Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:4][C:5](=[O:18])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:38])[O:34][CH:35]([CH3:37])[CH3:36]>ClCCl>[CH3:1][C:2]1[C:3]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:33]([O:34][CH:35]([CH3:37])[CH3:36])=[O:38])[CH2:22][CH2:21]2)=[CH:4][C:5](=[O:18])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1cn(-c2ccc(S(C)(=O)=O)cc2)c(=O)cc1OC1CCNCC1
Reactant: CC(C)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cn(-c2ccc(S(C)(=O)=O)cc2)c(=O)cc1OC1CCN(C(=O)OC(C)C)CC1

Procedure:
The compound obtained in Example 160, Step A (25 mg, 0.069 mmol) was dissolved in dichloromethane (0.5 mL) to which was then added triethylamine (0.029 mL, 0.207 mmol) and isopropyl carbonochloridate (10.1 mg, 0.083 mmol). After 45 minutes the solvent was removed in vacuo and the residue purified by passing through a UCT (United Chemical Technologies) 2.5 g C-18 cartridge (#CEC181(2500)6) and eluting as follows;
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Na+].[SH:16][CH2:17][CH2:18]O.OO>>[CH3:5][C:3]1[O:4][CH2:18][CH2:17][S:16][C:2]=1[C:1]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: CC(=O)CC(=O)Nc1ccccc1
Reactant: OCCS
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: CC1=C(C(=O)Nc2ccccc2)SCCO1
Temperature: 38 °C
Yield: 68.1 %

Procedure:
Acetoacetanilide (88.6 g, 0.5 mole) is dissolved under agitation, at room temperature, in 140 g aqueous 28.6% NaOH (0.5 mole). Crude di-(2-hydroxyethyl) disulfide (176 g), obtained by oxidation of 2-mercaptoethanol with 50% hydrogen peroxide, (i.e. an approx 68% aqueous solution) is added to the reaction mixture, which is then heated to 38° C. After 15 minutes 15% aqueous NaOH (16 g) is added and after a further 15 minutes the addition of 50% hydrogen peroxide is started. Subsequently the reaction is carried out as described in EXAMPLE 1. A total of 16.8 g 50% hydrogen peroxide is used. The extraction/acidification procedure, as well as the cyclization step, is carried out as in EXAMPLE 1. After the last water wash, following the cyclization, toluene is evaporated from the reaction mixture under vacuum, at up to 60°, and the residue is redissolved in 90 g isopropanol. After crystallization, filtration and drying, 80.2 g 5,6-dihydro-2-methyl-N-phenyl-1,4-oxathiin-3-carboxamide is obtained (yield 68.1% based on acetoacetanilide), M.P. 96.8°-98.0° C., Assay 98.9%.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[N:28]1([C:33]2[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=2)[CH:32]=[CH:31][CH:30]=[N:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:37](=[O:38])[C:36]5[CH:35]=[CH:34][C:33]([N:28]6[CH:32]=[CH:31][CH:30]=[N:29]6)=[CH:41][CH:40]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)c1ccc(-n2cccn2)cc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)c1ccc(-n2cccn2)cc1

Procedure:
The title compound, white solid (109 mg, 87%), MS (ISP) m/z=501.3 [(M+H)+], mp 229° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and 4-pyrazol-1-yl-benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.Cl[CH2:12][C:13](=[O:15])[CH3:14]>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([O:9][CH2:12][C:13](=[O:15])[CH3:14])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: CC(=O)CCl
Product: CC(=O)COc1c(C)cc(Br)cc1C

Procedure:
The title compound was prepared according to procedures analogous to those as described in Reference Example 25 by using 4-bromo-2,6-dimethylphenol and chloroacetone.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH2:29][C:30]#[N:31])=[CH:10][CH:9]=1.C(I)C>O1CCCC1.[Cl-].[NH4+]>[Cl:7][C:8]1[C:16]2[N:15]=[C:14]3[N:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])[CH2:18][CH2:19][CH2:20][N:13]3[C:12]=2[C:11]([CH:29]([CH2:1][CH3:2])[C:30]#[N:31])=[CH:10][CH:9]=1
Reactant: N#CCc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCC(C#N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
Potassium t-butoxide (315 mg, 2.81 mmol) was added to a stirred solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]acetonitrile (500 mg, 1.28 mmol) and ethyl iodide (499 mg, 3.20 mmol) in tetrahydrofuran (13 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The mixture was diluted with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethanol/ethyl acetate to give the title compound as a colorless crystal (202 mg, 0.481 mmol, 38%).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1.[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)CO.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.C(O)(C)C>[Cl:1][C:2]1[C:7]([S:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:9])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)c1I
Reactant: Sc1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: OCCO
Product: Nc1ccnc(Cl)c1Sc1ccccc1
Reaction time: 24 h
Yield: 91 %

