Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13](=[O:31])[CH:14]([CH2:27][N:28]([CH3:30])[CH3:29])[CH2:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[BH4-].[Na+]>CO>[C:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]([OH:31])[CH:14]([CH2:27][N:28]([CH3:29])[CH3:30])[CH2:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[CH:10][CH:11]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CN(C)CC1CC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccc(C(C)(C)C)cc2)C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)CC1CC(c2ccc(S(C)(=O)=O)cc2)=C(c2ccc(C(C)(C)C)cc2)C1O
Temperature: 20 °C
Yield: 50 %

Procedure:
A solution of 1.62 g of the 2-(4-tert-butylphenyl)-5-dimethylaminomethyl-3-(4-methanesulfonylphenyl)-cyclopent-2-enone, hydrochloride obtained according to Example 15 in 15 ml methanol was combined in portions with 0.40 g of sodium borohydride with stirring at a temperature of 20° C. Once addition was complete, the resultant reaction mixture was stirred for a further three hours and completely evaporated under reduced pressure. The residue was redissolved in 50 ml of distilled water and adjusted to a pH value of 11 with addition of potassium carbonate. Extraction was then performed three times with 20 ml portions of ethyl acetate and the combined extracts were washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated under reduced pressure. The resultant residue was purified by column chromatography on silica gel 60 (0.040–0.063 mm; E. Merck, Darmstadt, Germany) with a mixture of methanol and ethyl acetate in the ratio of 3:1 as eluent. 0.75 g of 2-(4-tert-butylphenyl)-5-dimethylaminomethyl-3-(4-methanesulfonylphenyl)-cyclopent-2-enol were obtained in the form of a colourless oil. This oil was redissolved in 25 ml of ethyl acetate and combined dropwise with stirring with 2 ml of a solution of hydrogen chloride in diethyl ether (5 wt. % HCl). A crystalline solid was obtained, which was isolated by suction filtration, washed with diethyl ether and dried under reduced pressure. 0.73 g of 2-(4-tert-butylphenyl)-5-dimethylaminomethyl-3-(4-methanesulfonylphenyl)-cyclopent-2-enol, hydrochloride (corresponding to 44.8% of theoretical) were obtained in the form of colourless crystals with a melting point of 223 to 224° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[N:13]=1.O>C1COCC1>[Br:11][C:12]1[N:13]=[C:14]([NH:1][C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccnc(N)n1
Reactant: Brc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc(Nc2cccc(Br)n2)n1
Temperature: 55 °C

Procedure:
A solution of 2-amino-4-methylpyrimidine (980 mg, 8.86 mmol) in THF (10 ml) was added dropwise to a cooled suspension of NaH (60% on oil, 1 g, 25.32 mmol) in THF (15 ml) under inert atmosphere. The reaction mixture was heated at 55° C. for 2 hours. The reaction was cooled down to 0° C. and a solution of 2,6-dibromopyridine (2 g, 8.44 mmol) in THF (20 ml) was added. The reaction mixture was heated at 80° C. for 5 hours. The reaction was cooled down to 0° C. and hydrolysed carefully with water (50 ml). After extraction with EtOAc (2×100 ml), the combined extractions were dried over MgSO4. After filtration and evaporation, N-(6-bromopyridin-2-yl)-4-methylpyrimidin-2-amine was obtained and purified dry flash chromatography over SiO2 eluting with DCM/MeOH(1%)/NEt3 (0.5%) (0.846 g, 38%). 1H NMR (300 MHz, DMSO-d6) δ 10.12 (br s, 1H), 8.44 (d, J=5.0 Hz, 1H), 8.36 (d, J=8.3 Hz, 1H), 7.69 (t, J=8.0 Hz, 1H), 7.18 (dd, J=7.6, 0.6 Hz, 1H), 6.91 (d, J=5.0 Hz, 1H), 2.42 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:5][N:4]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:1][CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:5][N:4]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1nnc(-c2ccccn2)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1nnc(-c2ccccn2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-(5-hydroxymethyl-1,3,4-thiadiazol-2-yl)-pyridine (6 gm), and triethylamine (13.1 ml) in dichloromethane (150 ml) was added methanesulfonylchloride (5.31 gm) at 0° C. The reaction mixture was stirred at 0° C. over a period of 1 h. The reaction was quenched by addition of water and layers were separated. Aqueous layer was extracted with dichloromethane (50 ml×2). Combined organic layer was washed with aqueous sodium bicarbonate solution followed by water and evaporated under vacuum to provide title compound in 7.5 gm quantity (88%) as oil.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]=2[N:4]([CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.[Li+].CCC[CH2-].CN([CH:29]=[O:30])C.O>C1(OC)C=CC=CC=1.CCOCC>[CH2:14]([O:13][CH2:12][N:4]1[C:5]2[C:10]([Cl:11])=[N:9][CH:8]=[N:7][C:6]=2[C:2]([CH:29]=[O:30])=[CH:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1ncnc2c(Br)cn(COCc3ccccc3)c12
Reactant: CN(C)C=O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: COc1ccccc1
Solvent: CCOCC
Solvent: O
Product: O=Cc1cn(COCc2ccccc2)c2c(Cl)ncnc12
Yield: 57.2 %

