Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([NH:26][C:27]([C:29]3[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=3[C:31]([OH:33])=O)=[O:28])=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:38]([O-:40])=[O:39]>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]([N:26]3[C:27](=[O:28])[C:29]4[C:30](=[CH:34][CH:35]=[CH:36][CH:37]=4)[C:31]3=[O:33])=[CH:14][N:13]=2)[CH:5]=[CH:4][C:3]=1[N+:38]([O-:40])=[O:39]
Reactant: Nc1nc(NCCNc2ncc(NC(=O)c3ccccc3C(=O)O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Solvent: CC(=O)O
Product: Nc1nc(NCCNc2ncc(N3C(=O)c4ccccc4C3=O)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
1 mmol of 2-{N-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]carbamoyl}benzoic acid was heated to 120° C. in acetic acid for four hours and then concentrated in vacuo to obtain 2-[2-({2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}amino)-4-(2,4-dichlorophenyl)pyrimidin-5-yl]isoindoline-1,3-dione.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].Br[CH2:15][C:16]1[C:20]2[CH:21]=[C:22]([N:25]3[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]3=[O:37])[CH:23]=[CH:24][C:19]=2[S:18][N:17]=1.Cl>O1CCCC1.CS(C)=O.C(Cl)Cl.C(OCC)C>[C:5]([CH:4]([CH2:15][C:16]1[C:20]2[CH:21]=[C:22]([N:25]3[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]3=[O:37])[CH:23]=[CH:24][C:19]=2[S:18][N:17]=1)[C:3]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])(=[O:6])[CH3:7]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CBr)c3c2)c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(=O)C(Cc1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12)C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A mixture of sodium hydride (60% in oil, 0.293 g, 7.33 mmol) in tetrahydrofuran is cooled to 0° C., treated dropwise with a solution of tert-butyl acetoacetate (1.00 mL, 6.03 mmol) in tetrahydrofuran, and stirred for several minutes. The resultant mixture is added dropwise to a solution of 3-[3-(bromomethyl)-1,2-benzisothiazol-5-yl]-1-methyl-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.40 g, 3.33 mmol) in methyl sulfoxide. After the addition is complete, the reaction mixture is poured into an ice-water mixture containing a trace of 10% hydrochloric acid. The resultant aqueous mixture is extracted with methylene chloride. the organic extracts are combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain an oil. Column chromatography of the oil using silica gel and 0%, 2%, 3%, and 15% diethyl ether in methylene chloride solutions gives the title product as a solid, mp 76-78° C.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: C1COCCN1
Product: Cc1ccccc1-c1nc(N2CCOCC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 101 %

Procedure:
In a similar manner to Example 1, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg) was reacted with morpholine (15.7 mg) to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(morpholine-4-yl)-5-oxopyrimido[4,5-b][1,5]diazocine (87.8 mg, 100%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:21][CH3:22])[C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[O:7][C:8]1[CH:9]=[C:10]([NH2:14])[CH:11]=[CH:12][CH:13]=1.C(OC(C)C)(C)C.[C:30]1([CH2:36][O:37][C:38](Cl)=[O:39])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)Cl>[CH2:36]([O:37][C:38](=[O:39])[NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([O:7][C:6]2[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:4]([CH:3]([O:2][CH3:1])[O:21][CH3:22])[CH:5]=2)[CH:9]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(OC)c1cc(Oc2cccc(N)c2)ccc1[N+](=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: COC(OC)c1cc(Oc2cccc(NC(=O)OCc3ccccc3)c2)ccc1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(3-dimethoxymethyl-4-nitro-phenoxy)-phenylamine (0.14 mol), prepared as in Example 65, and diisopropyl ether (0.16 mol) in DCM (1000 mL) was cooled to 10° C., and carbonochloridic acid phenylmethyl ester (also known as benzyl chloroformate) (0.16 mol) was added dropwise, then the reaction mixture was stirred overnight at room temperature and washed with H2O. The organic layer was separated, dried (MgSO4), filtered off and the solvent was evaporated. The residue was purified by column chromatography (eluent: 100% CH2Cl2). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.[CH2:25]([O:32][CH2:33][C:34](Cl)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][CH2:33][C:34]([N:12]1[CH2:13][CH2:14][CH2:15][N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:10][CH2:11]1)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)COCc1ccccc1
Reactant: Clc1ccc(N2CCCNCC2)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(COCc1ccccc1)N1CCCN(c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 452 %

