Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:20])[C@@H:10]([OH:19])[C:11]([F:18])([F:17])[C:12](OCC)=[O:13])=O)(C)(C)C>Cl.C(OCC)(=O)C>[F:17][C:11]1([F:18])[C@H:10]([OH:19])[C@H:9]([CH3:20])[NH:8][C:12]1=[O:13]
Reactant: CCOC(=O)C(F)(F)[C@H](O)[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@@H]1NC(=O)C(F)(F)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56 %

Procedure:
Ethyl 4-[(tert-butoxycarbonyl)amino]-2,4,5-trideoxy-2,2-difluoro-L-threo-pentonate (5.45 g) was dissolved in a 4 mol/L solution (100 mL) of hydrogen chloride/ethyl acetate, and the mixture was stirred at room temperature for 1.5 hr. The reaction solution was concentrated under reduced pressure, THF (200 mL) and diisopropylethylamine (9.9 mL) were added thereto, and the mixture was heated under reflux for 3 hr. The reaction solution was concentrated under reduced pressure and water (50 mL) was added to the residue. The mixture was extracted with ethyl acetate (100 mL×5) and ethyl acetate/THF=2/1 (100 mL×3). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound as a white powder (yield: 1.55 g, 46%).
Reaction SMILES: C([N:4]1[C:8]2[CH:9]=[C:10]([C:12]([O:14]C)=[O:13])[S:11][C:7]=2[CH:6]=[N:5]1)(=O)C.[OH-].[K+]>CO>[NH:4]1[C:8]2[CH:9]=[C:10]([C:12]([OH:14])=[O:13])[S:11][C:7]=2[CH:6]=[N:5]1
Reactant: COC(=O)c1cc2c(cnn2C(C)=O)s1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc2[nH]ncc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of methyl 1-acetyl-1H-thieno[3,2-c]pyrazole-5-carboxylate (F-5) (4.9 g, 21.8 mmol) in MeOH (15 mL) was added an aqueous KOH solution (6 N, 10 mL). The reaction mixture was stirred at room temperature for 2 h, and then concentrated in vacuo. Aqueous HCl (6 N) was added to adjust pH to 5-6. The precipitates were collected by filtration to afford the title compound (3.0 g).
Reaction SMILES: ClCCl.[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(N(CC)CC)C>[CH3:22][S:23]([O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCCCCCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCCCCCCc1ccccc1

Procedure:
To a mixture of 750 ml. of dichloromethane, 37.2 g. of 11-phenyl-1-undecanol (prepared as described in Example 6) and 32 ml. of triethylamine cooled in an ice-salt bath to -10° C. is added dropwise, over 15 minutes, 13.2 ml. of methanesulfonyl chloride. The mixture is cooled at -10° C. to -15° C. for 30 minutes and then washed with 300 ml. of cold water, 300 ml. of cold 10% hydrochloric acid, 300 ml. of cold 5% sodium carbonate and with 200 ml. of cold, saturated, sodium chloride solution. The organic layer is dried over magnesium sulfate and concentrated in vacuo to give a pale yellow oil.
Reaction SMILES: ClCl.[CH3:3][C:4]1[CH:12]=[C:11](Cl)[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:25][C:11]1[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:3])[CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: Cc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)O
Agent: ClCl
Product: Cc1cc(NCc2ccccc2)c(S(C)(=O)=O)cc1C(=O)O

Procedure:
in stage c) the chlorine substituent is converted into a benzylamino group by reacting 2-methyl-4-chloro-5-methylsulfonylbenzoic acid with benzylamine to give the corresponding intermediate 4-benzylamino-5-methylsulfonyl-2-methylbenzoic acid,
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH:10]=[CH:11][C:12]([O:14]CC)=O.[N+:17]([CH3:20])([O-])=O>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[CH:10]1[CH2:20][NH:17][C:12](=[O:14])[CH2:11]1
Reactant: CCOC(=O)C=Cc1cc(F)cc(F)c1F
Reactant: C[N+](=O)[O-]
Product: O=C1CC(c2cc(F)cc(F)c2F)CN1

