Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18](OC(C)(C)C)=O)[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-])=O.ClC1[C:39]2[C:34](=[CH:35][C:36]([O:40][CH3:41])=[CH:37][CH:38]=2)[N:33]=[C:32]([CH3:42])[N:31]=1>>[CH2:6]([NH:7][C:2]1[NH:26][C:3]2[C:2]([N:1]=1)=[N:7][CH:6]=[C:5]([C:8]1[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]4[C:39]5[C:34](=[CH:35][C:36]([O:40][CH3:41])=[CH:37][CH:38]=5)[N:33]=[C:32]([CH3:42])[N:31]=4)[CH2:13][C:12]=3[CH:25]=1)[CH:4]=2)[CH3:5]
Reactant: COc1ccc2c(Cl)nc(C)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3cnc(N)c([N+](=O)[O-])c3)cc2C1
Product: CCNc1nc2ncc(-c3ccc4c(c3)CN(c3nc(C)nc5cc(OC)ccc35)CCO4)cc2[nH]1

Procedure:
Prepared according to the method of example 11 by using tert-butyl 7-(6-amino-5-nitropyridin-3-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (Example 26) in step 1 and 4-chloro-7-methoxy-2-methylquinazoline in step 4. 1H NMR (400 MHz, DMSO-d6) δ 8.22 (s, 0.5H), 8.07 (s, 0.5H), 7.90 (d, 1H), 7.68-7.42 (m, 3H), 7.17-6.84 (m, 4H), 5.00 (s, 2H), 4.47-4.39 (m, 2H), 4.18-4.10 (m, 2H), 3.88 (s, 3H), 3.40-3.30 (m, 2H), 2.43 (s, 3H), 1.26-1.13 (m, 3H); MS (EI) for C27H27N7O2: 482 (MH+).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1)([O-:11])=[O:10].O>CN(C=O)C.C(OCC)(=O)C>[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[CH3:3])=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1nccn1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.9 %

Procedure:
Sodium hydride (2.45 g; 61.0 mmol, 60% dispersion in oil) was added to a solution of 2-methylimidazole (5.0 g, 60.9 mmol) in DMF (100 ml). The mixture was stirred at room temperature for 0.25 h before adding 4-nitrobenzyl bromide (13.2 g, 61.0 mmol) and heating at 110° C. for 2 h followed by stirring at room temperature for 16 h. Water (200 ml) and ethyl acetate (500 ml) were added, the aqueous separated and extracted with ethyl acetate (2×500 ml). The combined extracts were washed with water (3×250 ml), dried (MgSO4) and evaporated. The crude product was chromatographed on silica gel eluting with CH2Cl2 /MeOH (4%) to give the title-product (1.58 g, 10.5%); δ (360 MHz, CDCl3) 2.34 (3H, s, Me); 5.16 (2H, s, CH2); 6.67 (1H, d, J= 1.3 Hz, Ar-H); 7.03 (1H, d, J=1.3 Hz, Ar-H); 7.19 (2H, d, J=9.5 Hz, Ar-H); 8.22 (2H, d, J=9.5 Hz, Ar-H).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:6]2.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[CH2:25]([O:24][C:22]([CH2:21][CH2:20][CH2:19][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)[CH:4]=[C:5]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:23])[CH3:26]
Reactant: CCOC(=O)CCCBr
Reactant: CCOC(=O)c1cc2c(C)cccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1c(C(=O)OCC)cc2c(C)cccc21
Temperature: 25 °C