Procedure:
7-Bromo-5-(benzyloxymethyl)-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (3.73 g, 10.6 mmol) was dissolved in anhydrous anisole (48 ml) and then diluted with Et2O (145 ml) before being cooled to −78° C. at which point N-butyllithium (1.48M in hexane, 9.2 ml, 13.6 mmol) was added dropwise such that the temperature did not exceed −70° C. Within 2 minutes of the addition, DMF (8.5 ml, 0.123 mol) was introduced quickly (T≦−68° and the mixture stirred whilst warming to −40°, at which point water (20 ml) was added. The mixture was then extracted with EtOAc and the extract washed with brine and then dried and concentrated to an orange solid. Purification of this material was accomplished by chromatography over silica, eluting with 20→40% EtOAc/hexane, to give (a heart fraction of) the title aldehyde (1.83 g, 57.3%) as an off-white solid. 1H NMR (CDCl3) δ 10.35 (s, 1H), 8.89 (s, 1H), 8.14 (s, 1H), 7.35-7.20 (m, 5H), 5.90 (s, 2H), 4.60 (s, 2H).
Reaction SMILES: C(OC/C=C\COC(=O)C)(=O)C.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]([NH:24][C:25]1([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[NH2:46])[CH2:36][CH:35]2[OH:47])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23].[CH2:48]([N:50](CC)[CH2:51][CH3:52])[CH3:49]>ClCCl.CN(C)C=O>[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]([NH:24][C:25]1([C:31]([NH:33][CH:34]2[CH2:39][CH2:38][N:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=3[NH:46][N:50]3[CH2:51][CH:52]=[CH:49][CH2:48]3)[CH2:36][CH:35]2[OH:47])=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]
Reactant: CCN(CC)CC
Reactant: Nc1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Agent: CC(=O)OC/C=C\COC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC1(C(=O)NC2CCN(c3ccccc3NN3CC=CC3)CC2O)CCCCC1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of cis-2-buten-1,4-diol diacetate (1.15 g) in 30 ml of dichloromethane, was added the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-1-(2-aminophenyl)piperidin-3-ol (1.5 g) obtained in Step 2 of Example 43 in 20 ml of dimethylformamide. 0.44 ml of triethylamine was added to the reaction mixture, which was then stirred overnight at room temperature. 20 ml of ice water was added to the reaction mixture. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 0.7 g of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(SC1[N+]([O-])=CC=CC=1)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:49][C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[N:55]([NH2:59])[CH2:54][C:53]2([CH3:61])[CH3:60]>CN(C=O)C.O.CCOC(C)=O>[F:49][C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[N:55]([NH:59][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[CH2:54][C:53]2([CH3:61])[CH3:60]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Reactant: CC1(C)CN(N)c2ccc(F)cc21
Agent: CN(C)C(Sc1cccc[n+]1[O-])=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)NN1CC(C)(C)c2cc(F)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (348 mg, 1.5 mmol), HOTT (618 mg, 1.66 mmol), and DIPEA (700 μL, 4.01 mmol) in DMF (10 mL) is stirred at rt under N2 for 10 min. 5-Fluoro-3,3-dimethyl-2,3-dihydro-indol-1-ylamine (239 mg, 1.33 mmol) is added. The resulting mixture is stirred at 80° C. overnight. The mixture is cooled and portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 15% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-amide (416 mg, 80%) as a solid. MS: 395 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 10.43 (s, 1H), 8.99 (s, 1H), 8.28 (d, 1H), 8.15-8.11 (m, 1H), 7.66-7.58 (m, 1H), 7.46-7.39 (m, 1H), 7.06 (dd, 1H), 6.95-6.88 (m, 1H), 6.75-6.71 (m, 1H), 3.51 (s, 2H), 2.68 (s, 3H), 1.33 (s, 6H).