Procedure:
4-(2,3,5-trifluorophenyl)pyrrolidin-2-one x38 is synthesized from nitromethane and ethyl 3-(2,3,5-trifluorophenyl)acrylate according to the methodology described in Kenda B. et al., J. Med. Chem. (2004), 47, 530-549
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:17][CH:16]=3)=[N:6]2)[CH2:2]1.[C:28]([O:32][C:33]([N:35]([CH2:41][CH2:42][OH:43])[CH2:36][CH2:37][C:38](O)=[O:39])=[O:34])([CH3:31])([CH3:30])[CH3:29].Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2N=CC=CC=2N=N1>ClCCl>[NH2:14][C:13]1[N:12]=[CH:11][N:10]=[C:9]2[N:5]([CH:3]3[CH2:2][N:1]([C:38](=[O:39])[CH2:37][CH2:36][N:35]([CH2:41][CH2:42][OH:43])[C:33](=[O:34])[O:32][C:28]([CH3:29])([CH3:30])[CH3:31])[CH2:4]3)[N:6]=[C:7]([C:15]3[CH:16]=[CH:17][C:18]([O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][CH:20]=3)[C:8]=12
Reactant: CC(C)(C)OC(=O)N(CCO)CCC(=O)O
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2C1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(CCO)CCC(=O)N1CC(n2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
A mixture of 1-(3-azetanyl)-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.05 g, 0.00014 mol), 3-[(tert-butoxycarbonyl)(2-hydroxyethyl)amino]propanoic acid (0.038 g, 0.000175 mol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.034 g, 0.000175 mol), N,N-diisopropylethylamine (0.034 g, 0.00026 mol) and 1-hydroxy-7-azabenzotriazole (0.019 g, 0.00014 mol) in anhydrous dichloromethane (5 mL) was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure. The residue was purified by RP-HPLC (Hypersilprep HS C18, 8 μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield tert-butyl N-(3-{3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-azetanyl}-3-oxopropyl)-N-(2-hydroxyethyl)carbamate (0.040 g, 0.000070 mol).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:26]([O:59][CH3:60])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:57][CH3:58])[C@@H:36]([CH3:56])[C:37]([NH:39][C@@H:40]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:41]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1)=[O:42])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:66][CH2:67][CH2:68][C:69]([OH:71])=[O:70]>>[C:69]([CH2:68][CH2:67][CH2:66][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:61]([CH3:64])[CH2:62][CH3:63])[C@H:26]([O:59][CH3:60])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:57][CH3:58])[C@@H:36]([CH3:56])[C:37]([NH:39][C@@H:40]([CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:41]([N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][O:44]1)=[O:42])=[O:38])=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:12])[CH3:13])([OH:71])=[O:70]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
The title compound was prepared in analogy to the synthesis of Intermediate 61, by reaction of 50 mg of N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-{[(2S)-1-(1,2-oxazinan-2-yl)-1-oxo-3-phenylpropan-2-yl]amino}-3-oxopropyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate (Intermediate 14) with 4-oxobutanoic acid.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=1[O:15][CH3:16])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].OS(O)(=O)=O>[Pd].CC(O)=O>[CH3:16][O:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: COc1ccc(C)cc1C(=O)CCC(=O)O
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1ccc(C)cc1CCCC(=O)O
Reaction time: 3 h
Yield: 64.6 %

Procedure:
A mixture of 4-Keto-γ-(2-methoxy-5-methylphenyl)butyric acid (123 g, 0.55 mole), HOAc (1.5 L), and H2SO4 (3.2 mL) in the presence of Pd/C catalyst (12.2 g, dry) was hydrogenated under 3 atmospheres H2 pressure for 3 hours at room temperature. The resulting solution was filtered and was evaporated to the volume of 100 mL. Water (1000 mL) was added with stirring. The solid was filtered, dried (in-vacuo), and was recrystallized from ether/hexane to yield 74 g white solid,, (64%); m+ 208.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.[CH:11]1[C:24]2[CH:23]([C:25](Cl)=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1>>[C:7]([N:5]1[N:4]=[N:3][C:2]([NH:1][C:25]([CH:23]2[C:24]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[O:16][C:17]3[C:22]2=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:26])=[N:6]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Reactant: CC(C)(C)n1nnc(N)n1
Product: CC(C)(C)n1nnc(NC(=O)C2c3ccccc3Oc3ccccc32)n1

