Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([OH:19])=O)=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([F:12])[CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:54][CH2:55][C:56]([NH2:59])([CH3:58])[CH3:57]>CN(C=O)C.O>[NH2:59][C:56]([CH3:58])([CH3:57])[CH2:55][NH:54][C:17]([C:13]1[N:8]2[CH:9]=[C:10]([F:12])[CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:2]([F:1])=[CH:23][CH:22]=[CH:21][C:20]=3[F:24])[C:7]2=[N:15][C:14]=1[CH3:16])=[O:19]
Reactant: CC(C)(N)CN
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cc(F)cn2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(F)cn2c1C(=O)NCC(C)(C)N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
45 mg of 8-[(2,6-difluorobenzyl)oxy]-6-fluoro-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid Example 11A, 0.13 mmol, 1 equivalent), 65 mg of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU, 0.2 mmol, 1.5 equivalents) and 54 mg of 4-methylmorpholine (0.54 mmol, 4 equivalents) were initially charged in 0.9 ml of DMF. After 10 min at RT, 24 mg of 1,2-diamino-2-methylpropane (0.27 mmol, 2 equivalents) were added and the mixture was stirred at RT overnight. Another 22 mg equivalents of TBTU (0.07 mmol, 0.5 equivalents) and 12 mg of 1,2-diamino-2-methylpropane (0.13 mmol, 1 equivalent) were added and the reaction was stirred at RT for 2 h. Water was added and the reaction solution was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The residue was taken up in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate. The mixture was filtered and concentrated and the crude product obtained was purified by thick-layer chromatography (mobile phase: dichloromethane/2 N ammonia in methanol: 10:0.5). This gave 31 mg of the title compound (55% of theory; purity 98%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][C:11]1[C:12]([C:29]([CH3:32])([CH3:31])[CH3:30])=[C:13]([CH2:26][CH2:27][CH3:28])[C:14]2[O:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]=2[C:21]=1[C:22]([CH3:25])([CH3:24])[CH3:23])(=O)C.O>O1CCCC1>[OH:10][C:11]1[C:12]([C:29]([CH3:30])([CH3:32])[CH3:31])=[C:13]([CH2:26][CH2:27][CH3:28])[C:14]2[O:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]=2[C:21]=1[C:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: CCCc1c2c(c(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C)CC(C)(C)O2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCc1c2c(c(C(C)(C)C)c(O)c1C(C)(C)C)CC(C)(C)O2
Temperature: 25 °C
Yield: 32.1 %

Procedure:
Lithium aluminum hydride (0.08 g) was suspended in tetrahydrofuran (5 ml) under a nitrogen atmosphere. A solution of 5-acetoxy-4,6-di-tert-butyl-2,2-dimethyl-7-propyl-2,3-dihydrobenzofuran (0.60 g) in tetrahydrofuran (5 ml) was added dropwise to the suspension and the mixture was refluxed for 4 h. After cooling the reaction mixture to room temperature, water was added dropwise to quench the excess lithium aluminum hydride. Thereafter 1N aqueous sodium hydroxide (5 ml) was added and the mixture was subjected to extraction with diethyl ether, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (5% ethyl acetate in n-hexane) to afford 5-hydroxy-4,6-di-tert-butyl-2,2-dimethyl-7-propyl-2,3-dihydrobenzofuran [0.17 g (yield, 32%)] as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([O:10][CH3:11])=[N:8][C:7]([Br:12])=[CH:6][N:5]=1.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.Cl>C(COC)OC.O>[Br:12][C:7]1[N:8]=[C:9]([O:10][CH3:11])[C:4]([NH:3][S:19]([C:14]2[C:13]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:21])=[O:20])=[N:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Reactant: COc1nc(Br)cnc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1-c1ccccc1
Reaction time: 0.25 h