Reaction SMILES: [O:1]1[CH:5]([CH2:6]O)[CH2:4][C:3]2[CH:8]=[CH:9][C:10]3[C:15]([C:2]1=2)=[CH:14][CH:13]=[CH:12][CH:11]=3.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C.CC1C=CC(S(OCC2OC3C4C(C=CC=3C2)=CC=CC=4)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[N-:70]=[N+:71]=[N-:72].[Na+]>CN(C)C1C=CN=CC=1.CS(C)=O.O>[N:70]([CH2:6][CH:5]1[O:1][C:2]2[C:15]3[C:10]([CH:9]=[CH:8][C:3]=2[CH2:4]1)=[CH:11][CH:12]=[CH:13][CH:14]=3)=[N+:71]=[N-:72]
Reactant: OCC1Cc2ccc3ccccc3c2O1
Reactant: [N-]=[N+]=[N-]
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3ccc4ccccc4c3O2)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCC1Cc2ccc3ccccc3c2O1
Temperature: 70 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
Treatment of (±)-tert-butyl(2,3-dihydronaphtho[1,2-b]furan-2-ylmethoxy)dimethylsilane (2.70 g; 8.59 mmol) with tetrabutylammonium fluoride (9.4 mL, 1.0 M solution in tetrahydrofuran) generally according to the procedure described for Intermediate 6 gave (±)-2,3-dihydronaphtho[1,2-b]furan-2-ylmethanol. Treatment of the alcohol with p-toluenesulfonyl chloride (1.64 g, 8.59 mmol), 4-(dimethylamino)pyridine (0.105 g, 0.86 mmol), and triethylamine (1.67 g, 12.89 mmol) generally according to the procedure described for Intermediate 14 provided (±)-2,3-dihydronaphtho[1,2-b]furan-2-ylmethyl 4-methylbenzenesulfonate. To a solution of the tosylate in dimethylsulfoxide (50 mL) was added sodium azide (0.558 g, 8.59 mmol) and the reaction mixture was allowed to stir at 70° C. for 12 h, cooled to room temperature, diluted with water (200 mL) and extracted with diethyl ether (2×100 mL). The combined organic extracts were washed with water (4×75 mL), saturated aqueous sodium chloride (75 mL), dried (magnesium sulfate), and the solvent was removed in vacuo to provide a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 1:9) provided 1.38 g (71%) of (±)-2-(azidomethyl)-2,3-dihydronaphtho[1,2-b]furan as a colorless oil. Rf=0.46 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C13H11N3O.0.1H2O: C, 68.77; H, 4.97; N, 18.51. Found: C, 68.4; H, 4.62; N, 18.12.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[CH3:29][S:30]([O-:32])=[O:31].[Na+].CN(C)CCN>CS(C)=O>[CH3:29][S:30]([C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1)(=[O:32])=[O:31]
Reactant: CS(=O)[O-]
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Agent: CN(C)CCN
Agent: [Na+]
Solvent: CS(C)=O
Product: CS(=O)(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 125 °C
Reaction time: 5 h
Yield: 12 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 0.218 mmol) from Example 29, sodium methanesulfinate (90 mg, 0.436 mmol) and unsymmetrical N,N-dimethylethylene diamine (6 mg, 0.066 mmol) in anhydrous DMSO (1 mL) at rt was flushed with a stream of argon for 15 min. To the resulting mixture was added copper (I) trifluoromethane-sulfonate benzene complex (20 mg, 0.0328 mmol). The reaction vessel was sealed and the mixture was heated with stirring at 125° C. for 5 h. After cooling to rt, the reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((6-(methylsulfonyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (12 mg, 12%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.85-8.95 (br m, 2H), 8.61 (s, 1H), 8.02 (d, J=7.3 Hz, 1H), 7.69 (s, 1H), 7.18-7.35 (m, 2H), 5.56 (s, 2H), 4.79 (br s, 1H), 3.25-3.60 (m, 5H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55-1.70 (m, 2H), 1.08-1.36 (m, 4H). LCMS (ESI) m/z 458 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:16]([O:20][CH3:21])(=[O:19])[CH:17]=[CH2:18].C(N(CC)CC)C>CN(C=O)C>[CH2:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:18]=[CH:17][C:16]([O:20][CH3:21])=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: C=CC(=O)OC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccccc1OCc1ccccc1
Temperature: 120 °C
Yield: 55.1 %

