Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([O:25][CH:26]3[CH2:30][CH2:29][NH:28][CH2:27]3)[CH:24]=1)[C:12]2([CH3:32])[CH3:31].CCN(CC)CC.C(Cl)(=O)C>O>[C:3]([N:28]1[CH2:29][CH2:30][CH:26]([O:25][C:23]2[CH:24]=[C:19]([N:13]3[C:12]([CH3:32])([CH3:31])[C:11]4[C:15](=[CH:16][CH:17]=[C:9]([Cl:8])[CH:10]=4)[C:14]3=[O:18])[CH:20]=[N:21][CH:22]=2)[CH2:27]1)(=[O:4])[CH3:2]
Reactant: CC1(C)c2cc(Cl)ccc2C(=O)N1c1cncc(OC2CCNC2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Oc2cncc(N3C(=O)c4ccc(Cl)cc4C3(C)C)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.9 %

Procedure:
To a solution of 5-chloro-3,3-dimethyl-2-[5-(pyrrolidin-3-yloxy)-pyridin-3-yl]-2,3-dihydro-isoindol-1-one trifluoro acetic acid salt (94.2 mg, 0.2 mmol) was added Et3N (1 mmol) and acetyl chloride (23.4 mg, 0.3 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 1 hour before it was poured into H2O (1 mL) and extracted with EtOAc (15 mL×2). The combined organic layers were washed with brine, dried over anhy. Na2SO4, filtered and concentrated in vacuo to give a crude product which was purified by PrepHPLC to give the title compound (25.5 mg, 35%) as a white solid. MS: 400.2 (M+H+).
Reaction SMILES: [F:1][C:2]1([F:32])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C@@H:22]2CN2CCCC2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].CS(O[CH2:40][C:41]([F:44])([F:43])[F:42])(=O)=O.[CH3:45][N:46](C)[CH:47]=O>>[F:1][C:2]1([F:32])[CH2:3][CH2:4][N:5]([C:8]([C:10]2[N:11]([CH2:40][C:41]([F:44])([F:43])[F:42])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][C@@H:23]([N:46]([CH3:47])[CH3:45])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]1
Reactant: CN(C)C=O
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: O=C(c1cc2cc(C(=O)N3CCC[C@@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Agent: [H-]
Agent: [Na+]
Product: CN(C)[C@@H]1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3CC(F)(F)F)C1
Yield: 85 %

Procedure:
The title compound was synthesized in analogy to example 51, from [2-(4,4-difluoro-piperidine-1-carbonyl)-1H-indol-5-yl]-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (example 43), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a white foam (85%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH:47]=O)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:51][C@@H:52]1[CH2:57][NH:56][CH2:55][C@H:54]([CH3:58])[NH:53]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:49][CH3:50])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:41]5[CH:46]=[CH:45][CH:44]=[C:43]([CH2:47][N:56]6[CH2:55][C@H:54]([CH3:58])[NH:53][C@H:52]([CH3:51])[CH2:57]6)[CH:42]=5)[CH:36]=[CH:37][C:38]=4[O:39][CH3:40])=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(C=O)c3)ccc2OC)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)ccc2OC)c1
Yield: 67.6 %

