Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.Cl[C:17]([O:19][CH3:20])=[O:18]>CN(C1C=CN=CC=1)C>[C:17](=[O:18])([O:19][CH3:20])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)Cl
Reactant: CC1(c2cc(F)ccc2O)CCCCC1
Agent: CN(C)c1ccncc1
Product: COC(=O)Oc1ccc(F)cc1C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of 4-fluoro-2-(1-methylcyclohexyl)phenol (23.5 g, 113 mmol), TEA (31 mL, 226 mmol) and DMAP (700 mg, 5.7 mmol) in CH2C1-2 (250 mL) was added methyl chloroformate dropwise at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured onto crushed ice and extracted with CH2Cl2 (100 mL×3). The organic layer was washed with brine, dried over MgSO4, evaporated under vacuum. The crude product was purified by chromatography on silica gel diluted with (hexane:ethyl acetate=100:1) to give 4-fluoro-2-(1-methylcyclohexyl)phenyl methyl carbonate as red brown oil (43.9 g, 72.1% yield). 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, J=3.2, 11.2 Hz, 1H), 7.05-7.02 (m, 1H), 6.93-6.88 (m, 1H), 3.91 (s, 3H), 2.02-1.96 (m, 2H), 1.66-1.36 (m, 8H), 1.23 (s, 3H).
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1>>[OH:11][C@@H:6]([CH2:7][C:8](=[O:9])[O-:10])[CH2:5][N+:2]([CH3:4])([CH3:1])[CH3:3].[OH:11][C@H:6]([CH2:7][C:8](=[O:9])[O-:10])[CH2:5][N+:2]([CH3:4])([CH3:1])[CH3:3]
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Product: C[N+](C)(C)C[C@@H](O)CC(=O)[O-]
Product: C[N+](C)(C)C[C@H](O)CC(=O)[O-]

Procedure:
According to a preferred embodiment of the present invention, in the first step, to DL-carnitine is added dibenzoyl-L(+)tartaric acid and a lower alcohol, the mixture is dissolved under heat to form dibenzoyl-L(+)tartarates of D-carnitine and L-carnitine, and subsequently the tartarates are cooled to fractionally crystallize dibenzoyl-L(+)tartarate of L-carnitine.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[CH:18][C:17]=1[OH:24].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:24][C:17]2[CH:18]=[CH:19][C:20]([CH2:22][CH3:23])=[CH:21][C:16]=2[O:15][CH3:14])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: CCc1ccc(O)c(OC)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(Oc2ccc(S(C)(=O)=O)cc2)c(OC)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a suspension of Cu(OAc)2 (3.0 mmol; 543 mg), 4-(methanesulphonyl)benzeneboronic acid (4.0 mmol; 800 mg) and activated molecular sieves (800 mg) under air, in anhydrous dichloromethane (5 mL), were added 2-methoxy-4-ethylphenol (2.0 mmol; 0.28 mL), anhydrous triethylamine (10 mmol; 1.4 mL), and anhydrous pyridine (10 mmol; 0.8 mL). The reaction was stirred for 2 days at room temperature. The crude was filtered on silica gel, washed with ethyl acetate, concentrated. The residue was then purified by column chromatography (gradient cyclohexane/dichloromethane) to yield the title compound as clear oil (617 mg; 2.0 mmol; quantitative).
Reaction SMILES: [CH:1]1([N:5]2[CH2:18][CH2:17][C:8]3[NH:9][C:10]4[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][C:15]=4[C:7]=3[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH:1]1([N:5]2[CH2:18][CH2:17][C:8]3[N:9]([CH2:27][CH2:26][C:23]4[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][CH:24]=4)[C:10]4[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][C:15]=4[C:7]=3[CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: C=Cc1ccc(C)nc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C1CCC1)CC3
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C2CCC2)C1

