Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.CN(C)C=O.S(Cl)([Cl:19])=O>CCCCCC>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:19])=[O:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 99 %

Procedure:
13bk) 49.4 g of 4-bromo-2-chloro-benzoic acid were suspended in 60 ml of hexane, treated with 0.2 ml of N,N-dimethylformamide and 18.5 ml of thionyl chloride and boiled at reflux under argon for 15 hrs. The resulting solution was cooled to room temperature, filtered, evaporated and the residue was again evaporated with 60 ml of toluene. There were obtained 53 g (99%) of 4-bromo-2-chloro-benzoylchloride as a crude oil which crystallized upon standing, but which was used directly in the next step without further manipulation.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>CO.CC(O)=O>[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32][NH:1][C:2]2[CH:3]=[C:4]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[O:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:30][CH:29]=1
Reactant: Nc1cccc(-n2cnc3cc(C(=O)NCc4cccnc4)ccc32)c1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CC(=O)O
Solvent: CO
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1cccc(NCc2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1-(3-aminophenyl)-N-(pyridin-3-ylmethyl)-1H-benzimidazole-5-carboxamide (1.0 eq) and 4-chlorobenzaldehyde (1.0 eq) in MeOH:HOAc (10:1 v/v, 0.017M) was stirred for 15 min at rt prior to the addition of (polystyrylmethyl)trimethylammonium cyanoborohydride (3.5-5.0 mmol/g, 2.5 eq). The reaction mixture was shaken at rt overnight in a capped vial and then filtered through a plug of cotton wool. The resin was washed with MeOH and the combined filtrate and MeOH washings were concentrated under reduced pressure and purified by silica gel chromatography eluting with 5% MeOH in DCM to yield 1-{3-[(4-chlorobenzyl)amino]phenyl}-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide. 1H-NMR (CD3OD, 400 MHz): δ 4.38 (s, 2H), 4.89 (s, 2H), 6.68 (s, 1H), 6.76 (dd, J=2.0 Hz, 7.0 Hz, 2H), 7.20-7.45 (m, 7H), 7.81 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.89 (d, J=6.0 Hz, 1H), 8.26 (d, J=1.2 Hz, 1H), 8.42 (s, 1H), 8.45 (d, J=4 Hz, 1H), 8.60 (s, 1H). MS (ES+): m/z 469 [MH+]
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([CH3:11])(S(C)(=O)=O)[CH3:6].[F:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)[CH:17]=[CH:16][C:15]=1[C:27]([OH:33])([CH3:32])[CH2:28][C:29](=[NH:31])[NH2:30].C(=O)([O-])O.[Na+]>O1CCCC1.O>[F:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][N:21]=2)[CH:17]=[CH:16][C:15]=1[C:27]([OH:33])([CH3:32])[CH2:28][C:29]1[NH:30][CH:2]=[C:3]([CH:4]=[C:5]([CH3:11])[CH3:6])[N:31]=1
Reactant: CC(O)(CC(=N)N)c1ccc(-c2ccc(F)cn2)cc1F
Reactant: CC(C)(CC(=O)CBr)S(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=Cc1c[nH]c(CC(C)(O)c2ccc(-c3ccc(F)cn3)cc2F)n1

Procedure:
Step C In a quartz tube, 1-bromo-4-methyl-4-(methylsulfonyl)pentan-2-one (26 mg, 0.10 mmol), the di(trifluoroacetate) salt of (±)-3-[2-fluoro-4-(5-fluoropyridin-2-yl)phenyl]-3-hydroxybutanimidamide (105 mg, 0.202 mmol), and sodium hydrogen carbonate (53 mg, 0.63 mmol) were suspended in a mixture of tetrahydrofuran (1.5 mL) and water (0.5 mL). After being irradiated by microwave (120° C., 10 min), the reaction mixture was purified by reversed-phase high performance liquid chromatography to afford the di(trifluoroacetate) salt of the title compound. (M+H) found 370.
Reaction SMILES: C(O[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH3:36][N:37]([CH3:43])[CH2:38][CH2:39][CH2:40][CH2:41][NH2:42]>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:42][CH2:41][CH2:40][CH2:39][CH2:38][N:37]([CH3:43])[CH3:36])=[O:35])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: CN(C)CCCCN
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(Nc4ccccc4C(=O)NCCCCN(C)C)n3)cc2CC1

