Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([NH:6][C:5]1[CH:4]=[C:3]([C:2]([F:14])([F:15])[F:1])[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1)(=[O:18])[CH3:17]
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 98 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)aniline (1.28 g, 5 mmol, Aldrich) in acetic anhydride (5 mL) was stirred at room temperature for 12 h, then all of the solvent was removed to give 1.479 g (98%) of 1-acetamido-3,5-bis(trifluoromethyl)benzene as white needles. 1H NMR (CDCl3): δ 2.229 (s, 3H); 7.589 (s, 1H); 8.048 (s, 2H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C@H:7]([O:10][CH2:11][C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([C:22]([F:25])([F:24])[F:23])[CH:13]=2)[C@H:6]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:5]1)(=O)[CH3:2].CO.[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36]>C1COCC1.B>[C:34]([OH:39])(=[O:38])[C:35]([OH:37])=[O:36].[F:25][C:22]([F:23])([F:24])[C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=1)[CH2:11][O:10][C@H:7]1[CH2:8][CH2:9][N:4]([CH2:1][CH3:2])[CH2:5][C@H:6]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Agent: B
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CCN1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of the compound (0.88 g) obtained in Example 2 in THF (10 ml), 1 M borane and THF complex (10 ml) was added at 0° C., and the reaction mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled, and then methanol (2 ml) was added thereto, and concentrated under reduced pressure. To the obtained residue, 6 N hydrogen chloride (6 ml) and methanol (6 ml) were added, and the reaction mixture was stirred at 100° C. for 2 hours. The reaction mixture was cooled, and then made basic with an aqueous 12 N sodium hydroxide solution. The mixture was concentrated under reduced pressure, and then the product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (acetone:methanol=20:1), and treated with 1 equivalent of oxalic acid to obtain the title compound as colorless crystals (0.52 g, 61%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[Cu][C:16]#[N:17]>CN(C=O)C.O.CCOC(C)=O>[OH:14][CH:11]1[CH2:12][CH2:13][N:8]([C:5]2[N:4]=[CH:3][C:2]([C:16]#[N:17])=[CH:7][N:6]=2)[CH2:9][CH2:10]1
Reactant: OC1CCN(c2ncc(Br)cn2)CC1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cnc(N2CCC(O)CC2)nc1
Temperature: 140 °C

Procedure:
A mixture of 1-(5-bromopyrimidin-2-yl)piperidin-4-ol (5 g, 19.37 mmol) and copper(I) cyanide (6.94 g, 77 mmol) in DMF (48.4 mL) was heated at 140° C. for 18 h. The mixture was diluted with water (100 mL) and EtOAc (50 mL) and filtered through celite. The filtrate was extracted with EtOAc (3×20 mL). The combined organic fractions were washed with 1N HCl (20 mL) then dried over Na2SO4. The solvent was evaporated and the product was recrystallized from CH2Cl2/hexanes, filtered and washed with hexanes to afford the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:41]=[CH:40][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]5)=[CH:30][CH:29]=4)[C:21]4[N:22]([CH:24]=[CH:25][N:26]=4)[CH:23]=3)[CH:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:49](OC(=O)C)(=[O:51])[CH3:50].ClCCl>O>[C:49]([N:37]1[CH2:36][CH2:35][N:34]([C:31]2[CH:32]=[CH:33][C:28]([NH:27][C:20]3[C:21]4[N:22]([CH:24]=[CH:25][N:26]=4)[CH:23]=[C:18]([C:14]4[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]5[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:41][CH:40]=5)[CH:17]=[CH:16][CH:15]=4)[N:19]=3)=[CH:29][CH:30]=2)[CH2:39][CH2:38]1)(=[O:51])[CH3:50]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1ccc(C(=O)Nc2cccc(-c3cn4ccnc4c(Nc4ccc(N5CCNCC5)cc4)n3)c2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2ccc(Nc3nc(-c4cccc(NC(=O)c5ccc(C(C)(C)C)cc5)c4)cn4ccnc34)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-tert-butyl-N-{3-[8-(4-piperazin-1-yl-phenylamino)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-benzamide (16) (0.55 mmol), triethylamine (1.1 mmol), acetic anhydride (0.60 mmol), and dichloromethane (10 mL) is stirred at room temperature for 1 hr. Water (30 mL) is added, the mixture extracted with dichloromethane (2×50 mL), the extracts washed with water (2×30 mL) and brine (1×30 mL), dried over magnesium sulfate, and concentrated in vacuo. The residue is triturated with diethyl ether and ethyl acetate to give N-(3-{8-[4-(4-Acetyl-piperazin-1-yl)-phenylamino]-imidazo[1,2-a]pyrazin-6-yl}-phenyl)-4-tert-butyl-benzamide (17) as a cream solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=2[O:15][CH3:16])[N:3]=1.CI.[C:19](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:14]=[CH:13][C:11]([NH:12][CH3:19])=[CH:10][C:9]=2[O:15][CH3:16])[N:3]=1
Reactant: COc1cc(N)ccc1-n1nc(C)cc1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CNc1ccc(-n2nc(C)cc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 22.9 %