Procedure:
A mixture of ethyl 4-methyl-1H-indole-2-carboxylate (8.50 g, 41.8 mmol), 60% sodium hydride (1.67 g, 41.8 mmol) and N,N-dimethylformamide (150 ml) was stirred at room temperature until the reaction mixture became transparent. Subsequently, ethyl 4-bromobutyrate (8.16 g, 41.8 mmol) was added dropwise to the aforesaid mixture and the resulting mixture was stirred at 27°-29° C. for another 8 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate, and the extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane= 3/97) to obtain ethyl 1-(3-ethoxycarbonylpropyl)-4-methyl-1H-indole-2-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][CH:10]=[C:4]2[N:3]=1.[Br:11]N1C(=O)CCC1=O.O>ClCCl>[Br:11][C:10]1[CH:9]=[N:8][N:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[N:3][C:4]=12
Reactant: Clc1ccn2nccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: Clc1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a solution of 5-chloropyrazolo[1,5-a]pyrimidine (2.30 g, 15.0 mmol) in dichloromethane (100 mL) was added N-bromosuccinimide (2.67 g, 15.0 mmol) and the mixture allowed to stir at ambient temperature for 1 hour. The reaction mixture was poured into water, extracted with dichloromethane, and dried over sodium sulfate. The crude product was purified by column chromatography, eluting with 1% MeOH/dichloromethane and afforded 1.50 g (45%) of 3-bromo-5-chloropyrazolo[1,5-a]pyrimidine as a light yellow solid.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=1[Cl:15].[CH:16](=[O:18])[CH3:17].O>CCCCCC.C1COCC1>[Cl:15][C:8]1[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=1[CH:16]([OH:18])[CH3:17]
Reactant: CC=O
Reactant: COc1ccc(Br)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: COc1ccc(C(C)O)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 1.6M solution of n-butyllithium in hexane (4 ml) was added to a solution of 4-bromo-3-chloroanisole (CAS Reg. No. 50638-46-5, 1.3 g) in THF (20 ml) at −78° C. The mixture was stirred for 30 min at −78° C. Acetaldehyde (0.7 ml) was added to the mixture. The mixture was allowed to warm to room temperature. Water (50 ml) was added and extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated to an oil to give the title compound (983 mg) as colorless oil. MS (m/e)=186 [M+].
Reaction SMILES: C[C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][C:8]=3[C:9](=[O:11])[CH2:10][C:4]=2[CH:3]=1.[CH2:20](O)C.[BH4-].[Na+].O>CO>[CH3:20][C:19]1[CH:2]=[CH:3][C:4]2[CH2:10][CH:9]([OH:11])[C:8]3[CH:12]=[C:13]([S:16][CH3:17])[CH:14]=[CH:15][C:7]=3[O:6][C:5]=2[CH:18]=1
Reactant: CSc1ccc2c(c1)C(=O)Cc1cc(C)ccc1O2
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CSc1ccc2c(c1)C(O)Cc1ccc(C)cc1O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8.9 G. of 10,11-dihydro-2-methyl-8-methylthio-dibenz[b,f]oxepin-10-one are suspended in 65 ml. of ethanol and treated with a solution of 1.25 g. of sodium borohydride in 4.3 ml. of water. The mixture is stirred for 2 hours at room temperature. Then, 20 ml. of methanol are added thereto and the resulting mixture is heated at reflux for 15 minutes. Thereafter, the methanol and ethanol are removed by evaporation in vacuo. The residue is extracted with chloroform, the chloroform extracts are washed with water, dried and evaporated in vacuo. The residue is crystallized from diisopropyl ether, and there is obtained 10,11-dihydro-3-methyl-8-methylthio-dibenz[b,f]oxepin-10-ol having a melting point of 67°-69° C.
Reaction SMILES: [CH3:1][C:2]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)([CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH3:16])[CH2:3][CH:4]=O.[C:25]([NH:28][C:29]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:27])[CH3:26]>>[ClH:23].[CH3:1][C:2]([CH:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[N:7]1[CH3:16])([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=1)[CH2:3][CH2:4][N:32]1[CH2:31][CH2:30][C:29]([NH:28][C:25](=[O:27])[CH3:26])([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:34][CH2:33]1
Reactant: CC(=O)NC1(c2ccccc2)CCNCC1
Reactant: CN1C(=O)c2ccccc2C1C(C)(CC=O)c1ccc(Cl)c(Cl)c1
Product: CC(=O)NC1(c2ccccc2)CCN(CCC(C)(c2ccc(Cl)c(Cl)c2)C2c3ccccc3C(=O)N2C)CC1
Product: Cl

