Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:29])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][C:10]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:7])[CH3:6])C.[H][H]>C(O)C.[Pd]>[OH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:29])=[O:3])=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=1
Reactant: [H][H]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)cc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(Oc1ccc(O)cc1-c1ccccc1)C(=O)O

Procedure:
A solution of 2-(5-benzyloxy-biphenyl-2-yloxy)-2-methyl-propionic acid ethyl ester (3.58 g, 7.63 mmol maximum) in ethanol (75 mL) was treated with 5% Pd/C (3.0 g) and hydrogen (balloon, room temperature, 16 h). The mixture was filtered and concentrated to a viscous colorless oil (2.44 g, 107%): 1H NMR (400 MHz, CDCl3) δ1.25 (t, 3H, J=7.1 Hz), 1.27 (s, 6H), 4.20 (q, 2H, J=7.3 Hz), 4.95 (brs, 1H), 6.67 (dd, 1H, J=3.4, 8.8 Hz), 6.81 (d, 1H, J=3.4 Hz), 6.88 (d, 1H, J=8.8 Hz), 7.30 (dt, 1H, J=1.5, 7.3 Hz), 7.37 (dt, 2H, J=1.5, 7.3 Hz), 7.52 (dd, 2H, J=1.5, 6.8Hz).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:12][C:11]2[C:6]3=[C:7]([C:13]([C:15]4[C:16](=[O:31])[NH:17][C:18](=[O:30])[C:19]=4[C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[NH:22][CH:21]=4)=[CH:14][N:5]3[CH2:4]1)[CH:8]=[CH:9][CH:10]=2.[NH3:32].O1CCC[CH2:34]1>>[CH3:34][NH:32][CH2:2][CH:3]1[CH2:12][C:11]2[C:6]3=[C:7]([C:13]([C:15]4[C:16](=[O:31])[NH:17][C:18](=[O:30])[C:19]=4[C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[NH:22][CH:21]=4)=[CH:14][N:5]3[CH2:4]1)[CH:8]=[CH:9][CH:10]=2
Reactant: O=C1NC(=O)C(c2cn3c4c(cccc24)CC(CBr)C3)=C1c1c[nH]c2cc(F)ccc12
Reactant: N
Reactant: C1CCOC1
Product: CNCC1Cc2cccc3c(C4=C(c5c[nH]c6cc(F)ccc56)C(=O)NC4=O)cn(c23)C1
Temperature: 50 °C

Procedure:
3-(5-bromomethyl-5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(6-fluoro-1H-indol-3-yl)pyrrole-2,5-dione (330 mg, 0.69 mmol) was added to a solution of ammonia in tetrahydrofuran (2.0 M, 7 mL) in a pressure flask. The solution was heated at 50° C. for 26 hours. An additional 2.0 mL of ammonia in tetrahydrofuran (2.0 M) were added and the reaction mixture heated for another 18 hours. The reaction mixture was concentrated under reduced pressure and the residue subjected to silica gel chromatography to provide 210 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[O-].[K+].[SiH3][O-].[K+]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:28])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[C:19]([Cl:27])[CH:18]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OCC(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1Cl
Agent: C[Si](C)(C)[O-]
Agent: [K+]
Agent: [O-][SiH3]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(C(=O)O)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
A solution of 4-[2-(3-Chloro-4-methoxycarbonyl-phenoxy)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester from Example E41c.1 (4.5 g, 10.8 mmol) in THF at 0° C. was treated with potassium trimethylsilanolate (1.6 g, 10.9 mmol), and the mixture stirred at room temperature for 18 h. A further 1.6 g (10.9 mmol) potassium silanolate was added, and stirring continued at room temperature for 2 h. A further 1.6 g (10.9 mmol) potassium silanolate was added, and the mixture was stirred at 45° C. for 2 h. The mixture was then diluted with water and THF was removed in vacuo. The residue was washed with ether, cooled in an ice-bath and adjusted to pH5 with solid KHSO4 whereupon it was extracted with CHCl3 and CHCl3/isopropanol (90:10 v/v). The combined organics were dried and solvents were removed in vacuo to yield the title compound (3.7 g, 85%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]2[C:18]3[C:13](=[CH:14][C:15]([F:19])=[CH:16][CH:17]=3)[NH:12][N:11]=2)[CH2:6][CH2:5]1)[CH3:2]
Reactant: CC(=O)N1CCC(c2n[nH]c3cc(F)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 67.9 %

