Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:25][C:24]2[CH:23]=[CH:22][C:5]([C:6]([C:8]#[C:9][C:10]([O:12]CC3C=CC(OC)=CC=3)=[O:11])=[O:7])=[CH:4][C:3]=2[O:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]1[O:25][C:24]2[CH:23]=[CH:22][C:5]([C:6]([C:8]#[C:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][C:3]=2[O:2]1
Reactant: COc1ccc(COC(=O)C#CC(=O)c2ccc3c(c2)OCO3)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C#CC(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
A solution of 36.3 g (107 mmol) of 4-methoxybenzyl 3-[3,4-(methylenedioxy)benzoyl]propiolate in 300 ml of methylene chloride was treated at room temperature with 6.4 ml (215 mmol) of anhydrous trifluoroacetic acid. The reaction mixture was stirred at room temperature until crystallization began, then cooled to 0° and stirred for a further 30 minutes. The separated crystals were filtered off under suction, washed with cold methylene chloride and dried in a high vacuum. There was obtained 3-(3,4-(methylenedioxy)benzoyl]propiolic acid of melting point 137°.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.[OH-].[Na+]>CCO>[Cl:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(SCCCCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccc(SCCCCl)cc1
Yield: 98.2 %

Procedure:
A mixture of 1-chloro-3-(4-nitrothiophenoxy)propane (1.00 g, 4.32 mmmol), stannous chloride dihydrate (4.87 g, 21.58 mmol), and EtOH was heated under reflux for 3 hours. The mixture was cooled, 2.5 N NaOH (21 mL) was added, and the precipitate was removed by filtration. The filtrate concentrated to 10 mL and extracted with EtOAc. The extracts were dried (MgSO4) and concentrated to give 855 mg (98%) of product as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32]>>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([S:31]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=1)(=[O:33])=[O:32])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[S:19][CH:20]=[CH:21][N:22]=2)=[CH:16][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccn1
Reactant: COC(=O)CCCCCCNCc1ccc(-c2nccs2)cc1
Agent: Cl
Product: COC(=O)CCCCCCN(Cc1ccc(-c2nccs2)cc1)S(=O)(=O)c1ccccn1

Procedure:
The title compound of Step B was prepared following the procedure described in Step B of Example 1 from 7-(4-thiazol-2-yl-benzylamino)-heptanoic acid methyl ester, of Step A and pyridine-2-sulfonyl chloride hydrochloride, of Preparation 47. 1H NMR (400 MHz, CDCl3) δ 9.06 (d, 1H), 8.81 (m, 1H), 8.10 (m, 1H), 7.91 (d, 2H), 7.86 (m, 1H), 7.46 (m, 1H), 7.34 (m, 3H), 4.39 (s, 2H), 3.62 (s, 3H), 3.15 (t, 2H), 2.21 (t, 2H), 1.48 (m, 2H), 1.37 (m, 2H), 1.15 (m, 4H); MS 474 (M+1).
Reaction SMILES: [SH:1][CH:2]([CH:14]([C:19]([NH:21][C@H:22]([C:32]([NH:34][CH3:35])=[O:33])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:36](OC(=O)C)(=[O:38])[CH3:37].CN1CCOCC1>C(Cl)(Cl)Cl>[C:36]([S:1][CH:2]([CH:14]([C:19]([NH:21][C@H:22]([C:32]([NH:34][CH3:35])=[O:33])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])(=[O:38])[CH3:37]
Reactant: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(S)CC(=O)OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C(CC(C)C)C(CC(=O)OCc1ccccc1)SC(C)=O
Temperature: 0 °C
Reaction time: 72 h