Procedure:
N-{[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-{[3′-formyl-4-(methyloxy)-3-biphenylyl]methyl}-1,3-benzenedicarboxamide (54 mg, 0.00008 mol) in DCM, (2R,6S)-2,6-dimethylpiperazine (13.7 mg, 0.00012 mol) and sodium triacetoxyborohydride (34 mg., 0.00016 mol) and AcOH (6 uL) were agitated overnight on a shaker. LC-MS was used to monitor the reaction. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky white solid [41.8 mg (67.6%)]. LC-MS m/z 773 (M+H)+.
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7](C)=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH3:12][O:13][C:14]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([O:22][CH3:23])=[C:16]([CH3:24])[C:15]=1[CH2:25][CH2:26][C@:27]([CH3:31])([OH:30])[CH2:28][OH:29].N1C=CC=C[CH:33]=1.Cl>C(Cl)Cl>[CH3:12][O:13][C:14]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([O:22][CH3:23])=[C:16]([CH3:24])[C:15]=1[CH2:25][CH2:26][C@:27]([CH3:31])([OH:30])[CH2:28][O:29][S:1]([C:4]1[C:5]([CH3:33])=[CH:6][CH:7]=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: c1ccncc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)CO)c1C
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(C)c(OC)c(CC[C@](C)(O)COS(=O)(=O)c2ccccc2C)c1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
237 mg of tosyl chloride and 350 mg of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1,2-butanediol are dissolved in 1 ml of methylene chloride. 0.180 ml of pyridine are then added dropwise at 0° C. and the mixture is left to stand at 0° C. for 1 hour and then at room temperature for 16 hours. Thereupon, 1 g of ice and 0.3 ml of concentrated hydrochloric acid are added. The mixture is then extracted with methylene chloride, and the extract is dried and concentrated. There are obtained 511 mg (95%) of (S)-4-(2',5'-dimethoxy-3',4',6'-trimethylphenyl)-2-methyl-1-toluenesulphonyloxy-2-butanol.
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][N:8]1[CH:12]=[C:11]([C:13](=[O:23])[N:14]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])[N:10]=[C:9]1[C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=1[C:34]([N:36]1[CH2:45][CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:37]1)=[O:35])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:19]([N:14]([CH2:15][CH2:16][CH2:17][CH3:18])[C:13]([C:11]1[N:10]=[C:9]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=2[C:34]([N:36]2[CH2:45][CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH2:37]2)=[O:35])[N:8]([CH2:7][C:6]([OH:46])=[O:5])[CH:12]=1)=[O:23])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN(CCCC)C(=O)c1cn(CC(=O)OC(C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCN(CCCC)C(=O)c1cn(CC(=O)O)c(-c2ccc(C(=O)OC)cc2C(=O)N2CCc3ccccc3C2)n1
Reaction time: 1 h
Yield: 79.1 %

Procedure:
To a solution of methyl 4-(1-(2-tert-butoxy-2-oxoethyl)-4-(dibutylcarbamoyl)-1H-imidazol-2-yl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (300 mg, 0.44 mmol) in DCM (3.0 mL) was added trifluoroacetic acid (3.0 mL) at 0° C. The reaction mixture was allowed to room temperature and stirring was continued for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was dissolved in DCM and washed with sat. NaHCO3 solution. The organic layer was dried over Na2SO4 and concentrated to give the title compound (200 mg, 80%). MS(ESI) m/z 575.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([OH:15])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1.FC(F)(F)C(O[C:26]1[C:31]([F:32])=[C:30]([F:33])[C:29]([F:34])=[C:28]([F:35])[C:27]=1[F:36])=O.N1C=CC=CC=1>C1COCC1>[F:1][C:2]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:3]=1[NH:4][C:5]1[C:6]([C:13]([O:15][C:26]2[C:27]([F:36])=[C:28]([F:35])[C:29]([F:34])=[C:30]([F:33])[C:31]=2[F:32])=[O:14])=[CH:7][N:8]([CH3:12])[C:9](=[O:11])[CH:10]=1
Reactant: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)O)c(F)c1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1
Yield: 90 %

Procedure:
4-(2-Fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and pentafluorophenyl trifluoroacetate were reacted in the presence of pyridine in THF as for example 4, step A. The crude residue was purified by flash chromatography on silica gel (60% EtOAc/Hexane) to give 2,3,4,5,6-pentafluorophenyl 4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (90%). 1H NMR [400 MHz, (CD3)2SO] δ 9.02 (s, 1H), 8.60 (s, 1H), 7.33 (t, J=8.3 Hz, 1H), 7.20 (dd, J=11.6, 1.1 Hz, 1H), 7.09 (d, J=8.1 Hz, 1H), 5.24 (d, J=1.6 Hz, 1H), 3.48 (s, 3H), 2.34 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[C:5]([NH:14][CH3:15])[N:4]=1.ClC1C=CC=C(C(OO)=[O:24])C=1>C(Cl)Cl.CO>[CH3:1][S:2]([C:3]1[N:4]=[C:5]([NH:14][CH3:15])[C:6]([N+:11]([O-:13])=[O:12])=[C:7]([NH:9][CH3:10])[N:8]=1)=[O:24]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNc1nc(SC)nc(NC)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CO
Product: CNc1nc(S(C)=O)nc(NC)c1[N+](=O)[O-]