Procedure:
200 mg of 4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-methoxyaniline was dissolved in 6 ml of dimethylformamide, and 160 μl of methyl iodide and 636 mg of potassium carbonate were added and stirred at room temperature for 2.5 hours. To the reaction mixture, 50 ml of water was added and extracted with 50 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using preparative thin-layer silica gel column chromatography (hexane:ethyl acetate=1:3) to yield 48.7 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH3:23])[N:19]=3)[O:12]2)=[C:4]([NH:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[N:3]=1.[NH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CS(C)=O>[CH:18]([OH:22])=[O:36].[CH2:26]([CH:25]([NH:24][C:4]1[N:3]=[C:2]([NH:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[C@H:11]1[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]2[O:22][N:21]=[C:20]([CH3:23])[N:19]=2)[O:12]1)[CH2:28][CH3:29])[CH3:27]
Reactant: CCC(CC)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](c2nc(C)no2)[C@@H](O)[C@H]1O
Reactant: NCCN1CCOCC1
Solvent: CS(C)=O
Product: CCC(CC)Nc1nc(NCCN2CCOCC2)nc2c1ncn2[C@@H]1O[C@H](c2nc(C)no2)[C@@H](O)[C@H]1O
Product: O=CO
Temperature: 80 °C

Procedure:
Intermediate 11 (0.069 g, 0.163 mmol) and 4-(2-aminoethyl)morpholine (0.107 ml, 0.815 mmol) were dissolved in DMSO (0.03 ml) and heated at 80° C. for 26 h in a sealed vial (eg Reacti vial™), a further portion of 4-(2-aminoethyl)morpholine (0.053 ml, 0.407 mmol) was added after the first 20 h. The product was purified by Autoprep. HPLC to give the title compournd after freeze drying as a brown solid (0.059 g). LC/MS system B Rt=2.19 min, m/z=517MH+.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH2:11]([NH:18][C:8]([C:4]1[S:3][C:2]([Br:1])=[N:6][C:5]=1[CH3:7])=[O:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: Cc1nc(Br)sc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.3 %

Procedure:
To a solution of 2-bromo-4-methyl-thiazole-5-carboxylic acid (3.00 g, 13.5 mmol) in methylene chloride (20 mL) was added benzyl amine (1.60 mL, 14.9 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 6.57 g, 14.86 mmol) and N,N-diisopropylethylamine (4.71 mL; 27.02 mmol) and the mixture was stirred under nitrogen at room temperature for 16 hr. The reaction mixture was diluted with methylene chloride (100 mL), washed with water (100 mL) and brine (2×100 mL). The organic phase was dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (hexanes:ethyl acetate, 1:1) to provide 2-bromo-4-methyl-thiazole-5-carboxylic acid benzyl amide (3.50 g, 83% yield) as a yelloW solid. 1H NMR (400 MHz, CDCl3) δ 7.47-7.55 (m, 5H), 6.25 (bs, 1H), 4.75 (d, J=8.0 Hz, 2H), 2.79 (s, 3H); MS (M+H)+=312.1; Rt=1.31 min.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.[I:20]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>ClCCCl.O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]2[C:10]([I:20])=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1c(Br)cnc2c1ccn2COCC[Si](C)(C)C
Reactant: O=C1CCC(=O)N1I
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(Br)cnc2c1c(I)cn2COCC[Si](C)(C)C
Yield: 39 %

