Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[CH:10][N:9]=2)[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].[Cl-].[OH:25][NH3+:26]>C(O)C>[OH:25][N:26]=[C:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[CH:10][N:9]=2)[CH2:3][CH2:2]1
Reactant: O=C1CCC(Oc2ncnc3c2CCCC3)CC1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: ON=C1CCC(Oc2ncnc3c2CCCC3)CC1

Procedure:
A solution of 3.8 g (15.5 mmol) of 4-(cyclohexanone-4-oxy)-5,6,7,8-tetrahydroquinazoline in 50 ml of distilled ethanol is first treated with 2.9 g (34.2 mmol) of sodium acetate and then with 2.2 g (31.0 mmol) of hydroxyl ammonium chloride. The reaction mixture is refluxed for 4 hours, and the crystallized product (1.8 g) is subsequently removed by filtration with suction.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][S:9]1(=[O:18])=[O:17].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:25][S:26]([O:29][CH2:30][C:31]#[C:32][CH2:33]OS(C)(=O)=O)(=[O:28])=[O:27]>>[CH3:25][S:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][N:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[S:9]1(=[O:18])=[O:17])(=[O:28])=[O:27]
Reactant: CS(=O)(=O)OCC#CCOS(C)(=O)=O
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CS(=O)(=O)OCC#CCN1c2ccccc2N(c2ccccc2F)S1(=O)=O

Procedure:
In an analogous manner to general procedure IV, 1-(2-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared in an analogous manner as described in general procedure I, 0.79 g, 3.0 mmol) was treated with cesium carbonate (1.46 g, 4.5 mmol) and but-2-yne-1,4-diyl dimethane-sulfonate (3.63 g, 15.0 mmol) to give 0.55 g of 4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]but-2-yn-1-yl methanesulfonate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH3:16][Li]>C1(C)C=CC=CC=1.C(OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH3:16])=[CH:6][CH:7]=1
Reactant: Brc1ccc(N=Cc2ccccc2)cc1
Reactant: [Li]C
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(Nc1ccc(Br)cc1)c1ccccc1
Temperature: -40 °C
Reaction time: 3 h

Procedure:
To a solution of N-(4-bromophenyl)-N-(1-phenylmethylidene)amine (1.0 g, 0.00385 mol) in toluene (30 mL) cooled to −78° C., a 1.4M solution of methyl lithium in diethyl ether (5.5 mL) was added dropwise keeping the temperature below −75° C. The solution was warmed up to −40° C. and stirred at this temperature under an atmosphere of nitrogen for 3 hours. The reaction mixture was quenched by a dropwise addition of water and the layers were separated. The organic phase was washed with brine (50 mL), dried with magnesium sulfate and concentrated under reduced pressure to yield N-(4-bromophenyl)-N-(1-phenylethyl)amine (1.03 g, 0.00373 mol) as an off-white solid.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].Br[CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1.O>C1COCC1>[C:1]([N:8]1[CH2:15][C@H:14]([O:16][CH2:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Reactant: BrCc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2cccc3ccccc23)C[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
