Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[CH3:8][C:9]1[O:15]C(C)(C)[O:13][C:11](=O)[CH:10]=1>C1(C)C(C)=CC=CC=1>[C:11]([N:3]1[CH2:4][CH2:5][N:6]([C:11](=[O:13])[CH2:10][C:9]([CH3:8])=[O:15])[CH2:7][CH:2]1[CH3:1])(=[O:13])[CH2:10][C:9]([CH3:8])=[O:15]
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: CC1CNCCN1
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)N1CCN(C(=O)CC(C)=O)C(C)C1
Temperature: 115 °C
Yield: 98.7 %

Procedure:
To 2-methylpiperazine (81.90 g, 0.819 mol) in xylene (525 ml) at 133° C. was added with stirring 2,2,6-trimethyl-1,3-dioxen-4-one (232.48 g, 1.637 mol) in xylene (525 ml) over 10 minutes, during which the temperature decreased to 100° C. After heating to 115° C over 5 minutes vigorous effervescence commenced, and after heating to 124° C. over another 5 minutes distillation of acetone (through a Vigreux column) also commenced. Pot temperature was increased to 139° C. over a further 30 minutes, with collection of acetone distillate. After cooling to 20° C. overnight, supernatant liquid was separated from deposited syrup, which was dissolved in dichloromethane. Removal of solvent from combined solutions and drying (92° C./100 Pa) gave N,N′-bis(acetoacetyl)-2-methylpiperazine (BAAMPZ) as a viscous syrup (216.66 g, 99%), identified by 1H-NMR, 13C-NMR, FT-IR and Raman spectra.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:12][CH2:13][N:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N+:24]([O-:26])=[O:25])[CH2:15][CH2:16]2)[N:3]=1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Reactant: O=[N+]([O-])c1ccccc1Br
Product: Cc1cccc(C#CC=C2CCN(c3ccccc3[N+](=O)[O-])CC2)n1
Reaction time: 1 h
Yield: 27.7 %

Procedure:
A well homogenised mixture of the Compound of Example 3 (20 mg, 0.09 mmol) and 1-bromo-2-nitrobenzene (22.8 mg, 0.11 mmol) was stirred at 90° C. for 0.5 h, then at 110° C. for 1 h. The reaction crude was purified by flash chromatography (EtOAc—Petroleum Ether gradient from 3:7 to 4:6) affording the title product (8.3 mg).
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][N:4]=[C:5]([C:13](=[O:15])[CH3:14])[C:6]([O:8]C(C)(C)C)=[O:7].S(Cl)(Cl)(=O)=O>C(O)(=O)C>[F:1][CH:2]([F:16])[O:3]/[N:4]=[C:5](/[C:13](=[O:15])[CH3:14])\[C:6]([OH:8])=[O:7]
Reactant: CC(=O)C(=NOC(F)F)C(=O)OC(C)(C)C
Solvent: CC(=O)O
Solvent: O=S(=O)(Cl)Cl
Product: CC(=O)/C(=N/OC(F)F)C(=O)O
Temperature: 25 °C
Yield: 65.9 %

