Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68.5 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.16 g) in dichloromethane (3 mL) was added TFA (3 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (4 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, further purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/heptane) to yield the title compound as an off-white solid (0.098 g, 21%). MS (ISP) 476.0 [(M+H)+]; mp 225° C.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].CN(C)C1C=CC=CC=1.Cl[C:22]([O:24][CH3:25])=[O:23]>O1CCCC1>[CH3:25][O:24][C:22]([O:3][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([OH:11])=[O:10])=[O:23]
Reactant: O=C(O)C(O)c1ccccc1
Reactant: COC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)OC(C(=O)O)c1ccccc1
Reaction time: 0.5 h

Procedure:
60 gms. (0.4 moles) of DL-mandelic acid are dissolved in 50 ml. of tetrahydrofuran. 50 gms. (0.4 moles) of dimethylaniline are added and the mixture is cooled to -20°. 45 gms. (0.5 moles) of methyl chloroformate are added with vigorous stirring. After 30 minutes, the reaction mixture is poured into 500 ml. of ice-water and extracted with ethyl acetate. The organic phase is washed with 100 ml. of 2N HCl solution and concentrated after drying over sodium sulfate. A light oil is obtained which crystallizes on standing overnight. The product, DL-α-[(methoxycarbonyl)oxy]-phenylacetic acid is recrystallized from cyclohexane to obtain white crystals, m.p. 103°-105°.
Reaction SMILES: [C:1]([CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])#[N:2].[H-].[Na+].Br[CH2:15][C:16]1[CH:43]=[CH:42][C:19]([C:20]([NH:22][C:23]2[CH:28]=[C:27]([C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[CH:26]=[CH:25][C:24]=2[NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:21])=[CH:18][CH:17]=1>C1COCC1.C(OCC)(=O)C>[C:37]([O:36][C:35]([NH:34][C:24]1[CH:25]=[CH:26][C:27]([C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[CH:28][C:23]=1[NH:22][C:20]([C:19]1[CH:42]=[CH:43][C:16]([CH2:15][CH:3]([P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])[C:1]#[N:2])=[CH:17][CH:18]=1)=[O:21])=[O:41])([CH3:40])([CH3:39])[CH3:38]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(C#N)Cc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Temperature: 0 °C

Procedure:
Diethyl cyanomethylphosphonate (0.19 ml, 1.175 mmol) was dissolved in THF (7 ml). The solution was cooled to 0° C. Sodium hydride (0.0818 g, 2.045 mmol) was added to the reaction. The reaction was allowed to stir for several minutes. Tert-butyl [2-{[4-(bromomethyl)benzoyl]amino}-4-(2-thienyl)phenyl]carbamate (0.5047 g, 1.035 mmol) was added in a solution of THF. The reaction was allowed to slowly warm to room temperature and stir overnight. The reaction was diluted with ethyl acetate and quenched with saturated aqueous ammonium chloride. The aqueous layer was extracted with ethyl acetate three times. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was partially purified by column chromatography on silica gel. MS: cal'd 484 (MH+-Boc), exp 484 (MH+-Boc).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OB(O)c1ccccc1F
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccccc3F)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 2-fluoro-phenylboronic acid to give [1-(2-fluoro-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 319(MH+).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[CH:30]=[C:29]([Cl:31])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:33])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:25]3[CH:30]=[C:29]([Cl:31])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1
Reactant: NCCc1ccc2c(c1)OCO2
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(Cl)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCCc3ccc4c(c3)OCO4)c3cc(Cl)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-methylenedioxyphenethylamine is reacted with 4-(4-chloro-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-methylenedioxyphenethylamino)-6-chloro-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: S(Cl)(Cl)=O.[F:5][C:6]1[CH:7]=[C:8]([N+:16]([O-:18])=[O:17])[C:9]([OH:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].[CH3:19]O>>[F:5][C:6]1[CH:7]=[C:8]([N+:16]([O-:18])=[O:17])[C:9]([OH:15])=[C:10]([CH:14]=1)[C:11]([O:13][CH3:19])=[O:12]
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Thionyl chloride (5.88 g, 49.4 mmol) was added dropwise to anhydrous methanol (45 mL) at 5° C. The mixture was stirred at this temperature for 30 min. Then 5-fluoro-2-hydroxy-3-nitrobenzoic acid was added to the mixture and the resulting mixture was heated to reflux for 24 hr. Solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), washed with water (100 mL×3), brine (50 mL), dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=100:1 to 5:1) to give methyl 5-fluoro-2-hydroxy-3-nitrobenzoate (3.4 g, yield 80% for two steps). 1H-NMR (400 MHz, CDCl3-d) δ 4.04 (s, 3H), 7.88-7.90 (dd, J1=7.6 Hz, J2=3.2 Hz, 1H), 7.93-7.96 (dd, J1=7.6 Hz, J2=3.2 Hz, 1H), 11.74 (s, 1H); LC-MS (ESI) m/z 216 [M+1]+.
Reaction SMILES: C(O[C:4]([S-])=[S:5])C.[K+].[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[NH2:18])[C:14]([CH3:20])([CH3:19])[C:13](=[O:21])[C:12]2([CH3:23])[CH3:22].C(O)(=O)C>O>[SH:5][C:4]1[NH:18][C:17]2[CH:16]=[C:15]3[C:11](=[CH:10][C:9]=2[N:8]=1)[C:12]([CH3:23])([CH3:22])[C:13](=[O:21])[C:14]3([CH3:19])[CH3:20]
Reactant: CC1(C)C(=O)C(C)(C)c2cc(N)c(N)cc21
Reactant: CCOC(=S)[S-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Temperature: 20 °C
Yield: 78.8 %

