Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O/[C:4](=[C:9]1/[C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11][N:12]([CH3:15])[C:13]/1=[O:14])/[CH2:5][CH2:6][CH2:7][CH3:8])C.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][NH2:28]>C1(C)C=CC=CC=1>[CH3:15][N:12]1[C:13](=[O:14])/[C:9](=[C:4](\[NH:28][CH2:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)/[CH2:5][CH2:6][CH2:7][CH3:8])/[C:10]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[N:11]1
Reactant: NCc1ccccn1
Reactant: CCCC/C(OCC)=C1/C(=O)N(C)N=C1CC(=O)OC
Solvent: Cc1ccccc1
Product: CCCC/C(NCc1ccccn1)=C1/C(=O)N(C)N=C1CC(=O)OC
Yield: 92 %

Procedure:
The mixture of the above obtained methyl [(4Z)-4-(1-ethoxypentylidene)-1-methyl-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate (Compound of Formula (VII), 1.05 g) and 1-pyridin-2-ylmethanamine (0.262 mL) was stirred at room temperature in toluene (25 mL) for 0.5 h. The solvent was removed in vacuo. The resulting residue was dissolved in a minimum of CH2Cl2 and added dropwise to a stirred solution of 200 mL of cyclohexane resulting in the formation of a brown precipitate that was filtered off. This precipitate was proved to be the pure methyl [(4Z)-1-methyl-5-oxo-4-{1-[(pyridin-2-ylmethyl)amino]pentylidene}-4,5-dihydro-1H-pyrazol-3-yl]acetate (1.20 g). Yield 92%. MS (ESI+): 345.4; MS (ESI−): 342.5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.[CH3:16][C:17]1([CH3:24])[CH2:22][NH:21][C:20]([NH2:23])=[N:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.ClCCl>[CH3:16][C:17]1([CH3:24])[CH2:22][N:21]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:23]=[C:20]2[NH:19][CH2:18]1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: CC1(C)CN=C(N)NC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CC1(C)CNc2nc(-c3ccncc3)cc(=O)n2C1
Yield: 80.5 %

Procedure:
A mixture of 5.9 g (30.55 mmol) of ethyl 3-(4-pyridyl)-3-oxopropionate, 5.0 g (30.55 mmol) of 5,5-dimethyl-1,4,5,6-tetrahydro-2-pyrimidinamine monohydrochloride (prepared by analogy to U.S. Pat. No. 4,262,122) and 6.33 g (45.82 mmol) of potassium carbonate in 60 ml of ethanol was heated at reflux temperature during 12 h. The cooled suspension was filtered and the solvent removed by evaporation. The residue obtained was dissolved in dichloromethane and washed with water. The organic phase was dried and evaporated to give 6.30 g (80%) of product as a beige solid. Mp.: 152–154° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[O:15][C:14](=[O:16])[CH:13]=[C:12]([OH:17])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[C:24]([O:17][C:12]1[CH2:11][CH:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[O:15][C:14](=[O:16])[CH:13]=1)(=[O:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(O)=CC(=O)O1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC1=CC(=O)OC(CO[Si](C)(C)C(C)(C)C)C1

