Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][OH:11].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26]>O1CCCC1>[Cl:3][C:4]1[CH:18]=[C:17]([C:19]([F:21])([F:20])[F:22])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH2:10][O:11][CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CBr
Reactant: OCc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)COCc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Temperature: 40 °C
Yield: 51 %

Procedure:
3.25 parts by weight of 80% strength sodium hydride were suspended in 100 parts by volume of absolute tetrahydrofuran and a solution of 30 parts by weight of 3-(2'-chloro-4'-trifluoromethylphenoxy)-benzyl alcohol in 50 parts by volume of absolute tetrahydrofuran was then added, a little at a time. The mixture was stirred at 40° C. for half an hour and a solution of 15 parts by weight of methyl bromoacetate in 50 parts by volume of absolute tetrahydrofuran was added. The reaction mixture was then stirred at the boil for 2 hours, and was cooled and concentrated under reduced pressure. The oily residue was taken up in ether, and the organic phase was extracted with water, dried with magnesium sulfate and evaporated down under reduced pressure. Fractional distillation of the residue gave 19 parts by weight (51% of theory) of methyl 3-(2'-chloro-4'-trifluoromethylphenoxy)-benzoxyacetate (compound No. 4) of boiling point 150°-160° C./0.2 bar and refractive index nD25 : 1.5268.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[Cl-].[Al+3].[Cl-].[Cl-].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:9])[C:21]2[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=2)=[O:11])=[CH:20][CH:19]=1
Reactant: O=C(Cl)CCCCCCC(=O)Cl
Reactant: Fc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCCC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
Suberoyl chloride (40.8 g, 0.1933 mol) was added over a 30-45 minute period to a mechanically stirred suspension of aluminum chloride (64.4 g, 0.483 mol) in fluorobenzene (181 ml, 1.93 mol) maintained at 5°-10° C. The yellow slurry was allowed to warm to room temperature and was stirred overnight. The reaction mixture was poured onto approximately 1000 g of ice containing 75 ml of concentrated hydrochloric acid. The resulting suspension was separated by decantation and washed several times with water. The organic layer was distilled to remove excess fluorobenzene and the solid residue collected by filtration, washed with water, and dried at 100° C. The crude solid was recrystallized from approximately 500 ml of toluene to afford 43.0 g (67% yield) of 1,6-bis(4-fluorobenzoyl)hexane; mp 123°-124° C.; 'H NMR (CDCl3) δ1.0-2.1 (m, 8H, CH2), 2.97 (t, 4H, O=CCH2, J=7.0 Hz), 6.9-8.3 (m, 8H, aromatic). Anal. Calcd. for C20H20F2O2 : C, 72.71%; H, 6.10%; F, 11.50%. Found: C, 72.50%; H, 5.86%; F, 11.19%.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[C:13]([Cl:19])=[CH:12][C:11]=2[C:20](=O)[CH3:21])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:29].[Na+]>CO.C(#N)C>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[C:13]([Cl:19])=[CH:12][C:11]=2[CH:20]([NH2:29])[CH3:21])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cncn2c1N1CCN(C(C)=O)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CC(=O)N1CCN(c2c(C(C)N)cc(Cl)c3cncn23)CC1
Temperature: 65 °C
Yield: 87 %

Procedure:
A mixture of 1-[5-(4-acetylpiperazin-1-yl)-8-chloroimidazo[1,5-a]pyridin-6-yl]ethanone (12.6 mg, 0.0393 mmol) (10010-158P) and ammonium acetate (30.3 mg, 0.393 mmol) in methanol (0.4 mL) and acetonitrile (0.4 mL) was heated at 65° C. in a sealed vial for 1 hour. The mixture was cooled to room temperature and sodium cyanoborohydride (7.40 mg, 0.118 mmol) was added. The reaction was heated at 65° C. overnight. The mixture was diluted with methanol and purified on preparative LCMS using pH 10 buffer to give the desired compound (11 mg, 89%). LCMS calculated for C15H21ClN5O (M+H)+: m/z=322.1. found: 321.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=2[N+:17]([O-:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23]>>[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:13][C:12]3[CH:15]=[CH:16][C:9]([S:8][C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=4)=[C:10]([N+:17]([O-:19])=[O:18])[CH:11]=3)[CH2:33][CH2:32]2)[CH:26]=1)=[O:23]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cc1ccc(Sc2ccc(C=O)cc2[N+](=O)[O-])cc1
Product: Cc1ccc(Sc2ccc(CN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)cc2[N+](=O)[O-])cc1

