Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[OH:19].C([O-])([O-])=O.[K+].[K+].[CH3:26][N:27]([CH3:31])[C:28](Cl)=[S:29]>CC(C)=O.O.CN(C)C(Cl)=S>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[O:19][C:28](=[S:29])[N:27]([CH3:31])[CH3:26]
Reactant: O=C(N1CCc2ccc(Cl)c(O)c2CC1)C(F)(F)F
Reactant: CN(C)C(=S)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CN(C)C(=S)Oc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 91.1 %

Procedure:
Place 7-chloro-6-hydroxy-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (64.3 g, 219 mmol) in acetone (450 mL) and water (200 mL) with K2CO3 (91.8 g, 664 mmol) and dimethylthiocarbamoyl chloride (31.5 g, 255 mmol). Stir at ambient temperature for 1.25 h. Add additional dimethylthiocarbamoyl chloride (3 g, 24 mmol) and stir for an additional 1.75 h at ambient temperature. Add more dimethylthiocarbamoyl chloride (0.7 g, 5.7 mmol) and water (150 mL) to the mixture and stir for 0.5 h at ambient temperature. Slowly add water (500 mL) to the reaction over 2 h to promote crystallization and stir the resulting slurry at ambient temperature for 1.5 h. Collect the solid by filtration to give the desired intermediate (76 g, 91%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][CH:10]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14]([CH2:16][C:17]([N-:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([OH:28])[CH:22]=1)=[O:18])#[N:15]>>[OH:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[OH:27])[CH2:20][NH:19][C:17](/[C:16](=[CH:10]/[CH:9]=[CH:8]/[C:7]1[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)/[C:14]#[N:15])=[O:18]
Reactant: N#CCC(=O)[N-]Cc1ccc(O)c(O)c1
Reactant: O=CC=Cc1ccc([N+](=O)[O-])cc1
Product: N#C/C(=C\C=C\c1ccc([N+](=O)[O-])cc1)C(=O)NCc1ccc(O)c(O)c1

Procedure:
The compound was prepared as described in Example 3 by adding 4-nitrocinnamaldehyde (0.009 g, 0.05 mmol) to N-(cyanoacetyl)3,4-dihydroxybenzylamide (Example 2, 0.010 g, 0.05 mmol). After refluxing for 2 h and recrystallization from ethanol a yellow solid was obtained (0.007 g, 39%). The product gave the following analytical data:
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH2:3][CH:4]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[C:5]1[S:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[C:9]=1[CH3:10].[CH3:26][NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31]>>[CH3:26][N:27]([C:20]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][CH:4]([C:5]2[S:6][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[C:9]=2[CH3:10])[CH2:3][CH:2]([CH3:25])[CH3:1])=[CH:24][CH:23]=1)=[O:21])[CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: Cc1c(C(CC(C)C)Nc2ccc(C(=O)O)cc2)sc2ccccc12
Reactant: CCOC(=O)CCNC
Product: Cc1c(C(CC(C)C)Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)sc2ccccc12