Procedure:
5-Bromo-4-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (150 mg, 0.439 mmol) was dissolved in anhydrous 1,2 dichloroethane (6 mL), and N-iodosuccinimide (198 mg, 0.879 mmol) was added. The solution was stirred at 23° C. for 15 hours when ethyl acetate was added. A solution of water (25 mL) and aqueous saturated sodium bicarbonate (25 mL) was added. Layers were mixed well. The organic layer was stirred over sodium sulfate, filtered and concentrated in vacuo. The crude oil was purified by flash silica gel chromatography by using a gradient of ethyl acetate in hexanes to afford 5-Bromo-3-iodo-4-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (80 mg, 0.171 mmol, 39%) as a white soft solid. 8.39 (s, 1H), 7.93 (s, 1H), 5.54 (s, 2H), 3.47 (t, 2H), 2.85 (s, 3H), 0.79 (s, 2H), −0.11 (s, 8H); MS [MH+] m/z: 466.9, 468.9
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N+:8]([O-:10])[C:7]([CH3:11])=[CH:6][N:5]=1)(O)=[O:2].B#B.C(O)C.C([O-])([O-])=O.[K+].[K+]>COCCOCCOC.O1CCCC1>[OH:2][CH2:1][C:4]1[CH:9]=[N+:8]([O-:10])[C:7]([CH3:11])=[CH:6][N:5]=1
Reactant: Cc1cnc(C(=O)O)c[n+]1[O-]
Agent: B#B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cnc(CO)c[n+]1[O-]
Temperature: 0 °C
Yield: 88 %

Procedure:
Method B--To a solution of 2-carboxy-5-methyl-pyrazine-4-oxide (1.5 g) in diethylene glycol dimethyl ether (80 ml) addition was made at 0° C. under an atmosphere of nitrogen of a solution (1 M) of diborane in tetrahydrofuran (30 ml). To the reaction mixture maintained for 3 hours at 0° C. and 1 hour at room temperature, cautious addition was made of ethanol (50 ml) and then of a 0.5 M solution of alcoholic potash (25 ml). The resultant solution after evaporation at reduced pressure was taken up with chloroform which, on evaporation to dryness, gave 1.2 g of 2-hydroxymethyl-5-methyl-pyrazine-4-oxide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].Cl[CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1.[OH-].[Na+]>>[C:13]([C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[O:1][CH2:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1)(=[O:15])[CH3:14]
Reactant: COC(=O)Cc1ccc(O)c(C(C)=O)c1
Reactant: ClCc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(C(C)=O)c1

Procedure:
In analogy to the procedure of Example XIV, the title compound is prepared from 2.9 g (0.014 mol) of the compound from Example VIII, 2.5 g (0.014 mol) of 2-chloromethylquinoline and 0.56 g (0.014 mol) of sodium hydroxide.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2].CCO.O.NN>CCO.C1COCC1.[Ni]>[NH2:10][C:9]1[CH:8]=[CH:7][C:6]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15][CH2:14]2)=[CH:5][C:4]=1[NH:3][CH2:1][CH3:2]
Reactant: CCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1N
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a solution of tert-butyl 4-[3-(ethylamino)-4-nitrophenyl]-1-piperazinecarboxylate (1.028 g, 2.93 mmol) in 40 mL EtOH:THF (4:1) solvent system was added Raney-Ni (1 mL of a EtOH suspension) followed by addition hydrazine hydrate (0.734 g, 14.67 mmol). The mixture was stirred vigorously for 3 hours and then filtered through a Celite pad pretreated with water. The filtrate was concentrated and then purified by column chromatography on silica using CHCl3/MeOH/NH3 9:1:0.4% as eluent to give 0.877 g (93%) of a red oil. The oil was used immediately in the next reaction. HPLC purity>90%; MS (posEI) m/z=320 (M+);
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:18]1.C([O-])(=O)C.[K+].O1CCOCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN(C=O)C>[NH:13]1[CH2:14][CH2:15][N:16]=[C:12]1[CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([OH:18])[C:3]=2[CH2:4][CH2:5][O:6]1
Reactant: Brc1cccc2c1CCOC2C1=NCCN1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Oc1cccc2c1CCOC2C1=NCCN1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(5-bromoisochroman-1-yl)-4,5-dihydro-1H-imidazole (720 mg), bis(pinacolato)diboron (715 mg) bis(tri-t-butylphosphine)palladium(0) (39 mg), potassiumacetate (503 mg), dioxane (9 ml) and DMF (0.75 ml) was stirred under inert atmosphere in microwave reactor at 160° C. for 30 minutes. Additional bis(tri-t-butylphosphine)palladium(0) (21 mg) was added and heating continued for 15 minutes. The intermediate 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-1-yl)-4,5-dihydro-1H-imidazole (680 mg) was purified with separation method A and stirred with EtOAc (2 ml), water (2 mil) and hydrogen peroxide (35%, 0.07 ml) at ice bath temperature for 2 hrs. The title compound was purified with separation methods A and E. (Yield 45 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24]>C1COCC1>[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](/[N:12]=[C:6]1\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\1[CH2:4][CH2:3][O:2][CH3:1])=[O:24]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(Cl)c1ccccc1Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.5 %