Procedure:
The title compound is prepared from a mixture of 2-cyclobutyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:41](Cl)([C:44]1[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=1)(=[O:43])=[O:42]>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[N:11]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][Si:24]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[CH:25]([CH3:27])[CH3:26])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc3c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCc1c(C(=O)OC(C)C)ncc2c1c1cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc1n2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1 g of 4-methoxymethyl-6-(triisopropylsilyloxy)-beta-carboline-3-carboxylic acid isopropyl ester, 132 mg of 4-dimethylaminopyridine and 0.45 ml of triethylamine were mixed in 10 ml of dichloromethane at about 4° C. with 615 m of tosyl chloride and then stirred at room temperature for 1 hour. After 16 hours of standing at room temperature, it was diluted with dichloromethane and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution. After chromatography on silica gel in the system of cyclohexane/ethyl acetate 1:1, 1.32 g of the title compound was obtained from the isolated organic phase.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2.[O:16]1[CH2:21][CH2:20][CH:19]([CH:22]=O)[CH2:18][CH2:17]1.N1CCCCC1>CO.C(OCC)(=O)C>[O:1]=[C:2]1[C:11](=[CH:22][CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)CCCC2=O
Reactant: O=CC1CCOCC1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)c1ccc2c(c1)CCC(=CC1CCOCC1)C2=O
Yield: 49.4 %

Procedure:
A solution of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (2.9 mmol), tetrahydro-pyran-4-carbaldehyde (3.2 mmol), and piperidine (3.2 mmol) in 6 mL of methanol was heated to 65° C. overnight. The cooled mixture was diluted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel, eluting with ethyl acetate in hexane from 10% to 40%, to give 430 mg of the desired product. ES-MS m/z 301 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:16]=[CH:15][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C2CCCCCCCC2)BCCCCCCC1.[OH-:35].[Na+].OO>O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:35])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [OH-]
Reactant: C=CCCCOc1ccc(C(C)(C)C)cc1
Agent: B1CCCCCCCC1C1CCCCCCCC1
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(OCCCCCO)cc1
Temperature: 25 °C

Procedure:
The 5-(p-tert-butylphenoxy)-1-pentene (10.5 g) was treated with 115 ml 0.5M 9-borabicyclononane in tetrahydrofuran and the reaction mixture was stirred at reflux for one hour. The solution was cooled to room temperature and treated with 25 ml 3N sodium hydroxide, then 10 ml 30% hydrogen peroxide. After the bubbling ceased the reaction mixture was partitioned between 150 ml ether-150 ml water. The ether layer was removed, dried (MgSO4), and evaporated to a yellow oil which was chromatographed through 300 g, 90 to 200 mesh silica gel (2% MeOH/CH2Cl2 eluent) yielding a yellow oil which was vacuum distilled (126° C./0.75 mm) to a clear, colorless oil, 5-p-t-butylphenoxy-1-pentanol, 1.7 g.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:13]([O:15][C:16](=[O:40])[CH2:17][NH:18][C:19]1[C:23]([C:24](=[O:38])[NH:25][C:26](=O)[CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=2[F:36])=[CH:22][N:21]([CH3:39])[N:20]=1)[CH3:14].ClCCl>C1(C)C=CC=CC=1>[CH2:13]([O:15][C:16](=[O:40])[CH2:17][N:18]1[C:19]2=[N:20][N:21]([CH3:39])[CH:22]=[C:23]2[C:24](=[O:38])[N:25]=[C:26]1[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[C:30]=1[F:36])[CH3:14]
Reactant: CCOC(=O)CNc1nn(C)cc1C(=O)NC(=O)CCc1cccc(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2cn(C)nc21
Yield: 56.8 %

Procedure:
A suspension of p-toluenesulfonic acid monohydrate (200 mg) and 2-(4-(3-(2,3-difluorophenyl)-propanoylcarbamoyl)-1-methyl-1H-pyrazol-3-ylamino)-acetic acid ethyl ester (Int B60) (1.2 g, 3.04 mmol) in toluene (100 ml) was refluxed for 3 h. The mixture was cooled and dichloromethane (200 ml) was added. The resulting solution was washed with aqueous sodium bicarbonate solution, brine, dried (MgSO4) and evaporated. The residue was purified by flash chromatography (silica, 5% methanol/dichloromethane) to give the title compound as a cream solid (650 mg, 57%). 1H-NMR (DMSO) δ 1.20 (3H, t), 2.94-3.09 (4H, m), 3.95 (3H, s), 4.18 (2H, q), 5.05 (2H, s), 7.11-7.29 (3H, m), 8.39 (1H, s); MS (APCI+) found (M+1)=377; C18H18F2N4O3 requires 376.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[OH-].[Na+].[OH:27][CH:28]([CH3:37])[CH2:29][CH2:30][CH2:31]/[CH:32]=[CH:33]/B(O)O.OO>O1CCCC1.C(Cl)(Cl)Cl>[CH2:1]([O:11][C:12]1[CH:13]=[N:14][C:15]([C:18]2[CH:23]=[CH:22][C:21](/[CH:33]=[CH:32]/[CH2:31][CH2:30][CH2:29][CH:28]([OH:27])[CH3:37])=[CH:20][CH:19]=2)=[N:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1cnc(-c2ccc(Br)cc2)nc1
Reactant: CC(O)CCC/C=C/B(O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)O)cc2)nc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.7 %

