Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][C:8](=[S:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13](O)[CH2:14][CH2:15][CH3:16])[CH3:6].N1C=CC=CC=1>ClCCl>[CH2:5]([O:7][C:8](=[S:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([Cl:3])[CH2:14][CH2:15][CH3:16])[CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCCC(O)CCCCC(=S)OCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(Cl)CCCCC(=S)OCC
Reaction time: 1 h
Yield: 89.5 %

Procedure:
89.25 grams (0.7 mole) of thionyl chloride at +5° C. were slowly dropped into a solution of 137.0 grams (0.59 mole) of 6-hydroxy-8-methylthiooctanoic acid ethyl ester (VIb) and 1 ml of pyridine in 300 ml of dichloromethane. After stirring for 1 hour at +10° C. the mixture was heated for 3 hours at reflux and subsequently concentrated in a vacuum. The residue was treated with 200 ml of water and extracted with dichloromethane. After drying the combined extracts with sodium sulfate the solvent was removed in a vacuum. By fractional distillation there were obtained 125.1 grams (84% of theory) of 6-chloro-8-methylthiooctanoic acid ethyl ester as a colorless oil having a boiling point of 135° C. to 145° C. at 1 mbar.
Reaction SMILES: C([O:5][C:6]([C:8]([CH3:26])=[CH:9][C:10]1[C:11](=[O:25])[C:12]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:13]=2[NH:14][C:15](=[O:19])[C:16]=1[O:17][CH3:18])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:24][C:21]1[CH:22]=[CH:23][C:12]2[C:11](=[O:25])[C:10](/[CH:9]=[C:8](\[CH3:26])/[C:6]([OH:7])=[O:5])=[C:16]([O:17][CH3:18])[C:15](=[O:19])[NH:14][C:13]=2[CH:20]=1
Reactant: COc1c(C=C(C)C(=O)OC(C)(C)C)c(=O)c2ccc(Cl)cc2[nH]c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(/C=C(\C)C(=O)O)c(=O)c2ccc(Cl)cc2[nH]c1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 25.1 %