Procedure:
The benzyl ester (D8) (41 g, 0.088 mole) was dissolved in thiolacetic acid (170 ml) and left to stand at room temperature under nitrogen for 19 days. Volatile material was removed in vacuo and the residue chromatographed on silica gel with initially ether, rising slowly to ethyl acetate. After removal of high Rf impurities the title compound was obtained as a mixture of diastereomers as a pale yellow foam (29.76 g, 62.4%). (Found: C, 64.29; H, 7.16; N, 4.86. C29H38N2SO6 requires C, 64.18; H, 7.06; N, 5.16%). Later fractions contained olefinic material (D8). However, more complete reaction can be obtained by addition of a suitable base, for example triethylamine. An aliquot (2 ml) was removed from the above reaction mixture after 14 days, treated with triethylamine (3 drops) and left to stand for a further 5 days at room temperature under nitrogen. The same work-up procedure as for the bulk of the reaction mixture described above gave only the diastereomer mixture (E3) with no olefinic material remaining. 3-Mercapto-6-methyl-4-[[[1-(S)-[(methylamino)carbonyl]-2-(4-methoxyphenyl)ethyl]amino]carbonyl]heptanoic acid, benzyl ester (E4, Isomer A, 2.0 g 0.004 mol) was dissolved in chloroform (100 ml) under an atmosphere of nitrogen. The reaction mixture was cooled to 0° C. and acetic anhydride (2.04 g, 0.02 mol) was added followed by N-methylmorpholine (2.02 g, 0.02 mol). The reaction mixture was allowed to warm to room temperature, then stirred under nitrogen for 3 days.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]([OH:26])[C:23]([OH:25])=[O:24])[CH:5]=[C:6]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]=1[O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14].[C:27]1([C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[N+]=[N-])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>ClCCl.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH:22]([OH:26])[C:23]([O:25][CH:33]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:24])[CH:5]=[C:6]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:7]=1[O:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Reactant: COCCOCOc1cc(C(O)C(=O)O)cc(F)c1OCOCCOC
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: COCCOCOc1cc(C(O)C(=O)OC(c2ccccc2)c2ccccc2)cc(F)c1OCOCCOC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5.3 g of the acid of Step A were dissolved in 66 ml of dichloromethane and then 46 ml of a solution of diphenyl diazomethane at 6.5 g in ether were added at 15° C. The mixture was stirred for 16 hours at ambient temperature and then water was added, followed by decanting and acidifying with acetic acid. Washing with a saturated solution of sodium bicarbonate, drying and evaporating the solvents yielded after chromatography on silica and eluting with an ethyl acetate—hexane mixture (50-50) 4.0 g of the desired product with a Rf=0.17.
Reaction SMILES: [Si]([O:18][CH2:19][C@H:20]1[CH2:25][C@H:24]2[CH2:26][C@H:22]([C:23]2([CH3:28])[CH3:27])[C@@H:21]1[NH:29][C:30]1[C:35]([F:36])=[CH:34][N:33]=[C:32]([C:37]2[C:45]3[C:40](=[N:41][CH:42]=[C:43]([Cl:46])[CH:44]=3)[N:39](S(C3C=CC(C)=CC=3)(=O)=O)[CH:38]=2)[N:31]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl>C(#N)C.O1CCOCC1>[Cl:46][C:43]1[CH:44]=[C:45]2[C:37]([C:32]3[N:31]=[C:30]([NH:29][C@@H:21]4[C@@H:20]([CH2:19][OH:18])[CH2:25][C@H:24]5[CH2:26][C@@H:22]4[C:23]5([CH3:27])[CH3:28])[C:35]([F:36])=[CH:34][N:33]=3)=[CH:38][NH:39][C:40]2=[N:41][CH:42]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(N[C@@H]4[C@@H](CO[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)C[C@H]5C[C@@H]4C5(C)C)n3)c3cc(Cl)cnc32)cc1
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CC1(C)[C@H]2C[C@H](CO)[C@@H](Nc3nc(-c4c[nH]c5ncc(Cl)cc45)ncc3F)[C@@H]1C2
Temperature: 70 °C

