Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>C(NCC)C.[Pd](Cl)Cl.[Cu]I>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[C:34]#[C:33][CH2:32][CH2:31][OH:35]
Reactant: COc1ccc(Br)c(OC)c1
Reactant: C#CCCO
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COc1ccc(C#CCCO)c(OC)c1
Temperature: 55 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
1-Bromo-2,4-dimethoxybenzene (10 g 0.046 mol), palladium chloride (0.2 g 0.11 mmol) and triphenylphosphine (0.6 g 0.0023 mol) were dissolved in diethylamine (100 mL) under a nitrogen atmosphere. Copper (I) iodide (0.44 g 0.0023 mol) and 3-butyn-1-ol (7 mL 0.092 mol) were added into the reaction mixture at once. The mixture was stirred overnight at 55° C. under a nitrogen atmosphere. The catalyst was filtered off from the reaction mixture and the same amount of palladium chloride, triphenylphosphine, copper (I) iodide and 3-butyn-1-ol were added. The reaction mixture was stirred and heated at 85° C. for 48 hours. Then the solvent was removed at reduced pressure and water (approx. 100 mL) was added to the residue. The mixture was extracted with ethyl acetate (350 mL) passed through a pad of silica gel and concentrated. The product was purified by flash chromatography (silica gel, 1:1 hexanes/ethyl acetate). Compound 75 (4.2 g, 24%) was isolated as a brown oil. 1H NMR (300 MHz, CDCl3) δ2.24 (t, 1H), 2.73 (t, 2H), 3.80 (br s, 5H), 3.87 (s, 3H), 6.43 (m, 2H), 7.30 (m, 1H).
Reaction SMILES: [CH:1]([C:4]1[NH:14][C:7]2[C:8](=[O:13])[NH:9][CH:10]=[C:11](Br)[C:6]=2[N:5]=1)([CH3:3])[CH3:2].[C:15]([Cu])#[N:16]>CN(C=O)C>[CH:1]([C:4]1[NH:14][C:7]2[C:8](=[O:13])[NH:9][CH:10]=[C:11]([C:15]#[N:16])[C:6]=2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(Br)c[nH]c(=O)c2[nH]1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(C#N)c[nH]c(=O)c2[nH]1

Procedure:
By reaction of 2-isopropyl-3,5-dihydro-7-bromoimidazo-[4,5-c]pyridin-4-one with CuCN in DMF by customary methods (Ellefson et al., J. Med. Chem. 1976, 19), 2-isopropyl-3,5-dihydro-7-cyanoimidazo[4,5-c]pyridin-4-one is obtained. This is then hydrolysed and alkylated analogously to Examples 1 and 4 and hydrogenated analogously to Example 3. In this process, the carboxylic acid derivatives listed under Example 6 are obtained.
Reaction SMILES: [C:1]([O-])([O-])=O.[Cs+].[Cs+].Br[C:8]1[CH:9]=[C:10]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[O:14][C:11]2=[N:12][CH:13]=1.[CH3:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]=1B1OC(C)(C)C(C)(C)O1.[Si](C=[N+]=[N-])(C)(C)C>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[O:14][C:11]3=[N:12][CH:13]=[C:8]([C:26]4[CH:27]=[C:28]([CH:32]=[CH:33][C:25]=4[CH3:24])[C:29]([O:31][CH3:1])=[O:30])[CH:9]=[C:10]3[CH:16]=2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(-c2cc3cc(Br)cnc3o2)cc1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C)c(-c2cnc3oc(-c4ccc(F)cc4)cc3c2)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 101 %

