Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26]2[N:27]=[C:28]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([N:42]4[CH2:47][CH2:46][N:45]([CH:48]5[CH2:51][O:50][CH2:49]5)[CH2:44][CH2:43]4)=[CH:38][N:37]=3)[C:29]3[N:30]([CH:32]=[CH:33][N:34]=3)[CH:31]=2)[C:5]([CH2:22]C(=O)C)=[C:6]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[CH:7]=1.[OH2:52].[Li+].[OH-]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:26]2[N:27]=[C:28]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([N:42]4[CH2:47][CH2:46][N:45]([CH:48]5[CH2:49][O:50][CH2:51]5)[CH2:44][CH2:43]4)=[CH:38][N:37]=3)[C:29]3[N:30]([CH:32]=[CH:33][N:34]=3)[CH:31]=2)[C:5]([CH2:22][OH:52])=[C:6]([N:8]2[CH2:20][CH2:19][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[CH:18]=[C:10]3[C:9]2=[O:21])[CH:7]=1
Reactant: CC(=O)Cc1c(-c2cn3ccnc3c(Nc3ccc(N4CCN(C5COC5)CC4)cn3)n2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C1c2cc3c(n2CCN1c1cc(F)cc(-c2cn4ccnc4c(Nc4ccc(N5CCN(C6COC6)CC5)cn4)n2)c1CO)CCCC3
Yield: 52 %

Procedure:
A 100-mL single-neck round-bottomed flask was charged with 107a (150 mg, 0.21 mol) in THF/iPA/H2O (5 mL/5 mL/2 mL) and LiOH (85 mg, 3.5 mmol) while stirring. This mixture was stirred at 50° C. for 0.5 h. Then 20 mL H2O was added and the mixture was extracted with EA (30 mL×3). The combined organic layer was dried over Na2SO4 and concentrated to give a yellow solid, which was further purified by reverse-phase prep-HPLC to afford 107 as a white solid (74 mg, 52% yield). LCMS: [M+H]+ 664.3. 1H NMR (500 MHz, DMSO) δ 9.06 (s, 1H), 8.41 (s, 1H), 8.13-8.10 (m, 2H), 7.98 (d, J=2.5, 1H), 7.71 (s, 1H), 7.48-7.44 (m, 2H), 7.39-7.36 (m, 1H), 6.54 (s, 1H), 5.38 (m, 1H), 4.57-4.35 (m, 6H), 4.18-4.13 (m, 4H), 3.44-3.42 (m, 1H), 3.15 (s, 4H), 2.59 (d, J=3.0, 2H), 2.47-2.40 (m, 6H), 1.79-1.69 (m, 4H)
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH:17]([CH2:23][NH:24][C:25](=O)[CH2:26][CH3:27])[CH2:18]3)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl>C1COCC1.C(OCC)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][CH:17]([CH2:23][NH:24][CH2:25][CH2:26][CH3:27])[CH2:18]3)(=[O:11])=[O:12])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)NCC1Cc2cccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c2C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCNCC1Cc2cccc(NS(=O)(=O)c3ccc(C(C)C)cc3)c2C1
Yield: 48.3 %

Procedure:
N-[4-(4-Isopropyl-benzenesulfonylamino)-indan-2-ylmethyl]propionamide (0.30 g, 0.75 mmol) was dissolved in 10 mL of THF and 2.5 mL (26.1 mmol) of a borane-THF complex was introduced dropwise. The resulting mixture was stirred at reflux for 1 h. The solution was cooled, 3 mL of 2 N HCl was added slowly, and the mixture was stirred at reflux for 2 h. The cooled solution was quenched with water, then NaOH (2N) and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered, and the filtrate was evaporated in vacuo to give product as a white solid which was further purified by column chromatography using (dichloromethane-MeOH, 7-12%) to give an oil. The oil was dissolved in ethyl acetate and HCl (4M, dioxane) was added to give the product as a white solid (140 mg, 43%).
Reaction SMILES: Cl.[CH2:2]([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[CH2:10][CH2:9][C:8]=2[CH2:7]1)[CH2:3][CH2:4][CH3:5].[Li].N>C1COCC1.NC1C=CC=CC=1>[CH2:2]([N:6]1[CH2:15][CH2:14][C@@H:13]2[C@H:8]([CH2:9][CH2:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=32)[CH2:7]1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCN1CCC2=C(CCc3ccccc32)C1
Agent: Cl
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: Nc1ccccc1
Product: CCCCN1CC[C@H]2c3ccccc3CC[C@@H]2C1
Reaction time: 2 h
Yield: 34.8 %