Procedure:
Prepared by Procedure F and Scheme R using 4-[(4-methylphenyl)sulfanyl]-3-nitrobenzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/:e 504.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][CH2:5][CH2:6][OH:7].[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>O1CCCC1.C(OCC)(=O)C>[Si:8]([O:3][CH2:4][CH2:5][CH2:6][OH:7])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: OCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCCO
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a suspension of sodium hydride (0.1 mole) in anhydrous tetrahydrofuran (200 ml) cooled to 0° C. with stirring under an atmosphere of nitrogen is added a solution of 1,3-dihydroxypropane (0.1 mole) in tetrahydrofuran (150 ml) slowly over a period of 1 hour. Then a solution of tert-butyldimethylsilyl chloride (0.1 mole) in tetrahydrofuran (150 ml) is added slowly over a period of 1 hour. Stirring is continued for 6 hours. The mixture is then diluted with ethyl acetate (400 ml), washed with water (100 ml), brine (75 ml), dried and concentrated to afford the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH2:20][OH:21])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>C(Cl)Cl>[C:14]([O:13][C:11]([N:18]1[CH2:24][CH2:23][CH2:22][C@H:19]1[CH:20]=[O:21])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 100.4 %

Procedure:
A 2 L, 3-necked round bottomed flask equipped with an overhead stir and a N2 inlet was charged with a solution of oxalyl chloride (130 mL, 0.26 mol) in DCM (250 mL). The solution was cooled to −78° C., and a solution of DMSO (20 mL, 0.28 mol) in DCM (30 mL) was added dropwise. After 30 minutes, a solution of (S)—N-Boc-prolinol (40 g, 0.20 mol) in DCM (200 mL) was added dropwise. After 30 minutes, TEA (140 mL, 1.00 mol) was added to the solution, and the flask was transferred to an ice/water bath and stirred for another 30 minutes. The reaction mixture was diluted with DCM (200 mL) and washed successively with H2O, 1M HCl, saturated NaHCO3, and brine. The DCM layer was dried over Na2SO4, filtered, and concentrated to afford crude (S)-2-formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (40 g) as an oil, which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][B-](F)(F)F)[C@H:10]([CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[K+].Cl[C:22]1[CH:23]=[C:24]([C:37]2[N:42]=[C:41]([CH3:43])[N:40]=[C:39]([N:44]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=3)[CH2:45][C:46]3[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=3)[N:38]=2)[C:25]([NH:28][C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)=[N:26][CH:27]=1>>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([CH2:45][N:44]([CH2:54][C:55]2[CH:56]=[CH:57][C:58]([O:61][CH3:62])=[CH:59][CH:60]=2)[C:39]2[N:40]=[C:41]([CH3:43])[N:42]=[C:37]([C:24]3[CH:23]=[C:22]([CH2:14][N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@H:10]4[CH3:19])[CH:27]=[N:26][C:25]=3[NH:28][C:29]3[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=3)[N:38]=2)=[CH:51][CH:50]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C[B-](F)(F)F
Agent: [K+]
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)C[C@H]4C)cnc3Nc3ccc(OC)nc3)n2)cc1
Yield: 74.3 %

Procedure:
The title compound was prepared in an analogous manner to that described above in Example 157, Step 1, using potassium (R)-((4-(tert-butoxycarbonyl)-2-methylpiperazin-1-yl)methyl)trifluoroborate and 4-(5-chloro-2-(6-methoxypyridin-3-ylamino)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine to give (R)-tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-3-methylpiperazine-1-carboxylate (188 mg, 0.247 mmol, 74.3% yield) as a yellow syrup. m/z (ESI, +ve ion) 761.7 (M+H)+.
Reaction SMILES: CO.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=6)[CH:38]=5)[C:33]([CH3:46])=[CH:32][C:31]4=[O:47])[CH2:24][CH2:23]3)C(=O)OC(C)(C)C)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1.[ClH:48].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:48].[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:22]3[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][N:30]4[C:39]5[C:34](=[CH:35][CH:36]=[C:37]([C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=6)[CH:38]=5)[C:33]([CH3:46])=[CH:32][C:31]4=[O:47])[CH2:26][CH2:27]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(-c3ccccc3)ccc12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(-c3ccccc3)ccc12
Reaction time: 0.5 h

