cc1cc(CC(=O)O)n(C)c1
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1cc(C)cn1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 5.48 ml (0.042 mol) sample of diethyl sulfate was added to a suspension of 6.12 g (0.040) of 1,4-dimethylpyrrole-2-acetic acid and 16.6 g (0.12 mol) of potassium carbonate in 50 ml of DMSO. The mixture was stirred for 6 hours at room temperature. It was poured into water and extracted with ether. The ether extract was washed with brine, dried (MgSO4) and the solvent was evaporated in vacuo. The oily residue was distilled to give 6.0 g of ethyl 1,4-dimethylpyrrole-2-acetate, bp 68° at 0.005 Torr as a colorless oil.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].CC(C)([O-])C.[K+].[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22]Br)[CH3:19].Cl>CS(C)=O>[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])[CH3:19]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CCOC(CBr)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(CN1C(=O)C(=O)c2ccccc21)OCC
Reaction time: 0.5 h
Yield: 55 %

Procedure:
A solution of 31.8 g of isatin in 300 ml of dry dimethyl sulfoxide was added dropwise to a suspension of 25.4 g of potassium t-butoxide in 200 ml of dry dimethyl sulfoxide at 10° C. in a nitrogen stream. After stirring the mixture at that temperature for 30 minutes, 39 ml of bromoacetaldehyde diethyl acetal was added thereto, followed by stirring at 70° C. for 6 hours. The reaction mixture was poured into dilute hydrochloric acid and extracted with ethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform/ethyl acetate=20/1) to give 31.4 g (55%) of the title compound as a red powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([N+:14]([O-])=O)[C:3]=1[NH2:17].[Cl:18][C:19]1[C:20]([CH:29]=O)=[C:21]([O:27][CH3:28])[N:22]=[N:23][C:24]=1[O:25][CH3:26]>CO.[Pd]>[Cl:18][C:19]1[C:20]([C:29]2[NH:14][C:4]3[CH:5]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[CH:7]=[C:2]([CH3:1])[C:3]=3[N:17]=2)=[C:21]([O:27][CH3:28])[N:22]=[N:23][C:24]=1[O:25][CH3:26]
Reactant: COc1nnc(OC)c(C=O)c1Cl
Reactant: Cc1cc(N2CCOCC2)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: COc1nnc(OC)c(-c2nc3c(C)cc(N4CCOCC4)cc3[nH]2)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-methyl-4-morpholin-4-yl-6-nitro-phenylamine (0.252 g, 1.06 mmol) in methanol (15 mL) was added 10% palladium on carbon (25 mg) and the suspension flushed well with nitrogen, followed by hydrogen. The resulting suspension was stirred 8 hours at room temperature under an atmosphere of hydrogen (ca. 1 atm). The resulting suspension was filtered under nitrogen through a pad of Celite and washed with methanol (25 mL). This solution was cooled down to 0° C., the 5-chloro-3,6-dimethoxy-pyridazine-4-carbaldehyde (0.225 g, 1.12 mmol) in methanol (10 mL) was added and the reaction mixture was stirred exposed to air at 23° C. for 18 hours. MeOH was evaporated in vacuo and the crude material was purified by preparative HPLC (see method below) to give the title compound as a yellow solid. (0.265 g, 64%) HPLC: 99% (220 nm), LCMS (+ESI, M+H+) m/z 390, IR (KBr, cm−1) 3421, 2956, 2852, 1625, 1470, 1362; 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 7.17 (s, 0.3H) 6.88 (s, 0.3H), 6.80 (s, 0.7H), 6.74 (s, 0.7H), 4.14 (s, 0.9H), 4.13 (s, 0.9H), 4.12 (s, 2.2H), 4.11 (s,2.2H), 3.83 (m, 4H), 3.13 (m, 4H), 2.62 (s, 2.2H), 2.48 (s, 0.9H). Procedure for the Preparation of 2-(4-chloro-2,6-dimethoxy-pyrimidin-5-yl)-4-methyl-6-morpholin-4-yl-1H-benzimidazole
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[NH:13][C:12](=[O:14])[O:11][C:9](=O)[C:8]=12.[NH:15]1[CH2:22][CH2:21][CH2:20][C@H:16]1C(O)=O>CS(C)=O>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:11])[N:15]3[CH2:22][CH2:21][CH2:20][C@H:16]3[C:12](=[O:14])[NH:13][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Solvent: CS(C)=O
Product: COc1cccc2c1C(=O)N1CCC[C@H]1C(=O)N2