Procedure:
A solution of 0.104 g (0.374 mmol) of 3-butyl-1,2,3,4,5,6-hexahydro-benz[f]isoquinoline hydrochloride in 4 ml of anhydrous THF and 0.2 ml of aniline was added dropwise to a solution of 22 mg of lithium wire in 50 ml of liquid ammonia, cooled by a dry-ice/acetone bath. The cooling bath was then removed and the mixture was stirred under nitrogen for 2 h before quenching carefully with water (2 ml) and allowing the solvents to evaporate overnight. The residue was partitioned between ether and water, and the aqueous layer was reextracted with more ether. The combined ether extracts were dried (K2CO3) and evaporated in vacuo to leave a brown oil. This was chromatographed on flash silica eluting with 50% ethyl acetate/petroleum ether to give 31.7 mg (35%) of the title product as a colourless oil. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent, the title product hydrochloride was obtained as a white solid, m.p. 217°-221° C. (dec). NMR δ(D2O) 0.96 (3H, t, J=7 Hz), 1.41 (2H, m), 1.51-1.92 (6H, m), 2.66-2.75 (2H, m), 2.86-2.95 (3H, m), 3.12-3.19 (3H, m), 3.63 (1H, m), 3.77 (1H, m), 7.22-7.28 (3H, m), 7.34-7.37 (1H, m). m/z (CI+, NH3) 244 (M+H)+, 200 (M--CH2CH2CH3)+. Analysis calcd. for C17H26ClN: C, 72.96; H, 9.36; N, 5.01%. Found: C, 72.86; H, 9.31; N, 4.80%.
Reaction SMILES: [F:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][CH:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[CH:17]=[C:16]([C:18]4[N:26](COCC[Si](C)(C)C)[C:25]5[C:24](=[O:35])[N:23]([CH2:36][CH2:37][CH3:38])[C:22](=[O:39])[N:21]([CH2:40][CH2:41][CH3:42])[C:20]=5[N:19]=4)[CH:15]=[N:14]3)[CH2:8]2)=[CH:4][CH:3]=1>C(O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:44]=[CH:43][C:5]([CH2:6][CH:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[CH:17]=[C:16]([C:18]4[NH:26][C:25]5[C:24](=[O:35])[N:23]([CH2:36][CH2:37][CH3:38])[C:22](=[O:39])[N:21]([CH2:40][CH2:41][CH3:42])[C:20]=5[N:19]=4)[CH:15]=[N:14]3)[CH2:8]2)=[CH:4][CH:3]=1
Reactant: CCCn1c(=O)c2c(nc(-c3cnn(CC4=NOC(Cc5ccc(F)cc5)C4)c3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCn1c(=O)c2[nH]c(-c3cnn(CC4=NOC(Cc5ccc(F)cc5)C4)c3)nc2n(CCC)c1=O
Yield: 158 %

Procedure:
To a solution of 8-{1-[5-(4-Fluoro-benzyl)-4,5-dihydro-isoxazol-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (80 mg) in ethanol (5 ml) aq. HCl (2 N, 5 ml) was added and the reaction mixture was refluxed for 2 hrs. The volatiles were evaporated and the residue obtained was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue obtained was purified by column chromatography to obtain 8-{1-[5-(4-Fluoro-benzyl)-4,5-dihydro-isoxazol-3-ylmethyl]-1H-pyrazol-4-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (100 mg, 98%) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].C1(N=[C:20]=[O:21])CCCCC1.N12CCN(CC1)CC2.C(Cl)(Cl)=O>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([N:12]=[C:20]=[O:21])(=[O:10])=[O:11]
Reactant: O=C=NC1CCCCC1
Reactant: NS(=O)(=O)c1cc(Cl)ccc1Cl
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Solvent: Clc1ccccc1
Product: O=C=NS(=O)(=O)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Yield: 75 %