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-(4-dimethylamino-butyl)-benzamide was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and N(1),N(1)-dimethyl-butane-1,4-diamine in an analogous manner to Example 1396. Product isolated as an orange solid (31 mg, 51%). m.p.=132-134° C.; LCMS (m/e) 566 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.35 (s, 1H), 8.68 (d, 1H, J=8.4 Hz), 8.51 (s, 1H), 8.09 (s, 1H), 7.54 (d, 1H, J=7.8 Hz), 7.47-7.38 (m, 1H), 7.36 (s, 1H), 7.30-7.22 (m, 1H), 7.13-6.93 (m, 3H), 3.56 (t, 2H, J=4.8 Hz), 3.51-3.42 (m, 2H), 3.39 (s, 3H), 2.98-2.85 (m, 4H), 2.82-2.67 (m, 6H), 2.35 (t, 2H, J=5.8 Hz), 2.21 (s, 6H), 1.81-1.71 (m, 2H), 1.71-1.61 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([N+:29]([O-])=O)[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:18][CH:17]=2)[CH:8]=1)[CH3:2]>[Pd].C(Cl)(Cl)Cl.CCO>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH2:29])[CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:20][CH:21]=2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1cn(-c2ccc(Oc3ccccc3)cc2)c2ccccc12)[N+](=O)[O-]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)C(N)Cc1cn(-c2ccc(Oc3ccccc3)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.5 %

Procedure:
2-Amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester (33) was prepared as follows: Palladium on carbon (10% wet, 0.4 g) was added to a solution of compound 32 (1.2 g) in CHCl3 (10 mL) and EtOH (30 mL). The reaction mixture was shaken under hydrogen (50 PSI) for 24 hours at room temperature. After filtration on Celite, HCl (4N in 1,4-dioxane, 4 mL) was added and the solvents were evaporated under vacuum to give compound 33 as a blue solid (1.1 g, 90%): LC/MS: m/z=401.1 [M+H]+ (Calc: 400.5).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].Cl[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]([OH:35])=[O:34])[CH:28]=1.C(N(CC)CC)C>C(O)C>[C:33]([C:29]1[CH:28]=[C:27]([N:23]2[CH2:22][CH2:21][CH:20]([CH2:19][NH:18][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:17][C:6]=3[C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=3)=[O:8])[CH2:25][CH2:24]2)[CH:32]=[CH:31][N:30]=1)([OH:35])=[O:34]
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NCC1CCNCC1
Reactant: O=C(O)c1cc(Cl)ccn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)c1cc(N2CCC(CNc3ccc(Cl)cc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Yield: 81.8 %

Procedure:
Using a similar procedure to that described in Example 52, 5-chloro-N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethyl)aminobenzamide (166 mg, 0.44 mmol), 4-chloropicolinic acid (103 mg, 0.66 mmol), triethylamine (89 mg, 0.88 mmol, and ethanol (3 mL) yielded 180 mg (82%) of the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:11]Br.C(=O)(O)[O-].[Na+]>CCOCC>[CH:5]1[C:4]([C:1]([CH2:2][Br:11])=[O:3])=[CH:9][CH:8]=[C:7]([OH:10])[CH:6]=1
Reactant: BrBr
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: O=C(CBr)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-Acetylphenol (20 g) in ether (200 mL) was treated with bromine (6.8 mL) and stirred at ambient temperature for 18 hours. The solution was poured into saturated sodium bicarbonate, stirred for 30 minutes and the organic layer separated. The organic portion was washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to afford the title compound (30 g).
Reaction SMILES: [Cl:1][C:2]12[C:14]([Cl:16])([Cl:15])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]=[CH:8][C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19].OO.C(=O)([O-])[O-:23].[Na+].[Na+]>C(O)C>[Cl:1][C:2]12[C:14]([Cl:15])([Cl:16])[C:5]([Cl:17])([CH:6]3[CH:11]1[C:10](=[O:12])[CH:9]1[O:23][CH:8]1[C:7]3=[O:13])[C:4]([Cl:18])=[C:3]2[Cl:19]
Reactant: O=C1C=CC(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: O=C1C2OC2C(=O)C2C1C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl

Procedure:
38 g. of 1,2,3,4,9,9-hexachloro-1,4,4a,8a-tetrahydro-1,4-methanonaphthalene-5,8-dione, prepared according to Example 1, were added slowly to a solution of 200 ml. of ethanol containing 20 ml. of 30% hydrogen peroxide and 13 g. of sodium carbonate at such a rate that the temperature was maintained at 40°-50° C. The yellow color of the dione disappeared quickly. The solution was then cooled to 10°-13° C. and a white precipitate formed. This solid was filtered and recrystallized from ethanol, m.p. 180°-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][N:10]2[CH:14]=[CH:13][CH:12]=[C:11]2[C:15]([O:17]C)=O)=[CH:4][CH:3]=1.[CH2:20]([NH2:24])[CH2:21][CH2:22][NH2:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:9][N:10]4[CH:14]=[CH:13][CH:12]=[C:11]4[C:15](=[O:17])[N:23]2[CH2:22][CH2:21][CH2:20][NH:24]3)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccn1CC(=O)c1ccc(Cl)cc1
Reactant: NCCCN
Product: O=C1c2cccn2CC2(c3ccc(Cl)cc3)NCCCN12
Temperature: 180 °C
Yield: 10.6 %

Procedure:
Methyl 1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (100 mg, 0.36 mmol) was mixed with propane-1,3-diamine (0.9 g, 12.14 mmol) in xylenes (2 mL) and the mixture heated in the microwave at 180° C. for 1 hour (monitored by LCMS). The mixture was concentrated in vacuo and purified by flash chromatography using 2 to 10% MeON in CH2Cl2, to give 11a-(4-chlorophenyl)-1,2,3,4,11,11a-hexahydro-6H-pyrrolo[1′,2′:4,5]pyrazino[1,2-a]pyrimidin-6-one (123) (11.5 mg, yield 10%).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]([CH2:17][O:18][Si](C(C)(C)C)(C)C)[O:11][CH:12]1[CH2:16][CH2:15][CH2:14][O:13]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[O:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[O:11][CH:10]([CH2:9][OH:8])[CH2:17][OH:18]
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)OC1CCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCC(CO)OC1CCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To a solution of 4.25 g (11 mmol) 1,3-O-di-(t-butyldimethylsilyl)-2-O-tetrahydrofuranylglycerol in 30 ml tetrahydrofuran was added 30 ml of tetra-n-butylammonium fluoride (1 mol/1 in THF) dropwise and the mixture was stirred at ambient temperature for 2 hours. The reaction mixture was then concentrated and the residue was subjected to column chromatography (silica gel/methylene chloride-methanol) to provide 1.70 g (96%) of 2-O-tetrahydrofuranylglycerol.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:17][O-:18].[Na+].Cl>CO>[F:12][C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([C:13]([O:15][CH3:16])=[O:14])=[C:3]([CH2:2][O:18][CH3:17])[C:7]=2[CH:8]=1
Reactant: C[O-]
Reactant: COC(=O)c1oc2ccc(F)cc2c1CBr
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCc1c(C(=O)OC)oc2ccc(F)cc12
Yield: 63 %

