Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:6][CH:5]([OH:7])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.[CH3:26][CH2:27]O>B(F)(F)F.CCOCC>[CH3:1][C:2]1([CH3:25])[O:6][CH:5]([O:7][CH2:26][CH3:27])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: CCO
Reactant: CC1(C)OC(O)C(c2cccc(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Agent: FB(F)F
Solvent: CCOCC
Product: CCOC1OC(C)(C)C(c2ccc(S(C)(=O)=O)cc2)=C1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 5,5-dimethyl-2-hydroxy-3-(3-fluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2,5-dihydrofuran (Example 1, 500 mg, 1.38 mmol) in 5 mL of EtOH was added 3 drops of BF3.OEt2. The mixture was stirred at room temperature for 45 min, and the resulting precipitate was filtered and washed with EtOH to provide 497 mg of the title compound as a white solid.
Reaction SMILES: P(CN[CH2:7][C:8]([OH:10])=[O:9])(O)(O)=O.[C:11]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:13])[CH3:12]>>[C:11]([N:14]([CH2:7][C:8]([OH:10])=[O:9])[CH2:15][C:16]([OH:18])=[O:17])(=[O:13])[CH3:12]
Reactant: CC(=O)NCC(=O)O
Reactant: O=C(O)CNCP(=O)(O)O
Product: CC(=O)N(CC(=O)O)CC(=O)O

Procedure:
The preparation of N-(phosphonomethyl)glycine starting from N-acetglycine XVIII is depicted in Reaction Schemes 13 and 14. In this Reaction Scheme, N-acetglycine XVIII is carboxymethylated to yield N-acetyliminodiacetic acid XVI which is then converted to Glyphosate I as described in Reaction Schemes 6, 7, and 8.
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]([C:23]([F:26])([F:25])[F:24])=O.ClC1C=C(C(F)(F)F)C=C(Cl)C=1N>>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21][C:23]([F:26])([F:25])[F:24]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(=O)C(F)(F)F
Agent: Nc1c(Cl)cc(C(F)(F)F)cc1Cl
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F

Procedure:
European Patent publication No. 295117 describes the preparation of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulphinyl pyrazole starting from 2,6-Dichloro-4-trifluoromethylaniline to give an intermediate 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylthiopyrazole which is oxidized with meta-chloroperbenzoic acid in chloroform to give desired product.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Br:13][C:14]1[C:15](Cl)=[C:16]([N+:21]([O-:23])=[O:22])[C:17]([NH2:20])=[N:18][CH:19]=1>CC(O)C.CCN(C(C)C)C(C)C>[Br:13][C:14]1[C:15]([N:4]2[CH2:3][CH2:2][N:1]([CH2:7][C:8]3[S:9][CH:10]=[CH:11][N:12]=3)[CH2:6][CH2:5]2)=[C:16]([N+:21]([O-:23])=[O:22])[C:17]([NH2:20])=[N:18][CH:19]=1
Reactant: c1csc(CN2CCNCC2)n1
Reactant: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Nc1ncc(Br)c(N2CCN(Cc3nccs3)CC2)c1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 17 h
Yield: 59 %