Procedure:
Using 4-{[3-methyl-1-(3-methyl-1-benzothiophen-2-yl)butyl]amino}benzoic acid (300 mg) synthesized above and ethyl 3-(methylamino)propanoate (134 mg) and in the same manner as in Example A1(4), the title object compound (218 mg, 59%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([N+:21]([O-])=O)[CH:5]=1.CC(C)=O>CO.[Ni]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([NH2:21])[CH:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c(S(N)(=O)=O)c1
Agent: [Ni]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)c1cc(N)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
35 g (~0.1 mol) of 3-nitro-4-phenoxy-5-sulphamylbenzoic acid methyl ester are suspended in 150 ml of methanol and are hydrogenated with Raney nickel (5-10% in an autoclave at 40°-50° and 100 atmospheres gauge. The precipitated amino compound is dissolved by the addition of acetone on a steambath and the Raney nickel is removed by filtration.
Reaction SMILES: [N:1]1([CH2:6][NH:7][C:8]2[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24]>C(#N)C>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]([N:7]([CH2:6][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[C:8]1[N:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[N:13]=1)=[O:28])(=[O:25])=[O:24]
Reactant: O=C=NS(=O)(=O)c1ccccc1Cl
Reactant: Cc1cc(C)nc(NCn2cncn2)n1
Solvent: CC#N
Product: Cc1cc(C)nc(N(Cn2cncn2)C(=O)NS(=O)(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
4 g (0.019 mole) of 2-(1,2,4-triazol-1-ylmethylamino)-4,6-dimethylpyrimidine are suspended in 100 ml of absolute acetonitrile and then 4.3 g (0.019 mole) of 2-chlorophenylsulfonylisocyanate are stirred into the suspension. The batch is stirred for 24 hours at room temperature and the resultant solution is finally concentrated in a rotary evaporator. Crystals of the title compound precipitate and are recrystallized from ethyl acetate, affording 5 g (62% of theory) of the above urea, which melts at 152°-157° C.
Reaction SMILES: O1CCN(C=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])CC1.[O:18]=O>Cl[Cu].CS(C)=O>[N+:15]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH:8]=[O:18])([O-:17])=[O:16]
Reactant: O=O
Reactant: O=[N+]([O-])c1ccccc1C=CN1CCOCC1
Agent: Cl[Cu]
Solvent: CS(C)=O
Product: O=Cc1ccccc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
50 mmol of β-morpholino-2-nitrostyrene and 1 g of CuCl were initially introduced into 120 ml of DMSO and aerated at 60° C. for 90 min. using oxygen. After concentrating and customary working-up, 0.41 mol of o-nitrobenzaldehyde was isolated.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[CH:5][C:4]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[Br:14]Br>ClCCl>[Br:14][C:5]1[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:3]([CH2:1][CH3:2])[NH:7][N:6]=1
Reactant: CCc1[nH]ncc1-c1ccccc1
Reactant: BrBr
Solvent: ClCCl
Product: CCc1[nH]nc(Br)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 58.3 %

Procedure:
To a solution of 5-ethyl-4-phenyl-1H-pyrazole (3.34 g, 19.39 mmol) in dichloromethane (111.0 mL), was added bromine (1.49 mL, 29.09 mmol) at 25° C. The reaction was stirred at room temperature for 72 h and quenched with NaOH (aq.) to pH 12. The organics were separated. The aqueous layer was extracted again with DCM (3×). The combined organics were washed with brine, dried (MgSO4), filtered and concentrated to give a red oil. This oil was purified by flash chromatography to give the title compound as a yellow oil (2.84 g). LCMS m/z=251.2 [M+H]+.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C(C2C=CC=CC=2)[N:18]2[CH2:21][CH:20]([O:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:19]2)C=CC=CC=1.O>C(Cl)Cl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH:20]2[CH2:19][N:18]([C:1]([Cl:4])=[O:2])[CH2:21]2)=[CH:24][CH:25]=1
Reactant: Fc1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Reactant: O=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(Cl)N1CC(Oc2ccc(F)cc2)C1
Reaction time: 18 h

Procedure:
A solution of 52.09 g (0.527 mole) of phosgene in 500 ml of methylene chloride was stirred with 73 g (0.53 mole) of potassium carbonate under nitrogen atmosphere for 30 min, then treated with 146.3 g (0.439 mole) of 1-diphenylmethyl-3-(4-fluorophenoxy)azetidine in 300 ml of methylene chloride added dropwise. After stirring for 18 hr, the reaction mixture was treated with 200 ml of water added slowly. The aqueous phase was separated and the organic solution dried by filtration through Whatman phase separating filter paper then concentrated in vacuo to a pale amber oil. Trituration of the oil with 30/60 petroleum ether yield a crude tacky solid, 89.3 g (88.6%). A portion of this solid was recrystallized from 30/60 petroleum ether yielding a fine white crystalline product, m.p. 44°-52° C. A second recrystallization from isopropyl ether yielded fine white crystals, m.p. 57°-58.5° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:24]([C:36]3[N:40]([CH3:41])[CH:39]=[N:38][CH:37]=3)([C:26]3[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=3)[OH:25])[CH:8]=2)[N:3]=1.[NH:42]1[CH2:45][CH2:44][CH2:43]1.CN(C)C=O>C(OCC)(=O)C>[N:42]1([C:2]2[C:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=3)=[C:10]([Cl:23])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:24]([C:36]4[N:40]([CH3:41])[CH:39]=[N:38][CH:37]=4)([C:26]4[CH:27]=[N:28][C:29]([C:32]([F:33])([F:34])[F:35])=[CH:30][CH:31]=4)[OH:25])[CH:8]=3)[N:3]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: C1CNC1
Reactant: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(Cl)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cncc1C(O)(c1ccc(C(F)(F)F)nc1)c1ccc2nc(N3CCC3)c(Cc3ccc(C(F)(F)F)cc3)c(Cl)c2c1
Temperature: 100 °C