Procedure:
To a stirred suspension, under nitrogen, of 14.0 g of 3-(1-acetyl-4-piperidinyl)-6-fluoro-1H-indazole in 180 ml of tetrahydrofuran was added, dropwise, 55 ml of a 1M solution of lithium aluminum hydride in tetrahydrofuran. The reaction mixture was stirred under reflux for 1 hr and then stirred at ambient temperature for 15 hrs. The reaction mixture was cooled in an ice-salt bath and water was added slowly. The reaction mixture was filtered. The filter cake was washed with tetrahydrofuran and the filtrate was concentrated. Recrystallization of the residue from toluene afforded 9.0 g (68%) of product. Recrystallization of a 3.0 g sample from toluene yielded the analytical sample, mp 175°-178° C.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]([C:9]1[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[CH:11][N:10]=1)[CH2:7][NH2:8])[CH2:2][CH3:3].C(N(CC)CC)C.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29].O>ClCCl>[Cl:15][C:14]1[C:9]([C:6](=[N:5][O:4][CH2:1][CH2:2][CH3:3])[CH2:7][NH:8][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=2[C:25]([F:24])([F:35])[F:36])=[N:10][CH:11]=[C:12]([Cl:16])[CH:13]=1
Reactant: CCCON=C(CN)c1ncc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Yield: 87.2 %

Procedure:
In a solution of 151 mg of 2-amino-1-(3,5-dichloropyridin-2-yl)ethanone-O-propyloxime and 86 mg of triethylamine in 4 ml of dichloromethane, 154 mg of 2-(trifluoromethyl)benzoyl chloride was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 2 hours. After completion of the reaction, the reaction mixture was mixed with 10 ml of water and extracted with chloroform (30 ml×1), the resulting organic layer was washed with water (10 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 2:8 to 3:7) as the eluent to obtain 218 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: C=[CH:2][C@@H:3]1[C@:20]2([CH3:21])[C@H:6]([C@H:7]3[C@H:17]([CH2:18][CH2:19]2)[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:22])[CH2:13][CH2:14]2)[C:9](=O)[CH2:8]3)[CH2:5][CH2:4]1.[CH3:24]OC(OC)(C)C.CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[CH3:24][O:22][C:12]1[CH2:13][CH2:14][C@@:15]2([CH3:16])[C:10](=[CH:9][CH2:8][C@@H:7]3[C@@H:17]2[CH2:18][CH2:19][C@@:20]2([CH3:21])[C@H:6]3[CH2:5][CH2:4][C:3]2=[CH2:2])[CH:11]=1
Reactant: COC(C)(C)OC
Reactant: C=C[C@H]1CC[C@H]2[C@@H]3CC(=O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: C=C1CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
Refer to FIG. 190. To 17-methylenandrost-4-en-3-one (9, 2.0000 g, 7.0314 mmol) in 2,2-dimethoxypropane (9.4 ml, 76 mmol) and DMF (9.4 ml) were added 0.37 ml of anh. methanol and 47.0 mg of p-toluenesulfonic acid. After refluxing 4 h the reaction mixture was allowed to cool and then partitioned between 140 ml of hexanes and 90 ml of water. The organic phase was washed with two 90 ml portions of water+90 ml of brine, dried over magnesium sulfate, and flash filtered through a 30 mm dia.×37 mm high column of silica gel (200-400 mesh). Product continued eluting with 200 ml of hexanes. Concentration of the combined filtrates under reduced pressure and recrystallization of the residue from acetone/methanol gave very slightly yellow platelets (1.5291 g, 5.1231 mmol, 73%), m.p. 97-99° C., homogeneous to TLC (25% ethyl acetate/hexanes on silica gel, Rf 0.72).
Reaction SMILES: [C:1]1([NH:7][C@H:8]([C:10]([OH:12])=[O:11])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:13](OCCCC)=[O:14]>COCCOC>[N:13]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C@H:8]([C:10]([OH:12])=[O:11])[CH3:9])=[O:14]
Reactant: C[C@H](Nc1ccccc1)C(=O)O
Reactant: CCCCON=O
Solvent: COCCOC
Product: C[C@@H](C(=O)O)N(N=O)c1ccccc1
Reaction time: 2.5 h

