Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.CC(C)=CCC[N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:36])[C:22]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[OH:23])[CH2:16][CH2:15]1.Cl.Cl.NC1CCN([CH2:47][CH:48]2[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)CC1>>[CH:48]1([CH2:47][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21](=[O:36])[C:22]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[OH:23])[CH2:16][CH2:15]2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: NC1CCN(CC2CCCCCC2)CC1
Reactant: CC(C)=CCCN1CCC(NC(=O)C(O)(c2ccc(F)cc2)C2CCCC2)CC1
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Product: O=C(NC1CCN(CC2CCCCCC2)CC1)C(O)(c1ccc(F)cc1)C1CCCC1

Procedure:
The title compound was prepared in the same manner as described in Step 4 of Example 22 using 2-cyclopentyl-2-(4-fluorophenyl)-2-hydroxyacetic acid obtained in Example 55 and 4-amino-1-(cycloheptylmethyl)piperidine dihydrochloride.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N(CC)CC)C.[NH2:19][CH:20]([NH2:38])[C@@H:21]([OH:37])[C@@H:22]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>ClCCl>[C:30]([C@@H:22]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C@H:21]([OH:37])[C:20]([NH2:38])([NH2:19])[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])([O:32][C:33]([CH3:35])([CH3:36])[CH3:34])=[O:31]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](CC1CCCCC1)[C@H](O)C(N)N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H](CC1CCCCC1)[C@H](O)C(N)(N)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.18 ml of benzyl chloroformate are added at a temperature of 2° to 5° to a solution of 5.28 ml of triethylamine and 6.3 g of (2S,3S)-1-amino-3-BOC-amino-4-cyclohexyl-2-butanol in 120 ml of dichloromethane, and the solution obtained is stirred for 30 minutes at room temperature. The solution is then diluted with dichloromethane and washed with 0.25N hydrochloric acid, saturated aqueous sodium bicarbonate solution and water. The organic phase is dried over sodium sulphate and evaporated under vacuum. Chromatography of the residue on silica gel using toluene/ethyl acetate (3:1) as the eluant yields (2S,3S)-3-BOC-amino-1-Cbz-amino-4-cyclohexyl-2-butanol as a slightly yellowish oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.[C:14]([O:18][C:19](=[O:25])[NH:20][CH2:21][CH2:22][CH2:23]Br)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:14]([O:18][C:19](=[O:25])[NH:20][CH2:21][CH2:22][CH2:23][O:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: O=Cc1ccc(O)c2c1CCCC2
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(C=O)c2c1CCCC2
Yield: 59.8 %

Procedure:
4-Hydroxy-5,6,7,8-tetrahydro-naphthalene-1-carbaldehyde (109, 4.6 g, 29.1 mmol) (3-Bromopropyl)-carbamic acid tert-butyl ester (110, 4.6 g, 32 mmol), and potassium carbonate (6.03 g, 43.7 mmol) were stirred in 140 mL of dry DMF over night. The reaction mixture was poured into water and extracted with dichloromethane. The organic layer was washed with water and brine., dried with magnesium sulfate, filtered, concentrated and purified by flash chromatography (0-30% EtOAc/hexane) to give crude product, which was recrystallized from EtOAc/Hexane to give 5.8 g of 111, [3-(4-formyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-propyl]-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=[O:4].[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1>CN(C)C=O.O>[N:16]1([CH2:2][C:3]([C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]3)=[O:4])[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: O=C1CCc2cc(C(=O)CCl)ccc2N1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C(=O)Cn3ccnc3)ccc2N1