Procedure:
To a 75 mL sealed tube was added (2,4-dichloro-3-(4-(trifluoromethyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (2.50 g, 4.09 mmol, intermediate 60), azetidine (0.83 mL, 12.3 mmol) and dimethylformamide (30 mL). The reaction vessel was sealed and heated in a 100° C. oil bath. After overnight heating, the vessel was cooled and contents transferred to a separatory funnel with ethyl acetate dilution. The organic phase was extracted with a saturated, aqueous ammonium chloride solution and deionized water. The organic phase was separated, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. Chromatography on silica gel (dichloromethane increasing to 10% ((2M ammonia in methanol) in dichloromethane)) provided the title compound. MS (ESI): mass calcd. for C31H24ClF6N5O, 631.16; m/z found, 632.5 [M+H]+. 1H NMR (600 MHz, Chloroform-d) δ 8.81 (d, J=2.2 Hz, 1H), 8.05 (d, J=2.1 Hz, 1H), 7.87 (dd, J=8.3, 2.2 Hz, 1H), 7.70 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.46 (dd, J=8.8, 2.2 Hz, 1H), 7.21 (d, J=8.0 Hz, 2H), 7.09 (d, J=1.1 Hz, 1H), 6.19 (d, J=1.1 Hz, 1H), 4.32 (s, 2H), 4.13 (t, J=7.7 Hz, 4H), 3.31 (s, 3H), 2.29-2.20 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.[C:22]([NH:25][C:26]1[N:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)(=[O:24])[CH3:23]>>[C:22]([NH:25][C:26]1[N:31]=[CH:30][C:29]([NH:32][C:19]([C:6]2[N:7]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)[C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[O:21])=[CH:28][CH:27]=1)(=[O:24])[CH3:23]
Reactant: O=C(O)c1cc2cc(F)ccc2n1Cc1cccc(F)c1
Reactant: CC(=O)Nc1ccc(N)cn1
Product: CC(=O)Nc1ccc(NC(=O)c2cc3cc(F)ccc3n2Cc2cccc(F)c2)cn1

Procedure:
Compound No. 11 is prepared from 5-fluoro-1-(3-fluorobenzyl)-1H-indole-2-carboxylic acid (WO 2006/072736) and 6-acetylamino-3-aminopyridine according to a process similar to that described in example No. 3.
Reaction SMILES: [Cl:1][C:2]1[C:3](I)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClC1C=CC(B(O)O)=CC=1>[Cl:1][C:2]1[C:3]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=2)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Fc1cc(I)c(Cl)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1cc(-c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 140 °C
Yield: 107.4 %

Procedure:
A suspension of 5-chloro-2-fluoro-4-iodopyridine (2.57 g, 10 mmol), 4-chlorophenylboronic acid (1.72 g, 11 mmol) and Pd(Ph3P)4 (462 mg, 0.4 mmol) in a mixture of 2.0 M aqueous sodium carbonate (6 mL) and toluene (10 mL) was heated at 140° C. in a microwave oven for 30 min. Analysis by HPLC/MS indicated that the reaction was not complete. Additional 4-chlorophenylboronic acid (0.156 g, 1 mmol) was added, followed by Pd(Ph3P)4 (116 mg, 0.1 mmol). The reaction mixture was again heated at 140° C. in a microwave oven for 30 min. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc (50 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (120 g) eluted with a gradient of EtOAc (0-50%) in hexanes to afford 2.6 g of the product (60% pure) as an off-white solid. This was crystallized in EtOAc-hexanes to obtain the pure title compound (0.9 g) as a white solid. HPLC/MS: retention time=3.80 min, [M+H]+=242.0.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6]1)=[O:4].N1C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[Cl:27]>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]([S:28]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][CH:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:29])=[O:30])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: COC(=O)C1Cc2ccccc2N1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C1Cc2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Indoline-2-carboxylic acid methyl ester (33.0 g, 149.7 mmol) was dissolved in DCM (400 ml), and pyridine (37.8 ml, 463.2 mmol) was added thereto. A solution of 3,4-dichlorobenzenesulfonyl chloride (24.1 ml, 154.4 mmol) dissolved in DCM (100 ml) was then added, and the mixture was stirred overnight under reflux and then cooled to room temperature. The mixture was diluted with DCM and washed in succession with 0.5 M KHSO4, saturated NaHCO3 solution and saturated NaCl solution. The organic phase was dried (sodium sulfate) and concentrated in vacuo.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]=[CH:26][C:25]=1[C:34](Cl)=[O:35]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:34]([C:25]5[CH:26]=[N:27][C:28]6[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=6)[N:24]=5)=[O:35])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)c1cnc2ccccc2n1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cnc5ccccc5n4)nc3cc21