Procedure:
The title compound, white solid, m.p. 230-231° and MS: (neg. ions): m/e=348.2 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-tert-butyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>CN(C)C=O>[N:3]1([CH:13]([CH2:12][CH2:11][CH2:10][CH3:9])[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=C(CCCCCBr)OCc1ccccc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(C(=O)OCc1ccccc1)n1ccnc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a suspension of 9.74 g of 57% sodium hydride in 100 ml of dimethylformamide was added a solution of 15.0 g of imidazole in 500 ml of dimethylformamide at a temperature of 15°-25° C. The resulting mixture was heated to 60° C. for 1 hour, was cooled to room temperature and 62.8 g of benzyl 6-bromohexanoate was added. The mixture was heated to 60° C. for two hours, allowed to stand overnight at room temperature, and was evaporated. The residue was taken up in aqueous hydrochloric acid, washed with ether, made basic with sodium hydroxide and extracted with dichloromethane. The combined organic layers were dried, evaporated and distilled to yield 45.1 g (75%) of benzyl (1H-imidazol-yl)hexanoate.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([S:15](Cl)(=O)=O)[CH:12]=2)[O:7][CH2:6]1)=[O:4].COC(C1CC2C(=CC=C(SCC3SC(C4C=CC(C(F)(F)F)=CC=4)=NC=3C)C=2)OC1)=O>>[CH3:1][O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([SH:15])[CH:12]=2)[O:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1COc2ccc(S(=O)(=O)Cl)cc2C1
Agent: COC(=O)C1COc2ccc(SCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)cc2C1
Product: COC(=O)C1COc2ccc(S)cc2C1
Yield: 85 %

Procedure:
Compound 17C was prepared according to the method of example 1C utilizing compound 17B. Compound PPC was prepared in 85% yield. mp 83-84° C.; MS: 223 (M−1)+. Preparation of 6-[4-Methyl-2-(4-trifluoromethyl-pheny)-thiazol-5-ylmethylsulfanyl]-chroman-3-carboxylic acid methyl ester (Compound 17D)
Reaction SMILES: C([N:8]1[CH2:19][CH2:18][C:11]2([O:16][CH2:15][C:14](=[O:17])[NH:13][CH2:12]2)[CH2:10][CH2:9]1)C1C=CC=CC=1>C(O)C>[O:16]1[C:11]2([CH2:10][CH2:9][NH:8][CH2:19][CH2:18]2)[CH2:12][NH:13][C:14](=[O:17])[CH2:15]1
Reactant: O=C1COC2(CCN(Cc3ccccc3)CC2)CN1
Solvent: CCO
Product: O=C1COC2(CCNCC2)CN1
Yield: 138.9 %

Procedure:
To a solution of compound 399 (316.1 mg, 1214 μmol) in ethanol (15 mL) was added palladium hydroxide, 20 wt % pd (dry basis) on carbon, wet (300 mg, 427 μmol). After hydrogenating the reaction mixture at 50 psi for 6 days, the mixture was filtered thru a plug of celite and concentrated in vacuo to give compound 400 (287.0 mg). LCMS-ESI (POS), M/Z, M+1: Found 171.1, Calculated 171.1.
Reaction SMILES: [Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH2:6][CH2:5]1)=[O:3].[CH3:17]C1C(C)=CC=CC=1N1CCNCC1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1>ClCCl>[Cl:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:17])[C:11]=2[CH3:16])[CH2:6][CH2:5]1)=[O:3]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: Cc1ccccc1N1CCN(C(=O)Cl)CC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cccc(N2CCN(C(=O)Cl)CC2)c1C
Yield: 78 %

Procedure:
1-chlorocarbonyl-4-(2,3-dimethylphenyl)piperazine Compound 40A is prepared according to the procedure described for compound 15A, using the following reactants: 1-(2,3-dimethylphenyl)piperazine (3.94 g, 20.7 mmol); triphosgene (2.05 g, 6.9 mmol); pyridine (1.68 ml, 21 mmol); dichloromethane (150 ml).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:18][C:19]([C:21]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20]>ClCCl>[C:1]([O:9][CH2:18][C:19]([C:21]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:22]=1[N:23]([CH3:26])[CH:24]=[O:25])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C=O)c1cc(F)c(F)cc1C(=O)CCl
Reactant: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C=O)c1cc(F)c(F)cc1C(=O)COC(=O)c1ccccc1