Procedure:
Apart from the above, inner atmosphere of a four-necked flask equipped with a stirring device, a reflux condenser and a thermometer was replaced with nitrogen gas, and then the flask was charged with 6.6 g (17 mmol) of 5-decyloxy-2-(4-bromophenyl)-pyrimidine, 0.23 g (0.2 mmol) of tetrakis-triphenylphosphine-palladium, 2.4 g (60 mmol) of sodium hydroxide and 60 ml of tetrahydrofuran. Subsequently, 50 ml of a solution prepared by dissolving 20 mmol of the above-obtained E-6-hydroxy-1-heptenyldihydroxyborane in tetrahydrofuran was dropwise added thereto at room temperature. Then, the whole mixture was heated under reflux with stirring for 6 hours. After cooling the reaction mixture to room temperature, 5 ml of 10% aqueous solution of sodium hydroxide and 2 ml of 30% aqueous solution of hydrogen peroxide were added, and the resulting mixture was stirred for one hour. The mixture was extracted with ether, and the organic layer was twice washed with each 20 ml portion of saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 5.9 g (yield 82%) of (-)-5-decyloxy-2-{4-(6-hydroxy-1-trans-heptenyl)-phenyl}-pyrimidine, [α]D20 =-1.2 (c=1.0, CHCl3).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:23][C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)=[O:25])[N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccs2)n[nH]1
Reactant: O=C(CCl)N1CCN(c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)c1cc(-c2cccs2)nn1CC(=O)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
Protocol T was followed using 5-Thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-Chloro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1.5/1) afforded the title compound. 1H NMR (400 MHz, CDCl3): 7.34–7.38 (m, 1H), 7.24–7.26 (m, 1H), 7.12 (s, 1H), 7.04–7.08 (dd, 1H), 6.96–7.2 (m, 2H), 6.88–6.94 (m, 2H), 4.32–4.42 (q, 2H), 3.52–3.58 (m, 4H), 3.05–3.35 (m, 4H), 1.32–1.42 (m, 3H). 13C NMR (400 MHz, CDCl3): 164.2, 128, 126.8, 126.6, 120.2, 118.4, 115.2, 62.5, 54.2, 50.5, 42.6,44, 14.6.
Reaction SMILES: OC[C@@H](N)C(C)CC.COC(=O)[C@H]([C@H](CC)C)N.OCCN.[N+:23]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH2:36])=[CH:28][CH:27]=1)([O-:25])=[O:24].[N+](C1[C:49]2[C:44](=[CH:45]C=C[CH:48]=2)[C:43]([N:50]=[C:51]=[S:52])=[CH:42]C=1)([O-])=O>>[N+:23]([C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([N:36]=[C:51]2[NH:50][C@@H:43]([CH:44]([CH2:49][CH3:48])[CH3:45])[CH2:42][S:52]2)=[CH:28][CH:27]=1)([O-:25])=[O:24]
Reactant: Nc1ccc([N+](=O)[O-])c2ccccc12
Reactant: O=[N+]([O-])c1ccc(N=C=S)c2ccccc12
Agent: CCC(C)[C@H](N)CO
Agent: CC[C@H](C)[C@H](N)C(=O)OC
Solvent: NCCO
Product: CCC(C)[C@H]1CSC(=Nc2ccc([N+](=O)[O-])c3ccccc23)N1