Procedure:
Cs2CO3 (379 mg, 1.164 mmol) was added to a stirring solution of 5-bromo-2-(4-fluorophenyl)furo[2,3-b]pyridine (200 mg, 0.685 mmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (269 mg, 1.027 mmol), Pd(Ph3P)4 (158 mg, 0.137 mmol) in 1,4-dioxane (5.7 mL) and Water (1.1 mL). It was heated to 90° C. overnight. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, filtered and concentrated and diluted with MeOH/DCM and treated with TMS-diazomethane (685 μL, 1.369 mmol, 2M in ether). The mixture was allowed to stir for 1 hour. The reaction was concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the expected product methyl 3-(2-(4-fluorophenyl)furo[2,3-b]pyridin-5-yl)-4-methylbenzoate (250 mg, 0.692 mmol, 100% yield) by LCMS and NMR. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (1 H, d, J=2.26 Hz), 8.16 (1H, d, J=2.01 Hz), 8.01-8.10 (2H, m), 7.93 (1H, dd, J=7.91, 1.88 Hz), 7.85 (1H, d, J=1.76 Hz), 7.49-7.57 (2H, m), 7.36-7.44 (2H, m), 3.86 (3H, s), 2.34 (3H, s). LC-MS retention time: 2.55 min; m/z (MH+): 362. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters SunFire 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% acetonitrile/90% H2O/0.1% trifluoroacetic acid and solvent B was 10% H2O/90% acetonitrile/0.1% trifluoroacetic acid. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]([O:25]C)=[C:5]([CH2:11][CH2:12][C:13]2[CH:18]=[C:17]([O:19]C)[CH:16]=[C:15]([CH2:21][Br:22])[C:14]=2[O:23]C)[CH:6]=[C:7]([O:9]C)[CH:8]=1.C(#N)C.C(OCC)(=O)C>O>[CH2:12]([C:13]1[C:14](=[O:23])[C:15]([CH2:21][Br:22])=[CH:16][C:17](=[O:19])[CH:18]=1)[CH2:11][C:5]1[C:4](=[O:25])[C:3]([CH2:2][Br:1])=[CH:8][C:7](=[O:9])[CH:6]=1
Reactant: COc1cc(CBr)c(OC)c(CCc2cc(OC)cc(CBr)c2OC)c1
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1C=C(CBr)C(=O)C(CCC2=CC(=O)C=C(CBr)C2=O)=C1

Procedure:
0.85 g. (1.7 mmole) of 1,2-bis[3-(bromomethyl)-2,5-dimethoxyphenyl]ethane, prepared as described in Example IX above, was dissolved in 50 ml. of hot acetonitrile. This solution was cooled to a temperature just above the point at which it became cloudy and then there was added dropwise thereto a solution of 6.37 g. (11.6 mmole) of ceric ammonium nitrate in 8 ml. of water. Stirring of the mixed solution was continued for ten minutes after the addition of the ceric ammonium nitrate was complete, then the reaction mixture was diluted with water and extracted with methylene chloride. The organic extract was washed with water, dried over sodium sulfate and the solvent removed in vacuo to yield 0.75 g. of a dark brown solid. Trituration of this dark brown solid with a small quantity of ethyl acetate afforded 2,2'-ethylenebis[6-(bromomethyl)-p-benzoquinone] as a yellow-brown solid, the yield being 0.62 g. (83 percent of theoretical). Recrystallization from a mixture of ethyl acetate and hexane gave yellow-brown needles, melting point 146°-147° C. The infrared spectrum of the recrystallized material showed peaks at 1650, 1635 and 1615 cm-1, while the PNMR spectrum in deuterochloroform showed peaks at delta=2.72 (singlet, 4 protons, attributed to methylene protons), 4.25 (doublet, 4 protons, J=1.0 Hz., attributed to bromomethyl protons), 6.59 (doublet, 2 protons, J=2.2 Hz., attributed to protons on the quinone rings) and 6.85 (multiplet, 2 protons, attributed to protons on the quinone rings) ppm. The mass spectrum of the compound showed a peak at m/e 348 (M-80 for the formula C16H12O4Br2).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[C:16]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])(=[O:18])[CH3:17]
Reactant: Oc1cccc(F)c1F
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.1 %

Procedure:
To a solution of 2,3-difluorophenol (30.0 g, 231 mmol) and pyridine (18.6 mL, 231 mmol) in dichloromethane (230 mL) at 0° C. was carefully added acetyl chloride (16.4 mL, 231 mmol). The reaction was allowed to warm to ambient temperature and stirred for 16 h. The reaction mixture was then diluted with dichloromethane (100 mL), washed with 1N aqueous hydrochloric acid (2×50 mL) and brine (75 mL), and concentrated to produce 41.0 g (100%) of the title compound. MS (DCI/NH3) m/z 190 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:24][CH3:25])[N:20]([CH3:23])[C:21](=[O:22])[C:16]=4[C:15]([CH3:26])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Cl:31]N1C(=O)CCC1=O>ClCCl>[Cl:31][C:14]1[N:13]([CH2:12][C:11]2[CH:27]=[CH:28][C:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:30][CH:29]=3)=[CH:9][CH:10]=2)[C:17]2[N:18]=[C:19]([S:24][CH3:25])[N:20]([CH3:23])[C:21](=[O:22])[C:16]=2[C:15]=1[CH3:26]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1C
Solvent: ClCCl
Product: CSc1nc2c(c(C)c(Cl)n2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1C
Yield: 57.9 %