Procedure:
Prepared from 2-methylsulphenyl-4,6-bis(methylamino)-5-nitro-pyrimidine by reacting with m-chloroperbenzoic acid, Rf value: 0.36 (silica gel; methylene chloride/methanol=3:1)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])[CH:3]=1.[O:19]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C>C(O)C>[O:19]([C:26]1[CH:27]=[CH:28][C:29]([NH:30][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=3)[C:12]([O:14][CH3:15])=[O:13])[CH:3]=2)=[CH:31][CH:32]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)c1cccc(Nc2cc(Cl)ncn2)c1
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)c1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Temperature: 100 °C
Yield: 63.8 %

Procedure:
To a stirring solution of methyl 3-(6-chloropyrimidin-4-ylamino)benzoate (1.0 g, 3.8 mmol) and 4-phenoxy aniline (0.703 g, 3.8 mmol) in ethanol (5 mL) was added acetic acid (0.22 mL) and the reaction mixture was heated at 100° C. for 48 h. The reaction mixture was cooled, ethanol was removed under reduced pressure and the residue was dissolved in ethyl acetate (50 mL). It was washed with NaHCO3 solution (5 mL) and brine (5 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to yield methyl 3-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)benzoate (1 g, 66%) as an off-white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=O)=[S:4].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+]>ClC(Cl)C.O.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[S:4]
Reactant: CNC(=S)C1(c2cccnc2)CCCCC1=O
Reactant: Nc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: CNC(=S)C1(c2cccnc2)CCCCC1=Nc1ccccc1
Temperature: 25 °C

Procedure:
A stirred suspension of (±)-N-methyl-2-oxo-1-(3-pyridyl)cyclohexanecarbothioamide (2.5 g) and aniline (3.72 g) in anhydrous dichloroethane (30 ml) under an argon atmosphere was treated dropwise at 25° C. with titanium tetrachloride (0.8 ml). The reaction mixture was stirred at 25° C. until completion of the reaction (as judged by TLC analysis), and then it was poured into a solution of sodium bicarbonate (16.8 g) in water (100 ml) and stirred for 15 minutes. The mixture was filtered through a pad of celite and the aqueous layer was extracted with dichloromethane (3×75 ml). The combined organic solution was washed with aqueous sodium bicarbonate solution (100 ml; 10% w/w), with water (50 ml) and with saturated brine (100 ml), and then it was dried over sodium sulphate and concentrated in vacuo, to give N-methyl-2-phenylimino-1-(3-pyridyl)cyclohexanecarbothioamide in the form of a crude oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[CH2:10][C@@H:11]1[O:15][C:14](=[O:16])[N:13]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([F:29])[CH:18]=2)[CH2:12]1)(=O)=O.C(OCC)(=O)C.O>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[N:1]([CH2:10][C@@H:11]1[O:15][C:14](=[O:16])[N:13]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([F:29])[CH:18]=2)[CH2:12]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cn(-c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)cn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cn(-c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)cn1
Temperature: 90 °C
Yield: 71.7 %

