Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30]>C1COCC1>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:29](=[O:31])[CH3:30])=[CH:17][CH:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)cn1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: 0 °C
Yield: 84.6 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-ylamine (150 mg, 0.53 mmol) in THF (4 mL) was added triethylamine (65 mg, 90 μL, 0.64 mmol) and the resulting mixture cooled to 0° C. with ice. Then a solution of acetyl chloride (50 mg, 50 μL) in THF (1 mL) was added and the resulting mixture allowed to warm up to room temperature over 1 h. The mixture was then filtered and the filtrate evaporated before being diluted with methanol and potassium carbonate (10 mg) added. After one hour at room temperature the mixture was extracted with dichloromethane. The combined organic layers were then washed with water and then dried over sodium sulfate, filtered and evaporated to afford the title compound (145 mg, 84%) which was obtained as white crystals. MS: m/e=324.0 [M+H]+.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=1[CH:12]=[O:13].O>O1CCCC1>[F:9][C:10]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=1[CH:12]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[OH:13]
Reactant: Br[Mg]c1ccccc1
Reactant: COc1ccc(F)c(C=O)c1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(F)c(C(O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenylmagnesium bromide (1.6 mL, 1.0 M tetrahydrofuran solution, manufactured by Kanto Chemical Co., Inc.) was added to a solution of 2-Fluoro-5-methoxybenzaldehyde (500 mg, manufactured by Tokyo Chemical Industry Co., Ltd.) in tetrahydrofuran (16 mL, manufactured by Wako Pure Chemical Industries, Ltd.) at 0° C., and the mixture was stirred overnight at room temperature. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (3×20 mL), washed with brine (20 mL) and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1), to give 480 mg of the title compound. LC-MS: HPLC retention time 3.90 minutes, m/z 233 (M+H), condition B-1.
Reaction SMILES: Br[CH2:2][CH2:3][F:4].[I-].[Na+].C(=O)(O)[O-].[Na+].[C:12]([C@@H:15]1[CH2:19][C@H:18]([S:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[CH2:17][NH:16]1)(=[O:14])[NH2:13]>CN(C)C=O>[C:12]([C@@H:15]1[CH2:19][C@H:18]([S:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH2:17][N:16]1[CH2:2][CH2:3][F:4])(=[O:14])[NH2:13]
Reactant: COc1ccc(CS[C@@H]2CN[C@H](C(N)=O)C2)cc1
Reactant: FCCBr
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CS[C@H]2C[C@@H](C(N)=O)N(CCF)C2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
0.4 ml of 1-bromo-2-fluoroethane, 3.83 g of sodium iodide and 0.38 g of sodium bicarbonate were added to a solution of 1.2 g of (2S, 4S)-2-carbamoyl-4-(4-methoxybenzylthio)pyrrolidine dissolved in 12 ml of dry dimethylformamide, whilst ice-cooling, and the mixture was stirred at room temperature for 20 minutes and then at 40° C. for 20 hours. At the end of this time, the reaction mixture was poured into a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was subjected to column chromatography through silica gel (Katayama Chemicals Industries Co., silica gel 60K070). 838 mg of the title compound, melting at 122°-123° C., were obtained as a powder from those fractions eluted with ethyl acetate.
Reaction SMILES: C1(C)C=CC=CC=1.C1O[C:11]2([CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=3)[CH2:13][CH2:12]2)[O:10]C1.C(O)=O>O>[F:23][C:21]1[CH:22]=[C:17]([CH:14]2[CH2:13][CH2:12][C:11](=[O:10])[CH2:16][CH2:15]2)[CH:18]=[C:19]([F:24])[CH:20]=1
Reactant: Fc1cc(F)cc(C2CCC3(CC2)OCCO3)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: O=CO
Product: O=C1CCC(c2cc(F)cc(F)c2)CC1
Yield: 103.1 %