Procedure:
20 ml of water and 17.0 g of purified potassium ethylxanthate were added to 20.0 g of 5,6-diamino-1,1,3,3-tetramethyl-2-indanone, dissolved in 200 ml of alcohol, in a 750 ml sulfonation flask equipped with stirrer, thermometer, reflux condenser. The mixture was left to boil at reflux overnight, then diluted with 200 ml of water, neutralized with 20 ml of glacial acetic acid and stirrer at 60°-70° C. for an additional 1 hour. After cooling to 20° C., were removed by filtration under suction. There were obtained 18.8 g (78.9% of theory) of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno(5,6-d)-imidazol-6(1H)-one with a melting point above 300° C.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][O:8][C:9]1[C:14]([CH3:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[N:19]=[C:20]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=4)[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]=3[N:24]=2)=[CH:11][C:10]=1[CH3:37])(C)(C)C.O>FC(F)(F)C(O)=O>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][C:20]2[N:21]=[C:22]([O:25][CH2:26][CH2:27][CH3:28])[C:23]3[N:24]=[C:16]([C:12]4[CH:13]=[C:14]([CH3:15])[C:9]([O:8][CH2:7][C:6]([OH:38])=[O:5])=[C:10]([CH3:37])[CH:11]=4)[O:17][C:18]=3[N:19]=2)=[CH:31][CH:32]=1
Reactant: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(=O)OC(C)(C)C)c(C)c3)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCOc1nc(Cc2ccc(Cl)cc2)nc2oc(-c3cc(C)c(OCC(=O)O)c(C)c3)nc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The crude {4-[5-(4-chloro-benzyl)-7-propoxy-oxazolo[5,4-d]pyrimidin-2-yl]-2,6-dimethyl-phenoxy}-acetic acid tert-butyl ester obtained in step (a) was dissolved in trifluoroacetic acid and stirred for 3 h at room temperature. After addition of water the precipitate was isolated by filtration to yield 1.3 g of the crude title compound. 500 mg thereof were purified by preparative HPLC (method HPLC1) to yield 260 mg of the pure title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH2:8][C:9]1([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:17]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H-].[K+].[CH2:32](I)[CH3:33].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:8][C:9]1([CH2:15][N:16]2[CH2:17][CH2:18][N:19]([CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:20][CH2:21]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[CH2:32][CH3:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1(CN2CCN(Cc3ccccc3)CC2)CCCCC1
Reactant: CCI
Agent: [H-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC1(CN2CCN(Cc3ccccc3)CC2)CCCCC1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl[1-[(4-benzyl-1-piperazinyl)methyl]cyclohexyl]methylcarbamate (770 mg/1.92 mmol) in dimethylformamide (10 ml) was added potassium hydride (157 mg/3.84 mmol) at 0° C. and the resulting solution was stirred for 30 minutes at the same temperature. Ethyliodide (0.46 ml/5.76 mmol) was added to the solution and the resulting mixture was stirred for 6 hours at ambient temperature Water (20 ml) was added for quenching and the mixture was extracted with ethyl acetate (100 ml). The extract was washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (Si/230-400 mesh/20 g/dichloromethane:methanol=100:0-100:2-100:4-100:6) to give a colorless oil (730 mg/89%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)=[N:9][C:10]3[N:11]([N:13]=[CH:14][CH:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[F:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)[NH:31][C:30]=2[CH:40]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([CH:34]3[CH2:35][CH2:36][N:37]([CH2:20][C:19]4[CH:22]=[CH:23][C:16]([C:8]5[C:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)=[CH:12][N:11]6[N:13]=[CH:14][CH:15]=[C:10]6[N:9]=5)=[CH:17][CH:18]=4)[CH2:38][CH2:39]3)[NH:31][C:30]=2[CH:40]=1
Reactant: O=Cc1ccc(-c2nc3ccnn3cc2-c2ccccc2)cc1
Reactant: Fc1ccc2nc(C3CCNCC3)[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Fc1ccc2nc(C3CCN(Cc4ccc(-c5nc6ccnn6cc5-c5ccccc5)cc4)CC3)[nH]c2c1
Reaction time: 8 h
Yield: 59 %