Procedure:
Sodium azide (0.596 g, 9.08 mmol) and 18-crown-6 (0.025 g, 0.095 mmol) were added to a solution of (5R)-3-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-ylmethyl methanesulfonate (WO 01/81350) (3.161 g, 8.56 mmol) in DMF (8.5 ml). The reaction mixture was heated to 90° C. under an atmosphere of nitrogen for 19 h. It was poured into a mixture of ethyl acetate and water and was extracted three times with ethyl acetate. The combined organic layers were washed once with brine, dried over sodium sulfate, filtered and the solvent was removed under vacuum to give 1.94 g of product as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH:13]([C:31](=[O:34])[NH:32][OH:33])[CH2:12]1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[OH:33][NH:32][C:31]([CH:13]1[CH2:12][N:11]([C:9](=[O:10])[CH2:8][NH2:7])[CH2:16][CH2:15][N:14]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]#[C:29][CH3:30])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:34]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)CNC(=O)OC(C)(C)C)CC2C(=O)NO)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)CN)CC2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
To a solution of 0.157 g (0.31 mmol) of the product of Example 229, {2-[4-(4-but-2-ynyloxy-benzenesulfonyl)-3-hydroxycarbamoyl-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester, in 4.0 mL of methylene chloride was added 1.0 mL of trifluoroacetic acid. The resulting solution was stirred at room temperature for 1 h and then reduced to dryness. The resulting residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to furnish 0.121 g (95%) of 4-aminoacetyl-1-(4but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid hydroxyamide as a yellow solid. Electrospray Mass Spec: 411.1 (M+H)+
Reaction SMILES: O=[C:2]1[C:10]2([O:14][CH2:13][CH2:12][O:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:15]([N:18]3[CH2:22][CH2:21][CH2:20][C@H:19]3[CH2:23][O:24]OC)(=[O:17])=[O:16])[CH:8]=2)[N:3]1[CH2:27][C:28]1([CH2:35][NH2:36])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.N.[CH3:38]CO>>[CH3:38][O:24][CH2:23][C@@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[S:15]([C:7]1[CH:6]=[CH:5][C:4]2[N:3]3[CH2:27][C:28]4([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)[CH2:35][N:36]=[C:2]3[C:10]3([O:14][CH2:13][CH2:12][O:11]3)[C:9]=2[CH:8]=1)(=[O:16])=[O:17]
Reactant: COOC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCO1)C(=O)N2CC1(CN)CCCCCC1
Reactant: CCO
Agent: N
Product: COC[C@@H]1CCCN1S(=O)(=O)c1ccc2c(c1)C1(OCCO1)C1=NCC3(CCCCCC3)CN12
Yield: 58 %

Procedure:
A solution of 1-{[2′-oxo-5′-{[(2S)-2-(methoxyoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[1,3-dioxolane-2,3′-indol]-1′(2′H)-yl]methyl}-1-(aminomethyl)-cycloheptane (0.25 g, 0.49 mmol, 1 eq) in 2N ammonia/EtOH (5 mL) was heated in a sealed tube at 130° C. for 4 hours. After cooling, the mixture was concentrated and the residue was purified by chromatography on Biotage KP silica gel eluting with hexane/acetone (3:1) to give the title compound as an off-white solid (0.14 g, 58% yield). NMR (500 MHz, DMSO-d6): consistent. MS (API-ES+) m/z 490 [M+H].
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].[NH3:17].C(OCC)(=O)C.CCCCCC>C(#N)C.C(OCC)(=O)C.CCCCCC>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9](=[O:10])[NH2:17])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: N
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCCCCC
Product: CC(C)(C)c1ccc(C(N)=O)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 84.8 %

Procedure:
12.0 g (74.0 mmol) of N,N'-carbonyldiimidazole were added to a suspension of 15.03 g (67.3 mmol) of 4-t-butyl-3-nitrobenzoic acid in 150 ml of acetonitrile, and the resulting mixture was stirred for 1 hour, after which 20 ml (0.31 mol) of aqueous ammonia were added. The reaction mixture was stirred for 30 minutes, after which it was concentrated by evaporation under reduced pressure, and the concentrate was dissolved in ethyl acetate. The organic phase was washed with water, with 2N aqueous hydrochloric acid, with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 150 g of silica gel, using a gradient elution method, with mixtures of ethyl acetate and hexane ranging from 1:1 to 2:1 by volume as the eluent, to give 12.68 g (yield 85%) of the title compound as crystals, melting at 114°-115° C. (from ethyl acetate-hexane).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[NH:12][CH2:11][CH2:10][N:9]([C:13]2[C:22]3[CH:21]=[C:20]([CH3:23])[S:19][C:18]=3[NH:17][C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[CH2:8]1.[CH2:28]=O>ClC(Cl)C.O.[OH-].[Na+]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[N:12]([CH3:28])[CH2:11][CH2:10][N:9]([C:13]2[C:22]3[CH:21]=[C:20]([CH3:23])[S:19][C:18]=3[NH:17][C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[CH2:8]1
Reactant: C=O
Reactant: COCCCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(Cl)Cl
Product: COCCCC[C@H]1CN(C2=Nc3ccccc3Nc3sc(C)cc32)CCN1C
Reaction time: 8 h