Procedure:
To 50 ml of toluene was added 31 g (0.12 mol) of 4-(3,5-difluorophenyl)cyclohexanone monoethylene ketal obtained above and 76 g (1.7 mol) of formic acid, and the mixture was refluxed for 4 hours. The reaction solution was successively with water, a saturated aqueous sodium carbonate and water, dried over magnesium sulfate, and then the solvent was distilled off to afford 26 g of 4-(3,5-difluorophenyl)cyclohexanone.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])[C:3]=1[C:17]([OH:19])=O.Cl.C(N=C=NCCCN(C)C)C.[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>ClCCl>[F:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]1[CH2:44][CH2:43][N:42]([C:17]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:13]([F:14])([F:15])[F:16])=[N:5][O:6][C:2]=2[CH3:1])=[O:19])[CH2:41][CH2:40]1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2C(F)(F)F)c1C(=O)N1CCN(c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
5-methyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-carboxylic acid (500 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-fluorophenyl)piperazine (332 mg, 1.84 mmol) were dissolved in dichloromethane (30 mL), and stirred at room temperature for 8 hours. The resultant solution was washed with saturated sodium carbonate aqueous solution (30 mL), purified water (30 mL) and saturated sodium chloride aqueous solution (30 mL), respectively. Then, the organic layer was dried with anhydrous sodium sulfate, concentrated, and purified with column chromatography so as to provide a white solid required compound (528 mg, 1.34 mmol, 73%).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH3:15])[C:11]([CH3:14])([OH:13])[CH3:12])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[NH2:16][C:17]1[CH:18]=[C:19]([S:23]([CH3:26])(=[NH:25])=[O:24])[CH:20]=[CH:21][CH:22]=1.Cl>C(#N)C.O1CCOCC1>[Br:1][C:2]1[C:3]([NH:9][C@H:10]([CH3:15])[C:11]([OH:13])([CH3:14])[CH3:12])=[N:4][C:5]([NH:16][C:17]2[CH:18]=[C:19]([S:23]([CH3:26])(=[NH:25])=[O:24])[CH:20]=[CH:21][CH:22]=2)=[N:6][CH:7]=1
Reactant: C[C@@H](Nc1nc(Cl)ncc1Br)C(C)(C)O
Reactant: CS(=N)(=O)c1cccc(N)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: C[C@@H](Nc1nc(Nc2cccc(S(C)(=N)=O)c2)ncc1Br)C(C)(C)O

Procedure:
127 mg (0.43 mmol) of (R)-3-[(5-bromo-2-chloropyrimidin-4-yl)amino]-2-methyl-butan-2-ol in 1 ml of acetonitrile is added to 74 mg (0.43 mmol) of (RS)-S-(3-aminophenyl)-S-methyl sulfoximide in 0.5 ml of acetonitrile. It is mixed with 0.1 ml of a 4N solution of HCl in dioxane, and the batch is refluxed overnight. The solvent is drawn off, and the remaining residue is purified by chromatography (DCM/EtOH 9: 1). 37 mg (0.09 mmol, corresponding to 20% of theory) of the product is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C>C(OCCO)C.O>[CH3:15][C:4]1[CH:3]=[C:2]([N:24]2[CH2:25][CH2:26][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23]2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: Cc1cc(Cl)c2cc([N+](=O)[O-])ccc2n1
Solvent: CCOCCO
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc([N+](=O)[O-])ccc2n1

Procedure:
4-Chloro-2-methyl-6-nitroquinoline (0.2 g), 3-phenylpyrrolidine (0.14 g) and diisopropyl-ethylamine (0.27 mL) in 2-ethoxyethanol (4 mL) was heated in a microwave to 200° C. for 15 minutes. The reaction mixture was diluted with water and extracted with dichloromethane, washed with water, dried (Na2SO4), filtered and evaporated to give a yellow oil. The residue was purified by chromatography on silica, eluting with a mixture of dichloromethane, ethanol and ammonia (200:8:1). The desired fractions were concentrated to give the title compound as an orange oil.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([O:18][CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1C=CC=CC=1>[CH3:19][O:18][C:12]1[CH:17]=[CH:16][C:15]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:14][CH:13]=1
Reactant: COc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: COc1ccc(C(=O)c2ccccc2C(=O)O)cc1
Reaction time: 120 h
Yield: 80 %