Procedure:
N-Phenylalanine (825 mg) in 1,2-dimethoxyethane (20 ml) was treated with n-butyl nitrite (0.64 ml) and the mixture was stirred for 2.5 h and then the solvent was removed to leave crude N-nitroso-N-phenylalanine. This was dissolved in dichloromethane (10 ml), cooled in an ice-bath and treated with trifluoroacetic anhydride (1.06 ml). The mixture was stirred for 1 h and then the solvents were removed, toluene was added and removed using a rotary evaporator. The residue was chromatographed on silica gel eluting with ethanol/chloroform mixtures to give the sydnone (1 g), νmax (CH2Cl2) 1803(sh), 1763(sh), 1734, 1485, 1243, and 1065 cm-1 ; δ (CDCl3) 2.16 (3H,s), 7.51-7.73 (5H, m); Found m/z 176.0590; C9H8N2O2 requires 176.0586. The sydnone in xylene (8 ml) was treated with ethynyltributylstannane and the mixture was heated under reflux for 8 h. After standing for 16 h at room temperature the mixture was diluted with hexane(15 ml) and loaded onto silica gel and eluted with hexane (100 ml) followed by hexane/ethyl acetate mixtures to give 5-methyl-2-phenyl-3-(tri-n-butylstannyl)pyrazole (602 mg), δ (CDCl3) 0.87-1.76 (27H, m), 2.35 (3H, s), 6.25 (1H, s), 7.26-7.47 (5H, m); Found m/z 448.1900. C22H36N2Sn requires 448.1900.
Reaction SMILES: [C:1]1([CH:7]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][CH2:26][C:27]1[N:28]=[C:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:30][CH:31]=1>CCOC(C)=O.C(#N)C>[Cl-:25].[C:1]1([CH:7]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N+:13]([CH2:26][C:27]4[N:28]=[C:29]([C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[O:30][CH:31]=4)([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCCC1
Reactant: ClCc1coc(-c2ccccc2)n1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(O[C@H]1C[N+]2(Cc3coc(-c4ccccc4)n3)CCC1CC2)C(c1ccccc1)N1CCCCC1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 30 h
Yield: 35.1 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-phenyl-2-(piperidin-1-yl)acetate (100 mg, 0.30 mmol) in EtOAc (2 ml) and acetonitrile (1 ml), was added 4-(chloromethyl)-2-phenyloxazole (70.7 mg, 0.36 mmol). The reaction was stirred at room temperature for 30 hours and then the solvents were evaporated. Purification by flash chromatography (DCM/MeOH=9/1) followed by trituration with Et2O afforded (3R)-3-(2-phenyl-2-(piperidin-1-yl)acetoxy)-1-((2-phenyloxazol-4-yl)methyl)-1-azoniabicyclo[2.2.2]octane chloride (55 mg, 34.6% yield) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[N:3]=[N:4][C:5](Br)=[CH:6][CH:7]=1.[CH:9]1([NH2:13])[CH2:12][CH2:11][CH2:10]1.CCN(CC)CC>O1CCOCC1>[Br:1][C:2]1[N:3]=[N:4][C:5]([NH:13][CH:9]2[CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(Br)nn1
Reactant: NC1CCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Brc1ccc(NC2CCC2)nn1
Reaction time: 0.45 h
Yield: 55.2 %