Procedure:
A suspension of 452 g of 2,5-dichlorobenzene sulfonamide, 260 g of cyclohexylisocyanate and 10.0 g of "Dabco" (1,4-diazabicyclo[2,2,2]octane) in 2000 ml chlorobenzene was heated for one hour to reflux in a flask fitted with a water condenser and dry-ice condenser in series, a stirrer and a thermometer. Phosgene was then added into the vapor space of the flask at such a rate that the temperature of the reaction mass was maintained at 123°-125° C. due to refluxing phosgene. During 3 hours of operation a total of 260 g of phosgene was added. The dry-ice condenser was then removed and the reaction mass refluxed to drive off excess phosgene until the temperature reached 134° C. After cooling to room temperature and filtration, the solvent and cyclohexylisocyanate were recovered by distillation at 100 mm pressure. The resulting residue was then distilled at lower pressure. Obtained were 378 g (75% yield) of 2,5-dichlorobenzenesulfonylisocyanate (B.P. 105° C./0.35 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:21])[NH:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]1[C:38]2[C:33](=[N:34][C:35]([NH:39][CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=3)=[CH:36][CH:37]=2)[N:32]([CH2:49][C:50]2[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=2)[N:31]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:21])[N:13]([CH2:29][C:30]3[C:38]4[C:33](=[N:34][C:35]([NH:39][CH2:40][C:41]5[CH:42]=[CH:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=5)=[CH:36][CH:37]=4)[N:32]([CH2:49][C:50]4[CH:51]=[CH:52][C:53]([O:56][CH3:57])=[CH:54][CH:55]=4)[N:31]=3)[CH:14]=[CH:15][C:16]=2[C:17]([F:18])([F:19])[F:20])[CH:9]=1)[C:5]#[N:6]
Reactant: COc1ccc(CNc2ccc3c(CCl)nn(Cc4ccc(OC)cc4)c3n2)cc1
Reactant: N#Cc1cc(Cl)cc(Oc2c(C(F)(F)F)cc[nH]c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2ccc3c(Cn4ccc(C(F)(F)F)c(Oc5cc(Cl)cc(C#N)c5)c4=O)nn(Cc4ccc(OC)cc4)c3n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 3-chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile (3C, 0.150 g, 0.477 mmol) and potassium carbonate (0.066 g, 0.477 mmol) suspended in dimethylformamide (1 mL) was added 3-(chloromethyl)-N,1-bis(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-6-amine (0.202 g, 0.477 mmol) as a solution in dimethyl formamide (1 mL). The reaction mixture was allowed to stir at room temperature. After 16 hours, the reaction mixture was diluted with ethyl acetate (50 mL), washed with brine (3×25 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was adsorbed onto silica gel and purified by column chromatography on a pre-packed silica gel Redi Sep 40 gram column, eluting with 0-5% methanol in CH2Cl2 to afford the title compound. 1H NMR (DMSO-d6) δ 7.91 (d, J=7.0 Hz, 1H), 7.76-7.74 (m, 1H), 7.72-7.68 (m, 1H), 7.58-7.56 (m, 1H), 7.54 (d, J=8.6 Hz, 1H), 7.49-7.47 (m, 1H), 7.26 (d, J=8.6 Hz, 2H), 7.13 (d, J=8.6 Hz, 2H), 6.83 (d, J=8.6 Hz, 2H), 6.76 (d, J=8.6 Hz, 2H), 6.59 (d, J=7.2 Hz, 1H), 6.40 (d, J=8.9 Hz, 1H), 5.30 (s, 2H), 5.28 (s, 2H), 4.50-4.46 (m, 2H), 3.71 (s, 3H), 3.69 (s, 3H). LRMS (M+1)=700.6.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3]([O:5][CH2:6][C:7]([CH3:14])([CH3:13])[CH:8]([OH:12])[CH:9]([CH3:11])[CH3:10])=[O:4].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([O:12][CH:8]([CH:9]([CH3:10])[CH3:11])[C:7]([CH3:14])([CH3:13])[CH2:6][O:5][C:3](=[O:4])[CH:2]([CH3:15])[CH3:1])(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)C(=O)OCC(C)(C)C(O)C(C)C
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC(C(C)C)C(C)(C)COC(=O)C(C)C)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a one-liter, four-necked, round bottom flask equipped with stirrer, condenser, and thermometer, 200.0 parts of pyridine and 54.0 parts of 3-hydroxy-2,2,4-trimethylpentyl 2-methylpropionate were mixed under a nitrogen blanket and cooled to 0° C. using an ice water bath. To this, 57.0 parts of para-toluenesulfonyl chloride were added in portions over a thirty minute period. The solution was stirred for one hour at 0° C. and then allowed to stand for twenty-four hours at 15° C. The mixture was subsequently poured into one liter of ice water, which was then extracted with 700 parts of methylene chloride. The organic layer was washed successively with cold 6N sulfuric acid (until the water layer was acidic to pH paper); dilute sodium bicarbonate (three times with 500 part-portions); and water (twice with 500 part-portions). It was then dried over sodium sulfate, filtered, and the solvent removed in vacuo to yield the 1-isobutyryloxy-2,2,4-trimethylpentane-3-yl para-toluenesulfonate.
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:13]>CC(O)=O>[Br:1][C:6]1[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=[C:4]([CH3:3])[C:5]=1[OH:13]
Reactant: Cc1cc([N+](=O)[O-])ccc1O
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1cc([N+](=O)[O-])cc(Br)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.6 %