Procedure:
4-[2-(Tert-butoxycarbonyl)propenyl]-8-chloro-3-methyoxy-2,5-dioxo-2,5-dihydro-1H-benz[b]azepine (0.35 g) in methylene chloride (7 mL) was treated with trifluoroacetic acid. The solution was stirred under argon at room temperature for 40 minutes and then it was concentrated to a white solid. The solid was dissolved in hot methanol (30 mL). The solution was filtered and concentrated to 7 mL volume as a solid formed. The solid was filtered off, washed with cold methanol, and air-dried to give a white solid (0.0748 g); mp=277.4°-278.6° C. (dec); 1H NMR (d6 -DMSO) 7.17 (s,1) for olefin proton; MS: m/z=304, 322 (base peak)(M+1). Analysis for C15H12ClNO5 : Calculated: C, 56.00; H, 3.76; N, 4.35; Found: C, 55.86; H, 3.82; N, 4.32.
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([C:8]1[N:9]=[C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][C:16]=3[CH:17]=2)[S:11][CH:12]=1)([CH3:7])([CH3:6])[CH3:5].Cl>O1CCCC1>[C:4]([C:8]1[N:9]=[C:10]([C:13]2[O:14][C:15]3[CH:21]=[CH:20][C:19]([CH:22]([OH:23])[CH3:1])=[CH:18][C:16]=3[CH:17]=2)[S:11][CH:12]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: C[Mg]Br
Reactant: CC(C)(C)c1csc(-c2cc3cc(C=O)ccc3o2)n1
Agent: Cl
Solvent: C1CCOC1
Product: CC(O)c1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Methyl magnesium bromide (1M) in tetrahydrofuran (12.6 ml) was added dropwise over 30 minutes to a solution of 4-tert-butyl-2-(5-formylbenzofuran-2-yl)thiazole (3.0 g) in tetrahydrofuran (30 ml) under ice-cooling. After being stirred at same temperature for 15 minutes, the reaction mixture was poured into ice-water. The mixture was neutralized with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fractions containing the object compounds were combined and concentrated under recused pressure to give 4-tert-butyl-2-[5-(1-hydroxyethyl) benzofuran-2-yl]thiazole (2.04 g).
Reaction SMILES: [CH3:1][C:2]([CH3:17])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][CH2:14][C:15]#[CH:16])=[CH:8][CH:7]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)Cl>[O:26]1[C:2]([CH3:17])([CH3:1])[CH:3]1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][O:13][CH2:14][C:15]#[CH:16])=[CH:10][CH:11]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C#CCOCc1ccc(OCC=C(C)C)cc1
Solvent: ClCCl
Product: C#CCOCc1ccc(OCC2OC2(C)C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.15 g of p-[(3-methyl-2-butenyl)oxy]-α-propargyloxy-toluene is dissolved in 40 ml of methylene chloride and cooled to 0°C. (ice-bath cooling). 1.5 g of 80% by weight m-chloroperbenzoic acid is added portionwise to this mixture and the solution is thereafter stirred at 0°C. for 2 hours. The mixture is worked up as follows: diluted with 350 ml of methylene chloride; washed with ice-cold 1-N caustic soda; washed with saturated aqueous sodium chloride solution; dried over sodium sulfate; and evaporated. By chromatography on Kieselgel, there is obtained p-[(2,3-epoxy-3-methylbutyl)oxy]-α-propargyloxy-toluene; B.P. 120°-123°C/0.1 mmHg.
Reaction SMILES: CCN(CC)CC.[CH2:8]1[CH:12]2[CH2:13][NH:14][CH2:15][CH:11]2[CH2:10][N:9]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].Cl[C:24]1[N:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:27]=[N:26][N:25]=1>O1CCOCC1>[C:29]1([N:28]2[C:24]([N:14]3[CH2:13][CH:12]4[CH2:8][N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH:11]4[CH2:15]3)=[N:25][N:26]=[N:27]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: Clc1nnnn1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC2CN(c3nnnn3-c3ccccc3)CC2C1
Temperature: 115 °C

Procedure:
Et3N (5 mL) was added into a solution of tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1 g) and 5-chloro-1-phenyl-1H-tetrazole (1 g) in dioxane (50 mL). The mixture was heated to 115° C. for 24 hours. The reaction was quenched with water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic phase was dried over MgSO4 and concentrated to give a residue which was purified by silica gel chromatography to give tert-butyl 5-(1-phenyl-1H-tetrazol-5-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate.
Reaction SMILES: CO[C:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)=[C:4]([C:7]#[N:8])[C:5]#[N:6].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][C:24]=1[NH:32][NH2:33]>C(O)C>[NH2:6][C:5]1[N:32]([C:24]2[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[CH:27]=[CH:28][C:23]=2[Br:22])[N:33]=[C:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[C:4]=1[C:7]#[N:8]
Reactant: COC(=C(C#N)C#N)c1ccc(Oc2ccccc2)cc1
Reactant: NNc1cc([N+](=O)[O-])ccc1Br
Solvent: CCO
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn(-c2cc([N+](=O)[O-])ccc2Br)c1N
Temperature: 70 °C
Reaction time: 8 h
Yield: 20.8 %

Procedure:
To a solution of 2-(methoxy(4-phenoxyphenyl)methylene)malononitrile (392 mg, 1.42 mmol) in ethanol (30 mL) was added (2-bromo-5-nitrophenyl)hydrazine (300 mg, 1.29 mmol) in one portion, then the mixture was stirred at 70° C. under N2 overnight. The mixture was concentrated to dryness and chromatographed on 5 g of silica gel using PE/EA (10/1 to 2/1) as eluant to afford 128 mg (21%) of 5-amino-1-(2-bromo-5-nitrophenyl)-3-(4-phenoxyphenyl)-1H-pyrazole-4-carbonitrile as a yellow solid. MS (ESI) m/e [M+1]+ 476, 478.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][O:13]C1CCCCO1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][OH:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COC/C=C\COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CC(C)(C)OC(=O)COC/C=C\CO
Yield: 59.5 %