Procedure:
To 0.4 mL of methanol solution containing 47 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-methyl-2-oxo-7-phenylquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 0.4 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added, and stirred for 30 min. 0.8 mL of methanol and 0.8 mL of 4 mol/L hydrogen chloride/ethyl acetate solution were further added, stirred for 2 hours and allowed to stand at room temperature for 13 hours. Ethyl acetate was added, and the resulting solid was filtered to give 34 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methyl-7-phenylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH3:30])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.CN(C)C1C=CC=CC=1.[Cl:40][C:41]([Cl:46])([Cl:45])[C:42](Cl)=[O:43]>ClCCl>[Cl:40][C:41]([Cl:46])([Cl:45])[C:42]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH3:30])[CH:18]=3)=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)=[O:43]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-(2,2′-dimethyl-biphenyl-4-yl)-methanone of Step C (12.4 g, 31.6 mmol) and N,N-dimethylaniline (6.4 mL, 50.5 mmol) in dry dichloromethane (90 mL) at 0° C. under nitrogen, was added trichloroacetyl chloride (5.3 mL, 47.5 mmol). The reaction was then allowed to warm slowly to room temperature while stirring overnight. The reaction mixture then was washed with 2N hydrochloric acid (2×100 mL), water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a dark foam. Purification by filtration through a plug of silica gel (60 g) eluting with dichloromethane afforded the title compound (15.9 g, 94%) as a light orange solid, m.p. 212-214° C. MS [(+)ESI, m/z]: 537 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.[C:19]([O-])([O-])=O.[K+].[K+].CB(O)O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1
Reactant: COC(=O)c1scc(Br)c1OS(=O)(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB(O)O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1scc(Br)c1C
Temperature: 70 °C
Yield: 83.4 %

Procedure:
To a solution of methyl 4-bromo-3-{[(trifluoromethyl)sulfonyl]oxy}-2-thiophenecarboxylate (825 mg, 2.25 mmol) in dioxane/H2O (5 mL/1 mL) was added K2CO3 (930 mg, 6.75 mmol), tetrakistriphenylphosphine Pd(0) (260 mg, 0.22 mmol), and methylboronic acid (175 mg, 2.91 mmol). The reaction mixture was heated to 70° C. in a sealed tube for 12 h. The reaction solution was concentrated under vacuum and purified on silica gel (hexanes/EtOAc, 9:1) to give the title compound (441 mg, 84%) as a brown solid: LC-MS (ES) m/z 236 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[NH:15]=[C:16]1[N:20]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[C:19](=[O:27])[C:18]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[NH:17]1>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH2:7][N:24]1[CH2:25][CH2:26][CH:21]([N:20]2[C:19](=[O:27])[C:18]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=3)([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[NH:17][C:16]2=[NH:15])[CH2:22][CH2:23]1
Reactant: O=Cc1cc(Cl)ccc1O
Reactant: COc1ccc(C2(c3ccc(OC)cc3)NC(=N)N(C3CCNCC3)C2=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C2(c3ccc(OC)cc3)NC(=N)N(C3CCN(Cc4cc(Cl)ccc4O)CC3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
5-Chlorosalicylaldehyde (0.24 g, 1.53 mmol), sodium cyanoborohydride (0.33 g, 5.25 mmol) and 2-imino-5,5-bis(4-methoxyphenyl)-3-(piperidin-4-yl)imidazolidin-4-one (0.41 g, 1.04 mmol) were dissolved in ethanol and the solution was stirred at room temperature overnight. The mixture was extracted with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified over a silica column (MeOH/DCM=1/20) to give the title compound as a white solid (0.18 g, 33% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH:6]=[CH:5]2.FC(F)(F)C(O)=O>O1CCCC1>[NH:14]1[CH2:15][CH2:16][CH:11]([N:7]2[C:8]3[C:4](=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc3cc(N)ccc32)CC1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc2c(ccn2C2CCNCC2)c1
Yield: 38.6 %