Procedure:
4.8 g (0.025 mmol) of 6-methoxyisatoic acid anhydride and 3.0 g (0.026 mol) of L-proline in 40 ml of dimethyl sulphoxide is heated to 70° for 2 hours, the solvent is removed in a high vacuum and the oil obtained is heated to 170° for 15 minutes. After treatment with active carbon, the crude product is recrystallized from methanol, there being obtained (S)-1,2,3,11a-tetrahydro-6-methoxy-5H-pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione of melting point 247°-251°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:8][C:7](=[O:9])[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C1COCC1>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:1][CH2:2][C:3]2[NH:8][C:7](=[O:9])[CH:6]=[CH:5][CH:4]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: O=c1cccc(CO)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1cccc(=O)[nH]1)c1ccc(F)cc1
Reaction time: 0.33 h
Yield: 32.48 %

Procedure:
In Example 5, 0.2006 grams (1.60 mmole) of 6-(hydroxymethyl)pyridine-2(1H)-one was suspended in 160 mL of THF in a 250 mL round bottom flask under the presence of argon gas. Then, 0.0671 g (1.68 mmole) of 60% NaH dispersed in mineral oil was added and the solution was stirred for 20 min. 0.19 mL (1.58 mmole) of 4-fluorobenzoyl chloride was dissolved in 20 mL of THF and added dropwise into the alcohol reaction mixture at a rate of 10 μL/min. The reaction stirred for 48 hours under the presence of argon gas before being quenched with 20 mL of water. The reaction was washed with ethyl acetate (4×20 mL), the organic layers combined, washed with saturated NaHCO3 (4×20 mL), washed with Brine (3×20 mL) and finally dried over MgSO4. The solvent was removed in vacuo to produce a dull yellow solid. The compound was purified by column chromatography(methanol/dichloromethane). The result was a fine white powder. (0.1287 grams, 32.48% Yield). 1H NMR (DMSO-d6, 500 MHz) δ: 5.12 (s, 2H) 6.29-6.41 (m, 2H) 7.38 (t, 2H) 7.45 (t, 1H) 8.08 (t, 2H) 11.74 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[NH2:21])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(N(CC)CC)C.Cl[C:34](Cl)([O:36]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][C:2]1([CH3:25])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([N:18]4[C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[NH:21][C:34]4=[O:36])=[CH:14][CH:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(N)C(=O)Nc1ccc(Oc2cccc3c2C(C)(C)CO3)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)NC(=O)N(c2ccc(Oc3cccc4c3C(C)(C)CO4)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N1-{6-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-3-pyridinyl}-2-methylalaninamide (Intermediate 75, 7.5 mg) was dissolved in dry dichloromethane (1 ml). The reaction mixture was cooled down in an ice bath. Triethylamine (18.37 μl, 0.132 mmol) was added at 0° C. Then 0.5 ml of a solution of triphosgene in dry dichloromethane (0.012 mmol) was added dropwise. The solution was prepared with 7.18 mg of triphosgene dissolved in 1 ml of dichloromethane). The reaction mixture was stirred under argon during 10 min at 0° C., then during 30 min at room temperature. A saturated aqueous solution of NaHCO3 was added and the aqueous layer was extracted with dichloromethane 4 times. After drying over sodium sulphate, the solvents were removed under vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[O:5][C:6]1[C:7]([CH2:18][CH3:19])=[N:8][N:9]([CH2:13][C:14]([NH:16][NH2:17])=[O:15])[C:10]=1[CH2:11][CH3:12].[C:24](N1C=CN=C1)(N1C=CN=C1)=[O:25]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([Cl:23])[CH:22]=1)[O:5][C:6]1[C:7]([CH2:18][CH3:19])=[N:8][N:9]([CH2:13][C:14]2[O:15][C:24](=[O:25])[NH:17][N:16]=2)[C:10]=1[CH2:11][CH3:12]
Reactant: CCc1nn(CC(=O)NN)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1COCCO1
Product: CCc1nn(Cc2n[nH]c(=O)o2)c(CC)c1Oc1cc(Cl)cc(Cl)c1
Yield: 38 %