Commercially available Boc-4(R)-hydroxyproline (5.00 g, 21.6 mmol) was dissolved in THF (100 mL) and cooled to 0° C. Sodium hydride (60% dispersion in oil, 1.85 g, 45.4 mmol) was added portionwise over 10 minutes and the suspension was stirred at RT for 1 h. Then, 1-(bromomethyl)naphthalene (8.00 g, 36.2 mmol) (prepared as described in E. A. Dixon et al. Can. J. Chem., (1981), 59, 2629-2641) was added and the mixture was heated at reflux for 18 h. The mixture was poured into water (300 mL) and washed with hexane. The aqueous layer was acidified with 10% aqueous HCl and extracted twice with ethyl acetate. The organic layers were combined and washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (49:49:2 hexane: ethyl acetate: acetic acid) to give the title compound as a colorless oil (4.51 g, 56% yield). 1H NMR (DMSO-d6) indicated the presence of two rotamers: δ 8.05 (m, 1H), 7.94 (m, 1H), 7.29 (d, J=14 Hz, 1H), 7.55-7.45 (m, 4H), 4.96 (m, 2H), 4.26 (br. s, 1H), 4.12 (dd, J=J=8 Hz, 1H), 3.54-3.42 (m, 2H), 2.45-2.34 (m, 1H), 2.07-1.98 (m, 1H) 1.36 (s, (3/9) 9H), 1.34 (s, (6/9) 9H).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].Cl.[C:5]1([C:11]2([CH2:17][C:18](=O)[CH3:19])[CH:16]=[CH:15][CH2:14][CH:13]=[CH:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([BH3-])#N.[Na+]>CO>[CH3:19][CH:18]([NH:3][CH2:1][CH3:2])[CH2:17][C:11]1([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:15][CH2:14][CH:13]=[CH:12]1
Reactant: CC(=O)CC1(c2ccccc2)C=CCC=C1
Reactant: CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNC(C)CC1(c2ccccc2)C=CCC=C1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To 5.3 g. (about 8 equivalents) of ethylamine and 10 g. of molecular sieve 3A in 100 ml. absolute methanol are added at 0° C. 5.6 ml. of 5 N methanolic hydrochloric acid (2 equivalents) and then 3 g. of (1-phenyl-2,5-cyclohexadien-1-yl)-2-propanone in a small amount of absolute methanol. 0.63 g. (0.7 equivalent) of sodium cyanoborohydride is then added and the mixture is stirred at room temperature for 5 days. The mixture is worked-up in exactly the same manner as described in Example 16. The crude product is chromatographed on silica gel with methylene chloride/methanol (10:1). There is obtained α-methyl-N-ethyl-1-phenyl-2,5-cyclohexadien-1-ethylamine as an oily product. This product is converted as usual into the hydrochloride which, after crystallization from methylene chloride/ether, has a melting point of 151°-153° C.
Reaction SMILES: CCOP(OCC)([CH:6]1[NH:12][C:10](=[O:11])[NH:9][C:7]1=[O:8])=O.C(N(CC)CC)C.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>C(#N)C>[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=[C:6]2[NH:12][C:10](=[O:11])[NH:9][C:7]2=[O:8])[CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: CCOP(=O)(OCC)C1NC(=O)NC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.8 %

