Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(C1C2C(=CC=CC=2)C=CC=1)(C)C.C(C1C2C(=CC=CC=2)C=CC=1)(=[O:27])C>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:27]
Reactant: Oc1cccc2ccccc12
Reactant: CC(=O)c1cccc2ccccc12
Agent: CC(C)c1cccc2ccccc12
Product: Oc1ccc2ccccc2c1

Procedure:
990 parts of the same crude β-naphthol as used in Example 2 were melted and added to 1,300 parts of ethanol under stirring, and the mixture was heated while stirring until the crude naphthol was completely dissolved. Then the solution was gradually cooled to 0° C. with crystals separating. The mixture was then filtered using a centrifuge. 923 parts of the crystals were obtained with 230 parts being ethanol as a solvent. Therefore, it can be said that centrifugal removal of the mother liquor is not good. The crystals were dried to remove the ethanol and the β-naphthol thus obtained had a purity of 96.1% and contained 1.4% of α-naphthol, 0.3% of isopropylnaphthalene and 0.6% of acetylnaphthalene. The recovery of the β-naphthol obtained as crystals was 77.0%.
Reaction SMILES: Cl[C:2]1[N:3]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1>>[N:19]1([C:2]2[N:3]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Reactant: c1c[nH]cn1
Product: O=Cc1c(-n2ccnc2)n(-c2ccccc2)c2ccccc12
Yield: 12 %

Procedure:
2-Chloro-1-phenyl-1H-indole-3-carboxaldehyde is reacted with imidazole as described in Example 1 to afford 2-imidazol-1-yl-1-phenyl-1H-indole-3-carboxaldehyde (12% yield) as a white solid. LC/MS: 288 (M+H); RT 2.55 min; NMR (CDCl3): 9.94 (1H, s), 8.45 (1H, d), 7.63 (1H, s), 7.35-7.54 (6H, m), 7.17-7.29 (2H, m), 7.12 (1H, s), 7.03 (1H, s).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH:6]=[CH:7]1)[CH2:4][CH:3]([C:9](O)=O)[CH2:2]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:37][C:38]1[C:39](=[O:52])[N:40]([CH2:49][CH2:50][CH3:51])[C:41](=[O:48])[N:42]([CH2:45][CH2:46][CH3:47])[C:43]=1[NH2:44].CCN(C(C)C)C(C)C>CN(C=O)C>[CH:5]12[O:8][CH:1]([CH:7]=[CH:6]1)[CH2:2][CH:3]([C:9]1[NH:37][C:38]3[C:39](=[O:52])[N:40]([CH2:49][CH2:50][CH3:51])[C:41](=[O:48])[N:42]([CH2:45][CH2:46][CH3:47])[C:43]=3[N:44]=1)[CH2:4]2
Reactant: O=C(O)C1CC2C=CC(C1)O2
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2[nH]c(C3CC4C=CC(C3)O4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
To a solution of 8-oxa-bicyclo[3.2.1]oct-6-ene-3-carboxylic acid (0.25 mmol, 0.0386 g), HATU (0.25 mmol, 0.0952 g), and 5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione hydrochloride (Daly, J. W. et al., J. Med. Chem., 1985, 28 (4), 487) (0.25 mmol, 0.0658 g) in DMF (2.5 ml) was added iPr2NEt (0.75 mmol, 0.13 ml). The reaction was stirred overnight at room temperature. It was concentrated at the pump to remove DMF. The residue was dissolved in EtOAc and washed with 1N HCl, 5% NaHCO3, and brine and dried (MgSO4). Filtration and evaporation followed by flash column chromatography, eluting with a THF/CH2Cl2 gradient provided the desired product (0.067 g, 74%) as an oil that solidified on standing. 1H NMR (300 MHz, CDCl3): 0.90 (t, 3H, J=7.4 Hz), 0.97 (t, 3H, J=7.3 Hz), 1.53-1.72 (m, 6H), 1.95-2.03 (m, 2H), 3.0 (br m, 1H), 3.82-3.91 (m, 4H), 4.79 (br s, 2H), 6.18 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH2:34][F:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][CH2:34][F:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CCF)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(CCF)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
114 mg (211 μmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4-fluorobutanoyl}amino)benzoate (racemate) and 325 μl (4.22 mmol) of TFA were reacted according to General Method 2. The crude product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/water gradient (0 to 3 min 15% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 45 mg (44% of theory)
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([CH2:28][NH2:29])[C:5]([NH:7][C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH3:21])[CH:14]=2)[N:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:9]=1)=[O:6].[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31].C(N(CC)CC)C.O>CN(C)C=O>[C:22]1([N:10]2[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][CH3:21])[CH:14]=3)=[CH:12][C:8]([NH:7][C:5]([C@H:4]3[CH2:28][NH:29][C:30](=[O:31])[NH:3]3)=[O:6])=[N:9]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCc1cccc(-c2cc(NC(=O)[C@H](N)CN)nn2-c2ccccc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cccc(-c2cc(NC(=O)[C@H]3CNC(=O)N3)nn2-c2ccccc2)c1
Reaction time: 16 h
Yield: 47.2 %