Procedure:
Br2 (122.2 g, 0.765 mol) was added into a solution of 2-methyl-4-nitrophenol (90.0 g, 0.588 mol) in HOAc (1.17 L) at room temperature. The resulting solution was stirred at room temperature for 4 h. TLC showed the reaction was complete. The solution was added into ice-water (3 L) slowly and filtered. The filter cake was dissolved into EA (2.5 L) and washed with saturated NaHSO3 (3×500 mL). The EtOAc layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 2-bromo-6-methyl-4-nitrophenol (110 g, 80%) as yellow solid. 1H-NMR: 400 MHz, (CDCl3) δ: 8.30 (d, J=2.0 Hz, 1H), 8.05 (s, 1H), 6.22 (s, broad, 1H), 2.41 (s, 3H).
Reaction SMILES: [Cl-].[NH4+].[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)(=[O:39])=[O:38])[C:16]([C:18]4[CH:19]=[N:20][C:21]([N:24]5[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]5)=[N:22][CH:23]=4)=[CH:17][C:10]=23)[C:6]([C:46]2[CH:51]=[CH:50][C:49]([N+:52]([O-])=O)=[CH:48][CH:47]=2)=[N:5]1>O.CO.[Fe]>[NH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:6]2[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]4[N:15]([S:37]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)(=[O:38])=[O:39])[C:16]([C:18]5[CH:23]=[N:22][C:21]([N:24]6[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]6)=[N:20][CH:19]=5)=[CH:17][C:10]=34)=[CH:8][N:4]([CH3:3])[N:5]=2)=[CH:47][CH:48]=1
Reactant: Cn1cc(-c2ccnc3c2cc(-c2cnc(N4CCN(C(=O)OC(C)(C)C)CC4)nc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: Cn1cc(-c2ccnc3c2cc(-c2cnc(N4CCN(C(=O)OC(C)(C)C)CC4)nc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(N)cc2)n1
Temperature: 70 °C