Procedure:
In anhydrous dichloromethane (3 ml) was dissolved 7-[4-(4-chlorobenzoyl)benzyl]-3,5-dimethyl-2-methylthio-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (88 mg) and, under ice-cooling and stirring, N-chlorosuccinimide (28 mg) was added. After 2 hours of stirring, the solvent was distilled off under reduced pressure and the residue was purified by flash column chromatography (silica gel; chloroform) to provide the title compound (55 mg).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([N:25]5[CH2:29][CH2:28][NH:27][C:26]5=[O:30])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:34]>CN(C=O)C>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([N:25]5[CH2:29][CH2:28][N:27]([CH3:34])[C:26]5=[O:30])=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(N4CCNC4=O)ccc32)n1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](Nc1nccc(-n2cnc3cc(N4CCN(C)C4=O)ccc32)n1)c1ccccc1
Yield: 43.5 %

Procedure:
To a solution of 2-[(S)-1-Phenylethylamino]-4-[5-(imidazolidin-2-on-1-yl)benzimidazol-1-yl]pyrimidine (Example 385) (0.025 mmol) in anhydrous DMF (0.2 ml) under nitrogen was added NaH (60%) in one portion. After stirring for ten minutes, iodomethane (0.028 mmol) was added dropwise. The reaction was stirred at room temperature for 2.5 h. and quenched with water. The mixture was extracted with methylene chloride. The organic extracts were combined, washed with brine and dried over MgSO4. Removal of the solvent and subsequent purification by preparative thin layer chromatography (acetone/hexane system) provided 4.5 mg of the title compound. Mass spectrum (ESI) 414.3 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:44][C:45]([F:57])([F:56])[C:46]1[CH:47]=[C:48]([CH2:52][C:53](O)=[O:54])[CH:49]=[CH:50][CH:51]=1.CCN(C(C)C)C(C)C>O.CN(C)C=O>[F:44][C:45]([F:56])([F:57])[C:46]1[CH:47]=[C:48]([CH2:52][C:53]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:14]5[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=5[S:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:54])[CH:49]=[CH:50][CH:51]=1
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4)c12
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nccc2scc(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(C(F)(F)F)c3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
To a 4 mL screw cap vial was added 3-(2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (100 mg, 0.374 mmol) followed by HATU (142 mg, 0.374 mmol), 3-trifluoromethylphenyl acetic acid (76 mg, 0.374 mmol) and DIEA (0.261 mL, 1.496 mmol). N,N-Dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and left to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organics were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified via normal phase chromatography (0-10% MeOH/DCM). Fractions were collected and concentrated to afford 3-(1-{[3-(trifluoromethyl)phenyl]acetyl}-2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (106.1 mg) as an orange solid. LC/MS (ES) m/z=454.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.15 (d, J=8.3 Hz, 1H) 7.84 (d, J=6.1 Hz, 1H) 7.69 (s, 1H) 7.57-7.67 (m, 3H) 7.52 (s, 1H) 7.36 (d, J=5.8 Hz, 2H) 7.25 (d, J=8.1 Hz, 1H) 5.79 (br. s., 2H) 4.30 (t, J=8.5 Hz, 2H) 4.05 (s, 2H) 3.27 (t, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[C:9](Cl)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C>C(N(CC)CC)C>[C:9]([C:5]1[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=1)(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1nc[nH]n1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: NC(=O)c1n[nH]c(C(=O)c2ccccc2)n1

