Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][S:11]([CH3:13])=[O:12])[CH:5]=[C:4]([CH3:14])[C:3]=1[C:15]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]2[C:16]=1[CH2:17][CH2:18][C@H:19]2[O:25][C:26]1[CH:38]=[CH:37][C:29]2[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=2[CH:27]=1.[K].[OH:40]OS([O-])=O.[K+]>CO.O.C(#N)C.O>[CH3:14][C:4]1[CH:5]=[C:6]([O:8][CH2:9][CH2:10][S:11]([CH3:13])(=[O:40])=[O:12])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:15]1[CH:23]=[CH:22][C:21]([F:24])=[C:20]2[C:16]=1[CH2:17][CH2:18][C@H:19]2[O:25][C:26]1[CH:38]=[CH:37][C:29]2[C@H:30]([CH2:33][C:34]([OH:36])=[O:35])[CH2:31][O:32][C:28]=2[CH:27]=1
Reactant: O=S([O-])OO
Reactant: Cc1cc(OCCS(C)=O)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Agent: [K+]
Agent: [K]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: Cc1cc(OCCS(C)(=O)=O)cc(C)c1-c1ccc(F)c2c1CC[C@H]2Oc1ccc2c(c1)OC[C@H]2CC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-((3S)-6-((1R)-4-(2,6-dimethyl-4-(2-(methylsulfinyl)ethoxy)phenyl)-7-fluoro-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (70 mg) in methanol (1.5 mL) and water (0.75 mL) is added potassium peroxomonoslufate (Oxone®) (150 mg). The mixture is stirred for 3 hour at room temperature and then potassium peroxomonoslufate (Oxone®) (80 mg) is added. After stirring for 12 hours at room temperature the mixture is partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:50→0:100). The product thus obtained is dissolved in acetonitrile/water (1:1) and lyophilized to give the title compound. Yield: 7 mg; LC (method 4): tR=1.71 min; Mass spectrum (ESI+): m/z=555 [M+H]+.
Reaction SMILES: NCCNC[C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[C:9]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:8][N:7]=1.Cl[C:26]1[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[C:9]([C:20]2[NH:24][CH:23]=[CH:22][N:21]=2)=[CH:8][N:7]=[C:6]([N:21]([CH3:20])[CH2:22][CH2:23][NH:24][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:11]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NCCNCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: CN(CCNc1ccc([N+](=O)[O-])cn1)c1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1

Procedure:
Using the procedure described above in Example 139, reaction of (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]methylamine and 2-chloro-5-nitro-pyridine were reacted to afford [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]-methyl{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][C:4]([C:15]([O:17]C)=[O:16])=[CH:3]1.[OH-].[Na+]>C(O)C>[CH3:1][N:2]1[C:6]([C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][C:4]([C:15]([OH:17])=[O:16])=[CH:3]1
Reactant: COC(=O)c1cc(C(=O)c2ccccc2)n(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(C(=O)O)cc1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
The entire batch of methyl 1-methyl-5-benzoylpyrrole-3-carboxylate from Example 84 was combined with 200 ml. of ethanol and 100 ml. of 1 N sodium hydroxide and refluxed for 2 hours. The ethanol was boiled away, the aqueous residue was cooled to room temperature, extracted with 25 ml. of ether and acidified with conc. hydrochloric acid to yield crystalline product (4 g., m.p. 210°-212° C.). A portion (1.5 g.) was recrystallized from acetone to yield purified 1-methyl-5-benzoylpyrrole-3-carboxylic acid (925 mg., m.p. 215°-216.5° C., m/e 229).