Procedure:
To a 250 mL round flask was added 2-chloro-3-iodo-4-aminopyridine (5.0 g, 19.6 mmol), thiophenol (2.16 g, 19.6 mmol), CuI (0.187 g, 0.98 mmol), ethylene glycol (2.5 g, 39 mmol), potassium carbonate (5.4 g, 39 mmol), and 150 mL of isopropanol. The reaction was heated to reflux and stirred under a nitrogen atmosphere for 24 h. After cooling, the mixture was purified by a silica gel column. Yield (91%) of 2-chloro-3-phenylthio-4-aminopyridine was 4.2 g.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[O:3].Cl.[CH3:8][Si:9]([O:12][C:13](=[O:20])[C@H:14]([C@H:16]([CH2:18][CH3:19])[CH3:17])[NH2:15])([CH3:11])[CH3:10]>>[CH3:11][Si:9]([O:12][C:13](=[O:20])[C@H:14]([C@H:16]([CH2:18][CH3:19])[CH3:17])[NH:15][C:1](=[O:5])[C:2]([CH3:4])=[O:3])([CH3:8])[CH3:10]
Reactant: CC(=O)C(=O)Cl
Reactant: CC[C@H](C)[C@H](N)C(=O)O[Si](C)(C)C
Agent: Cl
Product: CC[C@H](C)[C@H](NC(=O)C(C)=O)C(=O)O[Si](C)(C)C

Procedure:
A method of synthesizing pyruvyl-isoleucine according to the invention the steps of reacting sodium pyruvate with oxalyl chloride to yield pyruvyl chloride, then reacting the pyruvyl chloride with a suspension of isoleucine trimethylsilyl ester hydrochloride to yield pyruvyl-isoleucine trimethylsilyl ester and then subjecting the pyruvyl-isoleucine trimethylsilyl ester to hydrolysis to yield pyruvyl-isoleucine. The pyruvyl-isoleucine synthesized via the method set forth above serves as a pyruvyl-amino acid pyruvate precursor.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6](=O)[CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=[CH:4][CH:3]=1.[NH2:18][C:19]1[CH:27]=[C:23]([C:24]([OH:26])=[O:25])[C:22]([OH:28])=[CH:21][CH:20]=1>C(O)(=O)C>[C:24]([C:23]1[CH:27]=[C:19]([N:18]2[C:9]3[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=3[CH:7]=[C:6]2[C:5]2[CH:16]=[CH:17][C:2]([OH:1])=[CH:3][CH:4]=2)[CH:20]=[CH:21][C:22]=1[OH:28])([OH:26])=[O:25]
Reactant: O=C(CC1CCCCC1=O)c1ccc(O)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccc(O)cc3)cc3c2CCCC3)ccc1O

Procedure:
A mixture of 11.5 g. (0.05 mole) of 2-(p-hydroxyphenacyl)cyclohexanone, 7.6 g. (0.05 mole) of 5-aminosalicylic acid, and 40 ml. of glacial acetic acid was heated under reflux under nitrogen for 1.5 hours, cooled and filtered to provide 10.6 g. (61%) of solid, m.p. 214°-217°. Recrystallization from acetonitrile gave crystals, m.p. 217°-219°.
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>ClCCl>[C:15]([O:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: ON1CCCCC1
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)ON1CCCCC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 76.6 %