Yield: 55.3 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.198 g) was suspended in dimethoxyethane (5 ml) and 2-amino-5-bromo-3-methoxypyrazine (0.405 g) was added with stirring. After 15 minutes, 2-biphenylsulphonyl chloride (0.5 g) was added and the mixture was stirred for 18 hours. The reaction mixture was poured into water (20 ml) and acidified to pH2 with concentrated hydrochloric acid and extracted with ethyl acetate (3×25 ml). The combined organic extracts were evaporated and the residue was purified by flash chromatography on silica gel (30 g), eluting with hexane/ethyl acetate/glacial acetic acid (160/40/1 v/v), to give N-(5-bromo-3-methoxy-2-pyrazinyl)-2-biphenylsulphonamide (0.46 g); 1H NMR (d6 -DMSO): 3.82(s,3H), 7.2-7.4(m,6H), 7.53-7.7(m,2H), 7.78(s,1H), 8.08(dd,1H), 10.33(br,1H); mass spectrum (+ve FAB, methanol/NBA): 420(M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1)[C:2]#[CH:3].[NH4+].[Cl-]>CCO.O.[Fe]>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[C:2]#[CH:3]
Reactant: C#CCOc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: C#CCOc1ccc(N)cc1

Procedure:
4-(Prop-2-ynyloxy)nitrobenzene (0.910 g, 5.13 mmol), iron (1.42 g, 25.3 mmol), and NH4Cl (0.719 g, 12.8 mmol) were vigorously stirred in EtOH/water (1:1, 55 mL) at 70° C. for 15 minutes. The reaction mixture was filtered hot through Celite and concentrated in vacuo. The residue was suspended in 10% 2N ammoniacal methanol in dichloromethane, sonicated, and filtered through Celite. Concentration gave 4-(prop-2-ynyloxy)aniline as a brown oil which was used without further purification. In general, isolated prop-2-ynyloxyanilines were unstable and were therefore used immediately after the second filtration. 1H NMR (CDCl3): δ 6.82 (d, J=8.7 Hz, 2H), 6.64 (d, J=8.7 Hz, 2H), 4.61 (d, J=2.4 Hz, 2H), 2.50 (t, J=2.4 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:47])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:45][CH3:46])=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[CH:25]=[CH:24][CH:23]=5)[C:19]4[CH:32]=[CH:33][N:34]([S:35]([C:38]5[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=5)(=[O:37])=[O:36])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:48][CH:49]([NH2:51])[CH3:50]>C1COCC1.C(OCC)(=O)C>[CH3:47][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:45][CH3:46])=[C:12]([NH:15][C:16]3[N:29]=[C:20]([NH:21][C:22]4[CH:23]=[CH:24][CH:25]=[C:26]([F:31])[C:27]=4[C:28]([NH:51][CH:49]([CH3:50])[CH3:48])=[O:30])[C:19]4[CH:32]=[CH:33][N:34]([S:35]([C:38]5[CH:39]=[CH:40][C:41]([CH3:44])=[CH:42][CH:43]=5)(=[O:37])=[O:36])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cccc(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Reactant: CC(C)N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(=O)NC(C)C)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Temperature: 40 °C
Reaction time: 16 h

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (265 mg, 0.404 mmol) in THF (5 mL) was added (1-methylethyl)amine (0.694 mL, 8.08 mmol). The resulting mixture was let stir at 40° C. for 16 h at which time it was diluted with ethyl acetate and washed with a saturated ammonium chloride solution, a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure. Residue was purified via SiO2 chromatography to afford 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-(1-methylethyl)benzamide. (210 mg, 0.294 mmol) as a yellow solid. (ESIMS (M+H)+=715)
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16](=[O:32])[C:17]1[CH:22]=[C:21](I)[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:33][Si:34]([C:37]#[CH:38])([CH3:36])[CH3:35].[Al]>CN(C=O)C.C(OCC)(=O)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)I>[CH2:8]([O:15][C:16](=[O:32])[C:17]1[CH:22]=[C:21]([C:38]#[C:37][Si:34]([CH3:36])([CH3:35])[CH3:33])[CH:20]=[CH:19][C:18]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OCc1ccccc1)c1cc(I)ccc1OCc1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: [Al]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Reaction time: 8 h
Yield: 93.2 %

Procedure:
Pd(PPh3)2Cl2 (194 mg, 0.277 mmol), copper iodide (106 mg, 0.554 mmol) and triethylamine (0.8 mL, 5.44 mmol) were added to a solution of 2-benzyloxy-5-iodo-benzoic acid benzyl ester (1.23 g, 2.77 mmol) and trimethylsilyl acetylene (0.5 mL, 3.32 mmol) in anhydrous DMF (15 mL) at room temperature. The flask was covered with aluminum foil and stirred overnight. The mixture was diluted with ethyl acetate (50 mL) and washed with water (3×), 1N HCl (1×) and brine (1×), dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography (5% ethyl acetate/hexanes) to afford 1.07 g (93%) of the title compound as an oil. 1H NMR (400 MHz, CDCl3) δ 7.98 (d, 1H, J=2 Hz); 7.52 (dd, 1H, J=9.1, 1 Hz); 7.38 (m, 10H); 6.95 (d, 1H, J=9.1 Hz); 5.31 (s, 2H); 5.17 (s, 2H); 0.1 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:13][C:14]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)[CH2:9][CH2:10][CH2:11][CH3:12]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:13][C:14]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][NH:16][CH2:15]1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCOC1(c2ccccc2)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCOC1(c2ccccc2)CNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
5.5 ml of trifluoroacetic acid are added to a solution containing 3.34 g (10 mmol) of 3-pentoxy-3-phenyl-1-(tert-butoxycarbonyl)azetidine dissolved in 10 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 2 hours 30 min and then concentrated. The crude product obtained is purified by silica gel chromatography (eluent 90/10 dichloromethane/methanol). 3.5 g in the form of a pale yellow oil are obtained with a yield of 100%.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Li+].[CH3:17][CH:18]([N-]C(C)C)C.ICC>C1COCC1>[CH2:3]([CH:2]([CH2:17][CH3:18])[C:1]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=1)=[O:5])[CH3:4]
Reactant: CCCC(=O)c1ccc(NC(C)=O)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(CC)C(=O)c1ccc(NC(C)=O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of N-(4-butyrylphenyl)acetamide (3 g, 14.6 mmol) in THF (300 mL) was added 2.0 M LDA in THF (18.3 mL) at −78° C. and then the reaction mixture was stirred for 1 h at −78° C. Iodoethane was added and stirred overnight at RT. The reaction mixture was quenched with sat. aq. NH4Cl and then extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and then concentrated. The crude product was purified by preparative TLC using 50% ethyl acetate in hexane as eluent to afford N-(4-(2-ethylbutanoyl)phenyl)acetamide as white solid. MS (ES+): m/z 234.28 (MH+).
Reaction SMILES: [CH3:1][N:2]([C:4]1[C:9]2[CH2:10][C@@H:11]3[C:21]([C:22](=[O:23])[C:8]=2[C:7]([OH:33])=[CH:6][CH:5]=1)=[C:20]([OH:24])[C@@:19]1([OH:25])[C@H:13]([C@H:14]([N:30]([CH3:32])[CH3:31])[C:15]([OH:29])=[C:16]([C:26]([NH2:28])=[O:27])[C:17]1=[O:18])[CH2:12]3)[CH3:3].[OH2:34].[ClH:35].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=[O:41]>CO>[CH3:32][N:30]([C@@H:14]1[C:15](=[O:29])[C:16]([C:26]([NH2:28])=[O:27])=[C:17]([OH:18])[C@:19]2([OH:25])[C@H:13]1[CH2:12][C@H:11]1[C:21]([C:20]2=[O:24])=[C:22]([OH:23])[C:8]2[C:9](=[C:4]([N:2]([CH3:3])[CH3:1])[CH:5]=[CH:6][C:7]=2[OH:33])[CH2:10]1)[CH3:31].[OH2:41].[OH2:34].[ClH:35]
Reactant: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Reactant: CN(C)c1ccc(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Agent: Cl
Solvent: O
Solvent: CO
Product: CN(C)c1ccc(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Yield: 99.4 %

Procedure:
Ten grams of a crude minocycline [HPLC. purity, 94.8% (percentage area)] was suspended at 15° to 20° C. in a mixed solvent of 30 ml of water and 45 ml of methanol and dissolved at a pH of 0.8 to 1.0 by adding conc. hydrochloric acid with stirring. Subsequently, 1 g of activated carbon and 10 mg of EDTA.2Na were added, and after 30 minutes' stirring, the activated carbon was separated by filtration. To the filtrate was added dropwise a 5% aqueous sodium hydroxide solution to adjust the pH of the filtrate to 4.0, whereby minocycline precipitated in the form of a hydrochloride. This hydrochloride was separated by filtration and dried in vacuo to obtain 11.0 g of a purified minocycline hydrochloride dihydrate [HPLC. purity, 99.4% (area percentage)].