Procedure:
To a solution of tert-butyl 2-difluoromethoxyimino-3-oxobutyrate (9.4 g) in acetic acid (9.4 ml) was added sulfuryl chloride (2.55 ml) under ice-cooling. After stirred at ambient temperature for an hour, the reaction mixture was concentrated under reduced pressure. The residual oil was dissolved in ethyl acetate. The ethyl acetate solution was washed with water, dried over magnesium sulfate, and evaporated in vacuo. The residue was crystallized with diisopropyl ether to give (Z)-2-difluoromethoxyimino-3-oxobutyric acid (4.73 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)=[O:24])[CH:21]=2)[N:16]=[C:15]([O:31][CH3:32])[C:14]=1[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>C1COCC1>[Cl:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([C:25]3[N:29]([CH3:30])[CH:28]=[N:27][CH:26]=3)([C:2]3[CH:7]=[N:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)[OH:24])[CH:21]=2)[N:16]=[C:15]([O:31][CH3:32])[C:14]=1[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([S:40]([CH3:43])(=[O:41])=[O:42])=[CH:38][CH:39]=1
Reactant: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Reactant: FC(F)(F)c1ccc(Br)cn1
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Isopropyl magnesium chloride LiCl complex (1.3 M in THF, 0.7 mL, 0.904 mmol) was added dropwise to a solution of 5-bromo-2-(trifluoromethyl)pyridine (0.2 g, 0.904 mmol) in dry THF 5 mL) at 0° C. The mixture was stirred at 0° C. for five minutes then at room temperature for 30 minutes. A suspension of (4-chloro-2-methoxy-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (0.085 g, 0.181 mmol, Intermediate 38: step b) in THF (5 mL) was added rapidly at 0° C. and the reaction mixture was stirred and allowed to warm to room temperature. The homogeneous amber solution was stirred at room temperature for 4 hours, then heated at 45° C. for 12 hours. Once cooled the reaction mixture was quenched with saturated aqueous NH4Cl, diluted with H2O and extracted with EtOAc (2×). The EtOAc extracts were washed with brine, dried (Na2SO4), filtered, evaporated in vacuo and chromatographed (DCM/MeOH) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 8.80 (s, 1H), 8.15 (d, J=2.0 Hz, 1H), 7.87-8.00 (m, 1H), 7.78-7.87 (m, 3H), 7.65 (d, J=8.1 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.46 (d, J=8.6 Hz, 2H), 7.32 (s, 1H), 6.33 (s, 1H), 5.30 (s, 1H), 4.37 (s, 2H), 4.08 (s, 3H), 3.36 (s, 3H), 3.01 (s, 3H); MS (ESI) 617.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:35]4[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=4)(N=CC4C=CC(OC)=CC=4)[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:16]=3)[N:11]([CH2:42][CH:43]3[CH2:45][CH2:44]3)[C:10](=[O:46])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)[OH:48].N([O-])=O.[Na+].C(OCC)(=O)C>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[C:12](=[CH:17][CH:16]=[C:15]([C:18]([C:35]4[CH:36]=[N:37][C:38]([Cl:41])=[CH:39][CH:40]=4)([OH:48])[C:19]4[N:20]([CH3:24])[CH:21]=[N:22][CH:23]=4)[CH:14]=3)[N:11]([CH2:42][CH:43]3[CH2:45][CH2:44]3)[C:10](=[O:46])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=NC(c2ccc(Cl)nc2)(c2ccc3c(c2)c(-c2cccc(Cl)c2)cc(=O)n3CC2CC2)c2cncn2C)cc1
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cncc1C(O)(c1ccc(Cl)nc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1
Temperature: 0 °C
Yield: 94 %

Procedure:
To a solution of the title compound of Example 43 (4.31 g, 6.64 mmol) in THF (30 ml) was added 38 ml of 1N sulfuric acid. After the mixture was cooled to 0° C., a solution of sodium nitrite (NaNO2, 1.45 g, 20.99 mmol) in water (10 ml) was added dropwise. The reaction mixture was stirred at ambient temperature for 7 hours after which time ethyl acetate was added. The organic layer was washed with saturated potassium carbonate, brine, dried over MgSO4 and concentrated under vacuum to give the crude product. It was chromatographed on silica gel with MeOH-CHCl3—NH4OH (2:98:0.1) as the eluents to afford the title compound of Example 6, 4-(3-chloro-phenyl)-6-[(6-chloro-pyridin-3-yl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one as a white solid (3.32 g, 94% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH:12]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH3:13])[CH2:11][O:10]1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:19]1([CH2:11][C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:10])[CH:12]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH3:13])[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: c1nc[nH]n1
Reactant: CC(n1cncn1)C1(c2ccc(F)cc2F)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(n1cncn1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 3 h

Procedure:
To a solution of 2-(2,4-difluorophenyl)-2-[1-(1H-1,2,4-triazol-1-yl)ethyl]oxirane (0.5 g, 1.9 m.Mole) in dimethylformamide (20 ml) was added 1,2,4-triazole (0.27 g, 3.8 m.Mole) and anhydrous potassium carbonate (0.27 g, 1.9 m.Mole). Heating, with stirring, was carried out for three hours at 85°. The solvent was evaporated, water (100 ml.) was added and the mixture was then extracted with methylene chloride (3×30 ml). The combined organic extracts were washed with water (3×20 ml), dried over anhydrous magnesium sulphate, and evaporated to an impure solid, weight 0.6 g.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[CH2:25][OH:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].O[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[Cl:24])(=[O:15])=[O:16])[CH2:11][C@H:10]2[CH2:25][O:26][C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: Oc1cccnc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2CO)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2COc2cccnc2)CC1