Procedure:
Into a solution of 3,6-dibromopyridazine (1.19 g, 5 mmol) in dioxane (5 mL) was added cyclobutylamine (0.39 g, 5.5 mmol), and Et3N (0.60 g, 6 mmol). The reaction was microwave at 90° C., 150 W for 0.45 h. The reaction was monitored by TLC and the crude product was purified by silica gel chromatography (eluent: 30% Ethyl acetate in n-hexane), to give the desired product (0.63 g, 55.3%). 1H NMR (300 MHz, CDCl3) δ: 7.25-7.28 (1H, d, J=9.0 Hz), 6.49-6.52 (1H, d, J=9.0 Hz), 5.27 (1H, s), 4.16-4.24 (1H, m), 2.40-4.49 (2H, m), 1.87-1.95 (2H, m), 1.75-1.84 (2H, m).
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9](=[O:22])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[N:20][N:19]=[N:18]3)=[CH:13][CH:12]=1)[CH2:2]2.Br[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=1.CCN(C(C)C)C(C)C>C(#N)C>[N+:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][CH2:24][N:8]2[CH:5]3[CH2:6][CH2:7][CH:1]2[CH2:2][N:3]([C:9](=[O:22])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]4[CH:21]=[N:20][N:19]=[N:18]4)=[CH:15][CH:16]=2)[CH2:4]3)=[CH:27][CH:28]=1)([O-:34])=[O:33]
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CCC(C1)N2
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CCC(C1)N2CCc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
1-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone (100 mg, 0.335 mmol) was combined with 1-(2-bromoethyl)-4-nitrobenzene (77 mg, 0.34 mmol) and Hunig's base (43.3 mg, 0.335 mmol) in acetonitrile (1 mL) and stirred at 60° C. for 5 h. Purification by mass-directed HPLC afforded the title compound. LC/MS: [(M+1)]+=448.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.C(N(CC)CC)C.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)C>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[CH:13][C:4]=1[CH2:3][N:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCNC1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1ccc2nc(CN3CCCNCC3)ccc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
After a mixture consisting of 2-chloromethyl-quinoline hydrochloride (63.16 g, 295 mmol), triethyl-amine (29.85 g, 295 mmol), homopiperazine (50.08 g, 591 mmol) and ethanol (600 ml) was stirred at room temperature for 2 days, the solvent was distilled off under reduced pressure. Water was added to the residue. After the resulting mixture was washed three times with ethyl ether, sodium chloride was added to the water layer, followed by extraction four times with chloroform-methanol (2:1). The extract was washed with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby 28.00 g of the title compound were obtained as a yellow oil (yield: 39.3%).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.Cl[C:11]1([C:17]([O:19][CH3:20])=[O:18])[C:15](=[O:16])[CH:14]=[CH:13][S:12]1>ClCCl>[OH:16][C:15]1[CH:14]=[C:13]([N:3]2[C:4]3[CH:5]=[N:6][CH:7]=[CH:8][C:9]=3[N:1]=[CH:2]2)[S:12][C:11]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: c1cc2[nH]cnc2cn1
Reactant: COC(=O)C1(Cl)SC=CC1=O
Solvent: ClCCl
Product: COC(=O)c1sc(-n2cnc3ccncc32)cc1O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a suspension of 6 g of 1H-imidazo[4,5-c]pyridine in 300 ml of anhydrous dichloromethane is slowly added a solution of 4.8 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate. The reaction mixture is stirred for 14 h at room temperature. The solvent is removed under reduced pressure and the residue is purified by flash chromatography [silica gel, elution gradient of toluene/ethyl acetate/acetic acid, 80/20/1 (v/v/v)] to 30/70/1 (v/v/v) to give the separated title compounds along with a small fraction of the isomeric mixture.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C.C(OC(=O)C)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:32][S:29]([N:16]([CH2:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][C:6]([OH:33])=[O:5])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[CH:22][CH:23]=1)(=[O:30])=[O:31]
Reactant: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(C)(=O)=O)c1
Solvent: CC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N(Cc1ccc(-c2nccs2)cc1)Cc1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.1 %