Reaction SMILES: [CH:1]1[N:6]=[C:5]([Cl:7])[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[CH3:20][C:21]1[N:22]([CH2:26][CH2:27][NH2:28])[CH:23]=[CH:24][N:25]=1.C(N(CC)CC)C>C(O)C>[ClH:7].[CH3:20][C:21]1[N:22]([CH2:26][CH2:27][NH:28][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[CH:23]=[CH:24][N:25]=1
Reactant: Cc1nccn1CCN
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nccn1CCNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Cl
Yield: 55 %

Procedure:
A suspension was prepared containing 1.64 g (5.74 mmol) of 6-chloropurine riboside in 12 ml of absolute ethanol. To the solution was added 0.72 g (5.7 mmol) of 2-(2-methyl-imidazol-1-yl) ethylamine (prepared in accordance with Z.Obsch. Chim. 11, 545 (1941); Chem Ab. 1941 6938) and 0.81 g (8.0 mmol) of triethylamine. The reaction mixture was heated under reflux for 77 hours. The solvent was removed in vacuo and chromatography of the residue on silica gel was performed by eluting with a mixture of 22 parts methanol, 88 parts methylene chloride, and one part ammonium hydroxide. The title compound was obtained as the free base yielding 1.2 g (55% yield). This material was converted to the hydrochloride salt by suspending in 20 ml of water at 0° and adding 1 normal hydrochloric acid until a pH of 2.6 was attained. The solution was frozen and lyophilized giving a white powder which was passed through a column of cellulose powder eluting with a mixture of 85 parts n-butanol and 15 parts water. The appropriate fractions were combined and concentrated to give a glass which was azeotroped twice with water and then dissolved in water, frozen and lyophilized giving 1.1 g (44% yield) of the title compound as a white powder.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:27])=[C:23]([Cl:26])[C:24]=3[Cl:25])=[O:19])[CH2:13][CH2:12]2)[CH:5]=1)(=O)[CH3:2].N1C=CC=CC=1.Cl.[NH2:35][OH:36]>CCO>[Cl:25][C:24]1[C:23]([Cl:26])=[C:22]([CH3:27])[NH:21][C:20]=1[C:18]([NH:17][CH:14]1[CH2:15][CH2:16][N:11]([C:6]2[CH:5]=[C:4](/[C:1](=[N:35]/[OH:36])/[CH3:2])[CH:9]=[C:8]([Cl:10])[N:7]=2)[CH2:12][CH2:13]1)=[O:19]
Reactant: NO
Reactant: CC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C/C(=N\O)c1cc(Cl)nc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[1-(4-Acetyl-6-chloropyridin-2-yl)piperidin-4-yl]-3,4-dichloro-5-methyl-1H-pyrrole-2-carboxamide (Example 115) (49 mg, 0.114 mmol) was dissolved in EtOH (2 ml). Pyridine (74 μl, 0.913 mmol) was added followed by hydroxylamine hydrochloride (63.4 mg, 0.913 mmol). The mixture was stirred at room temperature overnight. The product was purified by semi-prep reverse phase HPLC eluting with CH3CN/H2O (0.1% TFA). (28 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:14]C(=O)OC(C)(C)C)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.ClS([N:26]=[C:27]=[O:28])(=O)=O.O.C(=O)([O-])O.[Na+]>C(#N)C>[C:27](=[O:28])([O:1][CH2:2][CH:3]([NH2:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)[NH2:26]
Reactant: CC(C)(C)OC(=O)NC(CO)c1cccc(C(F)(F)F)c1
Reactant: O=C=NS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NC(=O)OCC(N)c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Of the compound from Example 59A, 93 mg (0.31 mmol) were introduced in 4 ml of acetonitrile under argon. At −15° C., 37 μl (0.43 mmol) of chlorosulphonyl isocyanate were added dropwise. After 30 min, the reaction solution was admixed with 8 ml of water and heated at 60° C. overnight. The reaction mixture was cooled and introduced into saturated sodium hydrogen carbonate solution. It was extracted with twice 10 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and freed from the solvent on a rotary evaporator. Drying in an HV gave 66 mg (64% of theory) of the title compound in 73% purity.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[C:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2C=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2C=O)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([OH:42])([C:38](F)(F)F)=[O:37].[H-].[Na+].C(Br)C1C=CC=CC=1.C[N:54](C=O)C>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17](=[NH:54])[NH2:18])[CH:15]=2)[C:10]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[C:38]([C:36]([OH:42])=[O:37])=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(-c2ccccc2Cc2cn(Cc3ccccc3)c3cc(C#N)ccc23)c(C=O)c1
Reactant: O=C(O)C(F)(F)F
Agent: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2ccccc2Cc2cn(Cc3ccccc3)c3cc(C(=N)N)ccc23)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.21 h
Yield: 83 %

Procedure:
Part A. 1-benzyl-3-(2′-formyl-4′-methoxy-biphenyl-2-ylmethyl)-1H-indole-6-carbonitrile: The compound of Example 1, Part B (0.1 g, 0.27 mmol) was dissolved in 2 mL DMF and cooled to 0° C. in an ice bath. To the cold solution was added sodium hydride (60% in oil, 12 mg, 0.30 mmol), and the mixture was stirred for 10-15 min followed by addition of benzyl bromide (0.036 ml, 0.30 mmol). The reactoin was then stirred overnight at rt. Work-up and chromatography provided the N-benzylindole (0.1 g, 83%) as a white solid. LRMS m/z 457.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([NH2:17])=[O:16])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:18][C:19]([F:31])([F:30])[O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[F:8][C:7]1[C:2]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][C:19]([F:18])([F:31])[F:30])=[CH:3][C:4]([N:9]2[C:13]([CH3:14])=[CH:12][C:11]([C:15]([NH2:17])=[O:16])=[N:10]2)=[CH:5][CH:6]=1
Reactant: Cc1cc(C(N)=O)nn1-c1ccc(F)c(Cl)c1
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cc(C(N)=O)nn1-c1ccc(F)c(-c2ccccc2OC(F)(F)F)c1
Temperature: 95 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
To a solution of the carboxamide (from step 2) (0.063 g, 0.2 mmol) and 2-trifluromethoxyphenyl boronic acid (0.076 g, 0.37 mmol) in dioxane (1 mL) were added NiCl2(dppf)2 (0.002 g, 1 mole %) and potassium phosphate (0.158 g, 0.74 mmol) and the mixture was stirred at 95° C. for 16 hours. After cooling, the reaction was partitioned between EtOAc and water. The organic phase was washed with saturated sodium bicarbonate, brine and then dried over sodium sulfate. The crude product, obtained upon concentration of the organic phase, was purified by reverse phase HPLC (acetonitrile/water system) (gradient: 10% to 90% acetonitrile over 10 minutes) to yield the titled product (0.009 g, 9.5%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH:9]=[N:10]2)=[CH:5][CH:4]=1.C1C=C(Cl)C=C(C(OO)=[O:31])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=3)[CH:9]=[N+:10]2[O-:31])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(-c2cnc3cc(OC)ccc3c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2cc3ccc(OC)cc3[n+]([O-])c2)cc1
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A mixture of methyl 4-(7-methoxyquinolin-3-yl)benzoate (632 mg, 2.16 mmol), m-CPBA (742 mg, 4.31 mmol) and DCM (10 mL) was stirred overnight. Saturated Na2CO3 solution was added and adjusted the pH>7, the organic layer was washed with water (50 mL×2), dried over NaSO4 and evaporated in vacuo to give the crude product as a yellow solid (540 mg, 81.0%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([OH:20])=[O:19])=[CH:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([O:20][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:19])=[CH:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)O)cc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)OCc3ccccc3)cc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
A solution of compound 31 (2.03 g, 7.4 mmol) in DMF (50 mL) was treated with sodium bicarbonate (1.8 g, 21.4 mmol), and benzyl bromide (4 mL, 33.6 mmol). The reaction mixture was stirred for 18 h at room temperature. Water (50 mL) was added and the product was extracted with ethyl acetate (80 mL×3). The solution was dried with sodium sulfate, concentrated in vacuo to give compound 32 (2.27 g, 84% yield) as a white solid. m.p.180°-182° C. 1H NMR (DMSO-d6, ppm): 11.93 (s, 1 H, NH), 7.51-7.02 (m, 9 H, Ar--H), 5.38 (s, 2 H, CH2C6 H5), 1,48 (s, 9 H, C(CH3)3). Anal. (C21H22 N2O4 0.25H2O), C, H, N.
Reaction SMILES: O[C:2]1[CH:16]=[CH:15][C:5]2[N:6](C3C=CC=CC=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.C1COCC1.[CH3:22][N:23]([CH:25]=[O:26])[CH3:24].[H-].[Na+].CN(C)C(Cl)=[S:32]>C1COCC1>[CH3:22][N:23]([CH3:24])[C:25](=[S:32])[O:26][C:7]1[NH:8][C:4]2[CH:3]=[CH:2][CH:16]=[CH:15][C:5]=2[N:6]=1
Reactant: CN(C)C=O
Reactant: CN(C)C(=S)Cl
Reactant: Oc1ccc2c(c1)ncn2-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=S)Oc1nc2ccccc2[nH]1
Temperature: 60 °C
Yield: 65 %

Procedure:
A solution of 5-hydroxy-1-phenylbenzimidazole (Example 14) (0.88 g, 4.10 mmol) in 1:1 THF/DMF (15 mL) was added dropwise under nitrogen to a stirred suspension of NaH (0.24 g of a 50% dispersion in oil, 5.00 mmol) in THF (10 mL). After 10 minutes a solution of dimethylthiocarbamyl chloride (0.57 g, 4.6 mmol) in THF (5 mL) was added and the solution was warmed at 60° C. for 1 hour. The cooled solution was partitioned between ether and 2N KOH and the organic portion was worked up and chromatographed on silica. Elution with EtOAc/petroleum ether (7:3) gave the O-benzimidazolyl dimethylthiocarbamate (0.76 g, 65%), mp (EtOAc/petroleum ether) 173-174.5° C.