Procedure:
To 6-t-butyldimethylsilyloxymethyl-5,6-dihydro-4-hydroxy-pyran-2-one (0.26 parts) in dichloromethane (3 cm3) at ambient temperature was added pyridine (0.1 parts) and then acetyl chloride (0.1 parts). After approximately 30 minutes at ambient temperature the reaction mixture was washed with water, dried over MgSO4 and evaporated to yield 4-acetoxy-6-t-butyldimethylsilyloxymethyl-5,6-dihydropyran-2-one (0.2 parts).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[OH-].[Na+]>[Zn].C(O)(C(F)(F)F)=O>[O:14]1[C:10]([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[CH:11][N:12]=[CH:13]1.[NH2:1][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2cnco2)c1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(-c2cnco2)c1
Product: Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
1 g (5.26 mmol, 1 eq.) of 5-(3-nitrophenyl)oxazole and 10 mL of TFA are introduced into a 1 L flask. 1 g of zinc is carefully added in a plurality of batches. The mixture is stirred for 2 hours at room temperature then is poured over ice. Sodium hydroxide is slowly added until the medium becomes basic, and the medium is extracted with diethyl ether. The organic phase is washed with a 1 M solution of HCl and the impurities are extracted with diethyl ether. The aqueous phase is again basified with sodium hydroxide and the product is extracted with diethyl ether. The organic phases are combined, dried over MgSO4 and filtered. After concentration to dryness, 700 mg (yield=83%) of aniline 3-oxazol-5-yl-phenylamine are obtained, in the form of a beige solid. The product is used without subsequent purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[O:4][N:3]=1.Cl.[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[CH:21][C:22]([NH:25][C@H:26]2[CH2:30][CH2:29][CH2:28][C@@H:27]2[NH2:31])=[N:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.CS(C)=O>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH:31][C@H:27]2[CH2:28][CH2:29][CH2:30][C@@H:26]2[NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:33])([F:17])[F:32])=[CH:24][N:23]=2)=[O:11])[O:4][N:3]=1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Reactant: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(C(F)(F)F)cn2)n1

Procedure:
A solution of 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid (CAS number 475105-77-2; 57.4 mg, 0.28 mmol), (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 72 mg, 0.26 mmol), HATU (146 mg, 0.38 mmol) and triethylamine (107 μl, 0.77 mmol) in dry DMF (852 μl) was stirred at room temperature for 72 hours. The reaction was diluted with DMSO and filtered through cotton wool before being purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[C:9]([CH3:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.O1CCCC1.[C].[Pd]>[C:1]([O:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[C:9]([CH3:16])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 106.2 %

Procedure:
The compound (55.6 g, 234 mmol) obtained in step A was dissolved in an ethanol (200 ml)-tetrahydrofuran (100 ml) mixed solvent. Then, 10% palladium carbon (containing water) (10 g) suspended in ethanol (20 ml) was added. Under a hydrogen atmosphere and at room temperature, the reaction mixture was stirred for 5 hr, and filtered off through celite. The obtained solution was concentrated under reduced pressure to give the title compound (51.5 g) as a bistered oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:32][CH:33]1[CH:40]2[CH2:41][CH:36]3[CH2:37][CH:38]([CH2:42][CH:34]1[CH2:35]3)[CH2:39]2.Cl.CCN(C(C)C)C(C)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:32][CH:33]2[CH:34]3[CH2:42][CH:38]4[CH2:37][CH:36]([CH2:41][CH:40]2[CH2:39]4)[CH2:35]3)=[O:8])=[CH:9][CH:10]=1
Reactant: NC1C2CC3CC(C2)CC1C3
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a solution of 4-fluorobenzoic acid (15.0 g, 0.11 mol) in DMF (400 mL) was added HOBt (24.59 g, 0.16 mol) and EDAC (20.53 g, 0.11 mol). The resulting mixture was stirred for 1 hr at room temperature at which time a solution of 2-amino-adamantane.HCl (20.1 g, 0.11 mol) and DIPEA (20.52 mL) in DMF (100 mL) was added dropwise. The mixture was stirred at room temperature for 16 hrs and the volatiles evaporated in vacuo. The residue was dissolved in AcOEt and washed with aq. NaHCO3, brine, dried (MgSO4), filtered and the solvent evaporated in vacuo affording 28.66 g, (98%) of 4-fluoro-N-adamantan-2-yl-benzamide as a solid.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[S:9]1[C:13]([CH:14]=O)=[CH:12][C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]1=2.[CH3:20][C:21]1([CH3:29])[O:28][C:26](=[O:27])[CH2:25][C:23](=[O:24])[O:22]1.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>CCO>[S:9]1[C:13]([CH2:14][CH:25]2[C:26](=[O:27])[O:28][C:21]([CH3:29])([CH3:20])[O:22][C:23]2=[O:24])=[CH:12][C:11]2[CH:16]=[CH:17][CH:18]=[CH:19][C:10]1=2
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1cc2ccccc2s1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CC1(C)OC(=O)C(Cc2cc3ccccc3s2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Proline (0.695 g, 5.98 mmol) was added to a solution of benzo[b]thiophene-2-carbaldehyde (5.00 g, 29.9 mmol) and Meldrum's acid (4.31 g, 29.9 mmol) in EtOH (50 mL). The mixture was stirred at room temperature for 1 hour and diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (7.57 g, 29.9 mmol) was added. Stirring was continued for 5 hours at room temperature and the precipitated product isolated by filtration rinsing further with iPrOH and dried under reduced pressure to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[CH3:22]O>S(=O)(=O)(O)O>[CH3:22][O:11][C:10](=[O:12])[C:9]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:8]=1[O:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=1
Reactant: CO
Reactant: COc1ccc(Oc2ccc([N+](=O)[O-])cc2C(=O)O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc(OC)cc1
Reaction time: 16 h