Procedure:
To a solution of the product of Example 126A (0.20 g, 1.1 mmol) and Et3N (0.3 mL, 2.2 mmol) in 25 mL THF was added 2-bromobenzoyl chloride (Aldrich, 0.18 mL, 1.4 mmol). This mixture stirred at ambient temperature for 20 hours then was concentrated under reduced pressure and the residue was diluted with 10 mL EtOAc and washed with 5 mL NH4Cl. The layers were separated and the aqueous layer was extracted (2×5 mL EtOAc). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure and purified via recrystallization with 50% hexanes/EtOAc to afford 0.18 g of the title compound (0.49 mmol, 46% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.26 (s, 3H), 2.28 (s, 3H), 3.30 (s, 3H), 3.78 (t, J=5.1 Hz, 2H), 4.42 (t, J=5.1 Hz, 2H), 7.22 (dt, J=7.8, 1.7 Hz, 1H), 7.34 (dt, J=7.5, 1.4 Hz, 1H), 7.63 (dd, J=8.0, 1.2 Hz, 1H), 7.90 (dd, J=7.6, 1.9 Hz, 1H); MS (DCI/NH3) m/z 369, 371 (M+H)+; Anal. calculated for C15H17BrN2O2S: C, 48.79; H, 4.64; N, 7.59. Found: C, 48.84; H, 4.49; N, 7.40.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=1.C(Cl)(=O)C.[I-:17].[Na+]>C(#N)C>[I:17][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: COC(=O)c1c(Cl)ccnc1C
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: COC(=O)c1c(I)ccnc1C
Temperature: 80 °C
Yield: 22.4 %

Procedure:
To a solution of methyl 4-chloro-2-methylnicotinate (6.00 g, 32.3 mmol) in acetonitrile (80 mL) was added acetyl chloride (3.45 mL, 48.5 mmol) followed by sodium iodide (48.5 g, 323 mmol). The reaction mixture was heated at 80° C. for 16 hrs. The reaction mixture was evaporated to dryness and the residue was adjusted to pH 6 by adding saturated potassium carbonate solution. The product was extracted with dichloromethane (250 mL). The organic phase was washed with brine (2×100 mL), dried over Na2SO4, and concentrated under reduced pressure to afford methyl 4-iodo-2-methylnicotinate (2.00 g, 7.22 mmol, 22% crude yield) as colorless semisolid which was carried on without further purifications. LC/MS (ESI) m/e 278.0 [(M+H)+, calcd for C8H9INO2 278.0]; LC/MS retention time (method C): tR=2.13 min.
Reaction SMILES: [C:1]1([CH:7]([CH2:13][S:14]([OH:17])(=[O:16])=[O:15])[CH2:8][S:9]([OH:12])(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[N+:23]([O-])([OH:25])=[O:24]>>[N+:23]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]([CH2:13][S:14]([OH:17])(=[O:16])=[O:15])[CH2:8][S:9]([OH:12])(=[O:11])=[O:10])=[CH:2][CH:3]=1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)(O)CC(CS(=O)(=O)O)c1ccccc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(C(CS(=O)(=O)O)CS(=O)(=O)O)cc1

Procedure:
2-Phenyl-propane-1,3-disulfonic acid (as prepared in the previous step) is treated with concentrated H2SO4 and fuming HNO3 according to the procedure of Example 2, step (a) to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]N=1.[C:8](=[O:11])([O-])[O-:9].[K+].[K+].Br[CH2:15]C(OCC)=O>CC(C)=O>[CH3:15][O:9][C:8](=[O:11])[CH2:4][C@@H:5]1[CH2:6][CH2:7][CH2:2][O:1]1
Reactant: Oc1ccccn1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)CBr
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C[C@@H]1CCCO1