Procedure:
A mixture of 57 g (0.4 mole) of phthalic anhydride and 43 mL (0.4 mole) of anisole in 400 mL of benzene was treated with 105 g (0.8 mole) of aluminum chloride at 5°. The reaction was kept for five days at 5°, poured into 600 mL of 2N aqueous HCl and ice and filtered. The residue was triturated in aqueous sodium carbonate and filtered repeatedly until the solid no longer contained product. The sodium carbonate extracts were combined, washed with ether, and acidified with 2N aqueous HCl. The product was extracted into ether, dried over sodium sulfate and stripped. It was recrystallized from toluene to provide 80% yield of product, mp 145-147.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][N:23]([CH3:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[CH3:22][N:23]([CH3:33])[C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:28]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Product: CN(C)c1cccc(C(=O)N2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)c1

Procedure:
Compound 46 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-(dimethylamino)benzoyl chloride and conditions outlined in procedure N. M.p.=170-172° C.; LCMS: 449 [M+H].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[C:10]([C:19]([NH:21][CH:22]3[CH2:24][CH2:23]3)=[O:20])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[C:25]([C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>CS(C)=O.[Cu]I>[CH:22]1([NH:21][C:19]([C:10]2[C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[N:14][C:13]=3[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:26]#[C:25][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[CH:3]=3)[N:9]=2)=[O:20])[CH2:24][CH2:23]1
Reactant: O=C(NC1CC1)c1nn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: C#Cc1cccnc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C(NC1CC1)c1nn(-c2cccc(C#Cc3cccnc3)c2)c2ncccc2c1=O
Yield: 18.9 %

Procedure:
To 1-(3-Bromophenyl)-N-cyclopropyl-4-oxo-1,4-dihydropyridino[2,3-c]pyridazine-3-formamide (1 g, 2.6 mmol) in 50 mL DMSO was successively added 3-ethynyl-pyridine (0.34 g, 3.3 mmol), bistriphenylphosphine palladium dichloride (0.53 g, 0.76 mmol), CuI (0.14 g, 0.74 mmol), triethylamine (0.63 g, 6.25 mmol), reacted in a microwave reactor at 100° C. for 90 min. After reaction was complete, extraction was performed with H2O/DCM, and organic phase was purified by preparation chromatography column to obtain product 0.2 g.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@H:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:18][OH:19]>>[OH:19][CH2:18][C@H:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Reactant: CC(C)(C)[C@@H](N)CO
Product: CC(C)(C)[C@H](CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (2R)-2-amino-3,3-dimethyl-1-butanol (CAN 112245-09-7) as starting materials and isolated (80 mg, 80%) as colorless oil; LC-MS (UV peak area, m/z) 100%, 327.1476 (MH+).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)=[O:7])(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([O:4][CH2:5][CH:6]([OH:7])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-:16])=[O:15])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)c1cccc([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(=O)OCC(O)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
2-(3-Nitrophenyl)-2-oxoethyl acetate (20 g) was dissolved in MeOH (200 mL) and cooled to 0° C. Sodium borohydride (6.78 g) was added pinch-wise to the reaction mixture and this was stirred for 2 hours at room temperature. The reaction was quenched by addition of acetone (10 mL) and the mixture concentrated to give a solid. The solid was treated with water (100 mL) and extracted with ethyl acetate (3×100 mL). The crude title compound obtained was used for next step without further purification (18 g, 89%).
Reaction SMILES: C(O[C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)C.[C:30]1([SH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[Na+]>CO>[C:30]1([S:36][C@H:5]2[NH:8][C:7](=[O:9])[C@H:6]2[NH:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: Sc1ccccc1
Reactant: CC(=O)O[C@@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1N[C@H](Sc2ccccc2)[C@@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
To a solution of 5.0 g of (3S,4S)-4-acetoxy-3-tritylamino-2-oxoazetidine in 100 ml of methanol are added under ice-cooling 1.6 ml of thiophenol and 15.5 ml of 1N aqueous solution of sodium hydroxide. The mixture is stirred for 20 minutes at the same temperature and for further 50 minutes at room temperature. The crystals separated out are collected by filtration to give 2.35 g of (3R,4R)-4-phenylthio-3-tritylamino-2-oxoazetidine (A). The filtrate is concentrated, and the residue is dissolved in ethyl acetate, washed with water, and concentrated. The residue is purified on a silica-gel column (ethyl acetate: n-hexane=1:1) to yield 2.65g of (3R,4S)-compound (B).
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]=[C:6]2[C:11](=[N:12][CH:13]=1)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]2[NH2:15].[NH2:16][CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(=O)(O)[O-]>CN(C)C(=O)C>[C:18]1([CH2:17][NH:16][CH2:3][C:4]2[N:5]=[C:6]3[C:11](=[N:12][CH:13]=2)[N:10]=[C:9]([NH2:14])[N:8]=[C:7]3[NH2:15])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: NCc1cccc2ccccc12
Reactant: Nc1nc(N)c2nc(CBr)cnc2n1
Agent: Br
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2nc(CNCc3cccc4ccccc34)cnc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 13.6 %