Procedure:
To a solution of 1-(2,4-dichloro-phenyl)-[1,4]diazepane (0.11 g, 0.45 mmol) in dichloromethane (5 mL) was added diisopropyl-ethylamine (0.082 mL, 0.47 mmol) and benzyloxyacetyl chloride (0.086 g, 0.47 mmol). The solution was stirred at room temperature for 1 h. The residue was chromatographed on silica gel using dichloromethane/ethyl acetate from 100% to 95% dichloromethane in a gradient fashion, to obtain the title compound as a gum (0.80 g, 46%). 1H NMR (300 MHz, CDCl3): δ 7.33 (m, 6H), 7.14 (m, 1H), 6.96 (m. 1H), 4.64 (m, 2H), 4.21 (m, 2H), 3.79 (m, 2H), 3.65 (m, 2H), 3.19 (m, 4H), 2.04 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11](C(O)=O)=[N:12][CH:13]=1)([O-:3])=[O:2].C1(P([N:34]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[O:7][C:8]1[CH:9]=[CH:10][C:11]([NH2:34])=[N:12][CH:13]=1)([O-:3])=[O:2]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(Oc2cccc([N+](=O)[O-])c2)cn1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Nc1ccc(Oc2cccc([N+](=O)[O-])c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.7 %

Procedure:
A mixture of 5-(3-nitrophenoxy)pyridine-2-carboxylic acid (10.4 g, 40.0 mmol), diphenylphosphoryl azide (10.8 mL, 50.0 mmol), triethylamine (6.92 mL, 50.0 mmol) and tert-butanol (200 mL) was stirred at room temperature for 3 hr, and then stirred with heating under reflux for 15 hr. The reaction mixture was concentrated under reduced pressure, trifluoroacetic acid (20 mL) was added to the residue, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, 8N aqueous sodium hydroxide solution (70 mL) was added to the residue, and the mixture was stirred with heating under refluxing conditions for 3 hr. After extraction with ethyl acetate (×3), the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (5.80 g, 63%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[C:8]([OH:13])=[N:9][CH:10]=[CH:11][CH:12]=2)[O:4][N:3]=1.[Br:14]Br>CC(O)=O>[Br:14][C:11]1[CH:12]=[C:7]([C:5]2[O:4][N:3]=[C:2]([CH3:1])[N:6]=2)[C:8]([OH:13])=[N:9][CH:10]=1
Reactant: BrBr
Reactant: Cc1noc(-c2cccnc2O)n1
Solvent: CC(=O)O
Product: Cc1noc(-c2cc(Br)cnc2O)n1

Procedure:
A solution 3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-ol in AcOH (0.2M) and bromine (1.2 eq) was stirred 18 h at 20° C. and then concentrated. The residue was co-evaporated with benzene (2×) and used as such in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](Cl)[CH:3]=1.[CH2:9]([N:11]([CH2:15][CH3:16])[CH2:12][CH2:13][NH2:14])[CH3:10].O>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:14][CH2:13][CH2:12][N:11]([CH2:15][CH3:16])[CH2:9][CH3:10])[CH:3]=1
Reactant: CCN(CC)CCN
Reactant: Clc1cc(Br)ccn1
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)CCNc1cc(Br)ccn1

Procedure:
In a microwave vial, 4-Bromo-2-chloro-pyridine (0.3 g, 1.56 mmol) and N,N-diethylethylenediamine (0.9 g, 7.8 mmol) were heated under microwave irradiations (180° C., 30 min). Water and Ethyl acetate were then added and the layers separated. The aqueous layer was extracted with ethyl acetate and the organics combined, washed twice with brine, dried over magnesium sulphate and concentrated under reduced pressure. The crude was used without further purification. Yield: 0.31 g, 71%. LCMS method: 2, RT: 0.47 min; MI: 272-274 [M+1].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][N:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:19][CH:20]([CH3:22])[CH3:21])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)=[CH:14][N:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(Br)cn1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(NC2CCN(S(C)(=O)=O)CC2)cn1
Temperature: 125 °C
Yield: 54.8 %