Procedure:
A mixture of 2-bromo-O-benzyl phenol (J. Med. Chem. (1992) 35:3483) (2.17 g; 8.25 mmol), methyl acrylate (0.83 g; 9.9 mmol), dichloropalladium(II)bis(triphenylphosphine) (150 mg) and triethylamine (2.51 g; 24.7 mmol) in 10 mL of DMF was heated in a sealed tube to 120° C. for 16 hrs. After cooling, the tube's contents were partitioned between ethyl acetate and water. Removal of the organic solvent and purification on silica gel (20% ethyl acetate/hexane) afforded 1.22 g (55%) of methyl 2-benzoxycinnamate, 1H NMR (CDCl3): δ 3.78 (s, 3H); 5.15 (s, 2H); 6.54 (d, 1H, J=16.2); 6.95 (m, 2); 7.33-7.41 (m, 6H); 7.52 (d, 1H, J=7.7).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([CH3:15])=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg+2].[Cl-].[Cl-].[CH2:19]=[O:20].Cl>C(#N)C>[CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:19]=[O:20])=[C:10]([OH:14])[C:9]=1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(O)cccc1Cc1ccccc1
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Product: Cc1c(Cc2ccccc2)ccc(C=O)c1O
Yield: 91 %

Procedure:
To a solution of 3-benzyl-2-methylphenol prepared as in Step 3 (1.06 g, 5.36 mmole) in anhydrous acetonitrile (25 mL) were added MgCl2 (0.776 g, 8.04 mmole), TEA (2.80 mL, 20.1 mmole) and paraformaldehyde (1.09 g, 36.2 mmole), and the resulting mixture was refluxed under a dry N2 atmosphere for 3 h. The mixture was then cooled, acidified with 1 N HCl and extracted with EtOAc (2×100 ml). The combined extracts were washed with brine (100 ml), dried over MgSO4, filtered and concentrated in vacuo to give 1.10 g (91% yield) of the product as a pale yellow oil: EIHRMS m/z 226.1008 (M+, C15H14O2, Calc'd 226.0994).
Reaction SMILES: I.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2(O)[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][C:4]=1[OH:18]>C(O)(=O)C>[Cl:2][C:3]1[CH:8]=[C:7]([CH:9]2[CH2:10][CH2:11][C:12]([CH3:15])([CH3:16])[CH2:13][CH2:14]2)[CH:6]=[CH:5][C:4]=1[OH:18]
Reactant: CC1(C)CCC(O)(c2ccc(O)c(Cl)c2)CC1
Agent: I
Solvent: CC(=O)O
Product: CC1(C)CCC(c2ccc(O)c(Cl)c2)CC1

Procedure:
50 1 of aqueous 57% hydriodic acid solution are added to 11.8 g of 2-chloro-4-(1-hydroxy-4,4-dimethylcyclohexyl)phenol in 200 ml of acetic acid. The reaction mixture is refluxed for 3 hours and the solvents are evaporated off under reduced pressure. Aqueous 40% sodium hydroxide solution, aqueous sodium carbonate solution and then aqueous sodium hydrogen sulphate solution are added and the resulting mixture is extracted with diethyl ether. The organic phase is dried over magnesium sulphate and the solvents are evaporated off under reduced pressure. The compound obtained is purified by chromatography on a column of silica gel, eluting with a 95/5 (v/v) cyclohexane/ethyl acetate mixture.
Reaction SMILES: [Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]Br.C1N2CN3CN(C2)CN1C3.C(O)(=[O:26])C.Cl>C(Cl)(Cl)(Cl)Cl.O>[Cl:1][C:2]([Cl:13])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:26]
Reactant: CC(=O)O
Reactant: ClC(Cl)=COc1cccc(CBr)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1cccc(OC=C(Cl)Cl)c1

Procedure:
3(2,2-Dichlorovinyloxy)benzyl bromide (2.5 g) was carefully added to a stirred solution of hexamethylene tetramine (2.1 g) in carbon tetrachloride (20 ml) at the ambient temperature. After 5 minutes the precipitate was collected by filtration and washed with acetone. The solid thus obtained was added to aqueous acetic acid solution (50% by weight, 16 ml) and the mixture refluxed for 1 hour. A mixture of water (16 ml) and concentrated hydrochloric acid (4.5 ml) was then added and the mixture refluxed for a further 15 minutes. After cooling the mixture was extracted with chloroform, the extracts washed with water (twice), dried over anhydrous magnesium sulphate and the solvent removed by evaporation under reduced pressure to yield a residue of substantially pure 3(2,2-dichlorovinyloxy)benzaldehyde, identification of which was confirmed by infra-red and nuclear magnetic resonance spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:30][S:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:36][C:35]5[CH:38]=[CH:39][C:32]([S:31][CH3:30])=[CH:33][CH:34]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: CSc1ccc(CBr)cc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccc(SC)cc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-methylsulfanyl-benzyl bromide following a procedure analogous to that described for Intermediate 7.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][C:19](O)=[O:20]>>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:6][C:19](=[O:20])[CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1
Reactant: O=C(O)Cc1ccccn1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)Cc1ccccn1