Procedure:
To a solution of 6-bromomethyl-2,4-pteridinediamine hydrobromide (51 mg, 0.2 mmol) in anhydrous N,N dimethylacetamide was added 1-aminomethyl-naphthalene (31.67 ul, 0.22 mmol). The reaction mixture was stirred at 50° C. overnight. The crude product was poured into saturated bicarbonate solution. The resulted precipitate was collected and purified by preparative HPLC. 9 mg product was obtained. Yield: 15%; 1H NMR(500 MHz, DMSO-d6): δ 4.6479(s, 2H ), 4.7893(s, 2H), 7.575–7.6244(m, 3H), 7.74232–7.7570(d, J=6.91 Hz, 1H), 7.9935–8.0276(dd, J1=8.06 Hz, J2 =8.995 Hz, 2H), 8.1670–8.1831(d, J=8.04 Hz, 1H), 8.8430(s, 1H); ESI-MS: m/z 332 (M++1)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:17]=3[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]4)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[CH3:27][C:28]1[CH2:29][C:30](=[O:33])[NH:31][N:32]=1>>[CH3:27][C:28]1[CH2:29][C:30](=[O:33])[N:31]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][N:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:25]=[CH:24][CH:23]=[C:22]5[C:17]=4[CH:18]=[CH:19][C:20]([CH3:26])=[N:21]5)[CH2:12][CH2:11]3)[CH:3]=2)[N:32]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(I)c4)CC3)cccc2n1
Reactant: CC1=NNC(=O)C1
Product: CC1=NN(c2cccc(CCN3CCN(c4cccc5nc(C)ccc45)CC3)c2)C(=O)C1
Yield: 58 %

Procedure:
The title compound was prepared in 58% yield according to the general procedure for the preparation of amides, ureas and carbamates (Method A) starting from 5-{4-[2-(3-iodophenyl)ethyl]-1-piperazinyl}-2-methylquinoline and 5-methyl-2,4-dihydro-3H-pyrazol-3-one.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:10](O)=[O:11]>ClCCl>[CH:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)=[O:11]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=CO
Solvent: ClCCl
Product: O=CN1CCc2ccccc21
Reaction time: 2.5 h

Procedure:
A solution of indoline (10 g, 840 mmol) in dichloromethane (400 mL) was treated with 88% formic acid (48.8 g, 924 mmol), heated to reflux, and stirred for 2.5 hours. The mixture was concentrated to 2/3 of the original volume, diluted with 1,2-dichloroethane (200 mL), and again concentrated to 2/3 of the original volume to provide a solution of N-formylindoline in 1,2-dichloroethane, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:8])[CH2:3][C:4]([CH3:7])([CH3:6])[CH3:5].[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl>>[CH3:8][C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:18]2[CH2:19][O:20]2)=[CH:11][CH:10]=1)([CH3:1])[CH2:3][C:4]([CH3:5])([CH3:6])[CH3:7]
Reactant: ClCC1CO1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Product: CC(C)(C)CC(C)(C)c1ccc(OCC2CO2)cc1