Procedure:
To a solution (50 mL) of methyl 3-(bromomethyl)-5-fluoro-1-benzofuran-2-carboxylate (5.87 g) synthesized above in methanol was added 28% solution (8.33 mL) of sodium methoxide in methanol, and the mixture was stirred with heating under reflux for 3 hr. 1N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (3.04 g, 63%) as a white solid.
Reaction SMILES: [O:1]([CH:9]([P:25](=[O:32])([O:29][CH2:30][CH3:31])[O:26][CH2:27][CH3:28])[CH2:10]/[CH:11]=[C:12](\[CH3:24])/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[Si](C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:1][CH:9]([P:25](=[O:32])([O:26][CH2:27][CH3:28])[O:29][CH2:30][CH3:31])[CH2:10]/[CH:11]=[C:12](\[CH3:24])/[CH2:13][CH2:14]/[CH:15]=[C:16](\[CH3:23])/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21]
Reactant: CCOP(=O)(OCC)C(C/C=C(\C)CC/C=C(\C)CCC=C(C)C)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)C(O)C/C=C(\C)CC/C=C(\C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of the diethyl [1-(t-butyldimethylsiloxy)-(E,E)-4,8,12-trimethyl-3,7,11-tridecatrienyl]phosphonate (55 mg, 0.113 mmol) in THF (1 ml), under argon, at 0° C. was added tetrabutylammonium fluride (0.113 ml of a 1.0M solution in THF, 0.113 mmol), and the mixture stirred at 0° C. for 1 hr. The solvent was evaporated in vacuo and the residue chromatographed on silica gel eluted with ethylacetate:hexanes, (3:1, v:v) to afford the title compound (37 m,g 88%) as an oil.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[C:11]3[CH3:16])=[CH:7][CH:6]=[CH:5][CH:4]=2.[Li]CCCC.[Sn:22](Cl)([CH3:25])([CH3:24])[CH3:23]>C(OCC)C>[CH3:16][C:11]1[C:10]2[C:15](=[C:2]([Sn:22]([CH3:25])([CH3:24])[CH3:23])[C:3]3[C:8]([N:9]=2)=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cccc2c(Br)c3ccccc3nc12
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cccc2c([Sn](C)(C)C)c3ccccc3nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 84 %

Procedure:
A solution of 9-bromo-4-methylacridine 9 (1 g, 3.7 mmol) in 50 ml anhydrous diethyl ether was cooled to −78° C. under nitrogen. To the solution was added 1.6 M n-BuLi in hexanes (0.74 mmol, 0.46 mL) dropwise over a period of 15 min and a 1.0 M solution of Me3SnCl in hexanes (0.81 mL, 0.81 mmol). The reaction solution mixture was allowed to warm to room temperature, stirred for 18 hours and concentrated in vacuo. Purification of the orange residue by flash chromatography (100:10:1 hexanes:ethyl acetate:triethyl amine) afforded 11 (1.1 g, 84%) as a yellow solid. GC-MS revealed contamination of the product with 5-10% 4-methylacridine that could not be separated by chromatography. The stannane was therefore employed in the Stille coupling with 1,8-dibromonaphthalene without further purification. 1H-NMR δ=0.67 (s, 9H), 2.95 (s, 3H), 7.41 (dd, J=6.9 Hz, J=8.8 Hz, 1H), 7.52 (ddd, J=1.4 Hz, J=6.5 Hz, J=6.5 Hz, 1H), 7.61 (d, J=6.9 Hz, 1H), 7.74 (ddd, J=1.4 Hz, J=7.4 Hz, J=7.4 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 8.12 (d, J=9.3 Hz, 1H), 8.28 (d, J=7.9 Hz, 1H). 13C-NMR δ=−4.63, 19.51, 125.33, 125.56, 128.42, 128.94, 129.30, 129.93, 131.38, 133.49, 133.62, 138.58, 147.36, 147.53, 156.78.
Reaction SMILES: C(O[C:4]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([C:12](=[O:16])[N:13]([CH3:15])[CH3:14])[S:6](=[O:18])(=[O:17])[N:5]=1)C.C[Si]([NH:23][Si](C)(C)C)(C)C>C(#N)C>[NH2:23][C:4]1[C:8]([O:9][CH2:10][CH3:11])=[C:7]([C:12](=[O:16])[N:13]([CH3:15])[CH3:14])[S:6](=[O:18])(=[O:17])[N:5]=1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: CCOC1=NS(=O)(=O)C(C(=O)N(C)C)=C1OCC
Solvent: CC#N
Product: CCOC1=C(C(=O)N(C)C)S(=O)(=O)N=C1N

Procedure:
To a solution of 60% pure 3,4-diethoxy-5-dimethylcarbamylisothiazole-1,1-dioxide (1.3 g) from Part C in acetonitrile (7 ml), under nitrogen, was added hexamethyldisilizane (0.90%, 4.3 mmol). This solution was heated at 50° for four hours. The reaction was then quenched with methanol (0.5 ml) and the solvent evaporated. This residue was chromatographed on silica gel eluting with 40% methanol/chloroform and the collected product residue triturated with ether to give 0.61 g, of title compound (mp 221°-223°).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C@@H:10]([N:12]=[N+]=[N-])[CH3:11]>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][C@@H:10]([NH2:12])[CH3:11]
Reactant: C[C@@H](Cc1cc(F)ccc1Cl)N=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@H](N)Cc1cc(F)ccc1Cl
Yield: 74.6 %