Procedure:
The resulting 2-(piperazin-1-ylmethyl)thiazole (supposedly 0.580 g, 3.18 mmol, 1 eq) was suspended in iPrOH (3.1 mL) and DIPEA (2.2 mL). To this solution, 5-bromo-4-chloro-3-nitropyridin-2-amine (0.800 g, 3.18 mmol, 1 eq) was added and the reaction mixture was heated and stirred for 17 h at 65° C. The mixture was filtered, washed with iPrOH (3×3 mL), Et2O (2×3 mL) and dried to give the title compound as a bright yellow powder (0.750 g, 59%); 1H-NMR (500 MHz, DMSO-d6): δ 2.65 (br s, 4H, piperazine N(CH2)2), 3.09 (m, 4H, piperazine N(CH2)2), 3.90 (s, 2H, NCH2), 6.98 (s, 2H, NH2), 7.66 (d, J=3.0 Hz, 1H, thiazole 5-H), 7.72 (d, J=3.0 Hz, 1H, thiazole 4-H), 8.16 (s, 1H, pyridine 6-H); LC (Method B)-MS (ESI, m/z): Rt=2.90 mins-399/401 [(M+H+), Br isotopic pattern, 100%].
Reaction SMILES: O.[I-:2].[I-].[I-].[I-].[CH2:6]([C:8]1[C:21]2[C:12](=[S+:13][C:14]3[C:19]([N:20]=2)=[C:18]([CH3:22])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=1)[CH3:7].[CH2:23]([C:25]1[C:38]2[C:29](=[S+:30][C:31]3[C:36]([N:37]=2)=[C:35]([CH3:39])[CH:34]=[CH:33][CH:32]=3)[CH:28]=[CH:27][CH:26]=1)[CH3:24].[CH2:40]([C:42]1[C:55]2[C:46](=[S+:47][C:48]3[C:53]([N:54]=2)=[C:52]([CH3:56])[CH:51]=[CH:50][CH:49]=3)[CH:45]=[CH:44][CH:43]=1)[CH3:41].C(C1[C:72]2C(=[S+]C3[C:70]([N:71]=2)=C(C)C=CC=3)C=CC=1)C.C(Cl)(Cl)Cl>>[I-:2].[I-:2].[I-:2].[CH2:6]([C:8]1[C:21]2[C:12](=[S+:13][C:14]3[C:19]([N:20]=2)=[C:18]([CH3:22])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[C:10]([N:37]([CH3:38])[CH3:36])[CH:9]=1)[CH3:7].[CH2:40]([C:42]1[C:55]2[C:46](=[S+:47][C:48]3[C:53]([N:54]=2)=[C:52]([CH3:56])[CH:51]=[CH:50][CH:49]=3)[CH:45]=[C:44]([N:71]([CH3:72])[CH3:70])[CH:43]=1)[CH3:41].[CH2:23]([C:25]1[C:38]2[C:29](=[S+:30][C:31]3[C:36]([N:37]=2)=[C:35]([CH3:39])[CH:34]=[CH:33][CH:32]=3)[CH:28]=[C:27]([N:20]([CH3:21])[CH3:19])[CH:26]=1)[CH3:24]
Reactant: CCc1cccc2[s+]c3cccc(C)c3nc12
Agent: [I-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1cc(N(C)C)cc2[s+]c3cccc(C)c3nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the stirred mixture of 1-ethyl-9-methylphenothiazin-5-ium tetraiodide hydrate (383 mg, 0.5 mmol) in anhydrous CHCl3 (20 mL) dimethylamine (0.5 mL, 1.0 mmol, 2 M solution in THF) was added drop wise over 4 h. The resulting mixture was stirred at room temperature overnight, concentrated to dryness.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([O:19][CH2:20][C:21]2[N:22]=[C:23]([CH3:26])[S:24][CH:25]=2)[CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[C@H:27]1([CH2:37]O)[C@@H:36]2[N:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([CH2:37][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]3[NH:11][C:12]4[C:17]([CH:18]=3)=[C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([CH3:26])[S:24][CH:25]=3)[CH:15]=[CH:14][CH:13]=4)=[O:9])[CH2:3][CH2:2]2)[CH:36]2[N:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)[CH2:30][CH2:29][CH2:28]1
Reactant: Cc1nc(COc2cccc3[nH]c(C(=O)NC4CCNCC4)cc23)cs1
Reactant: OC[C@@H]1CCCN2CCCC[C@H]12
Product: Cc1nc(COc2cccc3[nH]c(C(=O)NC4CCN(CC5CCCN6CCCCC56)CC4)cc23)cs1