Procedure:
The title compound was prepared in analogy to example 162 using (1R,2R,4S)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-hydroxymethyl-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 155) and 3-hydroxypyridine. White solid (34%). MS (EI): 478.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]1[C:17]([OH:19])=O.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[F:31][C:32]1[CH:40]=[C:39]2[C:35]([CH:36]=[N:37][NH:38]2)=[CH:34][C:33]=1[NH2:41]>C(Cl)Cl.N1C=CC=CC=1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]1[C:17]([NH:41][C:33]1[CH:34]=[C:35]2[C:39](=[CH:40][C:32]=1[F:31])[NH:38][N:37]=[CH:36]2)=[O:19]
Reactant: Nc1cc2cn[nH]c2cc1F
Reactant: CC1=C(C(=O)O)C(c2ccc(F)cc2F)CC(=O)N1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(F)cc2F)CC(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
The product from Step 2 (80 mg, 0.30 mmol) was suspended in CH2Cl2 (3 mL) under Argon. DMF (20 μL) was added, followed by oxalyl chloride (27 μL, 0.30 mmol). This mixture was stirred at room temperature for 30 min, and the resultant yellow solution was added to a solution of 6-fluoro-1H-indazol-5-amine (50 mg, 0.33 mmol) in pyridine (3 mL) at −15° C. under Ar. After the reaction was stirred at −15° C. for 15 min, the reaction mixture was allowed to warm to room temperature over 1 h. The mixture was then poured into EtOAc (50 mL), washed sequentially with aq. NH4Cl (20 mL), NaOH (10 mL, 2.5 N), HCl (10 mL, 1.0 N) and brine. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was triturated with 10% EtOAc/10% ether/80% hexanes to afford the title compound (78 mg, 65%). MS (ES+) m/e 401 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH3:24])(=[O:23])=[O:22].Cl.[NH2:26][OH:27].C(N(CC)CC)C.O>O1CCOCC1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:16])([F:17])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19](=[N:26][OH:27])[NH2:20])[C:3]=1[S:21]([CH3:24])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1c(C(N)=NO)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 5 h
Yield: 84.6 %

Procedure:
5-Amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-methylsulfonylpyrazole (500 mg, 1.3 mmol) and hydroxylamine hydrochloride (87 mg, 1.3 mmol) were dissolved in 5 ml of dioxane, and then triethylamine (130 mg, 1.3 mmol) was added at room temperature. After the mixture was stirred at room temperature for 5 hours, the reaction mixture was poured into 100 ml of iced water and extracted with 100 ml of ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated to obtain 470 mg (1.1 mmol) of the title compound as a pale pink crystal. Yield 87%.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([OH:22])=O)[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:56]1[CH2:61][CH2:60][CH2:59][CH2:58][CH:57]1[O:62][NH2:63]>CN(C=O)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:20]([NH:63][O:62][CH:57]4[CH2:58][CH2:59][CH2:60][CH2:61][O:56]4)=[O:22])[C:15]([CH2:16][CH2:17][CH2:18][OH:19])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NOC1CCCCO1)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCCO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-4-(3-hydroxypropyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (358 mg, 1.1 mmol) in DMF (8 mL) was added triethylamine (333 mg, 3.3 mmol), HATU (627 mg, 1.65 mmol) and O-(tetrahydro-2H-pyran-2-yl)-hydroxylamine. The resulting mixture was stirred for 2.5 h at room temperature. The mixture was concentrated. Purification by flash chromatography (Biotage) over silica gel (100% ethyl acetate) afforded the title product as brown oil (149 mg, 32% yield). LC-MS (APCl, M+H+): 428.2. HPLC: 96% purity.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][O:8][CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:11]=2)[CH:2]=1.Cl.[CH3:26][O:27][C:28](=[O:35])[C@H:29]([CH2:31][CH2:32][S:33][CH3:34])[NH2:30]>>[CH3:26][O:27][C:28](=[O:35])[C@H:29]([CH2:31][CH2:32][S:33][CH3:34])[NH:30][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][C:10]([CH2:9][O:8][CH2:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:11][C:12]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(COCc2cccnc2)cc1-c1ccccc1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(COCc2cccnc2)cc1-c1ccccc1

Procedure:
The desired compound was prepared by coupling of 4-(3-pyridylmethyloxymethyl)-2-phenylbenzoic acid with methionine methyl ester hydrochloride as described in Example 163D.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].C1C(=O)N([Br:19])C(=O)C1>CN(C=O)C>[Br:19][C:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11]
Reactant: Oc1ccc2c(c1)CCCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Oc1ccc2c(c1Br)CCCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 5,6,7,8-tetrahydro-2-naphthol (2.50 g, 16.9 mmol) in DMF (5 mL), is added dropswise NBS (3.0 g, 16.9 mmol). The solution is stirred at room temperature for 18 h. The mixture is washed with water, extracted with CH2Cl2, dried over MgSO4 and concentrated. The crude material is purified via Biotage, eluting with 5-40% EtOAc/hexanes to afford 1-bromo-5,6,7,8-tetrahydronaphthalen-2-ol.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28]C)=[O:27])[CH:18]=[CH:17]3)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O>CCOCC>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([OH:28])=[O:27])[CH:18]=[CH:17]3)[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)O)ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.2 %