Procedure:
To a solution of (R)-2,3-diamino-N-[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]-propionamide dihydrochloride (181 mg) in N,N-dimethylformamide (3 ml) were added 1,1′-carbonyldiimidazole (67 mg), and triethylamine (116 μl) at room temperature, and the mixture was stirred for 16 hours. To this reaction solution was added water, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with water and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (76 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11]OC)[C:3]=1[CH:4]=[O:5].CC(C)([O-])C.[K+].BrC[C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.O>CS(C)=O>[CH:4]([C:3]1[C:2]([OH:1])=[CH:9][CH:8]=[CH:7][C:6]=1[O:10][CH2:11][C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1)=[O:5]
Reactant: COCOc1cccc(O)c1C=O
Reactant: CCOC(=O)c1ccc(CBr)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(COc2cccc(O)c2C=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-hydroxy-6-methoxymethoxybenzaldehyde (0.91 g, 5.1 mM) in dry dimethyl sulphoxide (8 ml) was added potassium t-butoxide (0.57 g, 5.1 mM) with exclusion of moisture. After 10 mins, ethyl 4-bromomethylbenzoate (1.22 g, 5 mM) was added and the whole stirred at room temperature (18 hrs). The reaction mixture was poured into water (100 ml) and the liberated oil extracted into ether. The combined extracts were washed with 5% sodium carbonate solution, water, dried (sodium sulphate) and evaporated. The residual oil (ethyl 4-(2-formyl-3-methoxymethoxyphenoxymethyl)benzoate was dissolved in ethanol (30 ml) and treated with 3 M hydrochloric acid (30 ml) with stirring at 60° C. (30 mins). The solid was filtered off, washed with water, dried, and recrystallised from ethanol/water to give ethyl 4-(2-formyl-3-hydroxyphenoxymethyl)benzoate, m.p. 105°-ω° C. (identical to a sample previously prepared, Example 5(B)).
Reaction SMILES: [Na].CO[C:4]([C:6]1([CH2:17][NH:18][C:19](=[O:26])[CH2:20][C:21]([O:23][CH2:24]C)=[O:22])[CH2:9][N:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7]1)=[O:5]>CO.C1(C)C=CC=CC=1>[CH3:24][O:23][C:21]([CH:20]1[C:4](=[O:5])[C:6]2([CH2:9][N:8]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:7]2)[CH2:17][NH:18][C:19]1=[O:26])=[O:22]
Reactant: CCOC(=O)CC(=O)NCC1(C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Agent: [Na]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1C(=O)NCC2(CN(C(=O)OC(C)(C)C)C2)C1=O
Temperature: 90 °C
Yield: 48 %

Procedure:
Sodium metal (870 mg; 38 mmol) is dissolved in methanol (55 ml) and combined with a solution of 3-[(2-ethoxycarbonyl-acetylamino)-methyl]-azetidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester in toluene (165 ml). The reaction mixture is heated to 90° C. for 1 hour, cooled to 7-9° C. and the precipitated white crystals (Na-salt of title compound) filtered off. The crystals are dissolved in water, acidified by the addition of 2N HCl and extracted with CH2Cl2 three times. The combined organic phases are dried over Na2SO4, filtered, evaporated and yield the title compound as white crystals (5.6 g; 48%). A second crop of the title compound is obtained by evaporating the above toluene/methanol filtrate to almost dryness, taking up the resin in 2N HCl and extracting with CH2Cl2 three times. The combined organic phases are dried over Na2SO4, filtered, evaporated and yielded the second crop of title compound as brownish solid (3.22 g; 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Br[CH2:13][CH2:14][CH2:15][O:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:13][CH2:14][CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: BrCCCOC1CCCCO1
Reactant: N#CCc1ccc(Cl)c(Cl)c1
Product: N#CC(CCCOC1CCCCO1)c1ccc(Cl)c(Cl)c1