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH2:28][CH2:29][CH2:30][OH:31])(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>CN(C)C=O>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH2:28][CH2:29][CH2:30][O:31][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])(=[O:26])=[O:27])=[CH:23][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=S(=O)(CCCO)c1ccc(Br)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCS(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65.2 %

Procedure:
tert-Butyldimethylchlorosilane (508 mg) and diisopropylethylamine (587 μL) were added to a solution of 3-(4-bromophenylsulfonyl)propan-1-ol (784 mg) in N,N-dimethylformamide (4 mL), and the mixture was stirred at room temperature for 2.5 hours. tert-Butyldimethylchlorosilane (127 mg) and diisopropylethylamine (147 μL) were added to the reaction solution, and the mixture was stirred at room temperature for further two hours. tert-Butyldimethylchlorosilane (254 mg) and diisopropylethylamine (1.17 mL) were added to the reaction solution, and the mixture was stirred at room temperature for further 30 minutes. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1→33:1→19:1→9:1) to give the title compound as a white solid (720 mg, 65%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)#[CH:2].Br[C:11]1[CH:25]=[CH:24][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:11]2[CH:12]=[CH:13][C:14]([C:15](=[O:16])[C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[CH:24][CH:25]=2)=[CH:4][CH:5]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Br)cc1
Reactant: C#Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)c1ccc(C#Cc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
Into a 250 mL, 3-neck, round-bottom flask equipped with a magnetic stirrer, a thermocouple, and a condenser were placed 12.00 g (100.0 mMol) of 1-ethynyl-4-fluorobenzene, 27.93 g (100.0 mMol) of 4-bromo-4′-fluorobenzophenone (Rieke Metals, Inc.), 1.5 g of tetrakis(triphenylphosphine)palladium[0], and 150 mL of de-aerated triethylamine. The reaction mixture was heated to 80° C. with stirring under argon for 3 hr and then cooled to ambient overnight (16 hr) with stirring. The reaction mixture was filtered to remove a white precipitate of triethylamine hydrobromide. The triethylamine solvent was evaporated and the solids obtained were dissolved in dichloromethane. The resulting solution was washed with water (2×50 mL), 2% HCl (2×50 mL), brine, and then dried over sodium sulfate. After removal of the solvent, the crude 4-fluoro-4′-(4-fluorobenzoyl)tolane was purified by silica gel column chromatography using hexanes as the elutant. White crystals having a melting point of 190-191° C. were obtained in a yield of 81%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:13]=[C:14]([N:18]([CH3:23])[C:19](=[O:22])[CH:20]=[CH2:21])[CH:15]=[CH:16][CH:17]=3)[N:9]=[C:10](I)[C:3]=12.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>COCCOC.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:13]=[C:14]([N:18]([CH3:23])[C:19](=[O:22])[CH:20]=[CH2:21])[CH:15]=[CH:16][CH:17]=3)[N:9]=[C:10]([C:28]3[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=3)[C:3]=12
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: C=CC(=O)N(C)c1cccc(-n2nc(I)c3c(N)ncnc32)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: COCCOC
Product: C=CC(=O)N(C)c1cccc(-n2nc(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a stirred solution of N-(3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)phenyl)-N-methylacrylamide (50) (147 mg, 0.35 mmol) and 4-chlorophenylboronic acid (66 mg, 0.42 mmol) in DME/H2O(4 mL/1 mL) were added Pd(dppf)Cl2(14 mg, 0.018 mmol) and K3PO4.3H2O (280 mg, 1.05 mmol). The resulting mixture was purged with N2 (3×) and stirred at 80° C. overnight. Solvents were removed in vacuo. The residue was pre-purified by flash chromatography (silica gel, 0 to 10% MeOH in DCM with 0.3% TEA) and followed by prep HPLC to provide N-(3-(4-amino-3-(4-chlorophenyl)-1H-pyrazolo[3,4-c]pyrimidin-1-yl)phenyl)-N-methylacrylamide (51) (39 mg, 28%) as a white solid. LC-MS (ESI): m/z (M+1) 405.1. 1H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.26 (d, J=8.4 Hz, 1H), 8.14 (s, 1H), 7.76 (d, J=8.3 Hz, 2H), 7.62 (m, 3H), 7.28 (m, 1H), 6.17 (m, 2H), 5.59 (m, 1H), 3.30 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[CH2:16][C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: Brc1cccc2c1CCN2