Procedure:
To a solution of 1.00 g of 2-[4-(2-tetrahydropyranyloxy)-(Z)-2-buten-1-yloxy]acetic acid tert-butyl ester in 30 ml of methanol, 88 mg of pyridinium p-toluenesulfonate was added and the mixture was heated at reflux for 3 hours. The solvent was evaporated under reduced pressure and the reaction solution was extracted with ethyl acetate after adding water. After the extract was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to obtain 420 mg of the desired compound as an oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH:6]=[N:7][OH:8])=[CH:4][C:3]=1[CH3:11].BrN1C(=O)[CH2:16][CH2:15][C:14]1=O.ClC(C)=C.C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[CH:14]=[C:15]([CH3:16])[O:8][N:7]=2)=[CH:4][C:3]=1[CH3:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C=NO)ccc1Br
Agent: C=C(C)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(Br)c(C)c2)no1
Temperature: -15 °C
Reaction time: 2.5 h
Yield: 27.3 %

Procedure:
A solution of 4-bromo-3-methylbenzaldehyde oxime (D81) (2.68 g, 0.0125 mol) in dry dimethylformamide (30 ml) was treated over 15 minutes with N-bromosuccinimide (636 mg, 0.00357 mol), and reaction mixture stirred for 2.5 hours, then cooled to -15° C. 2-Chloropropene (3.45 ml, 0.0405 mol) was added in a single portion, followed by dropwise addition of triethylamine (1.35 ml, 0.0097 mol) in dry dimethylformamide (10 ml) over 0.5 hours maintaining the temp. at -10° C. The mixture was stirred at 0° C. for 1 hour, then stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue partitioned between K2CO3 solution and chloroform. The organic phase was dried (Na2SO4) and evaporated under reduced pressure and the residue purified by chromatography on silica gel eluting with 60-80 petroleum-ether and ethyl acetate, to afford the title compound (246 mg, 8%).
Reaction SMILES: [N:1]1([C@@H:7]2[CH2:12][CH2:11][C@H:10]([NH:13][CH:14]3[C:23]4[N:22]=[CH:21][CH:20]=[CH:19][C:18]=4[CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(OC([N:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[CH2:40]Cl)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.[I-].[K+]>CC#N>[NH:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=[C:32]1[CH2:40][N:13]([C@H:10]1[CH2:9][CH2:8][C@@H:7]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH2:12][CH2:11]1)[CH:14]1[C:23]2[N:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1
Reactant: c1cnc2c(c1)CCCC2N[C@H]1CC[C@@H](N2CCOCC2)CC1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1cnc2c(c1)CCCC2N(Cc1nc2ccccc2[nH]1)[C@H]1CC[C@@H](N2CCOCC2)CC1
Temperature: 25 °C

