Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([CH2:19][N:20]3[CH:24]=[C:23]([C@@:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]3)=[CH:7][CH:8]=2)[N:3]=1.[CH:33]1([Mg]Br)[CH2:35][CH2:34]1>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH:33]1([C:2]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][C:6]([CH2:19][N:20]4[CH:24]=[C:23]([C@@:25]([OH:32])([CH2:30][CH3:31])[C:26]([F:29])([F:28])[F:27])[N:22]=[N:21]4)=[CH:7][CH:8]=3)[N:3]=2)[CH2:35][CH2:34]1
Reactant: Br[Mg]C1CC1
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(Cl)nc3c2)nn1)C(F)(F)F
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccc(F)cc4)cc(C4CC4)nc3c2)nn1)C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-(1-{[2-chloro-4-(4-fluorophenyl)quinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1,1,1-trifluorobutan-2-ol (100 mg, 0.22 mmol) in THF (3 mL) was added Ni(dppp)Cl2 (12 mg, 0.02 mmol) and cyclopropylmagnesium bromide (0.5M, 1.3 mL, 0.66 mmol). The mixture was stirred at 60° C. for 2 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduce pressure. Purification on silica gel (eluting with acetone/dichloromethane, 1:9) gave the title compound MS (+ESI): 471 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.Cl[C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=1[S:24]([CH3:27])(=[O:26])=[O:25].C([O-])([O-])=O.[Cs+].[Cs+].C([O-])(O)=O.[Na+]>CN(C)C(=O)N(C)C>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([O:1][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:15]=3[S:24]([CH3:27])(=[O:25])=[O:26])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:12]
Reactant: COC(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Reactant: Cc1ccc2cc(O)ccc2n1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C(=O)N(C)C
Product: COC(=O)c1ccc(Oc2ccc3nc(C)ccc3c2)c(S(C)(=O)=O)c1
Yield: 85.4 %

Procedure:
2 g of 6-hydroxyquinaldine, 3.12 g of methyl 4-chloro-3-methylsulfonyl-benzoate and 12.28 g of Cs2CO3 are stirred in 50 ml of anhydrous tetramethylurea at 110° C. for 1 h. The mixture is cooled, 250 ml of saturated aqueous NaHCO3 solution are added and extraction is carried out 3 times with 125 ml of EA. The extracts are dried over Na2SO4, the solvent is removed in vacuo and the residue is chromatographed with MTB. 3.98 g of a colorless foam are obtained. Rf (MTB)=0.31 MS (ES): 372 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]\[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C1(P([N:42]=[N+:43]=[N-:44])(C2C=CC=CC=2)=O)C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1/[CH:16]=[CH:17]\[C:18]([N:42]=[N+:43]=[N-:44])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(/C=C\C(=O)O)c1OCc1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: Cc1cccc(/C=C\C(=O)N=[N+]=[N-])c1OCc1ccccc1
Temperature: 5 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed (2Z)-3-[2-(benzyloxy)-3-methylphenyl]prop-2-enoic acid (20 g, 74.54 mmol, 1.00 equiv), toluene (300 mL) and diphenylphosphoryl azide (25 g, 90.84 mmol, 1.20 equiv). This was followed by the addition of DBU (14 g, 91.96 mmol, 1.20 equiv) dropwise with stirring at 0-10° C. The resulting solution was stirred for 1 h at 0-10° C. in a water/ice bath. The resulting solution was diluted with 1 L of ethyl acetate. The resulting mixture was washed with 2×800 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:40). This resulted in 13 g (59%) of (2Z)-3-[2-(benzyloxy)-3-methylphenyl]prop-2-enoyl azide as a white solid. Rf: 0.44 (in ethyl acetate:petroleum ether=1:5).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:5][NH:6][CH:7]=1.[C:14]1([C:20]2(CC=C)C=CC=C(SSCC=C)[CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.BrC1C(C2C=NC=CC=2)=NNC=1>C(OCC)(=O)C>[C:14]1([CH:20]=[CH:21][CH2:1][S:2][C:3]2[C:4]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[N:5][NH:6][CH:7]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=CCSSC1=CC=CC(CC=C)(c2ccccc2)C1
Reactant: CSc1c[nH]nc1-c1cccnc1
Agent: Brc1c[nH]nc1-c1cccnc1
Solvent: CCOC(C)=O
Product: C(=Cc1ccccc1)CSc1c[nH]nc1-c1cccnc1
Yield: 22 %

Procedure:
Compound 21K was prepared following the procedure as described for the synthesis of compound 21A (see Scheme 3) using 3-phenyl-allyldisulfanyl-3-allylbenzene as the disulfide (Tetrahedron Letters, 42, 2001, 6741-6743) and 3-(4-bromo-1H-pyrazol-3-yl)-pyridine (compound 20A). (conditions flash chromatography (ethyl acetate)). Yield: 22%. (oil), (TLC ethyl acetate Rf 0.45).