Procedure:
This compound is synthesized from 4-(2-methyl-thiazol-4-ylmethoxy)-1H-indole-2-carboxylic acid piperidin-4-ylamide, (167, preparation see below) and (1R,9aR)-1-(octahydro-quinolizin-1-yl)-methanol analogously to the method described in example 127.
Reaction SMILES: C[O:2][C:3]([CH2:5][N:6]1[C:15]2[CH2:14][CH2:13][CH2:12][C:11](=[O:16])[C:10]=2[CH:9]=[CH:8][C:7]1=[O:17])=[O:4]>[OH-].[Na+]>[C:3]([CH2:5][N:6]1[C:15]2[CH2:14][CH2:13][CH2:12][C:11](=[O:16])[C:10]=2[CH:9]=[CH:8][C:7]1=[O:17])([OH:4])=[O:2]
Reactant: COC(=O)Cn1c2c(ccc1=O)C(=O)CCC2
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)Cn1c2c(ccc1=O)C(=O)CCC2
Reaction time: 2 h

Procedure:
Prepared by saponification from 1-methoxycarbonylmethyl-7,8-dihydro-2,5(1H,6H)-quinolinedione in 1 N sodium hydroxide solution at room temperature. The reaction mixture was adjusted to pH 2 after two hours and extracted with ethyl acetate.
Reaction SMILES: C([C:4]1[C:5](CC=C)=[C:6]([CH:8]=[CH:9][C:10]=1[C:11]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)([CH3:13])[CH3:12])[OH:7])C=C>C1(C)C=CC=CC=1.O1CCCC1>[OH:7][C:6]1[CH:5]=[CH:4][C:10]([C:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)([CH3:13])[CH3:12])=[CH:9][CH:8]=1
Reactant: C=CCc1c(O)ccc(C(C)(C)c2ccc(O)cc2)c1CC=C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Temperature: 70 °C

Procedure:
A 0.05 mL portion of hydrosilylation catalyst (a solution of platinum-olefin complex in toluene) was added to a solution of R7T8OSi(Me2)H, (R=cyclohexyl) (11.0 g, 10.2 mmol, 1eq) and diallylbisphenol A (12.6 g, 41 mmol, 4eq) in tetrahydrofuran (110 mL) contained in a thick walled glass reaction vessel. The reaction mixture was heated to 70° C. for 72 h. After this time the tetrahydrofuran solvent was removed to give a viscous, semisolid residue. Extraction of the residue with acetonitrile gave a white solid which was collected by vacuum filtration and dried to provide 13.6 g (96% of theory) of the mono-POSS bisphenol A as a pale yellow solid. The product was mono-allyl, mono-dimethylsiloxypropyl hepatcyclohexyloctasilsesquioxane bisphenol A (or monoPOSS-monoallyl-bisphenol A) (or R37T8 (R2 -R4)1) or CH2 =CHCH2 (HO)C6H3C(CH3)2C6H3 (OH)(CH2)3Si(CH3)2OSi8O12 (c--C6H11)7. This is a new chemical compound and an example of formula 4 (#4).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.[CH2:14]=[C:15]([CH3:17])[CH3:16].CS(O)(=O)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:15]([N:3]1[N:2]=[N:1][C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH:10]=[O:11])=[CH:12][CH:13]=2)=[N:4]1)([CH3:17])([CH3:16])[CH3:14]
Reactant: C=C(C)C
Reactant: O=Cc1ccc(-c2nnn[nH]2)cc1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)n1nnc(-c2ccc(C=O)cc2)n1