Procedure:
Prepared from L-leucine methyl ester HCl and 2-pyridylacetic acid according to the procedure from Example 14.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[C:4](=[O:14])[NH:3]1.[H-].[Na+].[CH3:18]O.IC>C1COCC1.O>[CH3:18][N:3]1[C:2]([CH3:15])([CH3:1])[C:10]2[C:5](=[C:6]([N+:11]([O-:13])=[O:12])[CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:14]
Reactant: CC1(C)NC(=O)c2c([N+](=O)[O-])cccc21
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)c2c([N+](=O)[O-])cccc2C1(C)C
Reaction time: 0.25 h
Yield: 66.2 %

Procedure:
A solution of 3,3-dimethyl-7-nitroisoindolin-1-one (Compound 148C, 100 mg, 0.48 mmol) in THF (5 mL), was treated with 60% NaH (58 mg, 1.44 mmol) and stirred for 15 minutes. Methanol (0.078 mL, 1.92 mmol) and iodomethane (0.12 mL, 1.92 mmol) were added to this solution and stirred at 50° C. overnight. Cold water (3 mL) was added, the reaction mixture was concentrated to remove THF and extracted with EtOAc (3×5 mL). The combined organic layer washed with brine, dried (Na2SO4) and concentrated to provide 70 mg of the title compound (66%). 1H NMR (CDCl3, 600 MHz): δ1.45 (s, 6H), 3.56 (s, 3H), 7.13 (dd, J=7.8, 84 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:59]1[CH:60]=[CH:61][C:62]([C:70]([OH:72])=[O:71])=[N:63][C:64]=1[O:65][CH2:66][CH:67]1[CH2:69][CH2:68]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:67]1([CH2:66][O:65][C:64]2[N:63]=[C:62]([C:70]([OH:72])=[O:71])[CH:61]=[CH:60][C:59]=2[N:1]2[CH2:4][CH:3]([OH:5])[CH2:2]2)[CH2:68][CH2:69]1
Reactant: OC1CNC1
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(O)c1ccc(N2CC(O)C2)c(OCC2CC2)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 36.8 %

Procedure:
To a mixture of azetidin-3-ol (CAN 45347-82-8, 200 mg, 3 mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (CAS 98327-87-8, 114 mg, 0.185 mmol), tris(dibenzylideneacetone)dipalladium (CAS 51364-51-3, 85 mg, 0.1 mmol) and cesium carbonate (CAS 534-17-8, 1.8 mg, 5.55 mmol) in toluene (8 mL) under nitrogen atmosphere, was added a solution of 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9 d, 500 mg, 1.85 mmol). The reaction mixture was stirred overnight at 110° C. The reaction mixture was concentrated in vacuo and the residue dissolved in water and extracted with ethyl acetate (1×30 mL). The aqueous layer was adjusted to pH=2 by addition of 1 N hydrochloric acid, the resulting precipitate was collected by filtration, the solid was lyophilized. The crude product was purified by flash chromatography (silica gel, 50 g, 0% to 100% ethyl acetate in petroleum ether) to give the desired product (180 mg) as a yellow solid; MS (EI): m/e=265.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][O:14][CH3:15])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH3:22][S:23]SC>C1COCC1>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1[S:9][C:10]([S:23][CH3:22])=[C:11]([CH2:13][O:14][CH3:15])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCc1csc(NC(=O)OC(C)(C)C)n1
Reactant: CSSC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCc1nc(NC(=O)OC(C)(C)C)sc1SC
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
(4-Methoxymethyl-thiazol-2-yl)-carbamic acid tert-butyl ester (840 mg, 3.4 mmol) was dissolved in dry THF (21 mL). At ˜−75° C. was added dropwise n-butyllithium solution 1.6 M in hexanes. (8.6 ml, 13.7 mmol). The dark-red mixture was stirred at ˜−75° C. for 30 min. At ˜−70° C. was then added dropwise methyl disulfide (970 mg, 10.3 mmol). The resultant yellow colored mixture was slowly warmed to rt and further stirred overnight. After quenching the reaction with saturated ammonium chloride solution, the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. After purification on silica gel with ethyl acetate and n-heptaene as eluents the title compound was obtained as a light yellow solid. (630 mg, 59%) MS (ISP): m/e 291.3 (M−H)+