Reaction SMILES: I[C:2]1[C:3]2[CH:17]=[CH:16][NH:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=2)[N:7]=1.[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](B(O)O)[CH:24]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.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>[Br:18][C:19]1[CH:24]=[C:23]([C:2]2[C:3]3[CH:17]=[CH:16][NH:15][C:4]=3[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[N:9]=3)[N:7]=2)[CH:22]=[N:21][CH:20]=1
Reactant: OB(O)c1cncc(Br)c1
Reactant: Cc1cccc(-c2nc(I)c3cc[nH]c3n2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1cccc(-c2nc(-c3cncc(Br)c3)c3cc[nH]c3n2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-iodo-2-(6-methyl-pyridin-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (Intermediate 3) (1 eq, 1.50 mmol, 530 mg) and 3-bromopyridine-5-boronic acid (ABCR GmbH & Co. KG, Karlsruhe, Germany) (1.1. eq, 1.65 mmol, 339 mg) in DME/EtOH (1:1, 6 ml) are added aqueous Na2CO3 solution (2 M, 3 eq, 4.50 mmol, 2.2 ml) and Pd(PPh3)4 (0.05 eq, 0.075 mmol, 89 mg). The resulting mixture is heated using microwave radiation at 120° C. for 20 min. After cooling down to r.t., the mixture is filtered and the resulting precipitate is washed with EtOH. The residue is suspended in DCM, filtered, and dried to give the title compound; [M+H]+=366/368; 1H-NMR (400 MHz, DMSO): δ 12.58 (s, 1H), 9.40 (m, 1H), 8.89 (m, 1H), H), 8.79 (m, 1H), 8.37 (t, 1H), 7.87-7.77 (m, 2H), 7.33 (t, 1H), 7.00 (m, 1H), 2.56 (m, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2/[CH:9]=[C:10]2/[C:11](=[O:16])[NH:12][C:13](=[O:15])[S:14]/2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:21](Cl)(=[O:23])[CH3:22].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>>[C:21]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2/[CH:9]=[C:10]2/[C:11](=[O:16])[NH:12][C:13](=[O:15])[S:14]/2)[CH2:2][CH2:3]1)(=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: O=C1NC(=O)/C(=C/c2ccccc2N2CCNCC2)S1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccccc2/C=C2\SC(=O)NC2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a mixture of (5Z)-5-(2-piperazin-1-ylbenzylidene)-1,3-thiazolidine-2,4-dione (Example 115) and acetyl chloride (36.1 mg, 0.46 mmol) was added triethylamine (93 mg, 0.92 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight and was then treated with sat'd aqueous NaHCO3 (˜25 mL). This mixture was allowed to stir at room temperature for 10 min, and was then extracted with DCM (3×25 mL). The combined organic extract was dried over anhydrous Na2SO4, filtered through a bed of Celite, and the filtrate was conc. in vacuo to afford the product which was purified via reverse phase HPLC (acetonitrile:water: 0.1% TFA=5% to 70%) to afford the title compound as a pale yellow solid (40.0 mg, 35.4%). 1H NMR (300 MHz, DMSO-D6) δ ppm 12.58 (brs, 1 H) 7.94 (s, 1 H) 7.47 (d, 2 H) 7.30-7.07 (m, 2 H) 3.60 (brs, 4 H) 2.90 (brs, 2 H) 2.85 (brs, 2 H) 2.04 (s, 3 H); m/z 331.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(N(CC)CC)C>CCO>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:7]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Cl)ncn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Clc1cc(N2CCOCC2)ncn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of 4,6-dichloropyrimidine (1.0 equiv.) in EtOH (0.44 M) was added morpholine (1.0 equiv.) followed by triethylamine (1.10 equiv.). The resulting mixture was stirred at RT for 16 hours. The reaction mixture was then concentrated in vacuo and dried under high vacuum over 20 h to yield 4-(6-chloropyrimidin-4-yl)morpholine as a white solid in 93% yield. LCMS (m/z) (M+H)=200.0/201.8, Rt=0.35 min. 1H NMR (400 MHz, <cdcl3>) δ ppm 3.53-3.71 (m, 4H) 3.72-3.83 (m, 4H) 6.51 (s, 1H) 8.39 (s, 1H) 11.75 (br. s., 1H).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]4[CH2:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25]4)=[CH:19][C:18]=3[F:32])=[CH:14][C:13]=2[CH:33]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO.C1COCC1>[F:32][C:18]1[CH:19]=[C:20]([CH2:23][N:24]2[CH2:25][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:27]2)[CH:21]=[CH:22][C:17]=1[C:15]1[O:16][C:12]2[CH:11]=[CH:10][C:9]([CH:1]([OH:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:33][C:13]=2[CH:14]=1