Procedure:
To a cooled, stirred mixture of 3 g. of 1,2,4-triazole-3-carboxamide and 4 g. of benzoyl chloride in 125 ml. of anhydrous diethyl ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 18 hours. The heterogeneous mixture is filtered and washed successively with diethyl ether, cold water and then diethyl ether and dried in vacuo for 4 hours yielding 4 g. of colorless solid. This solid is extracted with hot, dry acetonitrile and cooled yielding a solid product which is collected, washed with acetonitrile and dried in vacuo, yielding 1 g. of product, m.p. 174°-178° C. (dec.).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:12])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.Cl.C(OCC)C.C([O-])([O-])=O.[K+].[K+]>O.CN1C(=O)CCC1>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:12][C:6]1[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: BrCCCCCBr
Reactant: Oc1ccnc2cc(Cl)ccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1ccc2c(OCCCCCBr)ccnc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 12.3 %

Procedure:
7-Chloro4-quinolinol (2 g, 11.1 mmol), Li2CO3 (1.7 g, 22.3 mmol) and NMP (16 mL) were charged in a 100 ml round-bottomed flask equipped with a magnetic stirrer. 1,5-Dibromopentane (13.5 g, 55.7 mmol) was added and the reaction mixture was stirred for 1 h at 90° C. The reaction mixture was poured in 100 mL of H2O, extracted with EtOAc (300 mL). The organic layer was washed with water (30 mL), brine (2×30 mL), dried over MgSO4, filtered and evaporated at 30° C. to dryness. HCl 1M in diethyl ether (15 mL, 15 mmol) was added and the bis-alkylated product was precipitated and filtered. The precipitate was dissolved in water with K2CO3 (1.5 g, 11.1 mmol), extracted with EtOAc (300 mL). The organic layer was washed with brine (2×20 mL), dried over MgSO4, filtered and evaporated at 30° C. to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:MeOH=99.5:0.5 to 95:5) to give after evaporation 4-(5-bromopentyloxy)-7-chloroquinoline 33 (0.45 g, 12% yield) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:19])[C@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([O-:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[NH2:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[N:30][CH:29]=[CH:28]2>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:31]1[C:32]2[C:27](=[CH:26][C:25]([NH:24][C:10](=[O:12])[C@H:9]([N:8]([CH3:19])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:34][CH:33]=2)[CH:28]=[CH:29][N:30]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](C(=O)[O-])c1ccccc1
Reactant: Nc1ccc2cnccc2c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN(C(=O)OC(C)(C)C)[C@@H](C(=O)Nc1ccc2cnccc2c1)c1ccccc1
Reaction time: 4 h