Procedure:
To a stirred solution of diethyl 5-hydantoylphosphonate (10 g, 42.3 mmol) and triethylamine (5.70 g, 56 mmol), in dry acetonitrile (100 ml) at room temperature was added a solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (8 g, 36.3 mmol) in dry acetonitrile (75 ml), dropwise over 30 minutes. The resulting mixture was stirred at room temperature overnight, after which volatiles were removed in vacuo. The residue was diluted with 0.05N HCl (120 ml) and the precipitate collected by filtration. Recrystallization of this material with methylene chloride/methanol/diethyl ether afforded the title compound as a pale yellow solid (8.54 g). m.p. 220-222° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][C@@H:5]([NH:7][C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:4][N:3]1C(OC(C)(C)C)=O.Cl>CO.O1CCOCC1>[CH3:1][C@@H:2]1[NH:3][CH2:4][C@H:5]([NH:7][C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[CH2:6]1
Reactant: C[C@H]1C[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: C[C@H]1C[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CN1
Temperature: 25 °C
Reaction time: 4 h
Yield: 121.5 %

Procedure:
The intermediate of step F (0.6 g, 1.4 mmol) was dissolved in MeOH (3 mL) and a solution of 4 N HCl in dioxane (3 mL). After being stirred at room temperature for 4 hours, the solution was concentrated to give 0.56 g of the title compound. MS calculated (M+H)+ 330. found 330.2.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[CH:24]([NH:27][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)([CH3:26])[CH3:25]
Reactant: CC(C)N
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 97 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using isopropylamine (1 M in DMF) instead of methylamine, to the title compound (110 mg, 97%) which was obtained as an off white solid. MS: m/e=352.5 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[C:16]1[S:17][C:18]2[C:23]([N:24]=1)=[CH:22][CH:21]=[C:20]([C:25]1([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:27][CH2:26]1)[N:19]=2)[CH2:5][NH:6][CH2:7][C:8]([O:10]CC)=[O:9].O.O.[OH-].[Li+]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[C:16]1[S:17][C:18]2[C:23]([N:24]=1)=[CH:22][CH:21]=[C:20]([C:25]1([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:26][CH2:27]1)[N:19]=2)[CH2:5][NH:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)CNCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CNCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)-benzylamino)acetate (80 mg, 0.173 mmol) was dissolved in THF (1.4 mL) and water (347 μL) before lithium hydroxide monohydrate (21.82 mg, 0.520 mmol) was added and stirred at ambient temperature for 16 h. The reaction mixture was concentrated, acidified to pH 7 with 1 N HCl, filtered, and washed with water, DMSO, then water, and dried in a vacuum oven to give the title compound. MS (ESI) m/z: Calculated: 433.1; Observed: 433.8 (M++H).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:23][CH2:22][C:21]([C:30](O)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].S(Cl)(Cl)=O.[CH3:38][N:39]([CH:41]=O)[CH3:40]>C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:23][CH2:22][C:21]([C:30]([NH:24][C:18]4[CH:19]=[CH:33][C:15]([CH2:41][N:39]([CH3:38])[CH:40]5[CH2:7][CH2:6][O:5][CH2:1][CH2:2]5)=[CH:16][CH:17]=4)=[O:31])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)C=O
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CCCOC)cc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3CCCOC)cc1
Reaction time: 1 h

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxypropyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (200 mg) in THF (10 ml) were added thionyl chloride (0.064 ml) and DMF (one droplet) at room temperature, and the mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure, and the resulting residue was dissolved in THF (15 ml), which was added dropwise to a solution of 4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]aniline (107 mg) and triethylamine (0.37 ml) in THF (5 ml) at 0° C. The mixture was stirred at room temperature for 18 hours, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried with magnesium sulfate. After concentration under reduced pressure, the residue was purified with column chromatography (ethanol:ethyl acetate=1:3), and the resulting crystals were purified by recrystallization (hexane-ethyl acetate) to give 7-[4-(2-butoxyethoxy)phenyl]-1-(3-methoxypropyl)-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 104) (264.2 mg) as yellow crystals.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([CH2:11]Cl)=[N:9][CH:10]=1)=[O:5].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH3:2][O:3][C:4]([C:6]1[N:7]([CH3:13])[C:8]([CH2:11][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:9][CH:10]=1)=[O:5]
Reactant: COC(=O)c1cnc(CCl)n1C
Reactant: C1CCNC1
Agent: Cl
Product: COC(=O)c1cnc(CN2CCCC2)n1C

Procedure:
2-Chloromethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester hydrochloride (224 mg, 1 mmol) was dissolved in pyrrolidine (2.3 ml, 28 mmol) and stirred at ambient temperature for, the title compound was obtained as light yellow oil 45 min. After evaporation to dryness, the residue is taken up in ethyl acetate and saturated aqueous sodium carbonate (20 ml) and the phases separated. The aqueous phase is extracted twice with ethyl acetate (20 ml each) and the combined organic layers are dryed with magnesium sulfate and evaporated to dryness. Flash chromatography (silica, eluent dichloromethane7methanol 19:1) afforded the title compound as light yellow oil (61% yield). MS: m/e=224(M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>CCOC(C)=O.CC1C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Product: Clc1ncnc2c1ncn2C1CCCCO1
Temperature: 90 °C
Yield: 99.4 %