Procedure:
The above amine (69.0 mg, 0.22 mmol), 2-chloromethyl-benzimidazole-1-carboxylic acid tert-butyl ester (70.0 mg, 0.26 mmol), N,N-diisopropylethylamine (50 μL, 0.28 mmol), and potassium iodide (3.7 mg, 0.02 mmol) in CH3CN (1.5 mL) were stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and the solvent was removed under reduced pressure. Purification of the crude material by radial chromatography on silica gel (1 mm plate, NH4OH/MeOH/CH2Cl2, 1:1:98 then 1:2:97) afforded the desired compound (56.8 mg, 47%) as a pale yellow solid. 1H NMR (CDCl3) δ 1.30-1.34 (m, 2H), 1.45-1.66 (m, 11H), 1.88-2.01 (m, 4H), 2.05-2.16 (m, 4H), 2.40 (br m, 4H), 2.54 (t, 1H, J=4.4 Hz), 2.59 (t, 1H, J=3.9 Hz), 2.68-2.73 (m, 1H), 3.04-3.11 (m, 1H), 3.61-3.71 (m, 4H), 4.29 (dd, 1H, J=8.7, 5.7 Hz), 4.43 (s, 2H), 6.829 (dd, 1H, J=7.5, 4.8 Hz), 7.07 (d, 1H, J=6.9 Hz), 7.22-7.28 (m, 2H), 7.61-7.70 (m, 1H), 7.73-7.79 (m, 1H), 8.32 (dd, 1H, J=4.8, 1.5 Hz).
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:23]([CH2:24][C:25](O)=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[ClH:29].Cl.[NH:31]1[CH2:35][CH2:34][N:33]=[C:32]1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH2:44])=[CH:38][CH:37]=1>>[ClH:29].[NH:33]1[CH2:34][CH2:35][N:31]=[C:32]1[C:36]1[CH:37]=[CH:38][C:39]([CH2:42][CH2:43][NH:44][C:25](=[O:26])[CH2:24][CH:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]2[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:28])=[CH:6][CH:5]=2)(=[O:9])=[O:8])=[CH:40][CH:41]=1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Reactant: Cc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2CC(=O)O)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2CC(=O)NCCc2ccc(C3=NCCN3)cc2)cc1

Procedure:
The title compound was prepared from [5-(toluene-4-sulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethylamine dihydrochloride (Reference Example 2) according to the method described in Example 1e. MS (EI) 565.7 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH2:12]Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]([S:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][CH:20]=2)=[CH2:12])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)c1ccc(SC(CCl)S(=O)(=O)c2ccc(Cl)cc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C(Sc1ccc(C(C)(C)C)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
p-t-Butylphenyl 1-(p-chlorophenylsulfonyl)-2-chloroethyl sulfide (16.12 g, 40.0 mmoles) was dissolved in 80 ml of tetrahydrofuran at 25° C. The solution was treated with 5.6 ml (4.08 g, 40.3 mmoles) of triethylamine and allowed to stand for 30 minutes. After filtration had separated the triethylamine hydrochloride, the filtrate was freed of solvent by evaporation at reduced pressure. The residue was a colorless solid, m.p. 74°-79°. Recrystallization from 25 ml of ethanol gave 12.2 g (84%) of pure product m.p. 79°-81°.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](O)([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)[C:5](=[O:16])[N:6]2CCCCC.BrC1C=CC=C2C=1C(O)(C1C(O)=CC3OCOC=3C=1)C(=O)N2>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]([C:17]1[C:25]([OH:26])=[CH:24][C:20]3[O:21][CH2:22][O:23][C:19]=3[CH:18]=1)[C:5](=[O:16])[NH:6]2
Reactant: CCCCCN1C(=O)C(O)(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Agent: O=C1Nc2cccc(Br)c2C1(O)c1cc2c(cc1O)OCO2
Product: O=C1Nc2cccc(Br)c2C1c1cc2c(cc1O)OCO2