Reactant: COC(=O)C1CN(Cc2ccc(-c3cc4cc(C(=O)c5ccccc5)ccc4o3)c(F)c2)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(C(O)c5ccccc5)ccc4o3)c(F)c2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To solution of methyl 1-((4-(5-benzoylbenzofuran-2-yl)-3-fluorophenyl)methyl)-azetidine-3-carboxylate (190 mg, 428 μmol) in MeOH (5.0 mL; 0.14M) and THF (1.0 mL) was added sodium borohydride (130 mg, 3438 μmol) at 0° C., and the resulting mixture was stirred at 0° C. for 10 min, then at 25° C. for 30 min. Saturated aqueous ammonium chloride (10 mL) was added, and the resulting mixture was extracted twice with EtOAc (30 mL). The combined extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatographic purification of the residue (ISCO, 4 g, 0-100% EtOAc/hexanes) furnished (±)-methyl 1-((3-fluoro-4-(5-(hydroxy(phenyl)methyl)benzofuran-2-yl)phenyl)methyl)azetidine-3-carboxylate as a clear oil. MS (ESI) m/z: Calculated: 445.2; Observed: 446 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:20]([OH:22])=[O:21])[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][C:24]1C=CC(S(OC(C)C)(=O)=O)=C[CH:25]=1>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]([CH:24]([CH3:25])[CH3:23])[CH:12]=1)[C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)OC(C)C)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Product: CC(C)n1cc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)c2ccccc21
Yield: 43.3 %

Procedure:
The procedure of Referential Example 1(a) was repeated, except that N-tert-butoxycarbonyl-D-tryptophan (3.0 g) and isopropyl 4-methylbenzenesulfonate (3.17 g) were used, whereby the title compound (1.48 g) was yielded.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]/[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:8].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>C(Cl)Cl>[CH3:31][S:32]([O:1][CH2:2][CH2:3]/[CH:4]=[CH:5]/[CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23])=[O:8])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCOS(C)(=O)=O
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To a solution of (E)-tert-butyl 2-(6-hydroxyhex-2-enamido)phenylcarbamate (398 mg, 1 mmol) and triethylamine (151.5 mg, 1.5 mmol) in DCM (10 mL) was added methanesulfonyl chloride (127.6 mg, 1.1 mmol) at 0° C. and stirred for 0.5 hour, then the reaction was stirred at room temperature for 1 hr, then water (10 mL) was added, the mixture was extracted with DCM (3×20 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the desired compound of (E)-6-(2-(tert-butoxycarbonyl amino)phenylamino)-6-oxohex-3-enyl methanesulfonate (358 mg, yield 90%) as oil after purification by column chromatography (eluent: PE:EA=10:1). LC-MS found 399 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH:14]=[O:15])=[CH:11][S:12][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([CH2:14][OH:15])=[CH:11][S:12][CH:13]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2cscc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(-c2cscc2CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 4-(4-ethylphenyl)thiophene-3-carbaldehyde (0.44 g, 2.03 mmol) in MeOH (5 mL) was added sodium borohydride (144 mg, 3.812 mmol) under argon at 0° C. The resulting mixture was stirred at room temperature for 2 h. The residue was extracted with EtOAc, dried over Na2SO4 and purification was conducted using CombiFlash (eluent: 10% EtOAc in heptane to 20% to 40) to afford the title product as a white solid (0.43 g, 97% yield).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:15]=[C:16]([C:30]2([OH:36])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:17]=[C:18]([F:29])[C:19]=1B1OC(C)(C)C(C)(C)O1>>[F:29][C:18]1[CH:17]=[C:16]([C:30]2([OH:36])[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)[CH:15]=[C:14]([F:13])[C:19]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: COC(=O)c1ccc(F)c(Br)n1
Reactant: CC1(C)OB(c2c(F)cc(C3(O)CCOCC3)cc2F)OC1(C)C