Procedure:
A few of the inventive 1-hydroxypiperidine (0.96 g, 9.49 mmol) and triethylamine (1.50 mL, 10.8 mmol) were dissolved in anhydrous dichloromethane (40 mL) and cooled to 0° C. Methacryloyl chloride (1 mL, 10.2 mmol) was then added slowly, dropwise. The reaction was then slowly warmed to room temperature. After 2.5 h, the reaction mixture was washed with deionized water (40 mL), 1 M NaOH (20 mL), deionized water (20 mL), 5% citric acid (20 mL), and brine (20 mL). After drying over sodium sulfate and filtering, the product was concentrated by rotary evaporation and dried in vacuo to give and amber liquid. Flash chromatography on silica gel, eluting with dichloromethane, followed by 1-5% methanol:dichloromethane afforded piperidin-1-yl methacrylate as an amber liquid (1.23 g, 76%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.C(O[C:14](=[O:16])[CH3:15])(=O)C.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([C:23]2[N:28]=[CH:27][C:26]([C:29]3[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([NH:36][C:37]4[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][N:38]=4)[N:30]=3)=[CH:25][CH:24]=2)[CH2:19]1>C1COCC1>[CH3:35][C:33]1[CH:32]=[C:31]([NH:36][C:37]2[CH:42]=[C:41]([C:43]([F:44])([F:46])[F:45])[CH:40]=[CH:39][N:38]=2)[N:30]=[C:29]([C:26]2[CH:27]=[N:28][C:23]([N:20]3[CH2:21][CH2:22][C@H:18]([NH:17][C:14](=[O:16])[CH3:15])[CH2:19]3)=[CH:24][CH:25]=2)[CH:34]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(N3CC[C@H](N)C3)nc2)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H]1CCN(c2ccc(-c3cc(C)cc(Nc4cc(C(F)(F)F)ccn4)n3)cn2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N,N-Diisopropylethylamine (0.032 mL, 0.181 mmol), acetic anhydride (6.26 μL, 0.066 mmol), 6′-[(3S)-3-aminopyrrolidin-1-yl]-4-methyl-N-[4-(trifluoromethyl)pyridin-2-yl]-2,3′-bipyridin-6-amine (Example 5, 25 mg, 0.060 mmol), and THF (1 mL) were added to a flask and stirred at room temperature for 16 hours. The crude solution was purified via reverse phase high pressure liquid chromatography to afford N-[(3S)-1-(4-methyl-6-{[4-(trifluoromethyl)pyridin-2-yl]amino}-2,3′-bipyridin-6′-yl)pyrrolidin-3-yl]acetamide. MS ESI calcd. for C23H24F3N6O [M+H]+ 457. found 457. 1H NMR (500 MHz, DMSO-d6) δ 10.08 (s, 1H), 8.76 (s, 1H), 8.60 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.11 (m, 1H), 7.24 (s, 1H), 7.17 (d, J=5.0 Hz, 1H) 7.12 (s, 1H), 6.46 (d, J=8.8 Hz, 1H), 3.52-3.60 (m, 3H), 3.43 (m, 1H), 3.12 (m, 1H), 2.30 (s, 3H), 2.05 (s, 1H), 1.87-1.80 (m, 2H), 1.72 (s, 1H). rhSyk IC50=17 nM.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[CH2:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([NH:39][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:31])([F:29])[F:30])[C:9]=3[CH:17]=2)=[CH:19][CH:20]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Reactant: NCc1ccccc1
Product: O=C(NCc1ccccc1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with benzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=536.96 (M+H+); retention time=0.91 minutes.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[O:24])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH3:15][C:16]1[C:17]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:9][C:10]([CH3:13])=[N:11][N:12]=3)=[CH:4][C:3]=2[CH3:14])=[CH:18][C:19]([NH:22][C:23]([C:25]2[CH:29]=[CH:28][O:27][CH:26]=2)=[O:24])=[CH:20][CH:21]=1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1nnc(-c2ccc(-c3cc(NC(=O)c4ccoc4)ccc3C)c(C)c2)o1

Procedure:
Example 22 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-[1,3,4]oxadiazole and N-[4-methyl-3-(4,4,5,5, -tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 25).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH:17]=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[OH:19][C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:23]4[CH2:24][CH2:25][C:20]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)([OH:19])[CH2:21][CH2:22]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Product: OC1(c2ccccc2)CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Yield: 32 %

Procedure:
Using a procedure similar to that described in example 21 except starting with 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene (described in example 1i) and 4-hydroxy-4-phenylpiperidine, the title compound hydrochloride salt was obtained in 32% yield as a white powder, mp 260°-261° C. elemental
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]([C@@H:8]1[CH2:12][C@H:11]([N:13]([CH3:15])[CH3:14])[CH2:10][NH:9]1)=[O:7].[CH2:16](O)[CH2:17][CH2:18]C>>[CH2:4]([O:5][C:6]([C@@H:8]1[CH2:12][C@H:11]([N:13]([CH3:14])[CH3:15])[CH2:10][NH:9]1)=[O:7])[CH2:16][CH2:17][CH3:18]
Reactant: COC(=O)[C@@H]1C[C@H](N(C)C)CN1
Reactant: CCCCO
Agent: Cl
Product: CCCCOC(=O)[C@@H]1C[C@H](N(C)C)CN1
Temperature: 115 °C