Procedure:
A stirred solution of the hydrazide (275 mg, 0.77 mmol) of Example 11 and 1,1′-carbonyl diimidazole 187 mg, 1.16 mmol) in dioxane (50 ml) was heated under reflux for 18 hours. After cooling, the mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (50 ml) and washed with water (25 ml). The organic layer was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (95:5, by volume) to afford the title compound (112 mg) as a white solid m.p. 138–142° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=[O:12])[C:3]=1[C:13]([O:15]C)=O.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(OCC)C>C1(C)C=CC=CC=1>[CH:17]1([NH:23][C:13]([C:3]2[C:4](=[O:12])[NH:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1c(O)c2ccccc2[nH]c1=O
Reactant: NC1CCCCC1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)c1c(O)c2ccccc2[nH]c1=O
Temperature: 115 °C
Yield: 34.6 %

Procedure:
Methyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (Example 70) (2.70 g, 12.3 mmol) was suspended in toluene (27 mL), and cyclohexylamine (1.40 g, 14.1 mmol) was added. The reaction was heated at 115° C. for 5 hours, then cooled to room temperature. Diethyl ether (50 mL) was added, and the resultant precipitate was collected by filtration to give N-cyclohexyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxamide (1.22 g, 35%) as an off white solid. M.p.: 221° C. 1H NMR (400 MHz, DMSO-d6) δ 1.37 (m, 4H), 1.55 (m, 1H), 1.68 (m, 2H), 1.88 (m, 2H), 3.86 (m, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.68 (t, J=7.6 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 10.35 (d, J=7.6 Hz, 1H), 11.83 (bs, 1H). MS 287 (MH+).
Reaction SMILES: [C:1](#[N:5])[CH:2]([CH3:4])O.[CH3:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C1C=CC=CC=1>O>[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([CH:2]([CH3:4])[C:1]#[N:5])[CH2:9][CH2:8]1
Reactant: CN1CCNCC1
Reactant: CC(O)C#N
Solvent: O
Solvent: c1ccccc1
Product: CC(C#N)N1CCN(C)CC1

Procedure:
Lactonitrile (71.08 g.) is added in a dropwise manner to a stirred solution of 100.1 g. of 1-methyl-piperazine in 500 ml. of benzene. The resulting warm solution is heated at reflux under a water separator until the theoretical amount of water is collected (about 4 hours). The solution is evaporated at reduced pressure and the residue is fractionated. The product, 2-(4-methyl-1-piperazinyl)propionitrile, is obtained as an oil, b.p. 128°-130° C./23 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]=[C:10](Br)Br.[CH2:13]([NH2:16])[CH2:14][NH2:15]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]1[NH:15][CH2:14][CH2:13][N:16]=1
Reactant: Clc1cccc(Cl)c1C=C(Br)Br
Reactant: NCCN
Product: Clc1cccc(Cl)c1CC1=NCCN1

Procedure:
2-(2,6-Dichloro-benzyl)-4,5-dihydro-1H-imidazole was prepared from 1,3-dichloro-2-(2,2-dibromo-vinyl)-benzene and ethylene diamine in analogy to Example 1e): white crystals; MS (ISP): 233.1 (11%), 231.1 (63%) & 229.2 100%) (each [M+H]+).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[N:24]=[CH:23][C:22]3[CH2:21][CH:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:31]([F:34])([F:33])[F:32])[C:19]4[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=4[C:17]=3[N:16]=2)=[CH:10][CH:9]=1)(=O)=O.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(N(CC)CC)C>[CH3:39][N:40]1[CH2:45][CH2:44][N:43]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:24]=[CH:23][C:22]4[CH2:21][CH:20]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:31]([F:34])([F:33])[F:32])[C:19]5[CH:35]=[CH:36][CH:37]=[CH:38][C:18]=5[C:17]=4[N:16]=3)=[CH:10][CH:9]=2)[CH2:42][CH2:41]1
Reactant: CS(=O)(=O)OCCc1ccc(Nc2ncc3c(n2)-c2ccccc2C(c2ccccc2C(F)(F)F)C3)cc1
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Product: CN1CCN(CCc2ccc(Nc3ncc4c(n3)-c3ccccc3C(c3ccccc3C(F)(F)F)C4)cc2)CC1