Procedure:
A solution of (3-{[methanesulfonyl-(4-thiazol-2-yl-benzyl)-amino]-methyl}-phenoxy)-acetic acid tert-butyl ester (0.074 g) in 2 mL CH2Cl2 was cooled to 0° C. and 2 mL acetic acid tert-butyl ester (0.074 g) in 2 mL CH2Cl2 was cooled to 0° C. and 2 mL trifluoroacetic acid was added. The reaction was stirred at room temperature for 2 hours. The solvent was removed by evaporation azeotroping with CH2Cl2 to afford the title compound (40 mg). 1H NMR (400 MHz, CDCl3) δ 9.94 (bs, 1H), 8.14 (s, 1H), 7.81 (d, 2H), 7.55 (s, 1H), 7.37 (d, 2H), 7.18 (m, 1H), 6.90 (d, 1H), 6.80 (d, 1H), 6.63 (s, 1H), 4.58 (s, 2H), 4.35 (s, 2H), 4.29 (s, 2H), 2.93 (s, 3H); MS 431 (M−1).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:15][C:14](=[O:16])[CH:13](C(O)=O)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[CH:26]=1.[K].[OH-].[K+]>O>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[NH:15][C:14](=[O:16])[CH2:13][N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]=2[CH:26]=1
Reactant: O=C(O)C1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Agent: [K+]
Agent: [K]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Yield: 80 %

Procedure:
Acetic acid is added to a solution of 0.409 g. (0.001 moles) of 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid, monopotassium salt, potassium hydroxide (4306 CB) in 4 ml. of distilled water to adjust the solution to pH 4. The solution is heated on a water bath for 15 minutes; a solid precipitates which is separated, washed with water and dried; weight 0.216 g; m.p. 214°-216°C; yield 80%. This product is identical with the product obtained in Example 14.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].N#N.[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([F:26])=[CH:19][C:18]=1F>CN(C=O)C.O>[F:16][C:17]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[C:20]([F:26])=[CH:19][C:18]=1[CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1F
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1cc(F)c([N+](=O)[O-])cc1F
Temperature: -6 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled slurry of NaH (475 mg, 11.8 mmol, 60%) in dry DMF (10 mL) was added CH2(COOEt)2 dropwise under an N2 atmosphere. After 20 minutes, 1,2,4-trifluoro-5-nitrobenzene (1 g, 5.6 mmol) was added dropwise over 10 minutes and the mixture was stirred at −6° C. overnight. After the reaction was completed, the mixture was diluted with water and extracted with EtOAc. The organic layer washed with brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified chromatography to give diethyl (2,5-difluoro-4-nitrophenyl)propanedioate. 1H-NMR (400 MHz, CDCl3) δ ppm 7.87˜7.84 (m, 1H), 7.54˜7.58 (m, 1H), 4.98 (s, 1H), 4.23˜4.27 (m, 4H), 1.28 (t, J=7.0 Hz, 6H).
Reaction SMILES: [Na+].[CH:2]1([C:8]([O-:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.Br[CH2:12][CH2:13][CH3:14]>C1COCC1>[CH2:12]([O:9][C:8]([CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:10])[CH2:13][CH3:14]
Reactant: O=C([O-])C1CCCCC1
Reactant: CCCBr
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCOC(=O)C1CCCCC1
Temperature: 50 °C
Reaction time: 72 h
Yield: 74.1 %