Procedure:
To (R)-2-(tert-butoxycarbonyl(methyl)amino)-2-phenylacetate (E6) in DMF was added EDC, DMAP and 6-aminoisoquinoline. This mixture was stirred for 4 hours and the reaction was washed with NaHCO3 (sat), extracted with EtOAc, dried (Na2SO4), filtered and evaporated. Column chromatography (SiO2, Hexanes/EtOAc) gave pure (R)-tert-butyl 2-(isoquinolin-6-ylamino)-2-oxo-1-phenylethyl(methyl)carbamate (E7).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:15][CH:16]=C)[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1)=[O:4].C(OCC)(=[O:20])C>CC(O)C.O.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1([CH2:15][CH:16]=[O:20])[CH2:6][CH2:7][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: CCOC(C)=O
Reactant: C=CCC1(C(=O)OC)CCC(C(=O)OC)CC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)O
Solvent: O
Product: COC(=O)C1CCC(CC=O)(C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
1-Allyl-cyclohexane-1,4-dicarboxylic acid dimethyl ester (4.50 g, 17.71 mmol) was dissolved in 2-propanol (100.0 mL) and water (50.0 mL). To this was added an aqueous solution of NaIO4 (9.50 g, 44.3 mmol) in water (50.0 mL), followed by addition of OsO4 (0.025 g, crystals, in one portion). The reaction mixture was allowed to stir for 16 hours. Then, the reaction mixture was poured into ice water (50 mL) and ethyl acetate (EtOAc) (60 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic solutions were washed with brine, and concentrated to dryness. The material was then purified over silica gel column eluting with ethyl acetate in heptanes (0-60%) to afford 3.09 g (72%) of the title compound.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([I:26])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:27]([O:31][C:32]1[CH:37]=[CH:36][C:35]([Mg]Br)=[CH:34][CH:33]=1)([CH3:30])([CH3:29])[CH3:28].FC1C=CC([Mg]Br)=CC=1>O1CCCC1>[C:27]([O:31][C:32]1[CH:37]=[CH:36][C:35]([C@@H:24]([C:12]2[C:13]([CH:21]([CH3:22])[CH3:23])=[N:14][C:15]3[CH2:16][C:17]([CH3:19])([CH3:20])[CH2:18][C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[C:10]=3[C:11]=2[I:26])[OH:25])=[CH:34][CH:33]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)Oc1ccc([Mg]Br)cc1
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Agent: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(OC(C)(C)C)cc1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-iodo-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde. A 0.5 M solution of (4-tert-butoxyphenyl)magnesium bromide in tetrahydrofurane is used instead of 1 M solution of 4-fluorophenyl-magnesium bromide in tetrahydrofurane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]>CO>[F:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:19])=[O:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]
Reactant: COc1ccc(N)cc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Solvent: CO
Product: COc1ccc(NS(=O)(=O)c2ccc(F)c([N+](=O)[O-])c2)cc1
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
p-Anisidine (760 mg, 6.18 mmol) was added to a solution of 4-fluoro-3-nitrophenylsulfonyl chloride (740 mg, 3.09 mmol; Example A) in MeOH (10 ml) at ambient temperature. After stining at room temperature for 15 min, the reaction mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate and filtered through a pad of silica gel. Concentration of the filtrate, followed by chromatography, provided 603 mg (60% yield) of the title compound. 1H-NMR (CDCl3): δ 8.42 (1H, dd, J=2.3, 6.8 Hz), 7.88 (1H, ddd, J=2.4, 4.0, 8.8 Hz), 7.33 (1H, dd, J=8.8, 9.9 Hz), 6.98 (2H, m), 6.81 (2H, m), 6.45 (1H, s), 3.77 (3H, s). MS (EI): 326 (11, M+), 122 (100). Anal. Calcd. for C13H11FN2O5S: C, 47.85; H, 3.40; N, 8.59; S, 9.83. Found: C, 47.68; H, 3.44; N, 8.54; S, 9.88.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6]OS(=O)(=O)[N:3]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[N:15]1([C:21]2[CH:29]=[CH:28][CH:27]=[C:26]3[C:22]=2[CH:23]=[CH:24][NH:25]3)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(#N)C>[NH:25]1[C:26]2[C:22](=[C:21]([N:15]3[CH2:20][CH2:19][N:18]([CH2:6][C@@H:2]([CH3:1])[NH:3][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[CH2:17][CH2:16]3)[CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24]1
Reactant: C[C@@H]1COS(=O)(=O)N1c1ccccn1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Solvent: CC#N
Product: C[C@H](CN1CCN(c2cccc3[nH]ccc23)CC1)Nc1ccccn1
Temperature: 60 °C
Yield: 67.5 %

Procedure:
A solution of (R)-4-methyl-3-pyridin-2-yl-[1,2,3]-oxathiazolidine-2,2-dioxide (4.04 g 0.019 moles) prepared according to Example 1 and 4-piperazinoindole (3.80 g 0.019 moles) in acetonitrile (200 ml) was heated to 60° C. for 0.5 h then evaporated in vacuo. The residue was taken up into dilute hydrochloric acid (100 ml), warmed to 60° C. for 0.5 h, cooled, washed with ethyl acetate (2×100 ml), made basic with potassium carbonate, extracted into dichloromethane (3×100 ml), dried (MgSO4) then evaporated in vacuo to give a brown glass. This was purified on a silica column eluting with 10% propan-2-ol in dichloromethane to give (R)-1-(4-indolyl)-4-[2-methyl-2-(2-pyridinylamino)ethyl]piperazine (4.3 g) as a clear glass.
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.Cl>N1C=CC=CC=1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:12])[F:11])=[CH:5][C:4]=1[C:13]1[N:14]=[C:15]([NH:18][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[S:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nc(-c2cc(C(F)(F)F)ccc2F)cs1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3cc(C(F)(F)F)ccc3F)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 0.5 g of 4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-ylamine hydrobromide with 0.30 g of p-toluenesulfonyl chloride was stirred for 3 hours with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.3 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. 0.36 g of N-[4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-4-methyl-benzenesulfonamide separated as colorless crystals upon neutralization with concentrated hydrochloric acid.