Procedure:
A solution of 9.0 g of 6-(chloroacetyl)-3,4-dihydrocarbostyril and 13.4 g of imidazole in 40 ml of N,N-dimethylformamide was heated at 80° C. for 18 hours. The reaction mixture was diluted with 1000 ml of water and the precipitate filtered off, washed with water followed by a little acetone and dried under vacuum to afford 6-[(imidazol-1-yl)acetyl]-3,4-dihydrocarbostyril, having a melting point of 269°-273° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: C1=COCCC1
Reactant: Cc1ccc(CO)cc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(COC2CCCCO2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The solution of 9.85 g of 4-methyl-3-nitrobenzyl alcohol in 200 ml of dichloromethane is admixed successively with 10.9 ml of 3,4-dihydro-2H-pyran and 1.12 g of p-toluenesulphonic acid monohydrate. The reaction mixture is stirred at room temperature over 18 hours. The solution is poured onto 1M sodium hydrogencarbonate solution (300 ml) and extracted with tert-butyl methyl ether (2×300 ml). The organic phase is washed with brine (300 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.49 (1:2 EtOAc-heptane); Rt=4.73.
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[N:14]=2)[CH2:7]1)(=O)=O.[C:30]([O-:33])(=[S:32])[CH3:31].[K+]>CN(C)C=O>[C:30]([S:32][CH:6]1[CH2:7][N:8]([C:10]2[S:11][CH:12]=[C:13]([CH2:15][NH:16][C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[N:14]=2)[CH2:9]1)(=[O:33])[CH3:31]
Reactant: CS(=O)(=O)OC1CN(c2nc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(CNC(=O)OCc3ccc([N+](=O)[O-])cc3)cs2)C1
Temperature: 80 °C
Reaction time: 6.5 h
Yield: 55.6 %

Procedure:
To a solution of 3-methanesulfonyloxy-1-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (499.4 mg, 1.13 mmol) (obtained as described in Reference Example 62(4)) in dimethylformamide (25 ml) was added potassium thioacetate (1.0 g, 6.93 mmol) at room temperature, and the mixture was stirred in an oil bath (80° C.) for 6.5 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:acetonitrile (2:1) as the eluant to afford 3-acetylthio-1-[4-(p-nitrobenzyloxycarbonylaminomethyl)-1,3-thiazol-2-yl]azetidine (265.2 mg, yield 56%) as a pale brown solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:11][NH:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:11][N:12]([CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:13]
Reactant: BrCCc1ccccc1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(C)CCc1ccccc1

Procedure:
2-Phenylethyl bromide [0.01 mol.] and dimethylamine hydrochloride [0.02 mol.] are stirred at room temperature [24 hrs] and then refluxed [1 hr.] with potassium carbonate [0.06 in methanol. The insoluble materials are filtered and the solution evaporated and distilled to form N,N-dimethyl-2-phenylethylamine. The hydrochloride salt [m.p. 163-4° C.] is formed and recrystallized from ethanol. The structure was confirmed by its proton nmr spectrum, by its chemical ionization mass spectrum, and its correct elemental analyses.
Reaction SMILES: [C:1]([O:4][CH:5]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[F:26][C:27]([F:39])([F:38])[O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:4][CH:5]([C:13]1[CH:14]=[C:15]([C:32]2[CH:31]=[CH:30][C:29]([O:28][C:27]([F:26])([F:38])[F:39])=[CH:34][CH:33]=2)[CH:16]=[CH:17][CH:18]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C(=O)OC(C)(C)C)c1cccc(Br)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)OC(C(=O)OC(C)(C)C)c1cccc(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 130 °C

Procedure:
A mixture of compound 3 (811 mg, 2.46 mmol), Na2CO3 (650 mg, 6.13 mmol), Pd(PPh3)4 (207 mg, 0.18 mmol) and 4-trifluoromethoxy phenyl boronic acid (870 mg, 4.22 mmol) in acetonitrile (7.0 mL) and water (0.7 mL) was heated to 130° C. in the microwave for 30 minutes. The mixture was filtered through Celite® diatomaceous earth and washed with EtOAc. The filtrate was concentrated in vacuo and the resulting residue was purified by flash chromatography (80 g silica cartridge, 0-10% EtOAc/hexanes) to provide compound 4.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[CH2:14]([N:16]1[C:25]2[CH:24]=[CH:23][C:22]([CH:26]([CH3:28])[CH3:27])=[CH:21][C:20]=2[C:19](=[O:29])[C:18]2[C:30](=[O:37])[C:31]3[C:36]([C:17]1=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:15].Cl>C(Cl)Cl>[CH2:14]([N:16]1[C:25]2[CH:24]=[CH:23][C:22]([CH:26]([CH3:28])[CH3:27])=[CH:21][C:20]=2[C:19](=[O:29])[C:18]2[C:30]([OH:37])([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:31]3[C:36]([C:17]1=2)=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:15]
Reactant: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(=O)c1ccccc1-2
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCn1c2c(c(=O)c3cc(C(C)C)ccc31)C(O)(c1ccccc1)c1ccccc1-2