Procedure:
(1S)-1-(Hydroxymethyl)-2-methylbutylamine was made from (L)-isoleucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-2-methylbutanammonium chloride as described in Method B7a. 4-Nitro-1-naphthylamine was converted to 4-nitro-1-naphthyl isothiocyanate according to Method A2b. 4-Nitro-1-naphthyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-2-methylbutanammonium chloride to Method C1a to give (4S)-2-(4-nitro-1-naphthylimino)-4-(2-butyl)-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-nitro-1-naphthylimino)-4-butyl-3-isobutyl-1,3-thiazolidine.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[NH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[NH2:29]>C(O)(=O)C>[NH:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH2:22][CH2:23][C:24](=[O:26])[N:28]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[N:29]=3)=[CH:19][CH:20]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C(=O)CCC(=O)O)cc2)CC1
Reactant: NNc1ccccn1
Solvent: CC(=O)O
Product: O=C1CCC(c2ccc(OC3CCNCC3)cc2)=NN1c1ccccn1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To 4-[4-(3-carboxy-propionyl)-phenoxy]-piperidine-1-carboxylic acid tert-butyl ester (1.34 g, 3.55 mmol) in acetic acid (20 mL) was added 2-hydrazinopyridine (1.94 g, 17.8 mmol). After overnight stirring at 120° C., the reaction was concentrated under vacuum and the product was purified using a Single Step column (9:1 dichloromethane:methanol) to obtain 295 mg; MS m/z 351 (M+H).
Reaction SMILES: CN([C:5](=[O:18])[CH:6]([O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Br:17])[CH2:7][CH2:8][CH3:9])OC.O1CCC[CH2:20]1.C[Mg]Br.Cl>CCOCC>[Br:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[O:10][CH:6]([CH2:7][CH2:8][CH3:9])[C:5](=[O:18])[CH3:20]
Reactant: C1CCOC1
Reactant: CCCC(Oc1ccccc1Br)C(=O)N(C)OC
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CCCC(Oc1ccccc1Br)C(C)=O
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
6 g of N-methyl-O-methyl-2-(2-bromophenoxy)pentanohydroxamic acid and 190 ml of anhydrous tetrahydrofuran are placed in a 500 ml round-bottomed flask. The solution is cooled to -10° C. and 19 ml of a 3M solution of methylmagnesium bromide in ether are slowly added. The mixture is stirred for 45 minutes and 60 ml of a molar hydrochloric acid solution are slowly added. The mixture is extracted with 3×100 ml of ethyl ether. The combined organic phases are dried over magnesium sulphate, filtered and concentrated under vacuum to provide 5.13 g of 3-(2-bromophenoxy)-2-hexanone in the form of a colourless oil. Quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[O:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.C([Li])CCC.[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].[Cl-].[NH4+]>CCOCC.O1CCCC1>[Cl:1][C:2]1[S:3][C:4]([C:21]2([N+:18]([O-:20])=[O:19])[CH:22]=[CH:23][C:24]([CH2:25][OH:26])=[CH:27][CH2:28]2)=[CH:5][C:6]=1[O:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Clc1sccc1OC1CCCC1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=[N+]([O-])C1(c2cc(OC3CCCC3)c(Cl)s2)C=CC(CO)=CC1
Temperature: -78 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
To a solution of 2-chloro-3-cyclopentyloxythiophene (2.15 g, 10.6 mmol) in ether (27 mL) was added n-butyllithium (2.5 N in hexanes, 4.4 mL, 11 mmol) dropwise at −78° C. under argon. The mixture was allowed to reach 20-25° C. and stirred for 4 hours. After cooling back to −78° C., a solution of p-nitrobenzaldehyde (1.56 g, 10.3 mmol) in tetrahydrofuran (27 mL) was added dropwise. The mixture was stirred at −78° C. for 1 hour. Saturated ammonium chloride was added at −78° C. and the mixture was allowed to reach about 10° C. The crude product was extracted with ethyl acetate, washed with water, brine, dried (Na2SO4), and concentrated to dryness to give 4-(5-chloro-4-cyclopentyloxythien-2-yl)-(4-nitrophenyl)methanol (3.6 g), and was directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:39]=[CH:40][C:41]=1[F:42])[O:25][C:26]1[N:31]=[C:30]2[S:32][C:33]([NH:35][C:36](=[O:38])[CH3:37])=[N:34][C:29]2=[CH:28][CH:27]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[C:36]([NH:35][C:33]1[S:32][C:30]2[C:29]([N:34]=1)=[CH:28][CH:27]=[C:26]([O:25][C:24]1[CH:39]=[CH:40][C:41]([F:42])=[C:22]([NH:21][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[C:2]=3[Cl:1])[CH:23]=1)[N:31]=2)(=[O:38])[CH3:37]
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(N)c3)nc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)c3)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.1 %