Procedure:
Quinoxaline-2-carboxylic acid[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2-quinoxalinecarbonyl chloride (170 mg, 0.89 mmol). The title compound was obtained as yellow powder (158 mg, 42%).
Reaction SMILES: [CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]=[N:22][S:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][C:30]([CH3:33])([CH3:32])[CH3:31]>C1COCC1>[CH2:1]([C:8]1[O:12][C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])=[N:10][C:9]=1[CH:21]([NH:22][S:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)S(=O)N=Cc1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(NS(=O)C(C)(C)C)c1nc(-c2cc(F)ccc2F)oc1Cc1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 38.6 %

Procedure:
To a solution of (±)-N-((5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)methylene)-2-methylpropane-2-sulfinamide (770 mg, 1.91 mmol) in anhydrous THF (7.6 mL) was slowly added tBuLi (1.7 M solution in pentane, 3.34 mL, 5.74 mmol) at −78° C. After the reaction mixture was stirred at −78° C. for 3 h, the reaction was quenched with MeOH (2 mL) followed by addition of saturated NH4Cl solution (10 mL). Upon warming up to room temperature, the reaction mixture was stirred for 30 min and then extracted with EtOAc (50 mL). The organic layer was washed with water and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by automatic column chromatography to yield (±)-N-(1-(5-benzyl-2-(2,5-difluorophenyl)oxazol-4-yl)-2,2-dimethylpropyl)-2-methylpropane-2-sulfinamide (340 mg, 38.6%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 7.64 (1H, m), 7.38-7.27 (4H, m), 7.27-7.21 (1H, m), 7.12-6.99 (2H, m), 4.24 (1H, m), 4.12 (2Hm), 3.92 (1H, m), 1.27 (9H, s), 0.95 (9H, s). LC/MS (uplc): MH+ 461.2, 1.34 min.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[C:3]=1[F:23].C([Li])CCC.CN(C)[CH:31]=[O:32].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:23][C:3]1[C:4]2[O:8][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:6][C:5]=2[CH:21]=[CH:22][C:2]=1[CH:31]=[O:32]
Reactant: CN(C)C=O
Reactant: Fc1c(Br)ccc2c1OC(c1ccccc1)(c1ccccc1)O2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1F)OC(c1ccccc1)(c1ccccc1)O2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
5-Bromo-4-fluoro-2,2-diphenyl-1,3-benzodioxol (17.3 g) are dissolved in 150 ml of tetrahydrofuran, treated at -78° C. with 29.1 ml of a 0.6M solution of n-butyllithium in n-hexane and stirred at -78° C. for 15 minutes. Thereupon, 10 ml of dimethylformamide are added, after stirring for a further 15 minutes the mixture is treated with semi-saturated, aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried with magnesium sulphate and evaporated. The residue is crystallized from ethanol. After drying there are obtained 12.7 g of 4-fluoro-2,2-diphenyl-1,3-benzodioxol-5-carboxaldehyde as white crystals of m.p. 92°-94° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]([NH:8][C:9]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])=O)[CH3:2]>ClCCl.CO.[Cl-].[Zn+2].[Cl-]>[CH2:1]([O:3][C:4]1[CH:22]=[CH:21][CH:20]=[CH:19][C:5]=1[C:6]1[NH:13][C:11](=[O:12])[C:10]2[C:9](=[C:17]([CH3:18])[CH:16]=[CH:15][CH:14]=2)[N:8]=1)[CH3:2]
Reactant: CCOc1ccccc1C(=O)Nc1c(C)cccc1C(N)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CO
Product: CCOc1ccccc1-c1nc2c(C)cccc2c(=O)[nH]1
Temperature: 210 °C
Yield: 40.4 %