Procedure:
2M solution of phenyl magnesium bromide in THF (1.07 mL, 1.87 mmol) was dissolved in anhydrous methylene chloride. To this solution was added dropwise a solution of 5-ethyl-8-isopropyl-5,10-dihydro-11H-indeno[1,2-b]quinolin-10,11-dione (500 mg, 1.58 mmol) in anhydrous methylene chloride with ice cooling and stirring followed by stirring at room temperature overnight. The reaction mixture was treated with 10% hydrochloric acid. The organic layer was separated, washed sequentially with diluted hydrochloric acid and saturated sodium chloride solution and dried with sodium sulfate followed by evaporation to remove methylene chloride. The title compound was isolated by subjecting the residue to silica gel-chromatography (chloroform) and crystallization from diethyl ether. 1H-NMR (CDCl3) δ 1.30 (6H, d, CH(CH3)2), 1,79 (3H, t, NCH2CH3), 3.05 (1H, septet, CH), 4.81 (2H, q, NCH2), 5.18 (1H, s, H-11), 7.16-7.64 (10H, m, Ar—H), 7.96 (1H, d, H-6), 8.37 (1H, d, H-9)
Reaction SMILES: Br[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH2:13][CH3:14])[CH:5]=1)=[CH2:3].[Li]C(C)(C)C.[CH:20]([CH:22]=[CH2:23])=[O:21]>>[CH2:13]([O:12][C:6]1[CH:5]=[C:4]([C:2]([CH:20]([OH:21])[CH:22]=[CH2:23])=[CH2:3])[CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[CH3:14]
Reactant: C=C(Br)c1ccc(OC)c(OCC)c1
Reactant: C=CC=O
Agent: [Li]C(C)(C)C
Product: C=CC(O)C(=C)c1ccc(OC)c(OCC)c1
Yield: 86.2 %

Procedure:
According to the General Procedure C, 1-bromo-1-(3-ethoxy-4-methoxyphenyl)ethene (1.40 g, 5.44 mmol), t-BuLi (8.00 ml, 13.60 mmol) and acrolein (914 mg, 16.32 mmol) are converted to give after workup and chromatography [SiO2, PE/EE gradient from 5:1 to 2:1, Rf(PE/EE=2:1)=0.31] the title compound (1.10 g, 4.69 mmol) as a colorless oil;
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=2)[C:5](=[O:21])[N:4]([CH3:22])[CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:59][NH:60][CH2:61][CH2:62][OH:63]>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:60]([CH2:61][CH2:62][OH:63])[CH3:59])=[O:15])=[C:11]([N+:18]([O-:20])=[O:19])[CH:10]=2)[C:5](=[O:21])[N:4]([CH3:22])[CH:3]=1
Reactant: Cn1cc(Br)nc(Nc2ccc(C(=O)O)c([N+](=O)[O-])c2)c1=O
Reactant: CNCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCO)C(=O)c1ccc(Nc2nc(Br)cn(C)c2=O)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 90.6 %

Procedure:
4-(6-Bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-2-nitro-benzoic acid (3) (1.0 g, 2.72 mmol), (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate [BOP] (120 mg, 2.72 mmol,), diisopropylethylamine (1.42 mL, 8.15 mmol) and 2-methylaminoethanol (0.33 mL, 4.07 mmol) are dissolved in DMF (25 mL) at room temperature and allowed to react for 60 min. The reaction is quenched by the addition of water (120 mL) and the resulting suspension was allowed to stir for 15 min. The suspension is then filtered, washed with water (3×50 mL) and then air-dried to give 4-(6-bromo-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino)-N-(2-hydroxy-ethyl)-N-methyl-2-nitro-benzamide (4) as a yellow solid (1.05 g).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[CH2:23][CH2:22][C:21]2[C:24]([CH2:29]Cl)=[C:25]([Cl:28])[CH:26]=[CH:27][C:20]=2[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>CN(C=O)C>[NH2:1][C:2]1[S:6][C:5]([S:7][CH2:29][C:24]2[C:21]3[CH2:22][CH2:23][N:17]([C:15]([O:14][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:16])[CH2:18][CH2:19][C:20]=3[CH:27]=[CH:26][C:25]=2[Cl:28])=[N:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Reactant: Nc1nnc(S)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3nnc(N)s3)c2CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.4 %