Procedure:
To a solution of N-((1R,2S,3S,5R)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-6,6-dimethylbicyclo[3.1.1]heptan-2-yl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine, 77f, (0.037 g, 0.046 mmol) in acetonitrile (1.1 mL) was added HCl (0.221 mL of a 4 M solution in dioxane, 0.883 mmol). The mixture was heated to 70° C. for 18 h, during which a precipitate formed. The reaction was concentrated in vacuo and triturated three times with CH3CN to afford 4 mg of the desired product as a white solid: 1H NMR (300.0 MHz, MeOD) δ 8.72-8.64 (m, 1H), 8.39 (s, 1H), 8.32 (d, J=2.3 Hz, 1H), 8.21 (d, J=5.2 Hz, 1H), 4.71 (d, J=6.3 Hz, 1H), 3.67-3.57 (m, 2H), 2.33-2.26 (m, 1H), 2.10 (m, 1H), 1.78-1.70 (m, 1H), 1.28-1.25 (m, 7H) and 1.19 (s, 3H) ppm; LCMS RT=3.13 (M+H) 416.42.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.CN(C=O)C.Cl[CH2:16][C:17](=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20]>O>[OH:9][C:4]1[CH:3]=[C:2]([S:1][CH2:16][C:17](=[O:23])[CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:7]=[C:6]([OH:8])[CH:5]=1
Reactant: Oc1cc(O)cc(S)c1
Reactant: COC(=O)CC(=O)CCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC(=O)CSc1cc(O)cc(O)c1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a mixture of 5-sulfanylbenzene-1,3-diol (12.2 g) and DMF (dry) (100 mL) was added methyl 4-chloroacetoacetate (10.0 mL) at room temperature, and the mixture was stirred at 70° C. for 4 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with 1N HCl and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (15.1 g).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5](=[O:8])[CH:6]=[CH2:7].C(N([CH2:14][CH3:15])CC)C.[C:16](Cl)(=[O:26])[C:17]1[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:19](Cl)=[O:20]>CN(C)C1C=CN=CC=1.C1C2NC3C(=CC=CC=3)SC=2C=CC=1.O1CCCC1>[C:5]([O:4][CH2:3][CH2:2][O:1][C:16](=[O:26])[C:17]1[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:19]([O:1][CH2:2][CH2:3][O:4][C:5](=[O:8])[CH:14]=[CH2:15])=[O:20])(=[O:8])[CH:6]=[CH2:7]
Reactant: C=CC(=O)OCCO
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: C1CCOC1
Product: C=CC(=O)OCCOC(=O)c1ccccc1C(=O)OCCOC(=O)C=C
Temperature: 17 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
A five liter, three necked flask was equipped with a overhead stirrer, nitrogen atmosphere and addition funnel. The flask was charged with 636 g of 2-hydroxyethylacrylate (5.47 mol.), 547 g of triethylamine (5.41 mol.), 6 g of phenothiazine, 5 g of 4-dimethylaminopyridine and 3000 ml of tetrahydrofuran. The reaction was cooled to 17° C. with a water bath. Next, 563 g of phthaloyl chloride (2.75 mol.) was slowly added over 2.5 hours via the addition funnel. The reaction was stirred an additional 8 hours at room temperature. The triethylamine hydrochloride salt was removed by filtration and the mother liquor evaporated by rotoevaporation to yield an amber colored liquid. The liquid was placed under vacuum (15 mmHg, 2 kPa) and heated to 100° C. for one hour. The resulting liquid was collected to yield 995 g (99%) of the desired product. The product was confirmed by IR and 13C NMR. The preparation of di(acryloyloxyethyl)phthalate from phthalic anhydride and 2-hydroxyethylacrylate was reported in U.S. Pat. No. 3,336,418.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[ClH:19].[Cl:20][CH2:21][C:22]1[C:23]([NH:34][CH3:35])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Li+].[OH-]>C1(C)C=CC=CC=1.C(Cl)Cl>[ClH:20].[ClH:19].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:21][C:22]1[C:23]([NH:34][CH3:35])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: CNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NC)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 6 %