Procedure:
Following the procedure as described in PREPARATION 1D, and making non-critical variations to replace 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 4-bromo-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained (95%) as a cream solid: MS (ES+) m/z 348.5 (M+1), 346.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[C:20]([F:21])=[CH:19][C:18]([CH2:22][CH2:23][C:24](OCC)=[O:25])=[CH:17][C:16]=3[F:29])=[C:11]([C:30]([F:33])([F:32])[F:31])[S:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[C:20]([F:21])=[CH:19][C:18]([CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][C:16]=3[F:29])=[C:11]([C:30]([F:32])([F:33])[F:31])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1cc(F)c(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Into a 25-mL round-bottom flask, was placed ethyl 3-(4-[[3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propanoate (100 mg, 0.20 mmol, 1.00 equiv), tetrahydrofuran (2 mL). This was followed by the addition of a solution of LAH (7.5 mg, 0.20 mmol, 1.00 equiv) in tetrahydrofuran (1 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 60 min at 0° C. in a water/ice bath. The reaction progress was monitored by TLC/LCMS (ethyl acetate/petroleum ether=1:5). The reaction was then quenched by the addition of 5 mL of water. The resulting solution was extracted with 5×5 mL of ethyl acetate and the organic layers combined. The solvent was removed under vacuum. The crude product (90 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, 0.05% TFA/ACN=4/1 increasing to 0.05% TFA/ACN=0/1 within 20 min; Detector, UV 254 nm. This resulted in 28.9 mg (32%) of 3-(4-[[3-(4-chlorophenyl)-5-(trifluoromethyl)-1,2-thiazol-4-yl]methoxy]-3,5-difluorophenyl)propan-1-ol as a off-white solid. 1H NMR (300 MHz, CD3OD) δ 7.79 (d, J=6.6 Hz, 2H), 7.51 (d, J=8.7 Hz, 2H), 6.83 (d, J=9.6 Hz, 2H), 5.19 (s, 2H), 3.56 (t, J=6.3 Hz, 2H), 2.65 (t, J=7.5 Hz, 2H), 1.80-1.85 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C20H15ClF5NO2S, 464.0 (M+H). found 464.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:32]C(=O)C)=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:37])[C:5]([CH3:36])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:32])=[C:17]([CH:31]=2)[C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)=C(C)C1=O
Yield: 70.2 %

Procedure:
N-[5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-trifluoromethylaniline (0.087 g, 0.168 mmol) was dissolved in methanol (6 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:2) and then recrystallized from ether to obtain the titled compound (0.056 g, 0.118 mmol, 70%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12](=O)[C:13]([F:16])([F:15])[F:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH2:18]CC1C=C(C=CC=1)CN.O>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([NH2:18])[C:13]([F:16])([F:15])[F:14])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Reactant: NCc1cccc(CN)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: NC(c1cc(Cl)cc(C(F)(F)F)c1)C(F)(F)F
Reaction time: 12 h
Yield: 65.9 %

Procedure:
To a solution of 24.5 g of 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanone (88 mmol, 1 eq) in 200 ml of toluene were added 13.6 g of m-(aminomethyl)benzylamine (100 mmol, 1.13 eq). After the addition of a catalytic amount of p-TsOH.H2O (˜100 mg), the mixture was refluxed on a water separator for 12 h (approx. 5 ml of water were removed). Thereafter, another 5.5 g of m-(aminomethyl)benzylamine (40 mmol) were added and the mixture was boiled for a further 11 h. Subsequently, the toluene was distilled off (760 Torr). The resulting crude product was distilled under high vacuum (30-105° C. at 0.5 Ton). Further distillation by means of a Vigreux column (b.p. 105-108° C. at 25 Torr) gives 16.0 g of 1-[3-chloro-5-(trifluoromethyl)phenyl]-2,2,2-trifluoroethanamine (58 mmol, 65%) as a clear liquid.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21][C:22]3[CH:36]=[CH:35][C:25]([C:26]([O:28]CC[Si](C)(C)C)=[O:27])=[CH:24][CH:23]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2.C(OCC)(=O)C>C1COCC1>[CH3:1][C:2]1([CH3:37])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:35][CH:36]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2
Reactant: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Oc4ccc(C(=O)OCC[Si](C)(C)C)cc4)cc32)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Oc4ccc(C(=O)O)cc4)cc32)cc1