Procedure:
2-(4-Methoxy-phenoxy)-5-nitro-benzoic acid (2.5 g), (DE 2058295) in methanol (75 ml) containing conc. sulfuric acid (3 drops) was boiled for 16 h. Solvent was removed at reduced pressure, the residue dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate. The organic phase was dried (Na2SO4) and solvent removed at reduced pressure to give 2-(4-methoxy-phenoxy)-5-nitro-benzoic acid methyl ester (2.50 g). m/z (API+): 304 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([CH3:10])[CH:3]=1.[CH:11](O)=O>O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]2[N:9]=[CH:11][NH:8][C:6]=2[CH:7]=1
Reactant: Cc1cc(Br)cc(N)c1N
Reactant: O=CO
Solvent: O
Product: Cc1cc(Br)cc2[nH]cnc12
Temperature: 100 °C
Reaction time: 6 h
Yield: 0 %

Procedure:
To a solution of 5-bromo-3-methylbenzene-1,2-diamine (2.02 g, 10 mmol) was added water (10 mL) followed by formic acid (1.16 mL, 30 mmol). The mixture was stirred at 100° C. for 6 hours before cooling to room temperature. A solid precipitated from the solution and was allowed to sit at room temperature for 2 days. To this mixture was then added 1 N KOH (35 mL) and the solids were isolated by vacuum filtration. The solids were air dried and recrystallized from CHCl3 (70 mL) to provide 6-bromo-4-methyl-1H-benzimidazole (0.82 mg, 39%). Additional batches of product were obtained from the CHCl3 mother liquors (1.01 g, 48%).
Reaction SMILES: C[N:2]1[CH2:7][CH2:6][C:5]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][CH2:8]2)[CH2:4][CH2:3]1.[Cl:17]C(OC(Cl)C)=O>ClCCCl>[ClH:17].[NH:2]1[CH2:7][CH2:6][C:5]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][CH2:8]2)[CH2:4][CH2:3]1
Reactant: CN1CCC2(CCCc3ccccc32)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: Cl
Product: c1ccc2c(c1)CCCC21CCNCC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of the N-methylpiperidine (A1) (37 g, 172 mmol) in 1,2-dichloroethane (250 ml) was added 1-chloroethyl chloroformate (20.7 ml, 190 mmol) at 0° C. The solution turned to a solid. After 0.5 hours at room temperature, the reaction mixture was heated under reflux for 15 hours. After concentration, the residue was dissolved in methanol (250 ml) and heated at 50° C. for 2 hours. The mixture was cooled to room temperature, the precipitate was filtered and washed with ether to produce 3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine] HCl salt (A2). The filtrate was concentrated, suspended in ether, filtered, and the solid washed with MeOH and ether to give additional 3,4-dihydro-2H-spiro[naphthalene-1,4′-piperidine] HCl salt (A2). LC-MS: m/e=202.1 (M+H). R1=1.61 min. 1H-NMR (500 MHz, CDCl3): 9.74 (s, 2H), 7.58 (d, J=7.9, 1H), 7.22 (t, J=7.8, 1H), 7.14 (t, J=7.9, 1H), 7.08 (d, J=8.0, 1H), 3.47 (d, J=12.4, 2H), 3.22-3.18 (m, 2H), 2.88 (t, J=4.9, 2H), 2.81 (t, J=6.2, H), 2.60 (td, 2H), 1.93-1.89 (m, 2H), 1.83-1.77 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(N(C(C)C)CC)(C)C.Cl.[NH2:22][C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]1[OH:29]>ClCCl>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:22][C@@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N[C@@H]1CCCC[C@@H]1O
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(N[C@@H]2CCCC[C@@H]2O)ccc(C#N)c1Cl
Reaction time: 4 h
Yield: 29.6 %