Procedure:
A mixture of 5-bromo-pyridine-2-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (150 mg, 388 μmol), 4-amino-1-methanesulfonylpiperidine (82.8 mg, 465 μmol), Pd2(dba)3 (36 mg, 39 μmol), XantPhos (22 mg, 39 μmol), and sodium tert-butoxide (82 mg, 853 μmol) in toluene (4 mL) was degassed with nitrogen then heated at 125° C. for 30 minutes in a microwave reactor. Saturated aqueous NaHCO3 was added and then extracted with EtOAc, washed with brine, concentrated and purified by silica gel column chromatography (0-75% EtOAc in cyclohexane) to give the title compound (103 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.10 (d, 1H), 7.36 (d, 1H), 7.15 (d, 4H), 6.96 (dd, 1H), 6.81 (d, 1H), 3.50-3.52 (m, 5H), 2.89 (s, 5H), 1.99 (s, 2H), 1.43-1.47 (m, 3H), 0.83 (d, 6H). LCMS (m/z, Method A) ES+ 484.9 [M+1]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][CH2:11][CH2:10][C:8]3=2)[C:3](=O)[C:2]1=O.[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:12][CH2:11][CH2:10][C:8]3=2)[CH:3]=[CH:2]1
Reactant: O=C1Nc2c(ccc3c2CCO3)C1=O
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1cc2ccc3c(c2[nH]1)CCO3
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 42 %

Procedure:
A solution of 2,3,7,8-tetrahydro-1H-furo[2,3-g]indole-2,3-dione (9.05 g, 47.9 mmol) in tetrahydrofuran (100 mL) was stirred at −20° C. under an argon atmosphere. Solid sodium borohydride was added portionwise and the reaction was stirred for 20 min at −20° C. Boron trifluoride etherate (11.9 mL, 96 mmol) was added dropwise over 90 min, then the mixture was warmed to 0° C. and stirred for 1 h. The reaction was quenched with water (100 mL) and the solution was extracted with ethyl acetate (3×150 mL). The organic extracts were combined, dried (magnesium sulphate) and concentrated in vacuo to afford a yellow solid which was purified by column chromatography [SiO2; heptane-ethyl acetate (5:1)] to afford the title compound (3.2 g, 42.8%); analytical data as described above.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=[O:9])=[C:4]([NH:11][C:12]([C:14]([O:16]CC)=O)=[O:13])[CH:3]=1>CN(C)C=O.[Ni]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([OH:9])[C:14](=[O:16])[C:12](=[O:13])[NH:11]2
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Cl)ccc2n(O)c1=O
Yield: 77.3 %

Procedure:
A solution of 2 g (7.3 mmol) 4-chloro-2-ethoxalylamino-1-nitrobenzene in 50 ml dimethylformamide was hydrogenated at atm. pressure by using Ra-Ni (0.2 g) as a catalyst. The reaction mixture was filtered and evaporated in vacuo. The residue was stirred with water to give a crude product. Recrystallization (dimethylformamide-water) gave 1.2 g (78%) 6-chloro-1-hydroxyquinoxaline-2,3(1H,4H)-dione. M.p. >300° C. M.p. >300° C. 1H-NMR (DMSO-d6): 11.8 (2H, broad s), 7.2 (3H, m). MS (m/e): 212 (M+, 60%).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]([NH2:19])=[C:17]([OH:20])[C:16]([Cl:21])=[CH:15][C:14]=2[F:22])[C:3]1=[O:23].[C:24](Cl)(=O)[CH:25]([CH3:27])[CH3:26].C(N(CC)CC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]3[N:19]=[C:24]([CH:25]([CH3:27])[CH3:26])[O:20][C:17]=3[C:16]([Cl:21])=[CH:15][C:14]=2[F:22])[C:3]1=[O:23]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c(O)c2N)c1=O
Reactant: CC(C)C(=O)Cl
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CC(C)c1nc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1
Yield: 36.1 %

Procedure:
This compound was prepared in the manner of Step C of Example 1, using 0.52 gram (0.0015 mole) of 1-methyl-6-trifluoromethyl-3-(6-amino4-chloro-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione, 0.18 gram (0.0017 mole) of isobutyryl chloride, 0.24 gram (0.0017 mole) of triethylamine, and 0.09 gram (0.0004 mole) of pyridinium p-toluenesulfonate in 50 mL of xylene, yielding 0.22 gram of Compound 28. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:26]#[N:27])=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][N:14](C(OCC)=O)[CH2:13][C@@H:12]2[O:22][CH2:23][CH:24]=[CH2:25])=[O:9])[NH:5][C:6]=1[CH3:7].II.C[Si](C)(C)[Si](C)(C)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([C:26]#[N:27])=[C:4]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][NH:14][CH2:13][C@@H:12]2[O:22][CH2:23][CH:24]=[CH2:25])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1C#N
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: II
Agent: O=S([O-])([O-])=S
Solvent: Cc1ccccc1
Product: C=CCO[C@H]1CNCC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1C#N
Temperature: 25 °C
Yield: 33.3 %