Procedure:
174 mg (0.376 mmol) of methyl 2-{6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]quinolin-2-yl}benzoate obtained in Example 3 were mixed with 30.0 mg (0.751 mmol) of sodium hydroxide, 32 ml of water and 3 ml of ether and the mixture was stirred at room temperature for 24 hours. After concentrated under reduced pressure, the concentrate was partitioned between water and ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate followed by filtration. The resulting filtrate was concentrated under reduced pressure to obtain 134 mg of 2-{6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]quinolin-2-yl}benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=[O:24].[Br:26]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[Br:26][CH2:1][C:2]1[N:10]([C:11](=[O:12])[C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:9]2[C:4]([C:3]=1[CH2:22][C:23]([OH:25])=[O:24])=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2c(c1)c(CC(=O)O)c(CBr)n2C(=O)c1ccc(Cl)cc1
Reaction time: 12 h

Procedure:
Indomethacin A2 (R3=H, R1a=4-Cl) (1 g, 2.8 mmol) and N-bromosuccinimide (0.539 g, 3.08 mmol) were suspended in tetrachloromethane (50 ml) and kept at room temperature for 12 h. The reaction mixture was heated to boiling and filtered off from succinimide. The solid was washed with hot tetrachloromethane (150 ml). The solvent was evaporated in vacuo. Prepared 2-(1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl)-acetohypobromoanhydride was boiled in CCl4 (50 ml) for 1.5 h. 2-((2-(Bromomethyl)-1-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl)acetic acid 1 h (R1=4-chlorobenzoyl, R3═R4═R5═H, R6═CH3) was prepared and used in further reactions without additional purification.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)(=[O:13])[CH3:12].O>CC(C)=O>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[S:21]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:11](=[O:13])[CH3:12])=[CH:20][CH:19]=1)(=[O:23])=[O:22]
Reactant: CNCCc1ccccn1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc(S(=O)(=O)N(C)CCc2ccccn2)cc1
Temperature: 0 °C
Yield: 78.5 %

Procedure:
(prepared according to an analogous procedure described in U.S. Pat. No. 5,755,873) Step A: Methyl-(2-pyridin-2-ylethyl)amine (8.9 ml, 0.0643 mol) was dissolved in acetone (13 ml) and cooled to 0° C., 4-acetylaminobenzenesulfonyl chloride (5 g, 0.0214 mol) was added over 10 min. Additional acetone (5 ml) was added and the mixture was heated at reflux for 2 h. After cooling to rt, the mixture was added to water and extracted with EtOAc. The extracts were dried (MgSO4). The mixture was concentrated under reduced pressure and purified by flash chromatography (SiO2, EtOAc-MeOH/EtOAc 1:19) to give 5.6 g of N-{4-[methyl-(2-pyridin-2-yl-ethyl)sulfamoyl]phenyl}acetamide. Step B: The compound from step A (5.6 g) was suspended in water (22.4 ml), treated with concentrated HCl (13.4 ml), and the mixture heated at reflux for 1 h. After cooling to rt, NH4OH (13.7 ml) was added with stirring. The resulting mixture was extracted with CH2Cl2; the extracts were washed with water, dried (MgSO4), and concentrated under reduced pressure to give 4.8 g of 4-amino-N-methyl-N-(2-pyridin-2-ylethyl)benzenesulfonamide. LCMS: MH+=292.0.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:4]([O:6][CH3:7])=[O:5].[CH:13]([O:15][CH2:16][CH3:17])=[CH2:14]>C(OCC)(=O)C.P(Cl)(Cl)(Cl)=O>[CH2:13]([O:15][CH2:16][CH2:17][O:1][N:2]=[C:3]([C:8]1[S:9][CH:10]=[CH:11][CH:12]=1)[C:4]([O:6][CH3:7])=[O:5])[CH3:14]
Reactant: C=COCC
Reactant: COC(=O)C(=NO)c1cccs1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOCCON=C(C(=O)OC)c1cccs1
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To a stirred mixture of methyl 2-hydroxyimino-2-(thien-2-yl)acetate syn-isomer (3.98 g.) and ethyl vinyl ether (2.5 mls) in ethyl acetate (25 mls) was added phosphorus oxychloride (2 drops). After 20 mins. at 50° the ethyl acetate was washed with saturated sodium bicarbonate solution, dried over sodium sulphate and evaporated to an oil, giving methyl 2-(1-ethoxy)ethoxyimino-2-(thien-2-yl)acetate (syn-isomer) (5.7 g; 100%) λmax. (EtOH) 289 nm (ε 11,700), τ (CDCl3 ; 60 MHz) 2.61 (multiplet; thienyl H5), 2.82 to 2.97 (multiplet; thienyl H3 and H4), 4.64 (quarter, J 5 Hz; ##STR58## 6.06 (singlet, --COOCH3), 6.24 (quartet, J 7 Hz, OCH2), 8.56 (doublet J 5 Hz; CH--CH3), 8.79 (triplet, J 7 Hz; O.CH2CH3).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7](B(O)O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Br[C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[C:17]([Cl:22])[N:16]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Cl:22][C:17]1[N:16]=[C:15]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[N:3]=[CH:4]3)[C:20]([CH3:21])=[CH:19][CH:18]=1
Reactant: Cc1ccc(Cl)nc1Br
Reactant: Cn1ncc2cc(B(O)O)ccc21
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(Cl)nc1-c1ccc2c(cnn2C)c1
Temperature: 110 °C