Procedure:
A mixture of 2-chloro-4-fluoro-3-methyl-benzonitrile (500 mg, 2.95 mmol), diisopropylethylamine (1.29 mL, 7.37 mmol), and (1S,2R)-2-aminocyclohexanol hydrochloride (670 mg, 4.42 mmol, Acros®) is microwaved using a CEM® microwave at 190° C. for 2 h and 180° C. for 4 h. The mixture is diluted with dichloromethane and washed with 1 N HCl. The aqueous layer is extracted again with dichloromethane. The combined organic phases are dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue is purified using radial chromatography, eluting with 2% methanol/dichloromethane. The isolated product is recrystallized with ether and hexane to yield the title compound as a white solid (231 mg, 29%). LC-ES/MS m/z 265.0 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH3:35])[C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH3:14])[N:9]([CH2:15][C:16]3[CH:33]=[CH:32][C:19]4/[C:20](=[CH:29]/[C:30]#[N:31])/[C:21]5[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=5[CH2:23][CH2:24][C:18]=4[CH:17]=3)[C:8]=2[CH:34]=1)(O)=O.[OH2:36].[NH2:37][NH2:38]>ClCCl>[CH3:35][C:6]1[C:7]2[N:11]=[C:10]([CH2:12][CH2:13][CH3:14])[N:9]([CH2:15][C:16]3[CH:33]=[CH:32][C:19]4/[C:20](=[CH:29]/[C:30]#[N:31])/[C:21]5[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=5[CH2:23][CH2:24][C:18]=4[CH:17]=3)[C:8]=2[CH:34]=[C:4]([C:1]([NH:37][NH2:38])=[O:36])[CH:5]=1
Reactant: NN
Reactant: O
Reactant: CCCc1nc2c(C)cc(C(=O)O)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(C(=O)NN)cc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\C#N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.7 %

Procedure:
[step 1] (E)-[2-(6-Carboxy-4-methyl-2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]acetonitrile (274 mg, 0.59 mmol) obtained in Reference Example B8 was dissolved in dichloromethane (1 mL), N,N′-carbonyldiimidazole (CDI) (107 mg, 0.66 mmol) was added, and the mixture was stirred at room temperature for 20 min. To this mixture was added hydrazine monohydrate (89 mg, 1.77 mmol), and the mixture was stirred at room temperature for 3 hr. The mixture was concentrated under reduced pressure, water (20 mL) was added, and the precipitate was collected by filtration to give (E)-{2-[4-methyl-6-(hydrazinocarbonyl)-2-propylbenzimidazol-1-yl]methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene}acetonitrile (246 mg, 88%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=O.[K+].[K+].I[CH:18]([CH3:20])[CH3:19]>CN(C=O)C.CCOCC>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH:18]([CH3:20])[CH3:19])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(O)ccc1Br
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(Br)c(C#N)c1
Temperature: 60 °C
Yield: 78.4 %