Procedure:
A solution of benzoic acid (40.3 g) and triethylamine (61 ml) in dichloromethane (200 ml) was added dropwise over 20 minutes to the solution of 2'-(2-chloroacetyl)-4',5'-difluoro-N-methylformanilide at 0° under nitrogen and the resultant solution stirred overnight at ambient temperature. The mixture was washed with water (3×250 ml) and the solvent removed by distillation. The residue was purified by flash chromatography on a silica gel eluted with dichloromethane:methanol (50:1) to give the novel compound 2-[4,5-difluoro-2-(N-methylformamido)phenyl-2-oxoethyl benzoate in the form of an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=1)[NH2:23]>>[Cl:19][C:20]1[CH:21]=[C:22]([NH:23][C:2]2[C:11]3[C:6](=[CH:7][C:8]4[O:15][CH2:14][CH:13]([CH2:16][O:17][CH3:18])[O:12][C:9]=4[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: Nc1cccc(Cl)c1
Reactant: COCC1COc2cc3ncnc(Cl)c3cc2O1
Product: COCC1COc2cc3ncnc(Nc4cccc(Cl)c4)c3cc2O1
Yield: 61.8 %

Procedure:
The titled compound (25 mg, 63%, m.p. 277-282° C.) was prepared in a similar manner as in Example 8, except for employing 4-chloro-7-methoxymethyl-[1,4]dioxano[2,3-g]quinazoline (30 mg, 0.113 mmol) and 3-chloroaniline (28 mg, 0.226 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1.[OH-].[Na+]>Cl.C1COCC1.[Cl-].[Ti+3].[Cl-].[Cl-]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:3]=1)[NH2:8]
Reactant: CS(=O)(=O)Cc1cc(F)cc([N+](=O)[O-])c1
Agent: [Ti+3]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1cc(N)cc(F)c1
Reaction time: 16 h
Yield: 30.1 %

Procedure:
Titanium(III)chloride solution (about 15%) in about 10% hydrochloric acid (29 mL, Merck Schuchardt OHG) was added to a stirred solution of crude 1-fluoro-3-[(methylsulfonyl)methyl]-5-nitrobenzene (1.00 g) in THF (45 mL) at room temperature and the batch was stirred for 16 hours. The batch was cooled with an ice bath while 1N sodium hydroxide solution was added to raise the pH value of the reaction mixture to 8-9. It was stirred for 30 minutes at this temperature before the batch was extracted with ethyl acetate (2×). The combined organic phases were washed with brine, filtered using a Whatman filter and concentrated. The residue was purified by column chromatography (hexane/ethyl acetate 1:1 to ethyl acetate) to give the desired product (262 mg; 1.29 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([SH:27])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[N+:16]([O-:18])=[O:17])=[CH:23][CH:22]=1
Reactant: COc1ccc(S)cc1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Product: COc1ccc(Sc2ccc(C)cc2[N+](=O)[O-])cc1

Procedure:
The product from Example 6a (5.0 g, 175 mmol) was reacted with 4-methoxy-benzenethiol (2.45 g, 175 mmol) for 18 h following the procedure from Example 6b giving 1-(4-methoxy-phenylsulfanyl)-4-methyl-2-nitro-benzen, which was reduced with SnCl2 following the procedure from Example 5I giving 2-(4-Methoxy-phenylsulfanyl)-5-methyl-phenylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2].[CH:24]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:29][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Cl:22])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: OC1CCCC1
Reactant: CCOC(=O)c1c(Cl)nc2ccc(Cl)cc2c1-c1ccccc1
Product: CCOC(=O)c1c(OC2CCCC2)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
The title compound was prepared in analogy to example 11 step C from 2,6-dichloro-4-phenyl-quinoline-3-carboxylic acid ethyl ester (prepared as described in example 11 step B) and cyclopentanol. Colorless sticky liquid. (50 mg, 44%). LC-MS: 396 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:34])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([Cl:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:22][CH:21]=1)([CH3:17])[CH2:9][CH2:8]2)(=O)C.[O-]CC.[Na+].Cl>C(O)C.O1CCCC1>[Cl:33][CH:27]([CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][C:10]2([CH3:17])[CH2:9][CH2:8][C:7]3[C:12](=[C:13]([CH3:16])[C:14]([CH3:15])=[C:5]([OH:4])[C:6]=3[CH3:34])[O:11]2)=[CH:25][CH:24]=1)[C:28]([O:30][CH2:31][CH3:32])=[O:29]
Reactant: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(OC(C)=O)c(C)c(C)c3O2)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)C(Cl)Cc1ccc(OCC2(C)CCc3c(C)c(O)c(C)c(C)c3O2)cc1