Procedure:
The title compound was prepared from 4-(1,1,3,3-tetramethyl-butyl)-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:26]([NH:33][C:34](=[O:37])[CH2:35][Cl:36])=[N:25]1>C(#N)C>[Cl-:36].[O:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[C:26]([NH:33][C:34]([CH2:35][N+:1]23[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]2)[C@@H:3]([O:9][C:10]([C:12]2([C:19]4[S:20][CH:21]=[CH:22][CH:23]=4)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH2:2]3)=[O:37])=[N:25]1
Reactant: O=C(CCl)Nc1noc2ccccc12
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2cccs2)CCCCCC1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3cccs3)CCCCCC1)C2)Nc1noc2ccccc12
Product: [Cl-]
Reaction time: 144 h
Yield: 70.8 %

Procedure:
1-Thiophen-2-yl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 5d) (71 mg) and N-benzo[d]isoxazol-3-yl-2-chloro-acetamide (Example 4a) (54 mg) were dissolved in acetonitrile (10 mL) and left to stand for 6 days. The resulting crystals were filtered off and washed with diethyl ether (3×10 mL) to afford the titled compound (82 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:11][C@@H:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][C@H:13]2[F:25])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34]([Cl:37])(=[O:36])=[O:35]>>[ClH:37].[F:25][C@H:13]1[C@H:12]([O:11][C:4]2[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=[C:2]([NH:1][S:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[C:27]([F:26])([F:38])[F:39])(=[O:36])=[O:35])[CH:3]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2cc(N)cc3ccoc23)[C@H](F)C1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Product: Cl
Product: O=S(=O)(Nc1cc(O[C@@H]2CCNC[C@H]2F)c2occc2c1)c1ccccc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedure described for Example 84 starting from tert-butyl trans-4-[(5-amino-1-benzofuran-7-yl)oxy]-3-fluoropiperidine-1-carboxylate (Intermediate 53) and 2-(trifluoromethyl)benzenesulfonyl chloride. Yield: 49 mg (25%), HPLC purity=100%, m/z=459 (M+H)+, 1H NMR (270 MHz, methanol-d4) δ ppm 2.13-2.31 (m, 2H) 3.15-3.56 (m, 3H) 3.64-3.79 (m, 1H) 4.77-4.97 (m, 1H) 5.00-5.24 (m, 1H) 6.75 (d, J=1.98 Hz, 1H) 6.81-6.84 (m, 1H) 6.99 (d, J=1.73 Hz, 1H) 7.60-7.77 (m, 3H) 7.87-7.95 (m, 1H) 7.98-8.05 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:3]([CH2:14][CH3:15])=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cu](C#N)[C:17]#[N:18].N1C=CC=CC=1>C(Cl)Cl>[CH2:14]([C:3]1[C:2]([C:17]#[N:18])=[CH:7][CH:6]=[CH:5][C:4]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:15]
Reactant: N#C[Cu]C#N
Reactant: CCc1c(Cl)cccc1-c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1c(C#N)cccc1-c1ccccc1
Temperature: 25 °C

Procedure:
Under a dry nitrogen atmosphere a mixture of 3-chloro-2-ethyl-[1,1'-biphenyl] (2.3 g, 0.0106 mole), copper cyanide (1.4 g, 0.0016 mole) and pyridine (1.2 g, 0.016 mole) was heated at 195° for approximately 18 hours. The reaction mixture was cooled to room temperature to give a solid. The solid was dissolved in 300 ml of methylene chloride and washed with 25% aqueous ammonium hydroxide and the aqueous phase extracted with 250 ml of methylene chloride. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carbonitrile as a solid. A mixture of ethyl-[1,1'-biphenyl]-3-carbonitrile (2.2 g, 0.0106 mole), 40 ml of 10 N aqueous sodium hydroxide, and 40 ml of ethanol was heated at reflux for approximately 18 hours. The reaction mixture was cooled and the ethanol evaporated under reduced pressure. The remaining aqueous portion was diluted with 100 ml of water, then extracted with three 150 ml portions of methylene chloride. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated to give 2-ethyl-[1,1'-biphenyl]-3-carboxamide (2.4 g).