Procedure:
250 mg (0.84 mmol) 4-(6-phenylpyrazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 258 mg (1 mmol) 6-fluoro-2-piperidine-4-yl-1H-benzimidazole hydrochloride salt were treated as previously described. Additional NaBH(OAc)3 has been added after one, two and three hours (two equivalents each). After a further hour stirring at room temperature additional 26 mg 6-fluoro-2-piperidine-4-yl-1H-benzimidazole hydrochloride salt and two equivalents NaBH(OAc)3 were added. After stirring overnight and two further additions of NaBH(OAc)3 the solvents were evaporated. Workup and purification yields 249 mg of the desired compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[Na].[CH3:10][NH:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1>CO>[CH3:10][N:11]1[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[N:2][C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:12]1
Reactant: N#Cc1ccncc1
Reactant: CNNCc1ccc(Cl)cc1
Agent: [Na]
Solvent: CO
Product: Cn1nc(-c2ccc(Cl)cc2)nc1-c1ccncc1
Reaction time: 0.5 h

Procedure:
To 4-cyanopyridine (2 g.) in methanol (30 ml.) is added sodium (0.1 g.). After standing at room temperature 0.5 hour the solution is added to 1-methyl-2-p-chloro-benzylhydrazine (3.6 g.) in methanol (40 ml.). The reaction mixture is refluxed for 5 hours and concentrated to an oil which is solidified. After recrystallization from ethyl alcohol 0.5 g. of 1-methyl-3-(p-chlorophenyl)-5-(4-pyridyl)-1,2,4-triazole m.p. 191° C. is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.O=[C:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][C:2]1[C:3]2[N:9]3[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(O)c1-n1cccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc2c1-n1cccc1C1(CCNCC1)O2
Temperature: 25 °C
Reaction time: 12 h
Yield: 47.4 %