Procedure:
In an autoclave, 5.0 9 (28.7 mmol) of 4-(tetrazol-5-yl)-benzaldehyde (Step 35.1) in 33 ml of toluene are heated at 110° C. for 2 hours with -2.4 g of isobutene and 377 μl of methanesulfonic acid. When cold the reaction mixture is diluted with 50 ml of ethyl acetate, washed twice with sat. NaHCO3 solution, once with water and brine, dried (Na2SO4) and concentrated by evaporation. Crystallization from ethanol yields 4-(2-tert-butyl-tetrazol-5-yl)-benzaldehyde; 1H-NMR (DMSO-d6) 10.11 (s, HCO), 8.31 (d, J=8, 2H), 8.11 (d, J=8, 2H), 1.78 (s, 9H).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([C@H:7]([OH:14])/[CH:8]=[CH:9]/[C:10]([CH3:13])([CH3:12])[CH3:11])[O:5][C:4](=[O:15])[C@@H:3]1[O:16][CH3:17].Cl.[NH2:19][C@@H:20]1[C:26](=[O:27])[N:25]([CH2:28][CH3:29])[C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=2[O:22][CH2:21]1.C(C(CCCC)C([O-])=O)C.[Na+]>C1COCC1>[CH2:28]([N:25]1[C:24]2[CH:30]=[CH:31][CH:32]=[CH:33][C:23]=2[O:22][CH2:21][C@H:20]([NH:19][C:4](=[O:15])[C@H:3]([O:16][CH3:17])[C@H:2]([OH:1])[C@@H:6]([OH:5])[C@H:7]([OH:14])/[CH:8]=[CH:9]/[C:10]([CH3:13])([CH3:12])[CH3:11])[C:26]1=[O:27])[CH3:29]
Reactant: CCN1C(=O)[C@@H](N)COc2ccccc21
Reactant: CO[C@H]1C(=O)O[C@@H]([C@H](O)/C=C/C(C)(C)C)[C@H]1O
Agent: CCCCC(CC)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCN1C(=O)[C@@H](NC(=O)[C@H](OC)[C@H](O)[C@@H](O)[C@H](O)/C=C/C(C)(C)C)COc2ccccc21
Temperature: 25 °C
Yield: 217.5 %

Procedure:
181 mg of 2 (742 μmol), 180 mg of 20 (742 μmol) and 296 mg of sodium 2-ethylhexanoate (1.78 mmol) in 3 mL of THF are successively introduced into a 25 mL round-bottomed flask, with stirring and under an argon atmosphere. The stirring is maintained at RT for 24 h. The mixture is concentrated and 727 mg of crude product are obtained, which product is chromatographed on a silica cartridge [50 g, eluent heptane/AcOEt-heptanel (50/50), in an AcOEt-heptane (50/50) gradient: 0 to 100%]. 177 mg of expected product Ex9 are recovered.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]3[CH:18]=[N:19][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:22]=3)[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[F:26][C:23]([F:24])([F:25])[C:20]1[N:19]=[CH:18][C:17]([C:13]2[CH:12]=[C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[N:9][CH:8]=3)[CH:16]=[CH:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(-c3ccc(C(F)(F)F)nc3)c2)cn1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2ccnc(-c3ccc(C(F)(F)F)nc3)c2)cn1
Yield: 38.8 %

Procedure:
A solution of 4-((6-nitropyridin-3-yl)oxy)-6′-(trifluoromethyl)-2,3′-bipyridine (0.177 g, 0.489 mmol) in MeOH (10 mL) was treated with 10% Pd/C (50% wet, 0.052 g, 0.049 mmol) and hydrogenated (1 atm) for 5 h. The solid was removed via filtration through diatomaceous earth, and the filtrate was concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford 5-((6′-(trifluoromethyl)-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-amine (63 mg, 39%). 1H NMR (400 MHz, DMSO-d6): δ 9.39 (s, 1H), 8.66 (d, J=8.4 Hz, 1H), 8.57 (d, J=5.7 Hz, 1H), 8.00 (d, J=8.2 Hz, 1H), 7.85 (d, J=2.9 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 7.33 (dd, J=8.9, 3.0 Hz, 1H), 6.86 (dd, J=5.7, 2.4 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.05 (s, 2H); MS (ESI) m/z: 333.1 (M+H+).
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]([CH3:15])[CH2:8][CH2:9][N:10]1[CH:14]=[N:13][CH:12]=[N:11]1.CN([CH:19]=[O:20])C.[BH4-].[Na+].Cl>C1COCC1.O.CO>[CH3:6][N:7]([CH3:15])[CH2:8][CH2:9][N:10]1[C:14]([CH2:19][OH:20])=[N:13][CH:12]=[N:11]1
Reactant: CN(C)C=O
Reactant: CN(C)CCn1cncn1
Agent: Cl
Agent: [BH4-]
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCn1ncnc1CO
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 72.9 %