Procedure:
Concentrated HCl (0.3 ml) was added to a mixture of (2S,4S)-4-dimethylamino-pyrrolidine-2-carboxylic acid methyl ester dihydrochloride (400 mg) and 1-butanol (4 ml) and heated for 18 h at 115° C. After cooling the RM was evaporated then partitioned between DCM and aqueous NaHCO3 solution and the DCM layers dried and evaporated to give the title compound as a brown oil which was used without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:27]([O-])([OH:29])=[O:28].C([O-])(O)=O.[Na+]>CC(O)=O>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([N+:27]([O-:29])=[O:28])[CH:21]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])O
Reactant: O=C(NCCCCN1CCCC1)c1cc(Oc2ccc(O)cc2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(NCCCCN1CCCC1)c1cc(Oc2ccc(O)c([N+](=O)[O-])c2)ccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(4-hydroxy-phenoxy)-pyridine-2-carboxylic acid (4-pyrrolidin-1-yl-butyl)-amide (Step C, 2.0 g, 5.6 mmol) in HOAc (32 mL) at RT was added 70% HNO3 (0.56 g, 6.2 mmol). The reaction was stirred at RT for 18 h. An additional amount of 70% HNO3 (0.56 g, 6.2 mmol) was added dropwise over 10 min, and the reaction was stirred for 2 h, after which it was slowly added to saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was washed with NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography to yield the title compound. MS (MH+)=401.2; Calc'd 400.44 for C20H24N4O5.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1>C(Cl)Cl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([N:11]2[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: Clc1ccc(N2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.5 %

Procedure:
The crude 4-(4-Chloro-phenyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (3.10 g, 10.0 mmol) was dissolved in methylene chloride (1 mL) and treated with 4 N HCL/dioxane (10 mL, 40 mmol). The solution was stirred at rt for 1 hour. The reaction was concentrated in vacuo. The residue was diluted with saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3×30 mL). The combined organics were washed with brine, dried over MgSO4, and evaporated to yield 1.00 g (48%) of the title compound. 1H-NMR (CDCl3) δ 1.90 (2H, m), 2.23 (1H, brs), 2.83 (2H, m), 3.02 (2H, m), 3.54 (4H, m), 6.58 (2H, d, j=9.3 Hz), 7.13 (2H, d, j=9.3 Hz). ESI-MS m/z: 211 (M+1), FAS method rt: 1.04 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:29]([O:28][C:26](=[O:27])[CH2:25][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:3][C:2]=1[F:1])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(O)c2)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(OCc2cccc(OCC(=O)OC(C)(C)C)c2)c(F)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 105.8 %