Procedure:
3-Methyl-3-(3,4-dichlorophenyl)-3-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (isomer A described below) (0.3 g) was coupled to 4-acetamido-4-phenylpiperidine (0.25 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.354 g); mp 195-225° C.; MS: m/z=564(M+1); NMR(CDCl3): 1.0 (s,3), 1.91 (s,1), 2.50 (s,3), 2.98 (m,4), 3.37 (m,2), 7.22-7.72 (m,10), 7.79 (s,1), 8.13 (s,1). Analysis for C32H35Cl2N3O2.1.0 HCl.2.0 H2O: Calculated: C, 60.33; H, 6.33, N, 6.59; Found: C, 60.09; H, 5.97; N, 6.28.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[NH:10][N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[F:21][C:22]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1[CH2:24]Br.C([O-])([O-])=O.[K+].[K+].O>CC#N>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[N:10]([CH2:24][C:23]3[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:22]=3[F:21])[N:11]=[C:12]([C:13]3[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=3)[C:16]#[N:17])[C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CC(=O)N1CCc2[nH]nc(-c3cccc(C#N)c3)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N1CCc2c(c(-c3cccc(C#N)c3)nn2Cc2ccc(F)cc2F)C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
A mixture of 3-(5-Acetyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)-benzonitrile (3a) (0.48 g, 1.8 mmol), 2,4-difluorobenzyl bromide (0.41 g, 1.99 mmol) and K2CO3 (498 mg, 3.6 mmol) in 14 ml CH3CN was stirred at 80° C. for 16 h. A second portion of 2,4-difluorobenzyl bromide (0.41 g, 1.99 mmol) was added and the mixture was stirred for additional 7 h. Water was added, the mixture was extracted 3 times with ethyl acetate, the combined organic layers were dried over MgSO4, filtrated and the solution was evaporated to dryness. The crude product was crystallized from 10 ml 2-propanol and dried in vacuo to give 0.364 g of 3-[5-Acetyl-1-(2,4-difluoro-benzyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl]-benzonitrile (6a).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=3[O:18][CH3:19])=[N:9][N:10]=2)[CH:7]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][C:23]=1[OH:37]>>[OH:37][C:23]1[CH:24]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]4[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=4[O:18][CH3:19])=[N:9][N:10]=3)[CH:7]=2)[CH:26]=[CH:27][C:22]=1[O:21][CH3:20]
Reactant: COc1cc(C)ccc1-c1nnc2ccc(Cl)cn12
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1O
Product: COc1ccc(-c2ccc3nnc(-c4ccc(C)cc4OC)n3c2)cc1O

Procedure:
The title compound was prepared from 6-chloro-3-(2-methoxy-4-methylphenyl)-[1,2,4]triazolo[4,3-a]pyridine and 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol using a procedure similar to those described for the synthesis of Example 1d, and was isolated as yellow solids. 1H NMR (DMSO-d6): 9.23 (s, 1H), 7.91-7.86 (m, 2H), 7.69 (dd, J=9.6 and 1.5 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.16-6.99 (m, 5H), 3.84 (s, 3H), 3.80 (s, 3H), 2.45 (s, 3H). MS: m/z 362.2 [M+H+].
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].CO>O>[NH:10]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:13]2[C:12]([N:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2c[nH]c3ncccc23)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
Into a 50 mL round bottom flask purged and maintained with an inert atmosphere of nitrogen was placed tert-butyl 4-(1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)piperazine-1-carboxylate (400 mg, 0.90 mmol). To this was added NaOH (90 mg, 2.25 mmol). Addition of methanol (20 mL) was next. To the mixture was added H2O (8 mL). The resulting solution was allowed to react, with stirring, for 4 hours while the temperature was maintained at 90° C. in a bath of oil. The mixture was concentrated by evaporation under vacuum using a rotary evaporator. A filtration was performed and the filter cake was washed with H2O. This resulted in 180 mg (66%) of tert-butyl 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)piperazine-1-carboxylate as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 1.40 (s, 9H), 2.96 (m, 4H), 3.56 (m, 4H), 6.73 (s, 1H), 6.97 (d, 1H), 7.88 (d, 1H), 8.22 (d, 1H), 8.97 (s, 1H). m/z 303 (M++1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>>[CH3:20][N:21]([CH3:23])[CH:22]=[C:9]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:8][CH:7]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cc1ccc(C(F)(F)F)cc1
Product: CCOC(=O)C(=CN(C)C)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared in a manner similar to Example Preparation 10 using ethyl 2-(4-(trifluoromethyl)phenyl)acetate and 1,1-diethoxy-N,N-dimethylmethanamine to give the title compound. 1H NMR (400 MHz, chloroform-d) δ ppm 1.21 (t, J=7.1 Hz, 3 H) 2.71 (s, 6 H) 4.14 (q, J=7.2 Hz, 2 H) 7.31 (d, J=7.8 Hz, 2 H) 7.53 (d, J=7.8 Hz, 2 H) 7.61 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([OH:16])(=[O:15])[CH2:13][OH:14]>C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([O:14][CH2:13][C:12]([OH:16])=[O:15])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=C(O)CO
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Solvent: CCO
Product: O=C(O)COc1ccc(Br)cc1[N+](=O)[O-]
Yield: 70 %