Procedure:
BuLi (6.87 ml of a 1.6 M solution in hexanes, 11.0 mmol) was added dropwise over 2 min to a stirred solution of dimethyl(2-[1,2,4]triazol-1-ylethyl)amine (1.4 g, 10 mmol) in THF (50 ml) at −78° C. under nitrogen. The resulting mixture was stirred at −78° C. for 15 min, then warmed to −40° C. and re-cooled to −78° C. DMF (2.31 ml, 30 mmol) was added and the reaction mixture warmed to room temperature and stirred for 15 min. MeOH was added followed by NaBH4 (567 mg, 15 mmol) and the reaction mixture stirred for 30 min. H2O (10 ml) was added followed by 1N HCl (50 ml). The reaction was left to stand overnight. The solvent was removed under reduced pressure and the aqueous extracted with CH2Cl2 (5×75 ml). The combined organic extracts were washed with brine (25 ml), dried (MgSO4) and concentrated under reduced pressure. The crude residue was azeotroped with xylene (2×100 ml) to yield the alcohol (1.24 g, 73%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][CH:10]=[C:11]([CH3:19])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])[CH3:4].[CH3:20]I.[Na+].[Cl-]>C1COCC1.O.C(Cl)Cl>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH3:20])[CH:10]=[C:11]([CH3:19])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1[nH]cc(C)c1-c1ccccc1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(-c2ccccc2)c(C)cn1C
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
Sodium hydride (436 mg, 60% in mineral oil, 10.9 mmol) was added to a solution of 4-methyl-3-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.25 g, 5.45 mmol) in THF (10 mL) at 0° C. and under nitrogen as inert gas and the reaction mixture was stirred for 15 min. Then methyl iodide (1,547 g, 10.9 mmol) was added to the reaction mixture and the reaction mixture was stirred for 1 h at 0° C. and overnight at RT. After the addition of a few drops of water and aq. sat. NaCl solution (250 mL), extraction was performed with DCM (2×250 mL). After drying of the combined organic phases over sodium sulfate, filtration and removal of the solvent, purification was performed by means of column chromatography. The desired product 1,4-dimethyl-3-phenyl-1H-pyrrole-2-carboxylic acid ethyl ester (1.02 g, 77% of theoretical) was obtained.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:6]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[CH:16]=2)=[N:7][CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1>CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:6]2[C:5]([O:2][CH3:1])=[CH:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][N:7]=2)=[CH:16][C:17]=1[O:22][CH3:23]
Reactant: C[O-]
Reactant: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(-c2ncc(C(F)(F)F)cc2OC)ccc1Cl
Temperature: 0 °C

Procedure:
33.5 g of a 30% strength methanolic solution of sodium methoxide were added to a solution of 3.0 g (9.3 mmol) of 3-chloro-2-(4-chloro-3-methoxyphenyl)-5-trifluoromethylpyridine in 100 ml of methanol. The mixture was refluxed for 20 h and then poured into about 500 ml of ice-water. The product was extracted from the aqueous phase with 3×100 ml of methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated. The oily residue was induced to crystallize by trituration with n-hexane. Yield: 1.3 g of colorless crystals; melting point: 62°-63° C. (purity about 85%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4ccc(F)cc4F)c3O2)cc1
Product: CNCC1Cc2cc(Cl)cc(-c3ccc(F)cc3F)c2O1

Procedure:
The title compound was prepared (0.059 g, 48%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,4-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.162 g, 0.36 mmol) and methylamine (0.112 g, 3.6 mmol). mp 163-165° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]2([CH3:25])[CH3:24]>C(Cl)Cl>[CH3:10][O:11][C:12]1[C:21]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:20][C:19]2[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=2[CH:13]=1
Reactant: COc1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: CCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1cc2c(cc1OC)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure A and using AlCl3 (3.7 g, 27.5 mmol), CH2Cl2 (40 mL), propionyl chloride (2.4 mL, 27.5 mmol), and 6-methoxy-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene (Intermediate 2, 5.0 g, 22.9 mmol) in CH2Cl2 (10 mL) at ambient temperature for 1.5 h followed by recrystallization from Et2O, the title compound was obtained as a white solid (5.4 g, 86%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:20][C@H:21]([CH3:41])[CH2:22][O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[Si:24]([O:23][CH2:22][CH:21]([CH3:41])[CH2:20][C@H:9]([P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])([C:37]([CH3:38])([CH3:39])[CH3:40])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Reactant: C[C@@H](CBr)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)[C@@H](CC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 52.2 %