Procedure:
2-Bromo-5-hydroxy-benzonitrile (20.0 g, 10.1 mmol) and K2CO3 (5.60 g, 40.4 mmol) were taken-up in dry DMF (12.5 mL). 2-Iodopropane (2.00 mL, 20.2 mmol) was added and the reaction mixture was heated at 60° C. for 2 h. The mixture was diluted with ether (100 mL), filtered over celite and the filtrate was washed with water (3×50 mL) and brine (50 mL), dried over MgSO4, evaporated and purified by column chromatography (5-45% EtOAc/hexanes) to give 1.9 g (81%) of 2-bromo-5-isopropoxybenzonitrile as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.53 (d, J=9.0 Hz, 1H), 7.15 (d, J=2.9 Hz, 1H), 6.99 (dd, J=9.0, 3.0 Hz, 1H), 4.58-4.49 (m, 1H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 239.0, found 240.1 (M+1)+. Retention time: 1.81 minutes (3 min run).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH3:23][Si](C[Mg]Cl)(C)C.S(Cl)(Cl)=O>C1COCC1.C(OCC)C>[F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH:19]=[CH2:23])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: C[Si](C)(C)C[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: C=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
A dry, air-free, ice-cold solution of 2-formylphenyl 4-(trifluoromethyl)-benzenesulfonate (2.0 g, 6.1 mmol) in THF (7 mL) is treated with 6.8 mL of 1 M (trimethylsilylmethyl)magnesium chloride in diethyl ether. The reaction is stirred 30 minutes. Thionyl chloride (0.5 mL, 6.9 mmol) is added and the reaction is stirred at 0° C. for 1 h. The reaction is quenched with ice and extracted with ethyl acetate. The product is purified on silica gel in methylene chloride. A yield of 1.8 g of 2-vinylphenyl 4-(trifluoromethyl)benzenesulfonate is obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].Cl.[C:14]([O:17][CH2:18][CH3:19])(=[O:16])[CH3:15]>O1CCCC1>[F:1][C:2]([F:11])([F:12])[C:3]([OH:4])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:15][C:14]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(C)=O
Reactant: O=C(c1ccccc1)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)(c1ccccc1)C(F)(F)F
Reaction time: 4 h
Yield: 97 %

Procedure:
Under argon atmosphere, 20 mL (10.7 mmol, 2 equivalents) of the solution of ethyl bromozincacetate in tetrahydrofuran obtained in Example 43 was added dropwise to a solution of 0.75 mL (5.35 mmol) of trifluoroacetophenone in 2.75 mL of THF at 7˜9° C. The mixture was stirred at 4˜5° C. for 4 hours. 10 mL of 1N hydrochloric acid was added dropwise at 20° C. or lower, followed by dilution with 30 mL of ethyl acetate. Then, the layers were separated. The organic layer was washed successively with 5 mL (×2) of 1N hydrochloric acid, 5 mL of water, 5 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 5 mL (×2) of an aqueous saturated sodium chloride solution. After washing, the organic layer was dried with anhydrous magnesium sulfate. Concentration under reduced pressure afforded 1.54 g of the desired product (NMR yield 97%; internal standard dioxane).
Reaction SMILES: C[N:2]1[CH2:11][CH2:10][C@@H:9]2[C@H:4]([CH2:5][CH2:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=32)[CH2:3]1.N#CBr>C(Cl)(Cl)Cl>[CH2:10]1[C@@H:9]2[C@H:4]([CH2:5][CH2:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=32)[CH2:3][NH:2][CH2:11]1
Reactant: CN1CC[C@H]2c3ccccc3CC[C@@H]2C1
Agent: N#CBr
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)CC[C@@H]1CNCC[C@@H]21
Yield: 92 %