Procedure:
A mixture of 2-(2-ethoxybenzamido)-3-methylbenzamide (1.6 g, 0.0053 mol) and anhydrous zinc chloride (2.29 g, 0.016 mol) was heated at 210° C. for 5 minutes, then allowed to cool. The residue was dissolved in dichloromethane-methanol (90:10, 200 ml) and this solution washed with an aqueous solution of ethylenediamine tetraacetic acid disodium salt (12 g in 400 ml of water). The aqueous phase was then extracted with a mixture of dichloromethane-methanol (90:10, 2×50 ml) and the organic solutions combined, dried (Na2SO4) and evaporated under vacuum. The residue crystallized from ethanol to give the title compound as colourless needles (0.6 g, 40%), m.p. 177-180° C.
Reaction SMILES: [SH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[F:26][C:27]([F:31])([F:30])[CH2:28]I>>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH2:15][O:14][C:10]1[CH:9]=[C:8]([C:2]2([S:1][CH2:28][C:27]([F:31])([F:30])[F:26])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)[CH:13]=[CH:12][CH:11]=1
Reactant: SC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCOCC1
Reactant: FC(F)(F)CI
Product: FC(F)(F)CSC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCOCC1
Yield: 61 %

Procedure:
Using a similar procedure to that described in Example 1, 4-mercapto-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran was reacted with 2,2,2-trifluoroethyl iodide to give 4-[3-(naphth-2-ylmethoxy)phenyl]-4-(2,2,2-trifluoroethylthio)tetrahydropyran in 61% yield, m.p. 76°-78° C.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5]1([CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[C:21](Cl)(=[O:25])[CH:22]([CH3:24])[CH3:23]>C(Cl)Cl>[C:21]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH:8]=[CH:7][CH:6]=[C:5]2[CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17])(=[O:25])[CH:22]([CH3:24])[CH3:23]
Reactant: COC(=O)C(C)c1cccc2ccccc12
Reactant: CC(C)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)C(C)c1cccc2c(C(=O)C(C)C)cccc12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Under vigorous magnetic stirring, CH2Cl2 (125 cc) followed by AlCl3 (60 g) are added to a 500 cc three-necked flask provided with a cooling device with CaCl2 trap, a dropping funnel and a thermometer (said three-necked flask being immersed in a water-bath maintained at room temperature). Methyl 2-(1-naphthyl)-propionate (32.1 g) and isobutyryl chloride (18 cc) dissolved in CH2Cl2 (100 cc) are added thereto dropwise. The addition takes 2.5 hours. On completion of the addition, the ingredients are maintained in contact, with continued stirring. Hydrolysis is effected by pouring the reaction mixture over ice-water. The material is extracted with ether. The organic phase is washed over Na2SO4 ; the ether and CH2Cl2 are distilled off and the residual oil is distilled, to give the product named in the title.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[K+].[Cl:9][C:10]1[CH:26]=[CH:25][C:13]([O:14][C:15]2[CH:24]=[CH:23][C:18]([O:19][CH2:20][C:21]#[N:22])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1>O.C(O)CCC>[ClH:9].[Cl:9][C:10]1[CH:26]=[CH:25][C:13]([O:14][C:15]2[CH:24]=[CH:23][C:18]([O:19][CH2:20][C:21](=[N:2][OH:3])[NH2:22])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1
Reactant: N#CCOc1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCCCO
Product: NC(COc1ccc(Oc2ccc(Cl)cc2)cc1)=NO
Yield: 157.8 %

Procedure:
A suspension of 5.37 g (0.0772 mol) of hydroxylamine hydrochloride and of 7.72 g (0.0772 mol) of potassium bicarbonate in 8 ml of water is added, all at once, to a suspension of 10 g (0.0385 mol) of 4-(4-chlorophenoxy)-phenoxy-acetonitrile prepared as indicated in Example 29a), in 24 ml of n-butanol. The mixture is heated to the reflux temperature for 1 hour, the butanol is driven off, the residue is taken up in water and the insoluble matter is extracted with diethyl ether. The organic phase is washed with water, dried over dry sodium sulphate and evaporated, and the residue obtained is purified by washing with hot diisopropyl ether to give 10 g of brilliant white needles.