Procedure:
To a solution of 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (0.33 g, 1.5 mmol) produced in Example C61(v) in oxalyl chloride (1.5 mL) was added N,N-dimethylformamide (100 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixture of N,N-dimethylacetamide (1.5 mL) and tetrahydrofuran (1.5 mL), and the solution was added dropwise to a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]acetamide (0.33 g, 1.00 mmol) in N,N-dimethylacetamide (3 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (320 mg, 61%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[CH:7][C:8]=2[CH3:13])[N:3]=1.[CH3:15][O-:16].[Na+].[CH3:18][OH:19]>>[Cl:14][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[C:11]([O:19][CH3:18])[C:2]([O:16][CH3:15])=[N:3]2)=[C:8]([CH3:13])[CH:7]=1
Reactant: Cc1cc(Cl)cc2nc(Cl)c(Cl)nc12
Reactant: C[O-]
Reactant: CO
Agent: [Na+]
Product: COc1nc2cc(Cl)cc(C)c2nc1OC
Temperature: 0 °C

Procedure:
30 g (0.121 mol) of 2,3,7-trichloro-5-methylquinoxaline are introduced into 330 ml of methanol under argon at room temperature. 67.9 ml (0.364 mmol) of an about 5.4 molar solution of sodium methoxide in methanol is added dropwise to this and the mixture is stirred at reflux for 4.5 hours. After cooling to 0° C., the suspension is filtered off on a suction filter, and the filter residue is washed with methanol and dried in vacuo at 60° C. The title compound is obtained as brownish crystals of m.p. 94-96° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14])=O.Cl.[NH2:22][OH:23]>N1C=CC=CC=1.C(OC(=O)C)C>[Cl:1][C:2]1[C:3]([OH:20])=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])/[C:5](=[N:22]\[OH:23])/[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:8]=1[F:14]
Reactant: COc1ccc(C(=O)c2cccc(F)c2F)c(O)c1Cl
Reactant: NO
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(/C(=N\O)c2cccc(F)c2F)c(O)c1Cl

Procedure:
To a solution of 24 g of 3-chloro-2-hydroxy-4-methoxy-2',3'-difluorobenzophenone in 160 ml pyridine, 22 g of hydroxylamine HCl is added. The mixture is refluxed for 2 hours and the pyridine evaporated in vacuo. The residue is partitioned between ethyl acetate and 5% HCl. The ethyl acetate extract is washed with water, dried over Na2SO4 and evaporated to give a pale yellow solid which consists of two isomers. The solid is melted at 205° C. for approximately 13 minutes. The residue is dissolved in hot ethylacetate and then evaporated to dryness giving E-3-chloro-2',3'-difluoro-2-hydroxy-4-methoxybenzophenone oxime, mp 198°-199° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:18]([O:20][CH:21]=[CH2:22])[CH3:19].[CH2:23]([O:25][CH2:26][CH3:27])[CH3:24].O>O1CCOCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:21]([O:20][CH:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:23]([O:25][CH2:26][CH3:27])[CH3:24])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1)[CH3:19])[CH3:22]
Reactant: CCOCC
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: C=COCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(C)Oc1ccc(C(C)(C)c2ccc(OC(C)OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2,2-bis(4-hydroxyphenyl)propane (32.0 g, 0.14 mole) and vinyl ethyl ether (80.8 g, 1.12 mole) in 1,4-dioxane (130 ml), pyridinium p-toluenesulfonate (2.8 g) was added and reacted with stirring for 6 hours at 20°25° C. After reaction, ethyl ether (300 ml) and H2O (100 ml) were added to a reaction mixture, stirred for 30 min. at room temperature, and allowed to stand. The organic layer was washed thrice with H2O, dried over anhydrous MgSO4 and evaporated to give 50.8 g of 2,2-bis[4-(1-ethoxyethoxy)phenyl]propane as residual pale yellow oil.