Procedure:
A solution of 110.0 mg (0.213 mmol) 2- trimethylsilylethyl 4[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]oxy]-benzoate (Compound 38) and 167.3 mg of tetrabutylamrnmonium flouride (0.640 mmol, 0.64 ml of a 1M solution in THF) in 2.0 ml THF was stirred at room temperature for 22 hours. Ethyl acetate was added and the resulting solution washed with H2O and saturated aqueous NaCl then dried over MgSO4. Removal of the solvents under reduced pressure and washing of the residual solid with EtOAc and CH3CN afforded the title compound as a colorless solid. 1H NMR (d6-acetone): δ 8.10 (2H, d, J=8.8 Hz), 8.06 (1H, dd, J=2.0, 8.1 Hz), 7.82 (1H, d, J=1.9 Hz), 7.64 (1H, d, J=8.1 Hz), 7.35 (2H, d, J=8.6 Hz), 7.25 (4H, m), 6.08 (1H, t, J=4.7 Hz), 2.42 (2H, d, J=4.7 Hz), 2.35 (3H, s), 1.39 (6H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[C:13]([C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])=[C:12](Cl)[N:11]3[CH:24]=2)[CH:5]=[CH:6][CH:7]=1.C(C1(C)CCN([C:35]2[N:40]3C=C(C(OCC)=O)N=[C:39]3[CH:38]=[C:37]([CH3:49])[C:36]=2C(=O)C(OC)=O)CC1)CC=C>>[CH2:18]([O:19][C:37]1([CH3:49])[CH2:36][CH2:35][N:40]([C:12]2[N:11]3[CH:24]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=4)[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[C:13]=2[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])[CH2:39][CH2:38]1)[CH:17]=[CH2:13]
Reactant: COC(=O)C(=O)c1c(C)cc2nc(-c3cccc(Br)c3)cn2c1Cl
Reactant: C=CCCC1(C)CCN(c2c(C(=O)C(=O)OC)c(C)cc3nc(C(=O)OCC)cn23)CC1
Product: C=CCOC1(C)CCN(c2c(C(=O)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Yield: 77 %

Procedure:
Prepared from methyl 2-(2-(3-bromophenyl)-5-chloro-7-methylimidazo[1,2-a]pyridin-6-yl)-2-oxoacetate in 77% yield following the same procedure as ethyl 5-(4-(but-3-en-1-yl)-4-methylpiperidin-1-yl)-6-(2-methoxy-2-oxoacetyl)-7-methylimidazo[1,2-a]pyridine-2-carboxylate. 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 8.00 (s, 1H), 7.93 (d, J=7.6 Hz, 1H), 7.53-7.49 (m, 1H), 7.41 (br. s., 1H), 7.34 (t, J=7.8 Hz, 1H), 6.24-6.09 (m, 1H), 5.53 (d, J=16.9 Hz, 1H), 5.41 (d, J=10.2 Hz, 1H), 4.03-4.00 (m, 2H), 3.97 (s, 3H), 3.86 (t, J=11.3 Hz, 2H), 2.81 (d, J=7.6 Hz, 2H), 2.42 (s, 3H), 1.96 (d, J=12.6 Hz, 2H), 1.64 (br. s., 2H), 1.32 (s, 3H); LCMS (ESI, M+1): 526.2.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:13][C@@:12]([O:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])([C:14]([F:17])([F:16])[F:15])[CH2:11][C@@H:10]1[C@H:24]1[O:28]C(C)(C)[N:26]([C:31](=[O:33])[CH3:32])[C@H:25]1[CH2:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=1)=O)(C)(C)C>O1CCOCC1>[ClH:1].[F:41][C:39]1[CH:40]=[C:35]([CH:36]=[C:37]([F:42])[CH:38]=1)[CH2:34][C@H:25]([NH:26][C:31](=[O:33])[CH3:32])[C@H:24]([OH:28])[C@H:10]1[CH2:11][C@:12]([O:18][CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])([C:14]([F:17])([F:15])[F:16])[CH2:13][NH:9]1
Reactant: CC(=O)N1[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@](OCCC(C)C)(C(F)(F)F)CN2C(=O)OC(C)(C)C)OC1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1C[C@](OCCC(C)C)(C(F)(F)F)CN1
Reaction time: 2 h
Yield: 100 %

Procedure:
Add 4M hydrogen chloride in dioxane (8 mL) to (2R,4R)-2-[(4S,5S)-3-acetyl-4-(3,5-difluoro-benzyl)-2,2-dimethyl-oxazolidin-5-yl]-4-(3-methyl-butoxy)-4-trifluoromethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.084 g, 0.14 mmol). Stir 2 hours and evaporate to give the title compound as a foam (0.073 g, 100%).