Procedure:
To a mixture of 5-amino-1,3,4-thiadiazole-2-thiol (0.33 g, 2.5 mmol) in anhydrous DMF (8.5 mL) at room temperature add sodium hydride (0.1 g, 2.6 mmol, 60% dispersion in mineral oil) in portions. After stirring at room temperature for 10 min, add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.75 g, 2.3 mmol) in anhydrous DMF (5.6 mL). Stir at room temperature overnight and quench the reaction mixture with 10% aqueous NaHCO3 (25 mL). Extract the mixture with DCM (100 mL). Dry the organic phase over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM, load the solution on to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (hexane over 10 min; 100:0 to 50:50 hexane/EtOAc over 23 min; 50:50 to 0:100 hexane/EtOAc over 33 min; 35 mL/min) to obtain an oil. Add EtOAc (16 mL) to precipitate product. After stirring overnight, filter the slurry, wash the solid with EtOAc (10 mL) and dry to obtain the desired intermediate (0.583 g, 61%) as a white solid. MS (ES+) m/z: 427.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CC#N.CCOC(C)=O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:15][CH:16]=3)[C:11](=[O:19])[C:10]=2[C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: BrCCc1ccccc1
Reactant: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1C(c2cccnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCc3ccccc3)cc21
Temperature: 25 °C
Yield: 30 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-6-hydroxy-2-(pyridin-3-yl)-1H-inden-1-one (0.15 mol, 50 mg) obtained in Step 1 in CH3CN was added K2CO3(1.5 eq). 1-(2-bromoethyl)benzene (1.5 eq) was added dropwise and the resulting mixture was heated to reflux for 3 d. The reaction was cooled to room temperature and diluted with EtOAc. The organic layer was washed with H2O, dried over MgSO4, and concentrated in vacuo to obtain the title compound (30%).
Reaction SMILES: [NH:1]1[CH2:13][CH2:12][CH2:11][CH:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[CH2:2]1.F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22].[F-].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N+:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N:1]1[CH2:13][CH2:12][CH2:11][CH:3]([C:4]([O:6][C:7]([CH3:9])([CH3:10])[CH3:8])=[O:5])[CH2:2]1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)OC(=O)C1CCCNC1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1CCCN(c2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.2 %

Procedure:
To a solution of Example 437C (10.4 g, 56.1 mmol) in toluene (112 mL) was added 2-fluoronitrobenzene (6.0 mL, 56 mmol) and CsF (852 mg, 5.6. mmol). The reaction mixture was stirred under reflux conditions for 18 h, and allowed to cool to ambient temperature. The mixture was diluted with ethyl acetate (100 mL), washed with 10% HCl (2×50 mL), followed by brine (3×100 mL), then dried (Na2SO4) and evaporated in vacuo to obtain the title compound (16.5 g, 94%). MS (ESI) m/e 307 (M+H)+.
Reaction SMILES: Cl.[F:2][CH:3]([F:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].Cl[C:34]([O:36][CH3:37])=[O:35]>>[CH3:37][O:36][C:34]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:6]2[N:5]([CH2:4][CH:3]([F:2])[F:32])[C:13]3[C:8]([CH:7]=2)=[CH:9][C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:12]=3)=[O:25])[CH2:31][CH2:30]1)=[O:35]
Reactant: COC(=O)Cl
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3CC(F)F)CC1
Agent: Cl
Product: COC(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3n2CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-(2,2-difluoro-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and methyl chloroformate. Light-yellow solid. MS (m/z): 493.2 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:18]([O:20]C)=[O:19])=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1.CO.[OH-].[Na+].Cl>O>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:13][C:14]([C:18]([OH:20])=[O:19])=[C:15]([CH3:17])[N:16]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1oc(-c2ccc(OCCCCl)cc2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nc(-c2ccc(OCCCCl)cc2)oc1C(=O)O
Temperature: 60 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A suspension of methyl 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-oxazole-5-carboxylate ax60 (4.0 g, 12.9 mmol, 1 eq) in a 1:1 mixture of methanol and water (100 ml) is treated with a 1 M solution of sodium hydroxide (14 ml, 14 mmol, 1.1 eq). The mixture is stirred at 60° C. during 2 h, then the mixture is concentrated. The residue is taken up in water (20 ml) and a 1 M hydrochloric acid solution (14 ml, 14 mmol, 1.1 eq) is added. The resulting suspension is filtered and the filtrate is concentrated to give 3.4 g of 2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-oxazole-5-carboxylic acid i43.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][C:11]3[CH:15]=[CH:16][CH:17]=[CH:18][C:10]2=3)=[CH:6][CH:5]=1)([O-])=O.O.O.[Sn](Cl)Cl>CO>[O:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:7]2[CH:19]=[CH:20][C:4]([NH2:1])=[CH:5][CH:6]=2)[C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]1=2
Reactant: O=[N+]([O-])c1ccc(CN2CCOc3ccccc32)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: Nc1ccc(CN2CCOc3ccccc32)cc1
Temperature: 50 °C