Procedure:
To a stirred solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (250 mg, 1.01 mmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-methylquinolin-2-amine hydrochloride SLA 28154 (276 mg, 1.01 mmol) followed by a 2 N aq. LiOH solution (1.01 mL, 2.02 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with a CH2Cl2:MeOH=9:1 mixture (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 92:8) provided, after evaporation and drying, 39 mg of 6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (0.40 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to give 6,7-dimethoxy-4-((6-methoxy-2-(methylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 48 as a yellow solid (31 mg, 6% yield).
Reaction SMILES: [C:1]([C:5]1[CH:36]=[CH:35][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:20][CH:19]=[N:18][CH:17]=3)[C@@H:14]([N:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH2:22]3)[CH2:13][C@@:12]2([CH3:34])[C:27]([O:29]C(C)(C)C)=[O:28])=[O:10])=[CH:7][C:6]=1[Cl:37])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([C:5]1[CH:36]=[CH:35][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:20][CH:19]=[N:18][CH:17]=3)[C@@H:14]([N:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH2:26]3)[CH2:13][C@@:12]2([CH3:34])[C:27]([OH:29])=[O:28])=[O:10])=[CH:7][C:6]=1[Cl:37])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@]1(C)C[C@H](N2C=CN=CC2)[C@H](c2cncs2)N1C(=O)c1ccc(C(C)(C)C)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(C(=O)N2[C@@H](c3cncs3)[C@@H](N3C=CN=CC3)C[C@@]2(C)C(=O)O)cc1Cl

Procedure:
The tert-butyl ester from stage A was deprotected with TFA in a similar manner to that described in Example 1 to afford the title compound as a solid.
Reaction SMILES: C[NH:2][C:3](=[NH:5])S.OS(O)(=O)=O.[OH-].[K+].[C:13]([CH2:21][C:22]([O:24]CC)=O)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[NH2:5][C:3]1[O:20][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:21][C:22](=[O:24])[N:2]=1
Reactant: CNC(=N)S
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1nc(=O)cc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.2 %

Procedure:
To 9.45 g (0.034 M) of methylthiopseudourea H2SO4 is added 40.0 ml of H2O+8.0 g (0.142 M) of KOH. With vigorous stirring, 12.0 g (0.0625 M) of ethyl benzoylacetate (Aldrich) is also added and the heterogenous mixture allowed to stir at ambient temperature for 18 hours. The resulting solids are filtered and washed very well with H2O followed by ether. The solids are dried at 60° C. in a vacuum oven to yield 7.20 g (61.3 percent) of 2-amino-6-phenyl-1,3-oxazine-4-one. An analytical sample is recrystallized from 95 percent EtOH:DMF to yield 2-amino-6-phenyl-1,3-oxazine-4-one (m.p. 244-246 d).
Reaction SMILES: [Si](OCC[C:21]1[NH:22][C:23]2[C:28]([C:29]=1C(=O)C(OCC)=O)=[CH:27][C:26](Cl)=[CH:25][CH:24]=2)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:38](Br)([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[CH:38]([N:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:21]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=O)c1c(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[nH]c2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: c1ccc(C(c2ccccc2)n2ccc3ccccc32)cc1
Temperature: 25 °C
Yield: 45 %