Procedure:
The reaction between 28.1 g of 2,5-dibromonitrobenzene and 7.6 g of glycolic acid was carried out by heating in a 70% aqueous ethanol solution under alkaline conditions to give 19.3 g of 4-bromo-2-nitrophenoxyacetic acid as precipitated crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C:13]([F:16])([F:15])[F:14])=[N:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20](SC)=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.O[O:26][S:27]([O-:29])=O.[K+].[CH3:31]O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C:13]([F:14])([F:16])[F:15])=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([S:27]([CH3:31])(=[O:29])=[O:26])=[CH:21][CH:22]=2)=[CH:6][CH:7]=1
Reactant: CSc1ccc(-c2nc(C(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Reactant: O=S([O-])OO
Reactant: CO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2nc(C(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
A solution of imidazole from step 4 above (550 mg, 1.6 mmol) in methanol (10 ml) was stirred at 25° C. while a solution of OXONE® (1.6 g) in water (3 ml) was added. The reaction mixture was stirred for 3 hours at room temperature, poured into water (50 ml) and extracted with methylene chloride. After drying the organic layer (Na2SO4) and concentration, the residue was treated with cold ethyl acetate, filtered, and air dried to give 490 mg (80%) of the titled material which was identical with Examples 1 Method A and Method B.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23]>C(O)C>[CH2:1]([CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[CH2:11][CH2:10][C:9]1=[N:22][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)C(Cc1ccccc1)C(=O)CC2
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COc1ccc2c(c1)C(Cc1ccccc1)C(=NO)CC2
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 102.6 %

Procedure:
To a solution of 4.47 mmol of 1-benzyl-7-methoxy-3,4-dihydronaphthalen-2(1H)-one in 15 ml ethanol were added 5.59 mmol hydroxylamine hydrochloride (dissolved in 3 ml water). The solution was stirred at 65° C. for 1.5 h. The mixture was cooled to RT and concentrated. The residue was dissolved in methyl tert-butylether and washed with water (2×), dried over MgSO4 and filtered. Evaporation of the solvent gave 1.29 g of 1-benzyl-7-methoxy-3,4-dihydronaphthalen-2(1H)-one oxime (mixture of E- and Z-isomer, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8](O)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:5]=[CH:6][CH:7]=1.[C:22]([CH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1)#[N:23].S(=O)(=O)(O)[OH:37]>ClC1C=CC=CC=1Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:23][C:22]([CH2:24][C:25]2[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=2)=[O:37])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(CC#N)cc1
Reactant: Cc1cccc(C(O)c2ccccc2N2CCCCC2)c1
Reactant: O=S(=O)(O)O
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1ccc(CC(=O)NC(c2cccc(C)c2)c2ccccc2N2CCCCC2)cc1
Reaction time: 2 h