Procedure:
To a solution of (1S)-2-(2-chloro-5-fluorophenyl)-1-methylethyl azide (1.10 g, 5.15 mmol) in 100 mL of EtOAc was added Pd/C (300 mg of 10% Pd) and the mixture was hydrogenated under hydrogen balloon for 30 min. The catalyst was removed by filtration through celite, then passed through silica gel plug eluting first with EtOAc (40 mL), then MeOH/EtOAc/NH4OH 20:75:5 (120 mL). The fraction with product was evaporated to give (1S)-2-(2-chloro-5-fluorophenyl)-1-methylethylamine (721 mg, 67%) as pale yellow oil. ESI-MS: m/z (MH+) 188.3. 1H NMR (300 MHz, CDCl3): δ 7.30 (m, 1H), 6.86-6.97 (m, 2H), 3.26 (m, 1H), 2.66-2.84 (m, 2H), 1.40 (s, 2H), 1.15 (d, J=6.42 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3I)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:19]([C:21]([OH:26])([CH2:24][CH3:25])[C:22]#[CH:23])[CH3:20]>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[C:7]2[C:8](=[O:18])[N:9]([CH3:17])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:20]#[C:19][C:21]([CH2:24][CH3:25])([OH:26])[CH2:22][CH3:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN1Cc2c(I)ncn2-c2cccc(Cl)c2C1=O
Reactant: C#CC(O)(CC)CC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: CCC(O)(C#Cc1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2)CC

Procedure:
3.73 g (10 mmol) of 7-chloro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 2 hours with 1.40 g (12.5 mmol) of 3-ethyl-1-pentyn-3-ol, 70 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 10 mg of copper(I) iodide in 30 ml of diethylamine. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with ethyl acetate. After recrystallization from ethyl acetate there was obtained 7-chloro-3-(3-ethyl-3-hydroxy-1-pentynyl)-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 186°-188°.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14]#[N:15])=[C:11]([NH2:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14]#[N:15])=[C:11]([NH:13][C:21](=[O:22])[C:20]3[CH:24]=[CH:25][CH:26]=[C:18]([O:17][CH3:16])[CH:19]=3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(N)c2C#N)C1
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2sc3c(c2C#N)CCN(C(C)=O)C3)c1

Procedure:
Prepared according to general procedure A starting from 6-acetyl-2-amino-3-cyano4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (compound A3) and 3-methoxybenzoyl chloride.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([CH2:7][CH2:8][C:9]([F:33])([F:32])[C:10]([F:31])([F:30])[C:11]([F:29])([F:28])[C:12]([F:27])([F:26])[C:13]([F:25])([F:24])[C:14]([F:23])([F:22])[C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])(=[O:6])=[O:5].C(N(CC)CC)C.[Cl-].C([NH+](CC)CC)C>O1CCCC1>[CH:3]([S:4]([CH2:7][CH2:8][C:9]([F:33])([F:32])[C:10]([F:30])([F:31])[C:11]([F:28])([F:29])[C:12]([F:26])([F:27])[C:13]([F:24])([F:25])[C:14]([F:22])([F:23])[C:15]([F:20])([F:21])[C:16]([F:19])([F:18])[F:17])(=[O:6])=[O:5])=[CH2:2]
Reactant: O=S(=O)(CCCl)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 14.3 %