Procedure:
A solution tert-butyl diethylphosphonoacetate (64 g) in THF (100 mL) was added dropwise to a suspension of sodium hydride (containing 40% mineral oil, 13.2 g) in THF (400 mL) under ice-cooling, and the reaction mixture was stirred at room temperature for 75 minutes. A solution of ((R)-3-bromo-2-methylpropoxy)-tert-butyldiphenylsilane (99.4 g) in THF (100 mL) was added dropwise to the reaction mixture, which was then heated under reflux for 23 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 74.6 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[CH2:32][CH2:33][CH:34]([CH2:36][C:37]([OH:39])=[O:38])[S:35][C:24]1=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(OCC)(=O)C>[CH2:16]([N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]2[CH2:32][CH2:33][CH:34]([CH2:36][C:37]([O:39][CH:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:38])[S:35][C:24]1=2)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)CC1CCc2c(n(Cc3ccccc3)c3ccccc23)S1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(CC1CCc2c(n(Cc3ccccc3)c3ccccc23)S1)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
An excess of diphenyldiazomethane was added to a mixture of 100 mg of 2-(9-benzyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indol-2-yl)acetic acid (prepared as described in Example 83) in 5 ml of ethyl acetate, with stirring, at room temperature, and stirring was continued at this temperature overnight. At the end of this time, the solvent was removed by evaporation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a mixture of 6% v/v ethyl acetate in hexane as the eluent, to afford 139 mg of the title compound as an oil.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:4]=1.[Na+].[I-].[Si](Cl)(C)(C)C.CO>O.C(#N)C>[OH:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:4]=1
Reactant: CCCCCC(=O)OCc1nccc(OC)n1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Solvent: O
Product: CCCCCC(=O)OCc1nccc(O)n1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
3.1 g (13.0 mMol) hexanoic acid 4-methoxy-pyrimidin-2-ylmethyl ester and 5.85 g (39 mMol) NaI are dissolved in 130 ml (13 mMol) of a 0.1 M solution of water in acetonitrile at 60° C. Then 4.95 ml (39 mMol) Me3SiCl are added via syringe. The resulting suspension is stirred for 7 h at 60° C. and then cooled to rt again. Then 15 ml of MeOH are added dropwise. After stirring for 10 additional minutes, the reddish suspension is concentrated in vacuo. The residue is redissolved in 300 ml EtOAc and 100 ml sat. NaHCO3 solution, the aq. layer separated off and extracted with 2×300 ml EtOAc. The organic phases are washed with 50 ml of a 0.5 M solution of Na2S2O3 and brine, dried (Na2SO4) and concentrated. Crystallization from CH2Cl2 and hexane gives the title compound: m.p.: 78° C.; MS: [M+1]+=225.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]([O:22]CC)=[O:21]>CC(C)=O>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O:1][CH2:19][C:20]([OH:22])=[O:21])=[CH:3][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccnc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)COc1ccnc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.5 %

Procedure:
The mixture of 4-hydroxyquinoline (290 mg, 2.0 mmol), potassium carbonate (910 mg, 6.6 mmol), ethyl bromoacetate (500 mg, 3.0 mmol) and acetone (25 ml) was refluxed for 8 h. After cooling, the mixture was filtered to remove potassium carbonate. The filtrate was concentrated under reduced pressure. To this residue, 10 ml of dioxane and 14 ml 5% sodium hydroxide solution was added. After the mixture was stirred at room temperature overnight, it was acidified with concentrated hydrochloric acid to pH 3, and then extracted three times with ethyl acetate (20 ml each). Water layer was placed in cold room, and solid came out. The crystals were filtered with suction and washed with water, and then dried to give 120 mg quinoline-4-oxyacetic acid as gray crystals, mp 274-276° C.