Procedure:
To as solution of ethyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate (Intermediate 21, 1.1 g, 2.79 mmol) in toluene (190 mL) was added iodine (2.9 g, 11.16 mmol) followed by hexamethyldisilane (4.65 mL, 22.33 mmol). The reaction mixture was heated to reflux for 30 h and then cooled to room temperature. The reaction mixture was treated 10% sodium thiosulphate (150 mL) and the layers were separated. The aqueous layer was extracted with toluene and the organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification by column chromatography (silica, 4% methanol in dichloromethane) afforded 300 mg (33%) of 4-chloro-3-cyano-5-methyl-N-[(3S,4R)-3-(prop-2-en-1-yloxy)piperidin-4-yl]-1H-pyrrole-2-carboxamide
Reaction SMILES: O1CCOCC1.Cl.[C:8]([NH:11][C:12]1[CH:13]=[C:14]([CH:46]=[CH:47][C:48]=1[OH:49])[CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH:23][C:24](=[O:45])[CH2:25][NH:26][C:27](=[O:44])[C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[NH:36]C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)(=[O:10])[CH3:9]>CO>[C:8]([NH:11][C:12]1[CH:13]=[C:14]([CH:46]=[CH:47][C:48]=1[OH:49])[CH2:15][N:16]1[CH2:17][CH2:18][CH:19]([CH2:22][NH:23][C:24](=[O:45])[CH2:25][NH:26][C:27](=[O:44])[C:28]2[CH:33]=[C:32]([F:34])[C:31]([F:35])=[CH:30][C:29]=2[NH2:36])[CH2:20][CH2:21]1)(=[O:10])[CH3:9]
Reactant: CC(=O)Nc1cc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3NC(=O)OC(C)(C)C)CC2)ccc1O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)Nc1cc(CN2CCC(CNC(=O)CNC(=O)c3cc(F)c(F)cc3N)CC2)ccc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 4 M dioxane solution of HCl (0.50 mL) was added to a methanol (1 mL) solution of the 1-(3-acetylamino-4-hydroxybenzyl)-4-[[N-(2-(tert-butoxycarbonylamino)-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine obtained above, and the resulting solution was stirred at room temperature overnight and concentrated. The resulting residue was then dissolved in methanol, loaded onto a Varian™ SCX column, washed with methanol (5 mL×2), eluted with a 2 M methanol solution of NH3 (5 mL), concentrated and then purified by preparative TLC (SiO2, ethyl acetate/methanol=3:2) to thereby afford 1-(3-acetylamino-4-hydroxybenzyl)-4-[[N-(2-amino-4,5-difluorobenzoyl)glycyl]aminomethyl]piperidine (Compd. No. 2148) (2.3 mg, 9.2%). The purity was determined by RPLC/MS (98%). ESI/MS m/e 490.3 (M++H, C24H29F2N5O4).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13][O:14][C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]Br)[CH:17]=1.C1COCC1.C([O-])([O-])=O.[K+].[K+]>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.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:22][C:18]3[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=3)[C:15]([O:14][CH3:13])=[O:24])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cccc(Cc2ccc3[nH]ccc3c2)c1
Temperature: 80 °C
Yield: 48 %