Procedure:
To a solution of ammonium chloride (3.00 mmol) in H2O (5 ml) was added iron powder (1.66 mmol) followed by a solution of 1,1-dimethylethyl 4-{5-[4-[1-methyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-pyrimidinyl}-1-piperazinecarboxylate (0.333 mmol) in methanol (10 ml). The resulting mixture was heated at 70° C. for 2 hours, the hot solution filtered through a pad of celite 545 and concentrated to yield the title product as a yellow solid (quant.) which was used crude in the next step. ESMS [M+H]+: 692.2.
Reaction SMILES: [CH2:1]([CH:3]([C:7]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:8]=1[C:9]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=1)=O)[C:4]([CH3:6])=O)[CH3:2].S(=O)(=O)(O)O.O.[NH2:37][NH2:38].C([O-])(O)=O.[Na+].C>C(O)(C)C>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:9]2[C:8]3[CH:23]=[C:24]([O:29][CH3:30])[C:25]([O:27][CH3:28])=[CH:26][C:7]=3[CH:3]([CH2:1][CH3:2])[C:4]([CH3:6])=[N:38][N:37]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: NN
Reactant: CCC(C(C)=O)c1cc(OC)c(OC)cc1C(=O)c1cc(OC)c(OC)c(OC)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCC1C(C)=NN=C(c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC)cc21
Temperature: 60 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
1.40 g (3.36 mmoles) of 2-(1-ethylacetonyl)-3',4,4',5,5'-pentamethoxybenzophenone are dissolved in 5.4 ml of isopropanol, and 0.175 ml of concentrated sulfuric acid are added dropwise to the solution. The reaction mixture is heated to boiling, stirred at this temperature for one hour, thereafter the mixture is cooled to 60° C. and 0.41 ml (8 mmoles) of 98% hydrazine hydrate are added. The resulting mixture is stirred for a further hour. 0.154 g of sodium hydrocarbonate are added in portions to the mixture, the mixture is heated to boiling, decolorized with charcoal, filtered, the filtrate is evaporated, and the residue is passed onto a filter with a total amount of 25 ml of water. 0.835 g (60.5%) of the title compound are obtained; m.p.: 152°-155° C. When recrystallized from a small amount of isopropanol the product melts at 160°-162° C. C23H28N2O5 =412.5.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].[Li]CCCC.[O:17]1[C@H:19]([CH2:20][CH3:21])[CH2:18]1>C1COCC1>[F:9][C:8]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH2:18][C@H:19]([OH:17])[CH2:20][CH3:21]
Reactant: CC[C@@H]1CO1
Reactant: FC(F)(F)c1ccccc1I
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@@H](O)Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Iodobenzotrifluoride (3 g) was dissolved in THF (18 ml) and was cooled to −78° C. n-BuLi (2.5 M in hexanes, 13.23 ml) was added dropwise to the reaction mixture. After 1 h, (R)-(+)-1,2-epoxybutane (1.4 ml) in THF (18 ml) was added. The reaction temperature was slowly increased to rt. The mixture was poured into ice-water (100 ml), and the product was extracted with heptane. The organic phase was washed with brine and water, dried (Na2SO4) ja evaporated under vacuum. The title compound was obtained by separation method E. (Yield 1.05 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].[Al+3].[Cl-].[Cl-].[Cl-].O>C1(C)C=CC=CC=1>[CH3:3][C:2]1([CH2:3][C:2]([CH3:1])([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH3:1])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:2]([CH3:7])([C:1]2[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=2)[CH2:3]1
Reactant: C=C(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(CC1(C)CC(C)(c2ccccc2)c2ccccc21)c1ccccc1
Temperature: 0 °C
Yield: 46.6 %

Procedure:
To a four-necked 2000 ml-volume flask equipped with a stirring machine, a dropping funnel, a Dimroth condenser and a thermometer, there was added a solution of 300.4 g of α-methylstyrene in 1200 g of toluene, followed by setting the temperature thereof to 0° C. by dipping the flask in ice-water and gradual dropwise addition of 300 ml of a toluene solution containing a catalyst, i.e., 1.02 g AlCl3 -2.5 ml CH3NO3 to the contents of the flask with stirring. The reaction solution at the completion of the reaction-was colored pale yellow. After the completion of the reaction, water was gently dropwise added to the reaction system to thus decompose the catalyst. Then the organic phase was washed with water, dried and concentrated. Further the organic phase was subjected to vacuum distillation under a degree of vacuum of 670 Pa and at a temperature ranging from 218 to 221° C. to give 140.0 g of 1,3-dimethyl-3-phenyl-1-(2-methyl-2-phenylpropyl) indane (MPI).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]1[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([S:8][C:10]2[O:14][CH:13]=[C:12]([C:15]([OH:17])=[O:16])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: Fc1cccc(S)c1
Solvent: CN(C)C=O
Product: O=C(O)c1coc(Sc2cccc(F)c2)c1