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1ccc(CN2CCc3c(Br)cccc32)cc1
Yield: 91.5 %

Procedure:
To 4-bromoindoline (200 mg, 1.00 mmol) in 5 ml DMF was added 4-Fluorobenzylbromide (0.14 ml, 1.1 mmol) then add NaH (40 mg, 1.0 mmol) and stir at room temperature overnight. Work up by adding water and EtOAc and extract three times with EtOAc. Pool all organics and wash one time with brine then dry over sodium sulfate, filter and concentrate to dryness. The residue was purified by chromatography over silica gel (eluted with Hexanes/EtOAc 99:1 to 50:50) to provide 280 mg (92%) of product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:24]=[CH:23][C:12]2[C@:13]3([CH3:22])[C@@H:18]([CH2:19][CH2:20][C:11]=2[CH:10]=1)[NH:17][C:16](=[O:21])[CH2:15][CH2:14]3)#[N:2].[C:25](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:25][N:17]1[C@H:18]2[C@@:13]([CH3:22])([C:12]3[CH:23]=[CH:24][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:1]#[N:2])=[CH:10][C:11]=3[CH2:20][CH2:19]2)[CH2:14][CH2:15][C:16]1=[O:21]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccccc3C#N)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccccc4C#N)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2-cyanophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (55 mg, 0.17 mmol), 0.4 mL of t-butanol, and potassium t-butoxide (58 mg, 0.51 mmol). Methyl iodide (0.034 mL, 0.54 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 50 mg (87%) of the title compound as a white solid. mp 54°-55°. FDMS: m/e=330. α[D]589 =+74.33 (c=0.36, chloroform).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[C:11]([OH:13])=O.[H-].[Na+].[C:22]1([C:28]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:29]2[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][C:43]([CH2:46]Br)=[CH:42][CH:41]=3)=[N:32][N:31]=[N:30]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[C:54]1([C:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[N:29]2[C:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[CH:45]=[CH:44][C:43]([CH2:46][O:7][C:8]4[CH:9]=[C:10]([CH:14]=[CH:15][C:16]=4[N+:17]([O-:19])=[O:18])[C:11]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:13])=[CH:42][CH:41]=3)=[N:32][N:31]=[N:30]2)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc([N+](=O)[O-])c(OCc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 101.9 %

Procedure:
The compound ([3]-(32)-587) (0.99 g) prepared in Example 36 was dissolved in dry N,N-dimethylformamide (19 ml), and 50% sodium hydride (0.20 g) was added to the solution. The mixture was stirred at room temperature for 15 minutes. A solution of N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (2.19 g) in N,N-dimethylformamide (6.5 ml) was added to the solution. The mixture was stirred at room temperature for 39 hours. The reaction mixture was added to water (50 ml), and extracted with chloroform (100 ml). The organic layer was washed, dried over anhydrous sodium sulfate, and concentrated to obtain the compound (2.72 g) as a light yellow solid. The product was purified by silica gel column chromatography (Kieselgel 60=190 g, chloroform/ethyl acetate=7/3) to obtain the compound ([3]-(33)-587) (1.41 g)
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH:26]=[CH:25][CH:24]=[N:23]1>>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[N:22]1[CH:26]=[CH:25][CH:24]=[N:23]1)([O-:14])=[O:13]
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Reactant: c1cn[nH]c1
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cccn3)cc2c1=O
Yield: 27 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (30 mg, 0.0943 mmol) is reacted with 1H-pyrazole according to the GPB affording 9.4 mg (27%) of a red powder. Rt=3.64 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:28]([O:30]C)=[O:29])[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[C:6](/[N:14]=[N:15]/[N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:7]=1[C:8]#[C:9][Si](C)(C)C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:28]([OH:30])=[O:29])[C:5]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)=[C:6](/[N:14]=[N:15]/[N:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:7]=1[C:8]#[CH:9]