Procedure:
A suspension of 6-chloro-9H-purine (25.36 g, 164 mmol) and 4-methylbenzenesulfonic acid (0.565 g, 3.28 mmol) in EtOAc (250 mL) was treated with 3,4-dihydro-2H-pyran (44.9 mL, 492 mmol). The mixture was heated at 90° C. and the solid slowly dissolved over 1 h. The flask was removed from the oil bath and the cloudy, yellow solution was filtered and concentrated in vacuo. The pale yellow residue was dissolved in DCM and purified by flash chromatography (50% EtOAc/hexane) (1 L silica/4 L solvent) to give 6-chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (38.90 g, 99.3% yield) as a colorless oil which slowly crystallized. MS (ESI, pos. ion) m/z: 239.1 [M+H]+
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[F:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1>CS(C)=O>[F:9][C:10]1[CH:24]=[CH:23][C:13]([C:14]2([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:15][CH2:4]2)=[CH:12][CH:11]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Fc1ccc(C2(c3ccc(F)cc3)CO2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of dimethyl oxosulphonium methylide was prepared under nitrogen from sodium hydride (0.1 mol) and powdered trimethyl oxosulphonium iodide (0.1 mol) in dry dimethyl sulphoxide (100 ml). A solution of 4,4'-difluorobenzophenone (0.08 mol) in dimethyl sulphoxide (40 ml) was added dropwise at room temperature and the solution heated at 50° for 2 hours. After cooling to room temperature the solution was extracted with diethyl ether (400 ml), washed with water (3×250 ml), and dried over anhydrous sodium sulphate. Removal of the solvent gave 1,1-bis-(4-fluorophenyl)-ethylene oxide (95%) as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.C(N(CC)CC)C.[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17](Cl)=[O:18]>C(#N)C>[F:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:16]=1[C:17]([NH:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1)=[O:18]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Nc1cc[nH]n1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
To a stirred solution of 3-aminopyrazole (60 g, 0.722 mol, ABCR) in acetonitrile (500 ml) at 0° C. (ice/brine bath) was added, dropwise, triethylamine (201 ml, 1.44 mol) at such a rate to keep the temperature below 5° C. The reaction mixture was stirred at 0° C. for 0.5 h then a solution of 2,6-difluorobenzoyl chloride (127.5 g, 0.722 mol, Aldrich) in acetonitrile (200 ml) was added over approximately 1 h, keeping the temperature between 0-7° C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue partitioned between water (250 ml) and EtOAc (500 ml). Some solid formed at the interface, this was filtered off and turned out to be product—combined with isolated product at the end for drying. The aqueous layer was separated and extracted with EtOAc (2×500 ml). The combined organics were washed with water (500 ml), dried (MgSO4), charcoaled, filtered and concentrated under reduced pressure to give a yellow solid. The combined residues were triturated with DCM (500 ml) then water (100 ml) and the solid collected by filtration and dried on the sinter, then under high vacuum overnight to give the title compound as a white solid (108.5 g);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH:9]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19]I>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]([CH3:19])([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(C(=O)c1ccc(Cl)cc1)n1cncn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C(=O)c1ccc(Cl)cc1)n1cncn1
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
4'-Chloro-2-(1H-1,2,4-triazol-1-yl)propiophenone (2 g.) in dry tetrahydrofuran (30 ml) was added to a suspension of sodium hydride (480 mg. of a 60% dispersion in oil) in dry tetrahydrofuran (20 ml) at 0° under a nitrogen atmosphere. After stirring for 10 minutes, methyl iodide (2.28 g.) in dry tetrahydrofuran (10 ml.) was added dropwise and the reaction mixture was then stirred at 0° for 1 hour and then at room temperature overnight. The reaction mixture was then diluted with water (20 ml), extracted with ether (3×25 ml), and the combined organic extracts were washed with water and dried (MgSO4). The residue obtained after removal of the solvent was flash chromatographed on silica (150 g.) using ethyl acetate/hexane/diethylamine (50:50:3 v/v/v) for elution and the product-containing fractions on evaporation followed by crystallisation of the residue from ethyl acetate/hexane furnished the title compound, (1.68 g., 84% yield), m.p. 118°-9°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][S:10]([CH3:12])=O)=[C:4]([NH:14][CH3:15])[CH:3]=1.S([O-])(O)=O.[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][S:10][CH3:12])=[C:4]([NH:14][CH3:15])[CH:3]=1
Reactant: CNc1cc(F)ccc1C(=O)CS(C)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CNc1cc(F)ccc1C(=O)CSC
Reaction time: 72 h

Procedure:
A mixture of 1-(4-fluoro-2-methylaminophenyl)-2-methylsulphinylethanone (100 g), prepared in a similar manner to that described in Example 1, sodium hydrogen sulphite (1 kg) and water (2.5 1) was stirred under nitrogen and heated at 90°-105° for 3 hours. The mixture was allowed to cool and then stood at ambient temperature for 72 hours. The mixture was extracted with dichloromethane (3×250 ml) and the combined extracts evaporated to give a solid product. Crystallisation from hexane gave 1-(4-fluoro-2-methylaminophenyl)-2-(methylthio)ethanone, m.p. 61.5°-63°.
Reaction SMILES: [CH3:1][C:2](=[N:6][OH:7])[C:3](=[O:5])[CH3:4].[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O>C(O)(=O)C>[Br:8][C:9]1[CH:10]=[C:11]([C:12]2[O:5][C:3]([CH3:4])=[C:2]([CH3:1])[N+:6]=2[O-:7])[CH:14]=[CH:15][CH:16]=1
Reactant: CC(=O)C(C)=NO
Reactant: O=Cc1cccc(Br)c1
Solvent: CC(=O)O
Product: Cc1oc(-c2cccc(Br)c2)[n+]([O-])c1C
Yield: 74.1 %