Procedure:
To a stirred solution of crude hydroxy-pyridine 21c (4.92 g, 21.1 mmol) in acetone is added potassium carbonate (4.36 g, 31.6 mmol) and ethyl bromoacetate (3.5 mL, 31.6 mmol). The mixture is refluxed for 1 h, then quenched with water and extracted with EtOAc. The combined organic layers are washed with brine, dried (Na2SO4), filtered and concentrated to provide crude ester 21d, which is used as such in the next step.
Reaction SMILES: [Na+].[I-:2].CN[C@@H]1CCCC[C@H]1NC.Br[C:14]1[C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[S:17][CH:18]=1.C1(C)C=CC=C(C)C=1>CCCCCC.[Cu]I.COCCOCCOC>[I:2][C:14]1[C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[S:17][CH:18]=1
Reactant: [I-]
Reactant: Brc1csc2ccccc12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCCCCC
Solvent: COCCOCCOC
Solvent: Cc1cccc(C)c1
Product: Ic1csc2ccccc12
Temperature: 130 °C
Reaction time: 22 h
Yield: 93.4 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.0504 mmol, 5.0 mol %), NaI (300 mg, 2.00 mmol), evacuated and backfilled with argon. trans-N,N′-Dimethyl-1,2-cyclohexanediamine (16 μL, 0.10 mmol, 10 mol %), 3-bromobenzo[b]thiophene (131 μL, 1.00 mmol), m-xylene (0.80 mL), and diglyme (0.20 mL) were added under argon. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 130° C. for 22 h. The resulting suspension was allowed to reach room temperature, diluted with hexane (10 mL), and filtered through silica gel (2×2 cm) eluting with hexane (50 mL). The filtrate was concentrated, and the residue was purified by flash chromatography on silica gel to provide 3-iodobenzo[b]thiophene (243 mg, 93% yield) as a pale yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30]([OH:32])=O)[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[C:41]1([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30]([N:50]3[CH2:51][CH2:52][CH:47]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[CH2:48][CH2:49]3)=[O:32])[CH2:28][CH2:27][S:26]2(=[O:33])=[O:34])[C@H:10]([CH2:16][N:17]([CH3:18])[CH3:19])[CH2:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)N4CCC(c5ccccc5)CC4)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 22.5 %

Procedure:
2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7, 0.065 g, 0.108 mmol) was reacted with 4-phenylpiperidine (available from Aldrich Chemical Company, Inc., 1001 West Saint Paul Avenue, Milwaukee, Wis. 53233, USA; 0.023 g, 0.140 mmol) to form [2-(3-{[(6-chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidin-3-yl]-(4-phenyl-piperidin-1-yl)-methanone (0.018 g, 23%). m/z=741 (M+1); HRMS: calcd for C40H55ClFN4O4S. Calc [M+H+] 741.3611. found 741.3611.
Reaction SMILES: ClCCl.CO.N.[N+:7]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:14]=[CH:13]2)([O-])=O>C1COCC1>[NH2:7][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH:14]=[CH:13]2
Reactant: O=[N+]([O-])c1ccc2c(ccn2CCN2CCCC2)c1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2c(ccn2CCN2CCCC2)c1

Procedure:
Prepared analogously to Example 3.1.b. from 5-nitro-1-(2-pyrrolidin-1-ylethyl)-1H-indole in THF as solvent. Yield: 0.83 g (93.9% of theory); C14H19N3 (M=229.32); calc.: molecular ion peak (M+H)+: 230; found: molecular ion peak (M+H)+: 230; Rf value: 0.37 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].I[CH2:25][CH2:26][CH3:27].O>CN(C)C=O>[Br:1][C:2]1[C:3]2[N:4]([C:9]([N:14]([CH2:25][CH2:26][CH3:27])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CSc1nc2c(Br)cc(C)cn2c1NC(=O)OC(C)(C)C
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(C(=O)OC(C)(C)C)c1c(SC)nc2c(Br)cc(C)cn12
Reaction time: 0.17 h
Yield: 97.1 %

Procedure:
tert-Butyl N-[8-bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]carbamate (123 mg) was dissolved in N,N-dimethylformamide (10 mL), then sodium hydride (65% in oil; 15 mg) was added thereto under ice-cooling, and the mixture was stirred for 10 minutes. Iodopropane (67 mg) was added thereto under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The extracted organic layers were combined, dried over anhydrous magnesium sulfate and evaporated, to give the title compound (133 mg) as a brown oil.