Procedure:
Ethyl [2-({[tert-butyl(diphenyl)silyl]oxy}ethyl)-5-chloro-1H-indol-3-yl](oxo)acetate (Step 4, 1 eq), Ph2CHBr (1.5 eq) and Cs2CO3 (1.5 eq) were mixed in dry acetonitrile (0.1M). The mixture was heated to reflux for 2 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic phase was concentrated and the residue was chromatographed with CH2Cl2 as eluent to give the N-benzhydryl indole as an orange gum in 45% yield. m/z (M+H)+ 701.3
Reaction SMILES: [C:1]([N:4]1[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH:9]=[CH2:10])[CH2:7][C:6]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[N:5]1)(=[O:3])[CH3:2].Cl[SiH:26]([CH3:28])[CH3:27].O.CC[O:32]C(C)=O>C1(C)C=CC=CC=1.O.Cl.Cl.Cl[Pt](Cl)(Cl)Cl>[C:1]([N:4]1[C:8]([CH2:9][CH2:10][Si:26]([CH3:28])([CH3:27])[OH:32])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][C:6]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[N:5]1)(=[O:3])[CH3:2]
Reactant: C[SiH](C)Cl
Reactant: CCOC(C)=O
Reactant: C=CC1(c2ccccc2)CC(c2cc(F)ccc2F)=NN1C(C)=O
Agent: Cl[Pt](Cl)(Cl)Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)N1N=C(c2cc(F)ccc2F)CC1(CC[Si](C)(C)O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 100 mg (0.31 mmol) of 1-4 in 1 mL of toluene was added 51 μL (0.46 mmol) of chlorodimethylsilane and 13 mg (0.03 mmol) of hydrogen hexachloroplatinate(IV) hydrate. The reaction mixture was heated at 85° C. for 18 hours in a sealed tube before 500 μL of water was added. Heating was continued for 15 minutes then the reaction was cooled to room temperature, dumped into a separatory funnel containing EtOAc, washed successively with water, brine, dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with EtOAc/hexanes to provide 1-5 as a white solid. Data for 1-5: 1HNMR (500 MHz, CDCl3) δ 7.65 (m, 1H), 7.25 (m, 5H), 7.0 (m, 2H), 3.6-3.3 (m, 2H), 2.9 (m, 1H), 2.4 (m, 3H), 2.15 (m, 1H), 0.6-0.3 (m, 2H), 0.15 (m, 6H) ppm. HRMS (MALDI) calc'd M+H for C21H24F2N2O2Si: 403.1648 Found: 403.1637.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[CH3:7][C:8]([Si:11]([CH3:20])([CH3:19])[O:12][C@H:13]1[CH2:17][CH2:16][NH:15][C:14]1=[O:18])([CH3:10])[CH3:9].C(Br)C#C.O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:10][C:8]([Si:11]([CH3:20])([CH3:19])[O:12][C@H:13]1[CH2:17][CH2:16][N:15]([CH2:3][C:2]#[CH:1])[C:14]1=[O:18])([CH3:7])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: C#CCN1CC[C@H](O[Si](C)(C)C(C)(C)C)C1=O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 11.5 g of potassium tert-butoxide in 300 ml of dimethylformamide was cooled to -20° C. An 18 g portion of (S)-3-[[(1,1-dimethylethyl)dimethylsilyl]-oxy]-2-pyrrolidinone was added and the mixture stirred at -20° C. for 30 minutes. A 12 ml portion of 80% propargyl bromide in toluene was added and the reaction was allowed to warm to room temperature and was stirred for 1 hour. Water was added and the mixture was extracted with 5×100 ml of ether and 3×100ml of dichloromethane. The extracts were combined, backwashed with water, dried and concentrated in vacuo, giving 15.8 g of (S)-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-1-(2-propynyl)-2-pyrrolidinone [α]D26° =-44°-(dichloromethane); mp 35°-36° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[CH3:12][C:13]#[N:14]>CC1C=CC=C([Sn](CCCC)(CCCC)CCCC)N=1.C(OCC)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>[Cl:11][C:4]1[CH:3]=[C:2]([C:13]2[CH:12]=[CH:2][CH:3]=[C:4]([CH3:5])[N:14]=2)[N:7]=[C:6]2[NH:8][CH:9]=[CH:10][C:5]=12
Reactant: CC#N
Reactant: Clc1cc(Br)nc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[Sn](CCCC)(CCCC)c1cccc(C)n1
Solvent: CCOCC
Product: Cc1cccc(-c2cc(Cl)c3cc[nH]c3n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-4-chloro-1H-pyrrolo[2,3-b]pyridine (1 eq, 11.0 mmol, 2.76 g) in MeCN (20 ml), 2-methyl-6-tributylstannanyl-pyridine (see Chemistry, A European Journal (2005), 11 (23), 6818-6828) (1 eq, 11.0 mmol, 4.19 g) and Pd(PPh3)4 (0.01 eq, 0.110 mmol, 131 mg) are added. The resulting mixture is heated using microwave radiation for 15 min at 160° C. The mixture is diluted with diethyl ether and extracted with aqueous HCl solution (2 M). The aqueous layer is basified with aqueous NaOH solution (4 M) and extracted with DCM. The organic layer is dried with MgSO4, filtered, and concentrated. The residue is taken up in hexane and stirred at r.t. for 1 h. The suspension is filtered and dried giving the title compound; [M+H]+=244.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:11][C:12]1[N:13]=[C:14](Br)[C:15]2[N:16]([CH:18]=[CH:19][N:20]=2)[CH:17]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:14]3[C:15]4[N:16]([CH:18]=[CH:19][N:20]=4)[CH:17]=[C:12]([Br:11])[N:13]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Nc1ccc2ncsc2c1
Reactant: Brc1cn2ccnc2c(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cn2ccnc2c(Nc2ccc3ncsc3c2)n1