Procedure:
A mixture of 0.22 gm (0.8 m mol) of α-(3-methyl-phenyl)-2-piperidino-benzyl alcohol and 0.15 gm (0.8 m mol) of ethyl 4-cyanomethyl-benzoate in 2 ml of o-dichlorobenzene was added dropwise, at ambient temperature, to 1.5 ml of o-dichlorobenzene and 1.5 ml of concentrated sulfuric acid. After stirring for two hours, the mixture was poured onto ice water, extracted once with ether, made alkaline with dilute sodium hydroxide solution, and extracted with chloroform. The chloroform extract was concentrated by evaporation, and the residue was recrystallized from ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:25][C:26]([F:39])([O:30][C:31]1[CH:32]=[C:33]([CH2:37]Br)[CH:34]=[CH:35][CH:36]=1)[CH:27]([F:29])[F:28].O>COCCOC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH:16]([CH2:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:26]([F:25])([F:39])[CH:27]([F:28])[F:29])[CH:32]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (27.8 g, 133 mmol) in ethyl acetate (250 ml) were added N-bromosuccinimide (26.1 g, 147 mmol) and 2,2′-azobis(isobutyronitrile) (440 mg, 2.67 mmol), and the mixture was heated under reflux for 5 hrs. After concentration of the reaction solution, crystals were filtered with hexane and the filtrate was concentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-[4-(benzyloxy)phenyl]-3-oxopropanoate (37.8 g, 127 mmol) in 1,2-dimethoxyethane (250 ml) was added sodium hydride (60% in oil, 5.07 g, 127 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (50 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (500 ml), and the mixture was extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized from ethyl acetate-hexane to give the objective substance (43.4 g, 68%).
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].[C:33]([O:37][CH2:38][CH3:39])(=[O:36])[CH:34]=[CH2:35].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.CCOCC>[ClH:1].[ClH:1].[CH2:38]([O:37][C:33](=[O:36])[CH2:34][CH2:35][N:30]1[CH2:31][CH2:32][CH:27]([O:26][C:10]2[N:9]=[N:8][C:7]([CH2:3][CH2:4][CH2:5][CH3:6])=[C:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[CH:17][CH:18]=3)[CH:11]=2)[CH2:28][CH2:29]1)[CH3:39]
Reactant: C=CC(=O)OCC
Reactant: CCCCc1nnc(OC2CCNCC2)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1nnc(OC2CCN(CCC(=O)OCC)CC2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 135.9 %

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (Example 14, 2.0 mmol, 965 mg) in DCM (5 mL) was added ethyl acrylate (6.0 mmol, 0.66 mL), and DIEA (6.0 mmol, 1.05 mL). The mixture was stirred at room temperature over night then condensed. The residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (2.0 mL), 2N HCl in ether (2.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (792 mg). LCMS: m/z 512 [M+2]. 1H NMR (400 MHz, CD3OD): δ 7.30-7.34 (2H, m), 7.01-7.07 (3H, m), 5.47-5.53 (1H, m), 4.37-4.43 (1H, m), 4.20 (2H, q), 3.35-3.70 (5H, m), 2.87-2.95 (5H, m), 2.20-2.35 (4H, m), 1.96-2.03 (2H, m), 1.78-1.84 (2H, m), 1.35-1.64 (7H, m), 1.28 (3H, t), 1.20-1.26 (3H, m), 0.80 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][Cl:6].[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC1C=CC=CC=1C>[Cl-:6].[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][P+:16]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: ClCc1cccc(Br)c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1C
Product: Brc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Cl-]
Reaction time: 48 h
Yield: 81.1 %

Procedure:
A solution of 3-bromobenzyl chloride (20 g, 97 mmol) and triphenylphosphine (25.5 g, 97 mmol) in o-xylene (200 mL) was heated to 140° C. with stirring for 48 hours. The white precipitate was filtered, washed with hexane, and air dried to afford (3-bromo-benzyl)-triphenyl-phosphonium chloride (36.8 g, 95%) as a white crystalline solid. The crude was used in next step without farther purification. MS: m/z 431 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[CH3:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([CH3:18])[C:11]([OH:17])=[CH:12][CH:13]=2)[N:8]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:5][O:4][CH2:3][CH2:2][O:17][C:11]1[C:10]([CH3:18])=[C:9]2[C:14]([CH:15]=[CH:16][C:7]([CH3:6])=[N:8]2)=[CH:13][CH:12]=1
Reactant: COCCBr
Reactant: Cc1ccc2ccc(O)c(C)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COCCOc1ccc2ccc(C)nc2c1C
Yield: 16.9 %

Procedure:
1-Bromo-2-methoxyethane (0.64 g, 4.6 mmol), 2,8-dimethylquinolin-7-ol (1.0 g, 2.3 mmol) and potassium carbonate (0.96 g, 6.9 mmol) in acetone (15 mL) were heated to 70° C. in a sealed tube for 18 hours. After cooling, water (20 mL) was added and the aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-(2-methoxyethoxy)-2,8-dimethylquinoline (90 mg, 17% yield) as an oil