Procedure:
A mixture of 4-(4-nitrobenzyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.432 g, 1.6 mmol) and tin(II) chloride dihydrate (1.8 g, 8.0 mmol) in MeOH (10 mL) was heated to 50° C. After 3 hrs the mixture was concentrated in vacuo and the residue taken up in EtOAc. Saturated NaHCO3 was added and the mixture was filtered. The filtrate was washed with brine, dried with Na2SO4, concentrated in vacuo, and purified by silica gel chromatography using 20-100% Hexanes:EtOAc to afford 4-((2,3-dihydrobenzo[b][1,4]oxazin-4-yl)methyl)benzenamine as an orange oil. MS found: M+H+=241.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=1.C([Li])CCC.[B:20](OC)([O:23]C)[O:21]C.Cl>CCCCCC.C1COCC1>[CH:4]1[C:5]2[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[O:7][C:6]=2[CH:14]=[CH:2][C:3]=1[B:20]([OH:23])[OH:21]
Reactant: Brc1ccc2c(c1)oc1ccccc12
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc2oc3ccccc3c2c1
Temperature: -80 °C
Reaction time: 2 h
Yield: 23.6 %

Procedure:
In a 300 mL three-neck flask was put 3.6 g (14 mmol) of 3-bromodibenzofuran. The air in the flask was replaced with nitrogen. To this mixture was added 70 mL of THF, and this solution was cooled to −80° C. Then, 10 mL (16 mmol) of n-butyllithium (a 1.6 mol/L hexane solution) was dripped into this solution with a syringe. After that, this solution was stirred at the same temperature for 2 hours. Then, 3.4 mL (30 mmol) of trimethyl borate was added to this solution, and the mixture was stirred for 4 days while its temperature was returned to room temperature. After that, about 30 mL of diluted hydrochloric acid (1.0 mol/L) was added to this solution, followed by stirring for 1 hour. Then, the aqueous layer of this mixture was extracted with ethyl acetate, and the ethyl acetate solution and the organic layer were combined and washed with saturated brine. The organic layer was dried with magnesium sulfate. Then, this mixture was gravity filtered. The resulting filtrate was concentrated to give a solid. The solid was washed with hexane, whereby 0.70 g of a white powder was obtained in 27% yield, which was the substance to be produced.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)=O.O.[NH2:13][NH2:14]>CO>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([NH:13][NH2:14])=[O:2])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1ccc(Br)cn1

Procedure:
5-Bromo-pyridine-2-carboxylic acid methyl ester (J. Org. Chem., 2001, 66(2), 605-608, compound 4) (18.10 g, 83 mmol) and hydrazine monohydrate (12.5 mL, 250 mmol) were dissolved in methanol (400 mL) and the reaction mixture heated to reflux for 48 hours. The reaction mixture was then filtered and the precipitate collected dried in vacuo to yield the title product, 15.40 g.