Reactant: CCN(CC)/N=N/c1c(C#C[Si](C)(C)C)c(Cl)cc(C(=O)OC)c1-c1cccc(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C#Cc1c(Cl)cc(C(=O)O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Temperature: 65 °C

Procedure:
A solution of methyl 4-chloro-6-[(1E)-3,3-diethyltriaz-1-en-1-yl]-3′-fluoro-5-[(trimethylsilyl)ethynyl]biphenyl-2-carboxylate (3.3 g, 7.1 mmol) in methanol (11 mL) and tetrahydrofuran (11 mL) was treated with 1 M sodium hydroxide in water (29 mL, 29 mmol) dropwise and heated at 65° C. for 1 hour. The reaction mixture was cooled to 0° C. and treated with 3 M hydrogen chloride in water (12 mL, 36 mmol) dropwise. This mixture was poured into 1 M hydrogen chloride in water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (50 mL), dried with sodium sulfate, filtered, and concentrated to give the desired product (quantitative). This material was used without further purification. LCMS for C19H18ClFN3O2 (M+H)+: m/z=374.1; Found: 373.9.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14]([CH3:15])=[CH:13][C:12](=[O:16])[C:11]([C:17]([O:19][CH3:20])=[O:18])=[N:10]2)=[CH:5][CH:4]=1.OO.[OH2:23].C(O)(=[O:26])C>>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:14]([CH3:15])=[CH:13][C:12](=[O:16])[C:11]([C:17]([O:19][CH3:20])=[O:18])=[N:10]2)=[CH:7][CH:8]=1)(=[O:26])=[O:23]
Reactant: O
Reactant: CC(=O)O
Reactant: COC(=O)c1nn(-c2ccc(SC)cc2)c(C)cc1=O
Agent: OO
Product: COC(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)c(C)cc1=O
Temperature: 5 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a suspension of 2.9 g (0.01 mol) Methyl 1-(4-methylthiophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylate (see Example 24) in 50 ml of glacial acetic acid, cooled to 5° C., there is added dropwise 3.4 g (0.02 mol) of 30% hydrogen peroxide (aqueous). The mixture is stirred at 5° C. for 1 hr. and at room temperature for 2 days. To the mixture there is added 200 ml of water and it is allowed to stirr at room temperature for 1 hr. The suspension formed is vacuum filtered and the filter cake is recrystallized with methyl cellosolve to afford 1.15 g (36% yield) of product, mp 253°-257° decomp.
Reaction SMILES: C(NCC)C.C([Li])CCC.[CH:11]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23]Br)[CH3:20]>CCCCCC>[CH2:19]([O:21][CH:22]([O:25][CH2:26][CH3:27])[CH2:23][C:11]1([C:17]#[N:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:20]
Reactant: N#CC1CCCCC1
Reactant: CCOC(CBr)OCC
Agent: [Li]CCCC
Solvent: CCNCC
Solvent: CCCCCC
Product: CCOC(CC1(C#N)CCCCC1)OCC
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
51.7 ml (0.5 mol) of anhydrous diethylamine are added dropwise to 312.5 ml (0.5 mol) of a 15% solution of n-butyl-lithium in hexane at -10° C. under an inert gas blanket. The batch is stirred for 10 minutes and then cooled to -70° C. Within 30 minutes, 54.6 g of cyclohexane-carbonitrile are added dropwise, after a further 30 minutes 98.5 g of bromoacetaldehyde-diethylacetal are added within 1 hour, and the batch is maintained for 24 hours at low temperature. Subsequently, it is warmed to room temperature, given onto 100 g of ice, extracted twice with 500 ml of ethyl acetate, the organic phase is dried over sodium sulfate, concentrated in vacuo, and the residue is subjected to vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[C:20]2[CH2:21][CH2:22][N:23](C(=O)C(F)(F)F)[CH2:24][CH:25]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.CO.O>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=2)=[CH:33][CH:34]=1
Reactant: O=C(N1CC=C(c2cc(=O)[nH]c3ccc(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)cc23)CC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=c1cc(C2=CCNCC2)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A mixture of 6-(bis(4-chlorophenyl)methyl)-4-(1-(2,2,2-trifluoroacetyl)-1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one (23 mg, 0.041 mmol), Na2CO3 (22.8 mg, 0.165 mmol) in THF (0.8 mL), MeOH (0.5 mL) and a couple of drops of water was stirred at 30° C. for 3 hr. The solvent was evaporated and to the residue was added DCM and water. The organics were dried over anhydrous Na2SO4, filtered and concentrated to yield 6-(bis(4-chlorophenyl)methyl)-4-(1,2,3,6-tetrahydropyridin-4-yl)quinolin-2(1H)-one. (ES, m/z) [M+H]+ 461.1, 463.0.