Procedure:
2-(Perfluorooctyl)ethanyl 2-chloroethanyl sulfone (RF =C8F17, 5.74 g, 10.0 mmole) was dissolved in 40 ml of tetrahydrofuran (THF) at 45°, while stirring in a constant temperature oil bath. Triethylamine (1.52 g, 2.10 ml, 15.0 mmole) in 10 ml of THF was added and an exotherm carried the temperature to 51°. A precipitate of white solid triethylammonium chloride immediately began to form. After 1 hour at 45° the slurry was filtered while hot (Buchner funnel), rinsed with diethyl ether twice, and the clear filtrate evaporated on a rotary evaporator. The dry solid Et3N HCl weighed 1.35 g, 98.8% of theory. The evaporated solid 2-(perfluoro-octyl)ethanyl vinyl sulfone was taken to 40°/15 mm and weighed 5.38 g, 100% of theory; mp sinter 92° melt 93°-94.5°. The sulfone was heated further to 155° without evidence of decomposition. The sulfone was soluble in chloroform, and insoluble in carbon tetrachloride, benzene or ligroine (bp 60°-70°). The sulfone dissolved in hot benzene, but was insoluble in hot ligroine. A 1.00 g sample was dissolved in 8.0 ml of benzene by heating on a steam bath, with care to prevent foaming over; 8.0 ml of ligroine was added and the clear, colorless solution when cool gave 0.77 g of solid, mp sinter 94° melt 95°-96°. When concentrated to 4.0 ml volume a fraction, 0.11 g, mp 96°-97° was obtained. The original sample gave a single spot in TLC analysis. The infrared spectrum was identical to that of the C6 homolog of Example 1. The NMR spectrum was consistent with the proposed structure and resembled closely that obtained from the C6 homolog.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](Cl)=[N:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].[OH-:21].[K+]>C(O)(C)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[O:5][C:6]1[C:7](=[O:21])[NH:8][CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13]
Reactant: FC(F)(F)c1ccnc(Cl)c1Oc1cc(Cl)cc(Br)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=c1[nH]ccc(C(F)(F)F)c1Oc1cc(Cl)cc(Br)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a round bottom flask charged with 3-(3-bromo-5-chlorophenoxy)-2-chloro-4-(trifluoromethyl)pyridine (9.1 g, 25.3 mmol) and potassium hydroxide (3.96 g, 70.5 mmol) was added tert-butanol (100 mL). This suspension was placed in an oil bath at 75° C. After 48 hours, the reaction mixture was allowed to cool to room temperature and was quenched with saturated aqueous ammonium chloride (50 mL) and diluted with water (50 mL). The mixture was extracted with ethyl acetate (2×100 mL) and the combined organic fractions were washed with water (3×100 mL). The solvent was evaporated under reduced pressure to yield a solid. This was adsorbed onto silica and purified by column chromatography on a pre-packed silica gel Redi Sep 330 gram column, eluting with 0-5% methanol in CH2Cl2 to give the title compound. 1H NMR (DMSO-d6) δ 12.68 (s, 1H), 7.58 (d, J=6.8 Hz, 1H), 7.44-7.40 (m, 1H), 7.20-7.18 (m, 1H), 7.13-7.10 (m, 1H), 6.47 (d, J=6.8 Hz, 1H). FIRMS (M+1)=367.9295.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=CN=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2].[CH3:17][O:18][C:19]1[N:24]=C2NC=C(C(=O)C)C2=CC=1>>[C:1]([C:4]1[C:12]2[C:7](=[N:24][C:19]([O:18][CH3:17])=[CH:10][CH:11]=2)[N:6]([CH2:13][C:14]([OH:16])=[O:15])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cn(CC(=O)O)c2cnccc12
Reactant: COc1ccc2c(C(C)=O)c[nH]c2n1
Product: COc1ccc2c(C(C)=O)cn(CC(=O)O)c2n1

Procedure:
was prepared using similar procedures as described for the synthesis of (3-acetyl-pyrrolo[2,3-c]pyridin-1-yl)-acetic acid in Scheme A15 from 1-(6-methoxy-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanone. MS (UPLC/MS): 249.2 [M+H]+, 497.3 [2M+H]+, 519.3 [2M+Na]+, 247.1 [M−H]−, 293.2 [M+HCOO]−, 495.3 [2M+HCOO]−; tR (HPLC conditions f): 1.55 min. 1H-NMR (400 MHz, DMSO): δ (ppm): 12.3 (bs, 1H), 8.33 (d, 1H), 8.21 (s, 1H), 6.70 (d, 1H), 3.89 (s, 3H), 3.32 (s, 2H), 2.43 (s, 3H).