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C3(O)CCOCC3)cc2F)n1
Yield: 72 %

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) and 4-(3,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)tetrahydro-2H-pyran-4-ol (1.8 equiv.) at to give methyl 6-(2,6-difluoro-4-(4-hydroxytetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropicolinate in 72% yield. LC/MS=368.0 (MH+), Rt=0.75 min.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][CH:20]=1)[CH2:6][CH:7]1[C:12]([CH3:14])([CH3:13])[C:11](=[CH2:15])[CH2:10][CH2:9][N:8]1C=O.Br>O>[CH3:15][C:11]12[C:12]([CH3:13])([CH3:14])[CH:7]([NH:8][CH2:9][CH2:10]1)[CH2:6][C:5]1[CH:4]=[C:3]([OH:2])[CH:20]=[CH:19][C:18]2=1
Reactant: C=C1CCN(C=O)C(Cc2cccc(OC)c2)C1(C)C
Agent: Br
Solvent: O
Product: CC12CCNC(Cc3cc(O)ccc31)C2(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-(3-Methoxy-benzyl)-3,3-dimethyl-4-methylene-piperidine-1-carbaldehyde (for preparation see J. Med. Chem. 1997, 40, 2928-2939; 47.5 g) is combined with 48% HBr in water (300 mL). The mixture is heated to reflux temperature and stirred at this temperature for 24 h. After cooling to ambient temperature, the precipitate is separated by filtration, washed with water, and triturated with acetone. Then, the precipitate is taken up in a mixture of 1 N aqueous NaOH solution and CH2Cl2. The CH2Cl2 phase is separated, dried (Na2SO4), and concentrated. The residue is recrystallized from EtOAc to afford 6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-9-ol. The filtrate of the reaction mixture is combined with the water and acetone phases (from washing and triturating the precipitate) and basified using concentrated aqueous ammonia solution. The resulting mixture is extracted with CH2Cl2, the combined organic extracts are dried (MgSO4), and the solvent is evaporated. The residue is purified by chromatography on silica gel (EtOAc/MeOH/NH4OH 90:10:1->70:30:3) to afford 6,11,11-trimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocin-7-ol and 3,3,4-trimethyl-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-7-ol separated.
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11]([NH:13][C:14]([C:16]1[CH:17]=[C:18]([F:26])[C:19]([CH3:25])=[C:20](B(O)O)[CH:21]=1)=[O:15])[CH3:12].C(=O)([O-])O.[Na+].O>C(O)(C)C.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>[CH2:11]([NH:13][C:14](=[O:15])[C:16]1[CH:21]=[C:20]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[CH:4][CH:3]=2)[C:19]([CH3:25])=[C:18]([F:26])[CH:17]=1)[CH3:12]
Reactant: CCNC(=O)c1cc(F)c(C)c(B(O)O)c1
Reactant: Ic1ccc2cn[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCNC(=O)c1cc(F)c(C)c(-c2ccc3cn[nH]c3c2)c1
Temperature: 150 °C

Procedure:
A stirred mixture of 6-iodo-1H-indazole (0.5 g, {5-[(ethylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (Intermediate 17, 0.56 g), tetrakis(triphenylphosphine)palladium(0) (0.05 g) and aqueous sodium hydrogen carbonate (1M, 1 ml) in isopropanol (10 ml) was heated at 150° C. for 30 min in a microwave oven. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate (3×20 ml). The extracts were dried (Na2SO4) and concentrated under vacuum. The residual oil was purified by column chromatography on silica (50 g) eluting with ether/ethyl acetate (4:1). The resultant product was triturated with a small quantity of dichloromethane to give the title compound as a pale yellow solid (0.15 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:22])=[C:16]([CH:21]=2)[C:17]([O:19]C)=[O:18])=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9].[OH-].[Na+].Cl>CO.O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:12]2[CH:13]=[CH:14][C:15]([Cl:22])=[C:16]([CH:21]=2)[C:17]([OH:19])=[O:18])=[N:6][C:7]=1[C:8]([NH:10][CH3:11])=[O:9]
Reactant: CNC(=O)c1nc(-c2ccc(Cl)c(C(=O)OC)c2)cnc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)c1nc(-c2ccc(Cl)c(C(=O)O)c2)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.5 %

Procedure:
To a solution of methyl 5-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}-2-chlorobenzoate (96 mg, 31 mmol) in methanol/tetrahydrofuran (1:1, 5.0 mL) was added 2.0 N aqueous sodium hydroxide (0.16 g, 4.00 mmol). The reaction was stirred overnight at room temperature. Reaction was neutralized with 2.0 N aqueous hydrochloric acid (4 mL) and diluted with ethyl acetate (100 mL). The organic layer was washed with water (20 mL), saturated aqueous sodium chloride (30 mL), dried over magnesium sulfate, filtered, and concentrated to afford 5-{5-amino-6-[(methylamino)carbonyl]pyrazin-2-yl}-2-chlorobenzoic acid (45 mg, 48% yield). 1H NMR (400 MHz, d6-DMSO): 13.42 (br s, 1H), 8.90 (br s, 1H), 8.45 (d, 1H), 8.32 (dd, 1H), 7.85 (br s, 2H), 7.60 (d, 2H), 2.82 (s, 3H); MS (EI) for C13H11N4O3Cl: 307 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CS(O[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Fc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Sc2ccccc2F)CC1
Temperature: 80 °C
Yield: 97.8 %

Procedure:
A mixture of 2-fluorobenzenethiol (0.764 mL, 7.15 mmol), tert-butyl 4-((methylsulfonyl)oxy)piperidine-1-carboxylate (1.816 g, 6.5 mmol), and K2CO3 (1.348 g, 9.75 mmol) in ACN (16.25 mL) was heated at 80° C. overnight. The reaction mixture was poured into water and extracted twice with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure gave tert-butyl 4-((2-fluorophenyl)thio)piperidine-1-carboxylate as a yellow oil (1.98 g, 98%), which was carried forward without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:14][CH2:13][C:12](=[O:15])[NH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][N:20]=1.[Al]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:14][CH2:13][C:12](=[O:15])[N:11]([CH2:25][C:22]3[CH:21]=[N:20][C:19]([Cl:18])=[CH:24][CH:23]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CNC(c2ccc(F)c(Br)c2)=NN1
Reactant: ClCc1ccc(Cl)nc1
Agent: [Al]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CNC(c2ccc(F)c(Br)c2)=NN1Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
DMF was stirred for 10 min while being degassed with dry N2. 3-(3-bromo-4-fluorophenyl)-4,5-dihydro-1,2,4-triazin-6(1H)-one (200 mg 0.74 mmol) was then added and the mixture was degassed an additional 5 min. NaH (21 mg. 0.88 mmol) was added and the solution turned yellow; the solution was purged continuously with N2, then 2-chloro-5-chloromethypyridine (143 mg. 0.88 mmol) was added. The flask was covered with aluminum foil and stirred at approximately 25° C. for approximately 48 hours. TLC indicated a mixture of the desired product and three other components. The reaction mixture was poured into 20 mL water and 30 mL EtOAc, extracted 2× with EtOAc and the combined organics were washed with brine, dried over MgSO4, filtered and evaporated. The crude residue was purified via flash column (50% EtOAc/Hex) and evaporation of the product fractions gave ˜165 mg of material which (by NMR) appeared to be a mixture of the materials shown below.
Reaction SMILES: [C-:1]#[N:2].[Na+].[S:4]1[CH:8]=[CH:7][CH:6]=[C:5]1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Br)=[CH:13][CH:12]=1)=[O:10]>CS(C)=O>[C:5]1([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][C:1]#[N:2])=[CH:13][CH:12]=2)=[O:10])[S:4][CH:8]=[CH:7][CH:6]=1
Reactant: O=C(c1ccc(CBr)cc1)c1cccs1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1ccc(C(=O)c2cccs2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 5.9 parts of sodium cyanide in 40 parts of dimethyl sulfoxide is heated to 60° C and there are added at once 11.3 parts of α-bromo-p-tolyl 2-thienyl ketone (exothermic reaction: temperature rises to 100° C). The whole is stirred for 2 hours at 60° C. After cooling, the reaction mixture is poured onto water and the product is extracted three times with 450 parts of chloroform. The combined extracts are washed twice with 200 parts of water, dried and evaporated. The dark-coloured residual tar is extracted several times with ether. The combined ether extracts are stirred with activated charcoal, filtered and evaporated. The residue is triturated in petroleumether (solid carbon dioxide) and the whole is evaporated, yielding 2-[p-(2-thenoyl)phenyl] acetonitrile as a residue.