Procedure:
By the procedure of Example 13, m-fluorothiophenol (3.0 g., 23.4 mmoles) was reacted with cuprous oxide (1.67 g., 11.7 mmoles) in 30 ml. of dimethylformamide and then reacted further with 5-bromofuran-3-carboxylic acid in 30 ml. of dimethylformamide. Isolation of crude solids (920 mg.) was according to Example 9. Recrystallization from methanol/water, which included decolorization with activated carbon, gave purified 5-(3-fluorophenylthio)furan-3-carboxylic acid (500 mg., m.p. 101°-103° C., m/e 238).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1ccc(F)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. 1H-NMR (CDCl3): δ=2.75 (s, 3H); 3.84 (s, 3H); 7.10 (m, 2H); 7.47 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7][OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:11]I.Cl>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([CH2:7][O:8][CH3:11])=[CH:4][CH:3]=1
Reactant: CI
Reactant: OCc1ccc(Br)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1ccc(Br)s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.1 %

Procedure:
To a solution of (5-bromothiophen-2-yl)methanol (460 mg, 2.38 mmol) in 5 mL anhydrous tetrahydrofuran at room temperature was added carefully hexanes-washed sodium hydride (60% in oil, 143 mg, 3.57 mmol). After stirring at room temperature for 30 minutes, methyl iodide (0.3 mL, 4.76 mmol) was added in a single portion and the reaction mixture stirred for 16 h at room temperature. The reaction mixture was poured into 20 mL of 0.2 N hydrochloric acid. Organics were extracted with 1:1 ether/hexanes (3×25 mL), washed with 30 mL each of 5% aqueous sodium bisulfite solution and brine, dried over magnesium sulfate, filtered and concentrated. The crude residue was subjected to chromatography on silica gel with gradient elution (2-3% ethyl acetate in hexanes) to give 2-bromo-5-(methoxymethyl)thiophene (439 mg, 89%) as an oil. Used without further characterization.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:30])[C:17]([OH:29])([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=3)[C:18]([F:21])([F:20])[F:19])=[C:12]([Cl:31])[CH:11]=2)=[N:6][CH:5]=1.[Li+].[OH-].CO>C1COCC1>[Cl:31][C:12]1[CH:11]=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][N:6]=2)[CH:15]=[CH:14][C:13]=1[CH:16]([CH3:30])[C:17]([OH:29])([C:22]1[CH:27]=[CH:26][N:25]=[C:24]([CH3:28])[CH:23]=1)[C:18]([F:20])([F:19])[F:21]
Reactant: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccnc(C)c3)C(F)(F)F)c(Cl)c2)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C(O)(C(C)c2ccc(-c3ccc(C(=O)O)cn3)cc2Cl)C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To 6-{3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(2-methyl-pyridin-4-yl)-propyl]-phenyl}-nicotinic acid methyl ester (22 mg) aqueous 1N LiOH (5 ml), MeOH (2.5 ml) and THF (5 ml) were added. The resulting solution was stirred for 2 h at room temperature. Volatile solvents were removed in vacuo. The residual aqueous solution was diluted with water (10 ml) and washed with DCM (10 ml), then acidified to pH 6 with 1 N aqueous HCl and extracted with EtOAc. The combined EtOAc layers were dried over Na2SO4 and concentrated to give the title compound (21 mg) as a yellow oil. MS (m/e)=451.0 [M+H+].
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH2:25])[CH3:24])=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([C@@H:23]([NH:25][CH2:2][CH2:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([OH:9])[CH2:5][C:6]([CH3:8])=[CH2:7])[CH3:24])=[CH:19][CH:18]=1
Reactant: C=C(C)CC(O)(CCCl)c1ccccc1
Reactant: C[C@H](N)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(C)CC(O)(CCN[C@@H](C)c1ccc(Br)cc1)c1ccccc1
Temperature: 96 °C
Yield: 60.1 %

Procedure:
1-chloro-5-methyl-3-phenylhex-5-en-3-ol (1.28 g, 5.7 mmol), (S)-1-(4-bromophenyl)ethanamine (1.37 g, 1.2 equiv), KI (995 mg, 1.05 equiv), K2CO3 (1.57 g, 2 equiv) were mixed with acetonitrile (15 mL) and heated to reflux (oil bath 96° C.) for overnight. After being cooled to rt, the mixture was filtered, concentrated, and purified by chromatography on a 40-g silica gel column, eluted with 0-8% MeOH in CH2Cl2, to afford 1-((S)-1-(4-bromophenyl)ethylamino)-5-methyl-3-phenylhex-5-en-3-ol (1.33 g, 60%).