Procedure:
Prepare according to the method of example 11.1 using 3,4-dichlorophenylacetonitrile (50 mmol) and 2-(3-bromo-propoxy)-tetrahydro-pyran (50 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: O1CCOCC1.Cl[P:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na].[CH3:22][S:23]([N:26]1[CH2:30][C@H:29](OS(C)(=O)=O)[CH2:28][C@H:27]1[CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=[O:25])=[O:24]>O1CCCC1>[CH3:22][S:23]([N:26]1[CH2:30][C@@H:29]([P:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:28][C@H:27]1[CH2:36][O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])(=[O:24])=[O:25]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1S(C)(=O)=O
Agent: [Na]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](P(c2ccccc2)c2ccccc2)CN1S(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To 150 ml of dioxane were added 11.39 g (0.052 mol) of chlorodiphenylphosphine and 2.6 g (0.114 mol) of sodium, and the mixture was refluxed for 4 hours in nitrogen atmosphere. After allowing the mixture to stand for cooling, 50 ml of tetrahydrofuran was added to the reaction mixture, and a solution of 10.45 g (0.027 mol) of (2S,4R)-N-methanesulfonyl-2-tert-butyldimethylsilyloxymethyl-4-methanesulfonyloxypyrrolidine [V] in 100 ml of tetrahydrofuran was added dropwise to the mixture lest any air should enter in the reaction system. The mixture was stirred in nitrogen atmosphere at 0° C. for 2 hours and then at room temperature overnight and then any insoluble matter was removed, for example, by filtration. The filtrate was concentrated until dryness under reduced pressure and the residue was purified by column chromatography on silica gel whereby 7.93 g (yield: 62%) of an oily substance was obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:21])=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([CH3:20])[CH:14]=3)[CH:11]=2)[C:6](=[O:22])[C:5]([C:23]([O:25]CC)=[O:24])=[CH:4]1)[CH3:2].[OH-].[Na+].O.CO>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:21])=[C:10]([C:13]3[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([CH3:20])[CH:14]=3)[CH:11]=2)[C:6](=[O:22])[C:5]([C:23]([OH:25])=[O:24])=[CH:4]1)[CH3:2]
Reactant: CCOC(=O)c1cn(CC)c2cc(-c3cc(C)nc(C)c3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3cc(C)nc(C)c3)cc21
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
A mixture containing 98 g of ethyl 1-ethyl-6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylate, 50 ml of 35% aqueous sodium hydroxide solution, 500 ml of water and 100 ml of methanol was refluxed with stirring for 90 minutes and the resulting brown solution was acidified with acetic acid whereupon a light yellow precipitate separated. The mixture was allowed to stand at room temperature for about 2 hours and the precipitate was collected, washed successively with water and ethanol and then dried at 90°-95° C. to yield 86.8 g (95%) of 1-ethyl-6-fluoro-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxylic acid, m.p. >310° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7](Cl)=[O:8])[N:6]=1.ClC1S[CH:13]=[C:14](C(O)=O)[N:15]=1.S(Cl)(Cl)=O.C(N)C>O.CN(C=O)C>[Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:15][CH2:14][CH3:13])=[O:8])[N:6]=1
Reactant: O=C(Cl)c1csc(Cl)n1
Reactant: O=C(O)c1csc(Cl)n1
Agent: CCN
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CCNC(=O)c1csc(Cl)n1

Procedure:
2-Chloro-4-thiazolecarboxylic acid chloride (prepared from 2-chloro-4-thiazolecarboxylic acid, thionyl chloride and a catalytic amount of DMF) was reacted with 70% ethylamine in water to yield 2-chloro-N-ethyl-4-thiazolecarboxamide. This compound was reacted with TMSCl using the method of step c of Example 248. Purification by flash chromatography with 3% ethyl acetate-hexane gave 2.5 g of the title compound as a light yellow oil in 55.6% yield. nD26 1.5313.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[C:9]([CH3:25])[N:8]([C@@H:26]3[CH2:29][C@H:28]([CH2:30]O)[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[OH:43][CH:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)=[C:9]([CH3:25])[N:8]([C@@H:26]3[CH2:29][C@H:28]([CH2:30][N:47]4[CH2:48][CH2:49][CH:44]([OH:43])[CH2:45][CH2:46]4)[CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OC1CCNCC1
Reactant: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CO)C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1c(-c2cccc(OCc3ccccc3)c2)c2c(N)ncnc2n1[C@H]1C[C@@H](CN2CCC(O)CC2)C1