Reaction SMILES: CO.[Cl:3][C:4]1[C:14]([O:15][CH2:16][CH2:17][N:18]2[CH:22]=[N:21][N:20]=[N:19]2)=[C:13]([Cl:23])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7].[OH-].[Na+]>O>[Cl:3][C:4]1[C:14]([O:15][CH2:16][CH2:17][N:18]2[CH:22]=[N:21][N:20]=[N:19]2)=[C:13]([Cl:23])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(Cl)c(OCCn2cnnn2)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(Cl)c(OCCn2cnnn2)c1Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 85.7 %

Procedure:
To a methanol (15 ml) solution of ethyl 2,4-dichloro-3-[2-(1H-tetrazol-1-yl)ethoxy]benzoate (0.88 g) were added sodium hydroxide (0.16 g) and water (5 ml), and the mixture was stirred at room temperature for 7 hours. After the addition of water (20 ml) and concentration at reduced pressure, an aqueous sodium hydroxide solution was added and the mixture was washed with ethyl acetate (50 ml). The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off to obtain the desired 2,4-dichloro-3-[2-(1H-tetrazol-1-yl)ethyloxy]-benzoic acid (0.69 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1Br.[Li:16]C(C)(C)C.CCCCC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[Li:16]
Reactant: [Li]C(C)(C)C
Reactant: Fc1cccc(Oc2ccccc2Br)c1
Solvent: C1CCOC1
Solvent: CCCCC
Product: [Li]c1ccccc1Oc1cccc(F)c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1-(3-fluorophenoxy)-2-bromobenzene (1.27 g, 4.75 mmol) in THF (10 mL) at −70° C. was added 1.7 M t-BuLi in pentane (5.6 mL, 9.50 mmol) dropwise to keep the temperature below −70° C. The resulting solution was stirred at −70° C. for 30 min, and used for the next step directly.
Reaction SMILES: [NH2:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([OH:10])=O)=[CH:4][C:3]=1[Cl:21].ClC(OCC)=O.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:3]([Cl:21])=[CH:4][C:5]([C:6]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:7][C:8]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:10])=[CH:18][C:19]=1[Cl:20]
Reactant: C1COCCN1
Reactant: Nc1c(Cl)cc(C(=CC(=O)O)c2ccc(F)cc2)cc1Cl
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: Nc1c(Cl)cc(C(=CC(=O)N2CCOCC2)c2ccc(F)cc2)cc1Cl

Procedure:
This compound was prepared from 4-amino-3,5-dichloro-β-(4'-fluorophenyl)-cinnamic acid (isomer ratio A:B=3:1), ethyl chloroformate, triethylamine and morpholine analogous to Example 1(c).
Reaction SMILES: CN(C)C=O.[OH:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C>[CH2:23]([O:6][CH2:7][CH:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a 30 ml N,N-dimethylformamide solution of 2.4 g (11.15 mmol) of tert-butyl 4-hydroxymethyl-1-piperidinecarboxylate, 557 mg (60% in oil, 13.9 mmol) of sodium hydride and 1.86 ml (15.6 mmol) of benzyl bromide were added with ice cooling. The mixture was stirred at room temperature for 23 hours. Then, the reaction mixture was diluted with ethyl acetate, and the dilution was washed with water and a saturated aqueous solution of sodium chloride in this order. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain 3.5 g (quantitative) of the captioned compound.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C@H:17]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:36]1([C:39](Cl)=[O:40])[CH2:38][CH2:37]1>>[F:11][C:9]([F:10])([F:12])[C:7]1[CH:6]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([N:21]3[CH2:22][CH2:23][N:24]([C:39]([CH:36]4[CH2:38][CH2:37]4)=[O:40])[CH2:25][CH2:26]3)[C@H:17]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[CH2:16]2)=[O:14])[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:8]=1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCNCC2)[C@H](c2ccc(F)cc2)C1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(C(=O)C3CC3)CC2)[C@H](c2ccc(F)cc2)C1

Procedure:
The title compound, MS: m/e=572.1 (M+H+), was prepared in accordance with the general method of example 38 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[3-(4-fluoro-phenyl)-4-piperazin-1-yl-piperidin-1-yl]-methanone and cyclopropane carboxylic acid chloride.