Procedure:
To a solution of 3-methyl-2-(1H-pyrrol-1-yl)phenol (2.9 g, 16.6 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (3.6 g, 18.2 mmol) in dry dichloromethane (57.4 mL) was added TFA (2.5 mL, 33.1 mmol) over a 15 minutes period and the reaction was stirred at 25° C. for 12 hours. Another portion of TFA (2.5 mL, 33.1 mmol) was added at 25° C. and the reaction was stirred for 2 hours after which time a third portion of TFA (2.55 mL, 33.1 mmol) was added and the mixture was stirred at 25° C. for an additional 12 hours. The reaction mixture was diluted with CH2Cl2 (350 ml) and washed with 1M NaOH (50 ml). The organic phase was dried with MgSO4, filtered, evaporated to dryness and the resulting residue was purified by silica gel chromatography eluting with 0.5-40% MeOH in CH2Cl2 to yield 9-methylspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (2.0 g, 48%) obtained as a yellow oil. ESI-MS m/z calc. 254.1, found 255.3 (M+1)+. Retention time: 1.08 minutes (3 min run).
Reaction SMILES: [F:1][C:2]([F:12])([S:9]([O-:11])=[O:10])[C:3]([F:8])([F:7])[CH2:4][CH2:5][OH:6].[CH2:13]([NH+:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].OO.S([O-])([O-])=[O:23].[Na+].[Na+]>O>[F:12][C:2]([F:1])([S:9]([O-:23])(=[O:11])=[O:10])[C:3]([F:7])([F:8])[CH2:4][CH2:5][OH:6].[CH2:13]([NH+:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14]
Reactant: O=S([O-])[O-]
Reactant: O=S([O-])C(F)(F)C(F)(F)CCO
Agent: CC[NH+](CC)CC
Agent: OO
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])C(F)(F)C(F)(F)CCO
Temperature: 40 °C
Reaction time: 6 h
Yield: 40 %

Procedure:
A 500 mL reactor was charged with 112 g (46% purity, 0.17 moles) of triethylammonium 1,1,2,2-tetrafluoro-4-hydroxy-butane-1-sulfinate, 200 g of water and 41 g (0.36 mole) of 30% hydrogen peroxide, at room temperature, followed by 6 hours of stirring at 40° C. Upon confirming the termination of the reaction, a reaction liquid underwent cooling and 7.5 g of sodium sulfite was added to the reaction liquid, followed by stirring. Subsequently, a liquid obtained by distilling the solvent out of the reaction liquid was rinsed with 50 g of hexane, and then extracted with 100 g of chloroform. It was heated under a reduced pressure so as to distill a volatile component off and then dried, thereby obtaining 43 g of a target triethylammonium 1,1,2,2-tetrafluoro-4-hydroxy-butane-1-sulfonate. It exhibited a purity of 50% and a yield of 40% at this time. As a result of analysis, it was found that 4-bromo-3,3,4,4-tetrafluorobutan-1-ol which had been confirmed to disappear by the 1st step (sulfination step) was formed during this 2nd step (oxidation step) as a by-product in an amount of 9%.
Reaction SMILES: [P:1]([O-:12])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:2][CH2:3][CH2:4][CH2:5][CH3:6].[Na+].Cl[CH2:15][P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]>>[CH2:15]([P:1](=[O:12])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:2][CH2:3][CH2:4][CH2:5][CH3:6])[P:16](=[O:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19]
Reactant: CCOP(=O)(CCl)OCC
Reactant: CCCCOP([O-])OCCCC
Agent: [Na+]
Product: CCCCOP(=O)(CP(=O)(OCC)OCC)OCCCC
Yield: 43 %

Procedure:
Dibutyl diethyl methylenediphosphonate was prepared in 43% yield by reacting sodium dibutyl phosphite with diethyl chloromethylphosphonate, bp=140° (0.05 mmHg), (Kugelrohr).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:4]([F:12])[CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])([O:11][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[CH3:9])=[C:4]([F:12])[CH:3]=1
Reactant: CC(C)(O)c1ccc(Br)cc1F
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(OC1CCCCO1)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.5 %

Procedure:
To a stirred solution of 2-(4-bromo-2-fluoro-phenyl)-propan-2-ol (18.5 g, 79.4 mmol) and 3,4-dihydro-2H-pyran (10.9 mL, 119.1 mmol) in dichloromethane (165 mL) was added pyridinium-p-toluene sulfonate (2 g, 7.91 mmol) at room temperature. The resulting mixture was stirred at room temperature for 12 h, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (QingDao silica gel, 200-300 mesh, 25% ethyl acetate/hexanes) to afford 2-[1-(4-bromo-2-fluoro-phenyl)-1-methyl-ethoxy]-tetrahydro-pyran (9.7 g, 38.6%) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][Br:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc(Cl)cc1)N1CCCc2cc(O)ccc21
Reactant: BrCCCCCBr
Product: O=C(Oc1ccc(Cl)cc1)N1CCCc2cc(OCCCCCBr)ccc21