Procedure:
A solution of 2,3-butanedione monooxime (50 g, 0.49 mol) and 3-bromobenzaldehyde (101 g, 0.54 mol) in acetic acid (500 mL) was cooled to 0° C. and then gaseous HCl was bubbled through the solution for 35 min while the reaction was stirred in an ice bath. Diethyl ether (500 mL) was then added to the reaction to precipitate the product and the resultant slurry stirred 45 min at 0° C. before being filtered. The solids were rinsed with Et2O (50 mL), taken up in water (1 L) and concentrated NH4OH (60 mL) added to the slurry. This mixture was extracted with CHCl3, the organic layer was dried (MgSO4), and the solvent removed in vacuo to give 97.4 g (74%) of 2-(3-bromophenyl)-4,5-dimethyloxazole-3-oxide as a white solid. The compound should be used directly with 24-48 h. 1H NMR (300 MHz, CDCl3) δ 8.60 (s, 1H), 8.40 (d, J=8.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.38 (d, J=8.0 Hz, 1H), 2.39 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8]C2CCCCO2)[CH:5]=[C:4]([CH3:15])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:22]=[O:23])[CH:17]=1.[BH4-].[Na+].[C:26]([OH:38])(=O)[CH2:27][C:28]([CH2:33][C:34](O)=O)(C(O)=O)O>COCCOC.O1CCCC1>[CH3:15][C:4]1[CH:5]=[C:6]([OH:8])[CH:7]=[C:2]([CH3:1])[C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][O:23][CH:26]2[CH2:27][CH2:28][CH2:33][CH2:34][O:38]2)[CH:17]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Cc1cc(OC2CCCCO2)cc(C)c1-c1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: Cc1cc(O)cc(C)c1-c1cccc(COC2CCCCO2)c1
Reaction time: 3 h
Yield: 36 %

Procedure:
2′,6′-Dimethyl-4′-(tetrahydro-2H-pyran-2-yloxy)biphenyl-3-carbaldehyde (9.05 g, 29.2 mmol) was dissolved in a mixture of 1,2-dimethoxyethane (50 mL) and tetrahydrofuran (50 mL), and sodium borohydride (0.567 g, 15.0 mmol) was added under ice-cooling. The mixture was stirred at the same temperature for 3 hrs. 10% Aqueous citric acid solution was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15%-50% ethyl acetate/hexane) to give the title compound (3.24 g, yield 36%) as colorless crystals.
Reaction SMILES: OS(O)(=O)=O.[O-]S([O-])(=O)=O.[Mg+2].[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:16]([OH:18])=[O:17].[CH3:23][C:24](O)([CH3:26])[CH3:25]>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:16]([O:18][C:24]([CH3:26])([CH3:25])[CH3:23])=[O:17]
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(F)cc(F)c1
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
Concentrated H2SO4 (1.74 mL, 31.6 mmol) was added to a vigorously stirred suspension of MgSO4 (15.2 g, 126.4 mmol, 4 eq) in toluene (100 mL). The mixture was stirred for 15 minutes, after which 3,5-difluorobenzoic acid (5 g, 31.6 mmol) and t-BuOH (14.9 mL, 158 mmol, 5 eq) were added successively. The mixture was stoppered tightly and stirred at room temperature until the reaction was complete by TLC analysis. The reaction mixture was then quenched with saturated NaHCO3 solution and stirred until all MgSO4 had dissolved. The organic layer was washed with brine, dried over MgSO4 and concentrated to afford the crude product. The residue was purified by chromatography (silica, Hex) to give tert-butyl 3,5-difluorobenzoate (5.3 g, 78%) as a colorless oil.