Procedure:
tert-Butyl 4-(5-amino-1H-indol-1-yl)piperidine-1-carboxylate (7.95 mmol, 2.506 g) was stirred in tetrahydrofuran (10 mL)/trifluoroacetic acid (10 mL) at room temperature for 1 hour. The solvent was removed at reduced pressure. The resulting residue was passed down an SCX column to afford the title compound (660 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[CH:28]1.N1CCCCC1>CO>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:28]1
Reactant: CC(C)(C)OC(=O)N1CCCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]-1,4-diazepane-1-carboxylate (0.142 g, 0.392 mmol) in methanol (2 mL) was added with 1H-indole-3-carboxaldehyde (0.0569 g, 0.392 mmol) and piperidine (0.00334 g, 0.0392 mmol), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was subjected to silica gel column chromatography (chloroform/methanol). The resulting solid crude product was washed with a mixed solvent of hexane and ethyl acetate to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)-1,4-diazepane-1-carboxylate (0.141 g, 73%).
Reaction SMILES: [C:1]([C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[C:14]([NH:15][CH2:16][C:17]3[C:22]([CH3:23])=[CH:21][C:20]([F:24])=[CH:19][C:18]=3[CH3:25])[C:9]2=[N:8][C:7]=1[CH3:26])(OCC)=[O:2].O.O.O.O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C1(C)C=CC=CC=1>[CH3:23][C:22]1[CH:21]=[C:20]([F:24])[CH:19]=[C:18]([CH3:25])[C:17]=1[CH2:16][NH:15][C:14]1[C:9]2[N:10]([C:6]([CH2:1][OH:2])=[C:7]([CH3:26])[N:8]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1c(C)nc2c(NCc3c(C)cc(F)cc3C)cccn12
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(F)cc(C)c1CNc1cccn2c(CO)c(C)nc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
A solution of 0.6 g (1.7 mmol) of 3-carboethoxy-8-(2,6-dimethyl-4-fluorobenzylamino)-2-methylimidazo[1,2-a]pyridine in 30 ml toluene was cold with ice-water. Red-l 65% 2.1 g (6.6 mmol) in toluene was added during 30 min. The solution was stirred 1 h at rt. 25 ml of Rochelle-salt solution, (35 g sodium potassium tartrate tetrahydrate/250 ml water) was added dropwise and the organic layer was separated. The water layer was washed with methylene chloride which was separated. The combined organic solvents were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluent dichloromethane:methanol 95:5, to give 0.42 g, (79%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([F:11])[CH:4]=1.[CH3:12][O:13][C:14]1[CH:34]=[CH:33][C:17]([CH2:18][NH:19][S:20]([C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[F:11][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[O:9][CH3:10])[CH2:2][N:19]([CH2:18][C:17]1[CH:33]=[CH:34][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1)[S:20]([C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=1)(=[O:22])=[O:21]
Reactant: COc1ccc(CBr)cc1F
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc(OC)cc2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)c(F)c2)S(=O)(=O)c2ccc(C(=O)O)cc2)cc1

Procedure:
Prepared as in example 5-10 from 4-(bromomethyl)-2-fluoro-1-methoxybenzene and methyl 4-(N-(4-methoxybenzyl)sulfamoyl)benzoate (example 5-10b). MS (M−H, 458.10); NMR (400 MHz, CD3OD): δ, ppm: 3.73 (s, 3H), 3.80 (s, 3H), 4.24 (s, 2H), 4.28 (s, 2H), 6.75 (m, 4H), 6.88 (m, 1H), 6.97 (d, 2H, J=8.6 Hz), 7.88 (d, 2H, J=8.3 Hz), 8.14 (d, 2H, J=8.3 Hz).
Reaction SMILES: C[Si]([N:5]=[C:6]=[O:7])(C)C.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH:19]([CH2:21][NH:22][C:23]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[O:24])[O:18][C:17]2=[O:31])=[CH:12][CH:11]=1.CCOCC>ClCCl>[NH2:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:20][CH:19]([CH2:21][NH:22][C:23]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[O:24])[O:18][C:17]2=[O:31])=[CH:12][CH:11]=1)=[O:7]
Reactant: NCc1ccc(N2CC(CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Reactant: C[Si](C)(C)N=C=O
Solvent: ClCCl
Solvent: CCOCC
Product: NC(=O)NCc1ccc(N2CC(CNC(=O)c3ccc(Cl)s3)OC2=O)cc1
Reaction time: 8 h