Procedure:
Into a room temperature, stirred solution of (S)-10-[3-(4-methoxybutyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene (0.031 g, 0.08 mmol), and formaldehyde solution (0.082 mL, 0.10 mmol, 37% in H2O) in dichloroethane (0.5 mL) was added NaHB(OAc)3 (0.026 g, 0.12 mmol) and stirred overnight. Dilute the solution with H2O (20 mL), 1.0 N NaOH (1 mL) and extract with CH2Cl2 (3×40 mL). Dry the combined organic layers over Na2SO4, and filter. Concentrate the mixture under reduced pressure and purify by silica gel chromatography eluting with 10% (33% 2 M NH3 in MeOH/64% EtOH)/CH2Cl2. Combine the purified fractions, concentrate under reduced pressure, and place under vacuum to give the title compound: orange solid (0.014 g), mass spectrum (m/e):399.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O.[O-]CC.[Na+]>C(O)C>[CH3:23][O:24][C:25]1[C:26]([O:33][CH2:34][CH2:35][O:36][CH3:37])=[C:27](/[CH:28]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Reactant: COCCOc1c(C=O)cccc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COCCOc1c(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)cccc1OC
Yield: 51.5 %

Procedure:
The title compound was synthesized by condensation of Intermediate 15 (350 mg, 1.072 mmol) with 3-methoxy-2-(2-methoxyethoxy)benzaldehyde (316 mg, 1.501 mmol) in presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure of Example 24 to give 286 mg of the desired product as a pale yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 3.33-3.40 (m, 3H), 3.45-3.51 (m, 2H), 3.78 (s, 3H), 3.95-4.03 (m, 2H), 6.82 (d, J=15.6 Hz, 1H), 6.85-6.91 (m, 1H), 7.00 (d, J=4.2 Hz, 2H), 7.45-7.52 (m, 5H), 8.00 (d, J=4.8 Hz, 1H), 8.19 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 518.19 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].CN1CCCCC1.[OH-:17].[Na+].Cl>C(Cl)(Cl)Cl>[CH3:8][C:5]1[C:6](=[O:17])[CH:7]=[C:2]([CH3:1])[C:3](=[O:9])[CH:4]=1
Reactant: Cc1ccc(C)c(O)c1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN1CCCCC1
Product: CC1=CC(=O)C(C)=CC1=O

Procedure:
12.2 g of 2,5-dimethylphenol (0.1 mole), 1.98 g of cobalt di-(3-methylsalcylal)-3,3'-diimino-di-n-propylamine (0.0005 mole) and 0.5 g of N-methylpiperidine were dissolved in 200 ml of chloroform and then air was bubbled through the resulting solution at 15°C for 10 hours during which time the reaction was completed. After completion of the reaction, the reaction mixture was rendered basic by adding a 2% aqueous solution of sodium hydroxide to decompose peroxides present in the mixture followed by addition of dilute hydrochloric acid to render the solution acidic. The resulting solution was extracted with ether which was then distilled off to obtain 12.1 g of 2,5-dimethyl-parabenzoquinone (0.09 mole).
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]2[N:37]=[CH:36][CH:35]=[CH:34][N:33]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[N:37]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[NH:31][S:28]([C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]3[N:33]=[CH:34][CH:35]=[CH:36][N:37]=3)(=[O:30])=[O:29])=[CH:24][CH:23]=2)=[O:13])=[CH:23][CH:24]=1)(=[O:30])=[O:29]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(S(=O)(=O)Nc2ncccn2)cc1
Yield: 58.2 %

Procedure:
This compound was prepared according to the general methods described in Example 1 using 2,2'-dithiobisbenzoyl chloride (3.0 g, 8.7 mmol) in 30 mL dichloromethane and 4-amino-N-(2-pyrimidinyl) benzenesulfonamide (5.3 g, 21.7 mmol) in 100 mL pyridine. The crude product was recrystallized from a mixture of dimethylformamide, ethanol, and water to yield 3.9 g of the title compound, mp 280° C.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1>>[C:1]1([S:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:26][C@@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1cccc(Sc2ccccc2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: c1ccc(Sc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
The product from Example 71A and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound as a clear oil. (1.06 g, 46%).