Procedure:
A quantity of 0.15 g (1 mmole) of benzothiazol-6-ylamine is treated with 0.27 g (1 mmole) of 6,8-Dibromo-imidazo[1,2-a]pyrazine in acetonitrile with 3 eq of K2CO3 at reflux for 16 hrs. The reaction mixture is cooled partitioned between ethyl acetate and water, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford Benzothiazol-6-yl-(6-bromo-imidazo[1,2-a]pyrazin-8-yl)-amine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[N:6][C:5]([OH:8])=[C:4]2[S:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:3]=12.[C:16]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:3]2[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[S:9][C:4]=2[C:5](=[O:8])[N:6]([CH3:16])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc2c(Br)cnc(O)c2s1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Br)cn(C)c(=O)c2s1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90.4 %

Procedure:
To a solution of methyl 4-bromo-7-hydroxythieno[2,3-c]pyridine-2-carboxylate (300 mg, 1.04 mmol) stirred at 0° C. in DMF (6.6 mL) under an atmosphere of nitrogen was added K2CO3 (358 mg, 2.6 mmol). After stirring at 0° C. for 15 min, methyl iodide (177 mg, 1.3 mmol) was added dropwise. The ice bath was removed, and mixture was stirred at rt for 20 min, 50° C. for 2 h, and rt for 10 h. The reaction mixture was treated with water (8 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using a gradient of EtOAc (10 to 100%) in DCM to afford the title compound (284 mg, 90%) as a white solid. LCMS (M+H)+=303.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].OO.[S:11](=[O:15])(=[O:14])([OH:13])[OH:12]>C(O)(=O)C>[CH3:8][C:2]1[C:3]([CH3:7])=[CH:4][CH:5]=[CH:6][N+:1]=1[O-:12].[S:11](=[O:13])(=[O:12])([OH:15])[OH:14]
Reactant: Cc1cccnc1C
Agent: O=S(=O)(O)O
Agent: OO
Solvent: CC(=O)O
Product: Cc1ccc[n+]([O-])c1C
Temperature: 50 °C

Procedure:
One hundred g. of 2,3-lutidine was dissolved into 200 ml. of glacial acetic acid, followed by dropwise addition of 120 g. of 35% aqueous hydrogen peroxide solution at about 40° C. The mixture was allowed to react at 105° C. for about 2 hours. After completion of the reaction, the mixture was cooled down to about 50° C., followed by addition of 5.0 g. of p-formaldehyde. The resultant mixture was heated to 105° C. to cause the reaction to take place for about 10 minutes. The resultant mixture was cooled down to about 40° C., followed by addition of 150 g. of 98% sulfuric acid. The resultant mixture was subjected to distillation under reduced pressure to evaporate the glacial acetic acid off to give 2,3-dimethylpyridine N-oxide as a sulfuric acid solution.