Procedure:
In a 10 mL reaction vial, the 1-methyl-1H-indazol-5-ylboronic acid (500 mg, 2.84 mmol) and the 2-bromo-6-chloro-3-methylpyridine (585 mg, 2.84 mmol) were dissolved in dioxane (7 mL) and water (1.7 mL) under argon atmosphere. The mixture was bubbled with argon for 5 min. Then potassium carbonate (979 mg, 7.1 mmol) and Pd(PPh3)4 (49 3 mg, 0.428 mmol) were added sequentially. The resulting reaction mixture was then sealed and heated in oil bath at 110° C. for 2.5 h. Reaction was then partitioned between EtOAc (30 mL) and water (30 mL).The organic phase was washed with water (3×20 mL) and was concentrated. Residue was purified on silica gel column with 0-50% EtOAc/Hex to afford the title compound. LCMS-ESI+: calc'd for: C14H12ClN3: 258.1 and 260.1 (M+H+); found: 258.0 and 260.0 (M+H+).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:12](=[O:13])[CH2:11][CH:10]([C:14]([CH3:16])=[CH2:15])[CH2:9][CH:8]=1.Br>C1(C)C=CC=CC=1>[CH3:6][C:7]1[C:12](=[O:13])[CH2:11][C:14]([CH3:15])([CH3:16])[CH:10]=[CH:9][CH:8]=1
Reactant: C=C(C)C1CC=C(C)C(=O)C1
Agent: Br
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC1=CC=CC(C)(C)CC1=O
Temperature: 0 °C

Procedure:
To a 12 liter separatory funnel, 8 liters of ice/water and 122 ml sulfuric acid (concentrated) is placed. With stirring, the carvone hydrobromide reaction mixture is added to the reaction mass. 500 ml Toluene is then added to the reaction mass and the reaction mass is continued to be stirred. The reaction mass now exists in two phases; an aqueous phase and an organic phase. The aqueous phase is discarded and the organic phase is washed with 2 liters of water. The reaction mass is then added to a mixture of 200 ml saturated sodium bicarbonate and 1000 ml water. The resulting product has the structure: ##STR153## (crude reaction mass).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH2:9]([O:11][SiH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])[CH3:10].C1(C)C=CC=CC=1.C(O)(=O)C1C=CC=CC=1>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[CH2:8]([Si:12]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])[O:11][CH2:9][CH3:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: C=CCCCCCC
Reactant: CCO[SiH](OCC)OCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: O=C(O)c1ccccc1
Agent: [H+]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CCCCCCCC[Si](OCC)(OCC)OCC
Temperature: 50 °C
Yield: 91 %

Procedure:
224 mg Of octene-1, 328 mg of triethoxysilane and 56 mg of toluene were placed in a glass reaction tube and 8 mg of benzoic acid added. Then, 0.001 ml of an isopropyl alcohol solution of chloroplatinic acid (platinum content: 0.39%) was added to this mixture. The reaction tube was sealed with Teflon tape and heated for 30 minutes in an oil bath at 50° C. When the contents were analyzed by GC-MS following cooling, the conversion rate of octene-1 was 97.5% and n-octyltriethoxysilane was produced at a yield of 91%.