Procedure:
A solution of 0.218 g (1.08 mmol) of trans-1,2,3,4,4a,5,6,10b-octahydro-3-methyl-benz[f]isoquinoline in 3 ml of chloroform was added over 25 min to a solution of 0.140 g (1.32 mmol) of cyanogen bromide in 1 ml of chloroform under nitrogen whilst stirring magnetically. After completion of the addition, the reaction was heated to reflux for 75 min, then allowed to cool. The solvent was evaporated in vacuo, then 5 ml of 2M hydrogen chloride solution was added and the reaction was heated to reflux for 6 h, whilst stirring magnetically. After allowing to cool, the reaction mixture was made alkaline with 2M sodium hydroxide solution and extracted with ether (3×30 ml). The combined ether extracts were dried (K2CO3) and evaporated in vacuo to leave 0.186 g (92%) of the title product as a whitish solid. NMR δ(CDCl3) 1.35-1.56 (3H, m), 1.74-1.82 (1H, m), 2.35-2.50 (3H, m), 2.78-2.92 (3H, m), 3.11 (1H, m), 3.27 (1H, m), 7.06-7.17 (3H, m), 7.24 (1H, d).
Reaction SMILES: [H-].[Na+].[CH:3]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][N:16]=[C:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([CH2:30][OH:31])=[CH:25][C:24]=3[F:32])[CH2:19][CH2:18]2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])[CH3:4].CI.[CH3:35]C(OC)(C)C>CN(C=O)C.CO>[CH:3]([O:6][C:7]([N:9]1[CH2:14][CH2:13][CH:12]([O:15][N:16]=[C:17]2[CH2:18][CH2:19][N:20]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([CH2:30][O:31][CH3:35])=[CH:25][C:24]=3[F:32])[CH2:21][CH2:22]2)[CH2:11][CH2:10]1)=[O:8])([CH3:5])[CH3:4]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(CO)cc3F)CC2)CC1
Reactant: COC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CI
Solvent: CN(C)C=O
Product: COCc1cc(F)c(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)cc1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
NaH (60%, 10 mg, 0.25 mmol) was added to a solution of 48-1 (36 mg, 0.085 mmol) in 0.3 mL of DMF at 0° C. After 10 minutes, methyl iodide in MTBE (2M, 0.6 mL, 1.2 mmol) was added and the reaction was stirred at room temperature for 2 h. The mixture was quenched with water (2 mL) and extracted with 1 mL of ethyl acetate. The organic extract was dried under a stream of nitrogen and the residue was purified by preparative TLC(eluent: 30% EtOAc in hexane) to afford 49-1: LC-MS 408.1 (MH+-MeOH), tR=8.77 (Method 2). EC50: 265 nM.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C(C)(C)C)[C:5]([I:15])=[CH:4][CH:3]=1>Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([I:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)ccc1I
Agent: Cl
Product: Nc1nc(Cl)ccc1I
Temperature: 25 °C

Procedure:
A suspension of N-(6-chloro-3-iodopyridin-2-yl)-2,2-dimethyl propionamide (Preparation 108, 5.0 g, 14.8 mmol) in 1M HCl was heated to reflux for 4.5 h. The reaction was cooled to rt and then extracted with diethyl ether (2×50 mL). The organics were washed with Na2CO3 solution (2×50 mL) before being dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (SiO2, CH2Cl2) afforded the title compound. δH(CDCl3): 7.76 (1H, d), 6.46 (1H, d), 5.43-5.20 (2H, br s).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C:27](=[O:28])[CH2:26][CH:25]([C:29]([OH:31])=O)[CH2:24]3)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[NH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH:25]([C:29]([N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)=[O:31])[CH2:26][C:27]3=[O:28])=[CH:19][CH:18]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: C1CCNC1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)O)CC4=O)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CC(C(=O)N5CCCC5)CC4=O)cc3)CC2)c(C)c1
Yield: 43.5 %

Procedure:
Using 1-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-5-oxopyrrolidine-3-carboxylic acid (100 mg) described in Example 333 and pyrrolidine (17 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (49 mg) was obtained.