Procedure:
The title compound is prepared in analogy to Example 116 starting from 0.35 g (0.84 mmol) cis-{3-[4-amino-5-(3-benzyloxy-phenyl)-6-methyl-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}methanol and 0.328 g (1.69 mmol) p-toluenesulfonyl chloride in 3.5 ml dry pyridine, followed by 0.87 g (8.44 mmol) 4-hydroxypiperidine (Fluka, Buchs, Switzerland). Analytical HPLC: tR=8.76 min (Grad 1); ES-MS: m/eo=498.2; NMR (DMSO-d6; not all signals reported): 8.07/s (1H), 7.25-7.5/several m's (6H), 7.01/“d” (1H); 6.94/s (1H); 6.89/“d” (1H); 5.13/s (2H); 4.76/m (1H); 4.51/d (OH); 2.22/s (3H).
Reaction SMILES: C([Li])CCC.S1C2C=CC=CC=2C=C1.C(OCC)(=O)C(OCC)=O.[CH2:25]([O:27][C:28](=[O:40])[C:29](=O)[C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[CH:34]=1)[CH3:26].Cl.[NH2:42][OH:43]>O1CCCC1.C(O)C.C(O)(=O)C>[OH:43][N:42]=[C:29]([C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[CH:34]=1)[C:28]([O:27][CH2:25][CH3:26])=[O:40]
Reactant: NO
Reactant: CCOC(=O)C(=O)c1cc2ccccc2s1
Agent: Cl
Agent: [Li]CCCC
Agent: c1ccc2sccc2c1
Solvent: C1CCOC1
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)c1cc2ccccc2s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (25 ml of 1.6N solution in hexanes) was added dropwise to a stirred solution of benzothiophene (5.36 g, Lancaster) in tetrahydrofuran (80 ml) under argon and cooled to -78° C. When the addition was complete the reaction was stirred at -78° C. for 10 min and then at room temperature for 20 min. The solution was then added via a cannula to a stirred solution of diethyl oxalate (11.68 g), cooled to -78° C. The mixture was stirred at -78° C. for 0.5 h and then at room temperature for 1 h. Acetic acid (1.5 ml) was added to the mixture which was then partitioned between ethyl acetate and water. The organic phase was washed three times with water, then with sodium bicarbonate solution, water and brine. The solution was dried over magnesium sulphate and evaporated. Column chromatography using gradient elution (Kieselgel:9:1 to 4:1 hexane:ethyl acetate) gave a mixture of ethyl-2-oxo-2-(2-benzothienyl)acetate and diethyl oxalate. The mixture was dissolved in ethanol (50 ml) and hydroxylamine hydrochloride (435 mg) was added. The mixture was stirred at room temperature for 3 days, then the solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over magnesium sulphate and evaporated. The isomers of the title oxime were separated by column chromatography of the residue (Kieselgel:4:1 hexane:ethyl acetate). Isomer A: 887 mg, νmax (CHCl3)/cm-1 3564, 3309 and 1736. δH (250 MHz; CDCl3), 1.46 (3H, t, J 7.08), 4.53 (2H, q, J 7.11), 7.31-7.42 (2H, m), 7.46 (1H, s), 7.72-7.82 (2H, m), 8.83 (1H, s); m/z (EI) 249 (M+). Isomer B: 624 mg, νmax (CHCl3)/cm-1 3545, 3249, 1731. δH (250 MHz; CDCl3), 1.49 (3H, t, J 7.19), 4.49 (2H, q, J 7.25), 7.35-7.47 (2H, m), 7.86-7.93 (2H, m), 8.40 (1H, s), 10.43 (1H, br.s); m/z (EI) 249 (M+).
Reaction SMILES: CN(C)P(=O)(N(C)C)N(C)C.Br[C:13]1[C:14](=[O:24])[O:15][C:16]2[C:21]([C:22]=1[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=2.[C:25]1([S:31][Si](C)(C)C)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[C:25]1([S:31][C:13]2[C:14](=[O:24])[O:15][C:16]3[C:21]([C:22]=2[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C[Si](C)(C)Sc1ccccc1
Reactant: O=c1oc2ccccc2c(O)c1Br
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC#N
Product: O=c1oc2ccccc2c(O)c1Sc1ccccc1
Yield: 70.4 %