Procedure:
To a solution of ethyl 3-{3-fluoro-4-[(3-hydroxybenzyl)oxy]phenyl}propanoate (0.30 g, 0.94 mmol) and tert-butyl bromoacetate (0.92 g, 4.70 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (0.52 g, 3.76 mmol), and the mixture was stirred at 60° C. for 12 hours. The reaction mixture was diluted with ethyl acetate, filtered, washed with water, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (hexane/ethyl acetate=6:4) to give the title compound (0.43 g, yield 99%) as an oily matter.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:12][C:13]([N:15]1[CH2:20][CH2:19][S:18][C:17]2[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:16]1=2)=O)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].B>C1COCC1>[OH:1][CH2:2][CH2:3][N:4]([CH2:12][CH2:13][N:15]1[CH2:20][CH2:19][S:18][C:17]2[CH:21]=[C:22]([N+:25]([O-:27])=[O:26])[CH:23]=[CH:24][C:16]1=2)[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8]
Reactant: CC(C)(C)OC(=O)N(CCO)CC(=O)N1CCSc2cc([N+](=O)[O-])ccc21
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCO)CCN1CCSc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of tert-butyl 2-hydroxyethyl(2-(7-nitro-2H-benzo[b][1,4]thiazin-4(3H)-yl)-2-oxoethyl)carbamate (250 mg, 0.629 mmol) in THF (10 mL) was cooled to 0° C. then treated with borane in THF (1M) (6.29 mL, 6.29 mmol) The resulting bright yellow solution was allowed to warm to room temperature and then stirred at this temperature for 2.5 days. The mixture was cooled to 0° C., and the reaction was then carefully quenched with MeOH (dropwise addition at first; 20 mL total). The cooling bath was removed, and the yellow solution was stirred for 20 minutes then concentrated. The orange residue was dissolved in MeOH (50 mL) and concentrated to dryness. This residue was dissolved in EtOAc (20 mL) and filtered through a pad of silica gel. The silica pad was eluted with EtOAc (100 mL). The filtrate was concentrated to give an orange residue which was dried under reduced pressure for 4 hours (230 mg, 95%). 1H-NMR (CDCl3) δ 7.97 (brs, 1H), 7.87 (brd, J=8.7 Hz, 1H), 6.85-6.71 (m, 1H), 3.81 (brs, 5H), 3.61 (brs, 2H), 4.54-3.31 (m, 4H), 3.02 (overlapping t, 2H), 1.47 (brs, 9H); ESI-MS (m/z, %): 406 (M+Na, 60), 384 (MH+, 10), 328 (60), 284 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[C:13]([CH3:35])=[C:14]([C:18]4[C:30]5[C:29]6[C:24](=[CH:25][C:26]([OH:31])=[CH:27][CH:28]=6)[NH:23][C:22]=5[C:21]([C:32]([NH2:34])=[O:33])=[N:20][CH:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1.[C:36](=[O:39])([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C:12]3[C:13]([CH3:35])=[C:14]([C:18]4[C:30]5[C:29]6[C:24](=[CH:25][C:26]([O:31][CH2:5][CH2:6][N:7]7[CH2:12][CH2:36][O:39][CH2:9][CH2:8]7)=[CH:27][CH:28]=6)[NH:23][C:22]=5[C:21]([C:32]([NH2:34])=[O:33])=[N:20][CH:19]=4)[CH:15]=[CH:16][CH:17]=3)[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(O)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2cnc(C(N)=O)c3[nH]c4cc(OCCN5CCOCC5)ccc4c23)cccc1N1Cc2ccc(Cl)cc2C1=O
Temperature: 100 °C
Yield: 21.2 %

Procedure:
A mixture of 4-(3-(6-chloro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-hydroxy-9H-pyrido[3,4-b]indole-1-carboxamide (50 mg, 0.104 mmol), 4-(2-chloroethyl)morpholine, HCl (67.4 mg, 0.362 mmol), and cesium carbonate (202 mg, 0.621 mmol) in DMF (6 mL) was heated at 100° C. for 3 hr. The mixture was diluted with ethyl acetate (100 mL) and filtered through CELITE®. The filtrate was washed with water (2×30 mL) and brine (30 mL), and dried over anhydrous MgSO4. After the solvent was removed under vacuum, the residue was purified by reverse phase HPLC. The correct fractions were concentrated under vacuum, basified with saturated NaHCO3 solution, and extracted with ethyl acetate (3×30 mL). The combined extract was washed with brine (30 mL) and dried over anhydrous MgSO4. Removal of solvent under vacuum provided the purified product (7.1 mg, 0.011 mmol, 10.9% yield) as a pale yellow sold. LCMS (M+H)+=596.29. 1H NMR (500 z, DMSO-d6) δ: 11.72 (s, 1H), 8.36 (s, 1H), 8.25 (s, 1H), 7.86 (s, 1H), 7.82-7.78 (m, 3H), 7.72 (d, J=6.9 Hz, 1H), 7.59 (m, 1H), 7.50 (m, 1H), 7.43 (s, 1H), 7.22 (br. S, 1H), 6.79 (br. S, 1H), 5.10 (d, J=17.6 Hz, 1H), 5.00 (d, J=17.6 Hz, 1H), 4.23 (m, 2H), 3.81-3.53 (m, 8H), 2.81 (m, 2H), 1.92 (s, 3H).
Reaction SMILES: [NH3:1].[Br:2][C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[C:5]([CH2:13]Br)[CH:4]=1.[OH-].[NH4+]>CO>[Br:2][C:3]1[CH:4]=[C:5]2[C:6](=[CH:11][CH:12]=1)[C:7](=[O:8])[NH:1][CH2:13]2
Reactant: N
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: O=C1NCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
Ammonia gas was purged to a stirring solution of methyl 4-bromo-2-(bromomethyl)benzoate (200 mg, 0.649 mmol) in methanol at 0° C. for 10 min. To the resulting reaction mixture ammonium hydroxide (0.5 mL) was added and the reaction mixture was stirred at RT for 16 h. The obtained solid was separated by filtration and dried to afford 5-Bromoisoindolin-1-one as a solid (100 mg, 72%).