Procedure:
0.48 g of ethyl 3-[4-(6-acetoxy-2,5,7,8-tetramethylchroman-2-ylmethoxy)phenyl]-2-chloropropionate was dissolved in a mixture of 3 ml of absolute ethanol and 2 ml of dry tetrahydrofuran. An ethanolic solution of sodium ethoxide (prepared by dissolving 49.0 mg sodium in 2 ml of absolute ethanol) was added dropwise, under a nitrogen stream at 10°-13° C., to the resulting solution. The mixture was then reacted for 21 hours at 0°-5° C., after which 0.22 g of concentrated hydrochloric acid dissolved in 99.5% ethanol was added dropwise, with ice-cooling. The solvent was then distilled off from the reaction mixture under reduced pressure; the separated light reddish oil was extracted with chloroform; and the extract was washed with water and then dried over anhydrous sodium sulfate. The crude product obtained by distilling the chloroform off from the extract under reduced pressure was subjected to silica gel column chromatography, and the desired ethyl 2-chloro-3-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-ylmethoxy)phenyl]propionate was obtained from the fractions eluted with benzene. Rf value on thin layer chromatography: 0.60 [silica gel; developing solvent; benzene:ethyl acetate=10:1 by volume].
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.[CH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=1.C(N(CC)CC)C.O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[CH:28]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]=[CH:22]1
Reactant: C1=CCCCCC1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C1C=CCCCC1
Temperature: 65 °C

Procedure:
To 5-amino-3-cyano-4-iodo-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole (2.23 g, 5 mmol, WO97/07102) and cycloheptene (3 ml) in dry DMF (25 ml), under a nitrogen atmosphere, was added bis(triphenylphosphine)palladium dichloride (100 mg, 0.13 mmol), cuprous iodide (100 mg) and triethylamine (2 ml). The mixture was heated at 65° C. for 18 h. A further 3 ml of cycloheptene was added and the mixture heated at 70° C. for 82 h. The cooled mixture was poured into water (500 ml) and extracted with DCM (2×100 ml). The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo to leave a brown oil. This was purified by silica chromatography (eluting with hexane/diethyl ether 1/1 v/v). The resulting cream solid was further purified by silica chromatography (eluting with hexane, hexane/diethyl ether 19/1, hexane/diethyl ether 9/1 and finally hexane/diethyl ether 3/1) to yield 564 mg of the title compound as a cream solid.
Reaction SMILES: [S:1]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].[H-].[Na+].[CH:22]1[CH:27]=[CH:26][C:25]([CH2:28]Br)=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:28]([O:4][C@@H:3]1[C@@H:5]([O:6][CH2:28][C:25]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)[C@@H:7]([O:8][CH2:28][C:25]2[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=2)[C@@H:9]([CH2:11][O:12][CH2:19][C:16]2[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=2)[O:10][C@H:2]1[S:1][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)[C:25]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(S[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(S[C@@H]2O[C@H](COCc3ccccc3)[C@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 177.6 %

Procedure:
p-Methylphenyl 1-thio-β-D-galactopyranoside (1.0 g, 3.5 mmol) was dissolved in dry DMF (15 mL) and cooled to −10° C. At this temperature (840 mg, 35 mmol) NaH was added and the mixture allowed to warm up to rt. and stirred for an additional 10 min. Then BnBr (4.1 mL, 35 mmol) was added, and the mixture was stirred for 5 h. At 0° C. 10 mL H2O was added and the mixture extracted with EtOAc (3×50 mL). The organic layer was dried over MgSO4 and evaporated to dryness. Flash chromatography using Hexane/EtOAc (5:1) gave the title compound as a white solid (2.01 g, 89%). [α]D22 −1.2° (c, 0.5, CHCl3); 1H-NMR (400 MHz, CDCl3), δ 2.27 (s, 3H), 3.56–3.65 (m, 4H), 3.89 (t, 1H, J=9.4 Hz) 3.97 (s, 1H), 4.42 (ABq, 2H, J=11.6 Hz), 4.594.60 (m, 3H), 4.70 (m, 3H), 4.73 (ABq, 2H, J=10.1 Hz), 4.95 (d, 1H, J=11.5 Hz), 6.98 (d, 2H, J=8.6 Hz), 7.25–7.47 (m, 22H); 13C-NMR (400 MHz, CDCl3), δ 21.04, 68.68, 72.63, 73.48, 74.34, 75.54, 77.16, 77.24, 84.13, 87.95, 127.36, 127.49, 127.60, 127.65, 127.71, 127.78, 127.86, 128.09, 128.26, 128.35, 129.49, 132.10; HRMS (M+Cs) calcd for C41H42O5SCs 779.1807. found 779.1782.