Procedure:
1 ml of hexamethylphosphoric triamide and 1.0 g (4.15 mmoles) of 3-bromo-4-hydroxycoumarin were added to a solution of 0.91 g (5.0 mmoles) of phenylthio(trimethyl)silane in 25 ml of dry acetonitrile. After refluxing for 1 hour, the mixture was evaporated and the residue was dissolved in 125 ml of ethyl acetate. The solution obtained was washed twice with 125 ml of water and the ethyl acetate layer was dried and evaporated to dryness. The solid residue was washed with 100 ml of heptane and then with three portions of 50% ethanol, was vacuum dried at 40° C. to obtain 0.79 g (70.5% yield) of 3-phenylthio-4-hydroxycoumarin melting at 186°-189° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[CH:13]=[N:14][C:15](C(O)=O)=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.S1C=CC=C1C1N2C=NC(C(O)=O)=C2N=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[CH:13]=[N:14][CH:15]=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1
Reactant: O=C(O)c1ncn2c(-c3cccnc3)ccnc12
Agent: O=C(O)c1ncn2c(-c3cccs3)ccnc12
Product: c1cncc(-c2ccnc3cncn23)c1

Procedure:
4-(3-Pyridyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid (prepared as described in Example 20) can be substituted for 4-(2-thienyl)imidazo[1,5-a]pyrimidine-8-carboxylic acid in the procedure of Example 21, to produce 4-(3-pyridyl)imidazo-[1,5-a]pyrimidine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)[C:12](=[O:15])[NH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br-].[Li+].Br[CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][C:31]=1[Br:36]>CN(C=O)C.COCCOC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2[S:17][CH:18]=[C:19]([CH3:21])[N:20]=2)[C:12](=[O:15])[N:13]([CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][C:31]=2[Br:36])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1csc(-c2cc(OCc3ccccc3)c[nH]c2=O)n1
Reactant: BrCCCc1ccncc1Br
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: Cc1csc(-c2cc(OCc3ccccc3)cn(CCCc3ccncc3Br)c2=O)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
Prepared by a modification of the procedure reported in Tetrahedron Lett., 1995, 8917. 5-Benzyloxy-3-(4-methylthiazol-2-yl)-1H-pyridin-2-one (3.3 mmol) was dissolved in DMF (5 ml) and DME (20 ml). The reaction mixture was cooled to 0° C. and treated with sodium hydride (3.5 mmol). After 10 min, the reaction mixture was treated with lithium bromide (6.6 mmol) and stirred for 15 min at room temperature. The reaction mixture was treated with a solution of 4-(3-bromopropyl)-3-bromopyridine (5.0 mmol) in DME (5 ml) and then it was heated at 75° C. for 60 h. The reaction mixture was cooled, acidified, and washed with ethyl acetate. The aqueous layer was basified and extracted with ethyl acetate. The organic extracts were dried (MgSO4), filtered, and evaporated in vacuo. Purification by column chromatography gave the product as a yellow foam (2.74 mmol, 82%). δH (250 MHz; CDCl3) 8.65 (1H, s), 8.60 (1H, brd), 8.41 (1H, d, J=7.1), 7.40-7.33 (5H, m), 7.16 (1H, d, J=7.3), 7.03 (1H, s), 7.00 (1H, d, J=4.6), 5.02 (2H, s), 4.13 (2H, t, J=10.4), 2.79-2.72 (2H, m), 2.53 (3H, s), 2.17-2.04 (2H, m).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:8]([CH2:9]O)=[CH:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)=[N:5]1.S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[Cl:26][CH2:9][C:8]1[N:4]([CH2:3][C:2]([F:23])([F:22])[F:1])[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=2)[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(-c2ccc(OC(F)(F)F)cc2)nn1CC(F)(F)F
Solvent: ClC(Cl)Cl
Product: FC(F)(F)Cn1nc(-c2ccc(OC(F)(F)F)cc2)cc1CCl

Procedure:
In analogy to the procedure described for example 1 b], [2-(2,2,2-trifluoro-ethyl)-5-(4-trifluoromethoxy-phenyl)-2H-pyrazol-3-yl]-methanol (example 15 b]) was reacted with thionyl chloride in chloroform to yield 5-chloromethyl-1-(2,2,2-trifluoro-ethyl)-3-(4-trifluoromethoxy-phenyl)-1H-pyrazole as colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH2:15])[CH2:3]1.N1C=CC=CC=1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.O>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[NH:15][S:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:35])=[O:34])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1ccccc1N)N2
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(C)(C)CC(c1ccccc1NS(=O)(=O)c1ccccc1)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4,4,6-trimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (150 mg, 0.56 mmol) and pyridine (0.5 mL) in dichloromethane (2 mL) was added benzenesulfonyl chloride (72 μL) at ice-bath under nitrogen. After addition, the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Sodium sulfate, removed the solvent under reduced pressure, the residue was purified by HPLC to give N-[2-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzensulfonamide LC/MS m/e obsd. (ESI+) [(M+H)+] 407.3.