Procedure:
At room temperature, 0.19 ml (0.82 mmol) of trimethylsilylisocyanate are added dropwise to a mixture of 30 mg (0.082 mmol) of N-({3-[4-(aminomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)-5-chloro-2-thiophene-carboxamide (from Example 148) in 1.0 ml of dichloromethane. The mixture is stirred overnight and, after addition of ether, the product is then obtained by filtration. Yield: 21.1 mg (52% of theory),
Reaction SMILES: C(N(CC)CC)C.[NH:8]([CH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:20])(=[O:19])[NH:11]1)[NH2:9].[O:21]([C:28](Cl)=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1>[O:21]([C:28]([NH:9][NH:8][CH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[S:12](=[O:20])(=[O:19])[NH:11]1)=[O:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NNC1NS(=O)(=O)c2ccccc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(NNC1NS(=O)(=O)c2ccccc21)Oc1ccccc1
Reaction time: 2 h
Yield: 80.2 %

Procedure:
5 g (0.05 mol) of triethylamine are added to 9.8 g (0.05 mol) of 3-hydrazino-2H,3H-1,2-benzisothiazole 1,1-dioxide in 100 ml of dioxane, and 8.6 g (0.55 mol) of phenoxycarbonyl chloride, dissolved in 25 ml of dioxane, are then added dropwise to the stirred mixture. After about 2 hours, the precipitated salt is filtered off under suction and washed with 15 ml of cold dioxane, and the combined mother liquors are evaporated down. Crystallization from ethanol gives 12.8 g (81% of theory) of 3-phenoxycarbonylhydrazino-2H,3H-1,2-benzisothiazole 1,1-dioxide of melting point 216° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]([CH3:18])[C:11](=[O:19])[CH:10]=2)=[C:4]([F:20])[CH:3]=1.FC1C=C(I)C=CC=1NC1C([N+]([O-])=O)=CNC(=O)C=1.C1C(=O)N([Cl:47])C(=O)C1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]([CH3:18])[C:11](=[O:19])[C:10]=2[Cl:47])=[C:4]([F:20])[CH:3]=1
Reactant: Cn1cc([N+](=O)[O-])c(Nc2ccc(Br)cc2F)cc1=O
Reactant: O=C1CCC(=O)N1Cl
Agent: O=c1cc(Nc2ccc(I)cc2F)c([N+](=O)[O-])c[nH]1
Solvent: CN(C)C=O
Product: Cn1cc([N+](=O)[O-])c(Nc2ccc(Br)cc2F)c(Cl)c1=O
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 77 %

Procedure:
A suspension of 4-(4-Bromo-2-fluoro-phenylamino)-1-methyl-5-nitro-1H-pyridin-2-one (451 mg, 1.323 mol), synthesized using the same procedures as for the synthesis of 4-(2-Fluoro-4-iodophenylamino)-5-nitropyridin-2(1H)-one, and NCS (286 mg, 2.14 mmol) in dry DMF (13 mL) was heated to 50° C. The solution became clear in 5 minutes, and the solution turned into light orange. The heating was continued over the 48 hours. At this time, LC/MS indicated there was 77% of the title product in the reaction mixture. The heating temperature was then raised to 70° C. and kept at that temperature for additional 4 hours. Water was added until the yellow precipitate formed. The stirring was continued at r.t. for 30 min. The precipitate was then filtered, washed with water (5 mL) and dried under high vacuum overnight. The title compound was used for the next reaction without further purification. (424 mg, 85% yield).