Procedure:
To cyclohexanecarboxylic acid sodium salt (5.0 g, 33.3 mmol) in THF (80 mL) tetrabutylammonium bromide (1.074 g, 3.33 mmol) and 1-bromopropane (4.545 g, 49.95 mmol) in THF (120 mL) were added. The mixture was stirred 72 h at 50° C., cooled to room temperature and filtered. The precipitate was washed with THF. The filtrate was concentrated and the residue diluted with TBME. The solution was washed with water and the aqueous phases were re-extracted with TBME. The organic phases were combined, dried over sodium sulfate and evaporated to afford 4.2 g (74%) cyclohexanecarboxylic acid n-propyl ester as a liquid, GC purity 99% (area). 1H-NMR (CDCl3, 400 MHz): ppm 0.94 (t, 3H), 1.15-1.36 (m, 3H), 1.38-1.50 (m, 2H), 1.55-1.81 (m, 5H), 1.85-1.92 (m, 2H), 2.23-2.32 (m, 1H), 4.02 (q, 2H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:36]=[CH:35][C:34]([C:37]([O:39]C)=[O:38])=[CH:33][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([N:21]([CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:22][CH2:23][CH3:24])[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[ClH:43]>O1CCCC1.CO>[ClH:43].[ClH:43].[CH:1]1([C:7]2[C:8]3[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([N:21]([CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:22][CH2:23][CH3:24])[C:14]=2[O:13][CH2:12][CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCN(CCN1CCCCC1)c1cccc2c1OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCN(CCN1CCCCC1)c1cccc2c1OCCn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 65 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
To a solution of methyl 12-cyclohexyl-4-{N-[2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylate (3.25 g, 5.98 mmol) in tetrahydrofuran (16 ml) and methanol (8 ml) was added 4N aqueous sodium hydroxide solution (4.5 ml), and the mixture was stirred at 65° C. for 2 hr. The reaction mixture was adjusted to pH 6.5 with 2N hydrochloric acid and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. 4N HCl-ethyl acetate solution (10 ml) was added to a solution of the residue in chloroform, and the solvent was evaporated under reduced pressure. A mixed solvent (hexane:ethyl acetate=4:1) was added to the residue and the precipitated solid was collected by filtration to give 12-cyclohexyl-4-{N-[2-(piperidin-1-yl)ethyl]-N-propylamino}-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-9-carboxylic acid dihydrochloride (3.41 g, yield 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:24])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:22][CH3:23])=[C:16]([CH:19](O)[CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:27])=O>>[ClH:1].[Cl:27][CH:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:22][CH3:23])[N:12]=[CH:11][N:10]=[C:9]2[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:24])[CH3:20]
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C(C)O
Reactant: O=S(Cl)Cl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C(C)Cl
Product: Cl

Procedure:
1-{4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}ethanol was reacted with thionyl chloride using an analogous procedure to that described for the equivalent step in Example 62 to give 6-(1-chloroethyl)-N-(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4-amine hydrochloride; 1H NMR Spectrum: (DMSO d6) 1.97 (d, 3H); 4.07 (s, 3H); 5.66 (q, 1H); 7.37 (m, 2H); 7.56 (m, 1H); 7.65 (m, 1H); 8.87 (s, 1H); 9.04 (s, 1H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[O:6]1[CH:8]([CH2:9][CH3:10])[CH2:7]1>>[C:1]([N:5]1[CH2:7][CH:8]([CH2:9][CH3:10])[O:6][C:8]([CH2:9][CH3:10])([OH:6])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2].[C:1]([N:5]([CH2:7][CH:8]([OH:6])[CH2:9][CH3:10])[CH2:7][CH:8]([OH:6])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1CO1
Reactant: CC(C)(C)N
Product: CCC(O)CN(CC(O)CC)C(C)(C)C
Product: CCC1CN(C(C)(C)C)CC(O)(CC)O1
Yield: 30 %
Yield: 61 %

Procedure:
tert-Butylamine (17.0 g, 0.23 mol) and 1,2-epoxybutane (50 g, 0.69 mol) were subjected to a reaction as described in Example 1 above. A 61% yield of 4-tert-butyl-2,6-diethyl-2-hydroxymorpholine was obtained along with a 30% yield of N-tert-butyl-bis-(2-hydroxybutyl)amine.