Procedure:
In analogy to example 1.4, 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester and 1,5-dibromopentane (80%) were converted to yield 6-(5-Bromo-pentyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenyl ester as colorless oil, MS: 451 (M, 1Br, 1Cl).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH3:12][C:13]([SH:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:3]([S:16][C:13]([CH3:15])([CH3:14])[CH3:12])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: CC(C)(C)S
Reactant: O=Cc1c(F)ccc(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1c(Br)ccc(F)c1C=O
Temperature: 50 °C
Yield: 50.7 %

Procedure:
A mixture of 3-bromo-2,6-difluorobenzaldehyde (2.00 g, 9.05 mmol), 2-methyl-2-propanethiol (0.917 mL, 8.13 mmol), and potassium carbonate (1.5 g, 11 mmol) in DMF (6 mL) was heated to 50° C. overnight in a sealed tube. The material was extracted with EtOAc, and washed with water (3×). Purification of the organic layer by column chromatography (1 to 2% EtOAc:hexanes) afforded 1.2 g (51%) of the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 1.34 (s, 9 H), 7.07-7.16 (m, 1 H), 7.91 (dd, J=9.0, 5.2 Hz, 1H), 10.56-10.63 (m, 1 H).
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].CS(O[CH2:17][CH2:18][CH2:19][CH2:20][O:21][CH3:22])(=O)=O>CN(C=O)C>[CH3:22][O:21][CH2:20][CH2:19][CH2:18][CH2:17][N:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1nc2c([nH]1)CCCC2
Reactant: COCCCCOS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCCCn1cnc2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 198.2 %

Procedure:
4,5,6,7-Tetrahydro-1H-benzimidazole (2.45 g) was dissolved in DMF (20 ml), sodium hydride (60% in oil, 880 mg) was added, and the mixture was stirred at room temperature for 30 min. 4-Methoxybutyl methanesulfonate (1.28 g) was added, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (2.90 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[OH-].[NH4+:13]>CO>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][NH2:13])[CH:7]=1
Reactant: ClCCCOc1cccnc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCCCOc1cccnc1
Temperature: 100 °C
Yield: 20.1 %

Procedure:
The 3-chloro-1-(3-pyridyloxy)propane (1.98 g, 11.6 mmol) was dissolved in methanol (25 mL) and added to concentrated ammonium hydroxide solution (29.7%, 14.8 M, 55 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 6 h. After cooling, the mixture was concentrated by rotary evaporation. Saturated NaCl solution (10 mL) was added to the residue, and the solution (pH 6) was extracted with ether (3×25 mL) to remove impurities. The aqueous layer was basified to pH 10 with 10% NaOH solution, and the mixture was extracted with chloroform (4×25 mL). The combined chloroform extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 0.354 g (20.1%) of an oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]1=O.[BH4-].[Na+].Cl>C1COCC1.CO>[CH3:1][C:2]1[CH2:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC1Cc2c(cccc2-c2ccccc2)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC1=Cc2cccc(-c3ccccc3)c2C1
Temperature: 0 °C

Procedure:
50 g (0,226 mol) of 2 were dissolved in 450 cm3 of THF/MeOH (2:1) and, while stirring at 0° C., 12.8 g (0.34 mol) of sodium borohydride were added a little at a time. The mixture was stirred for a further 18 hours. The reaction mixture was poured onto ice, acidified with concentrated HCl to a pH of 1 and extracted a number of times with Et2O. The combined organic phases were washed with saturated aqueous NaHCO3 solution and NaCl solution and then dried (MgSO4). The solvent was removed under reduced pressure and the crude product was, without further purification, taken up in 1 dm3 of toluene, admixed with 2 g of p-toluenesulfonic acid and heated under reflux for 2 hours. The reaction mixture was washed with 200 cm3 of saturated aqueous NaHCO3 solution and the solvent was removed under reduced pressure. The crude product was purified by filtration through 500 g of silica gel (hexane/CH2Cl2). This gave 42 g (90%) of 3 as a colorless oil.