Procedure:
Indole-5-boronic acid, 193 mg (1.2 mmol) and methyl-3-(bromomethyl)benzoate, 230 mg (1.0 mmol) were added into a 100 ml round-bottomed flask containing 15 ml THF, then 50 mg Pd(PPh3)4 was added, followed by 2 ml 2M K2CO3. The mixture was stirred and heated to 80° C. under N2 protection for over 4 hours. The reaction was monitored by TLC. After the reaction was completed and the mixture was cooled to room temperature, 10 ml H2O was added and the product extracted with ethyl acetate (15 ml×3). The organic solvent was combined and dried with anhydrous Na2SO4, filtered and evaporated to dryness. The crude product was purified by chromatographic column using hexane:ethyl acetate (7:1) as eluent. 260 mg methyl 3-(1H-indol-5-ylmethyl)benzoate was obtained as a pale yellow solid, yield 48%. Saponification of the ester yielded the target compound, 8.2 mg target compound was obtained as a grey powder. Mass calculated for C16H13NO2: 251; LCMS: 252.6 (M+H)+; 1HNMR (400 MHz, DMSO-d6) δ ppm 7.78 (1H, s), 7.74 (1H, d, J=7.9 Hz), 7.50 (1H, d, J=7.3 Hz), 7.38 (2H, m), 7.29 (2H, m), 6.95 (1H, dd, J=8.5 Hz, J=1.2 Hz), 6.35 (1H, s), 4.05 (2H, s).
Reaction SMILES: [C:1]1([Si:7](Cl)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH:32]=[CH:31][C:30](=[O:33])[NH:29][C:28]1=[O:34]>N1C=CC=CC=1>[C:1]1([Si:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][N:27]2[CH:32]=[CH:31][C:30](=[O:33])[NH:29][C:28]2=[O:34])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=c1ccn(CCCCCO)c(=O)[nH]1
Solvent: c1ccncc1
Product: O=c1ccn(CCCCCO[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1

Procedure:
A solution of triphenylsilyl chloride (81 mg; 0.27 mmol) in pyridine (1 ml) was added to a solution of alcohol (25) (50 mg; 0.25 mmol) in dry Pyridine (1 ml) under atmosphere of nitrogen, at room temperature.
Reaction SMILES: [CH:1]([C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH3:23])[CH2:15][NH:16][S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[CH:10][CH:9]=2)[CH:4]=1)=[O:2].[BH4-].[Na+]>C(O)C>[OH:2][CH2:1][C:3]1[S:7][CH:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]([CH3:23])[CH2:15][NH:16][S:17]([CH:20]([CH3:22])[CH3:21])(=[O:19])=[O:18])=[CH:12][CH:13]=2)[CH:4]=1
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2csc(C=O)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2csc(CO)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.6 %

Procedure:
To solution of 0.09 g (0.3 mmol) of material from Example 69 in 2 mL of ethanol was added 0.01 g (0.3 mmol) of sodium borohydride. The mixture was stirred at ambient temperature for 16 hours and concentrated in vacuo. The residue was partitioned between 5 mL of ethyl acetate and 5 mL of water. The organic layer was separated and the aqueous layer was extracted three times with 3 mL each of ethyl acetate. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (1 g silica gel, 50% ethyl acetate/hexane) of the residue afforded 0.06 g (69%) of the title compound.
Reaction SMILES: COC1C=C(C2C=C(N)NN=2)C=CC=1.C(N(C(C)C)CC)(C)C.Br[CH2:25][CH2:26][CH2:27][C:28]([NH:30][C:31]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=2)[NH:33][N:32]=1)=[O:29].[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CC(N(C)C)=O.C(Cl)Cl>[CH3:43][O:42][C:38]1[CH:37]=[C:36]([C:34]2[NH:33][N:32]=[C:31]([NH:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)[CH:35]=2)[CH:41]=[CH:40][CH:39]=1
Reactant: COc1cccc(-c2cc(NC(=O)CCCBr)n[nH]2)c1
Reactant: C1COCCN1
Agent: COc1cccc(-c2cc(N)[nH]n2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: COc1cccc(-c2cc(NC(=O)CCCN3CCOCC3)n[nH]2)c1
Temperature: 60 °C

Procedure:
A solution of 4-bromobutyryl chloride chloride (0.104 mL, 0.9 mmol) in dry DMA (1 mL) was cooled to −10° C. (ice/water bath) under N2; 5-(3-methoxy-phenyl)-2H-pyrazol-3-ylamine (170 mg, 0.9 mmol) and diisopropylethylamine (0.315 mL, 1.8 mmol) in dry DMA (1 ml) were added. Upon complete conversion to the intermediate 4-bromo-N-[5-(3-methoxy-phenyl)-1H-pyrazol-3-yl]-butyramide (as monitored by LC-MS), morpholine (0.079 mL, 0.9 mmol) was added and the mixture was heated at 60° C. for 16 hours. The residue was dissolved in DCM (2 mL) and washed with sat. Na2CO3 solution, The organic phase was concentrated under reduced pressure and the crude product was purified by SiO2 column (gradient from Acetonitrile 100% to MeCN/MeOH, NH3 90/10). The fractions containing the title compound were collected to afford 17 mg (5.5% of yield).