Procedure:
This was synthesized by using 4-(6-(2-(trifluoromethyl)phenyl)-5,6-dihydrobenzo[h]quinazolin-2-ylamino)phenethyl methanesulfonate, N-Methylpiperazine and triethylamine as described in general procedure 2 to afford the desired product. M.p.=157-158° C. 1H NMR 400 MHz (DMSO-d6) δ 9.55 (s, 1 H); 8.38-8.34 (m, 2 H), 7.82-7.49 (m, 3 H), 7.58 (t, 1 H), 7.51-7.40 (m, 3 H), 7.27 (d, J=8.4 Hz, 1 H), 7.18-7.15 (m, 2 H), 6.77 (d, J=7.6 Hz, 1 H), 4.64 (t, J=7.6 Hz, 1 H), 3.35 (bs, 2 H), 3.17-3.08 (m, 3 H), 2.69-2.65 (m, 2 H), 2.50-2.31 (m, 7 H), 2.15 (s, 3 H). LCMS 544 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.Cl.[NH2:22][C@@H:23]([C:28]([NH:30][CH2:31][C:32]([NH:34][C@H:35]([C:43]([NH:45][CH:46]1[CH:53]2[CH2:54][CH:49]3[CH2:50][CH:51]([CH2:55][CH:47]1[CH2:48]3)[CH2:52]2)=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:33])=[O:29])[CH2:24][CH2:25][S:26][CH3:27]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([NH:22][C@@H:23]([C:28]([NH:30][CH2:31][C:32]([NH:34][C@H:35]([C:43]([NH:45][CH:46]1[CH:53]2[CH2:54][CH:49]3[CH2:50][CH:51]([CH2:55][CH:47]1[CH2:48]3)[CH2:52]2)=[O:44])[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:33])=[O:29])[CH2:24][CH2:25][S:26][CH3:27])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CSCC[C@@H](N)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1C2CC3CC(C2)CC1C3
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](Cc1ccccc1)C(=O)NC1C2CC3CC(C2)CC1C3

Procedure:
The title compound was prepared by the general method of Example 1 using t-butoxycarbonyl-L-phenylalanine (2.3 g, 8.6 mmole) and the title product of Example 6 (4.5 g, 8.6 mmole) in 50 ml of dichloromethane stirred with 5A molecular sieves. The crude product was purified by column chromatography on silica gel, giving 4.7 g of analytically pure title compound.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10]/[CH:11]=[CH:12]/[CH2:13][OH:14])=[CH:5][CH:4]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]#[C:10]/[CH:11]=[CH:12]/[CH:13]=[O:14])=[CH:7][CH:8]=1
Reactant: OC/C=C/C#Cc1ccc(C(F)(F)F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C/C=C/C#Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
In 4 ml of methylene chloride were dissolved 350 mg (1.56 mmol) of (E)-5-[4-(trifluoromethyl)phenyl]-2-penten-4-yn-1-ol, and 3.5 g of active manganese dioxide were added to the solution, followed by stirring of the resulting mixture at room temperature for 30 minutes. The solid was removed by filtration and the filtrate was concentrated. Then, the filtrate was subjected to column chromatography using 10 g of silica gel and eluted with a mixed solvent of ethyl acetate-hexane (1:24) to obtain 245 mg (yield: 70%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)(=O)C.CCCCCC>[C:22]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OCCCCCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OCCCCCc1ccccc1
Yield: 28 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 5-phenyl-1-pentanol (56 mg, 0.34 mmol) as the coupling partner. Chromatography (gradient 5–95% ethyl acetate/hexane) through SiO2 yielded 6 mg (28%) of the titled compound. ESI-MS m/z 438 (MH+), 436 (M−H−).