Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]([Cl:20])=[C:7](Cl)[N:6]=1)=[O:4].[CH3:22][N:23]1C(=O)CCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].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].[C-]#N.[C-]#N.[Zn+2]>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])=[C:9]([F:19])[C:8]([Cl:20])=[C:7]([C:22]#[N:23])[N:6]=1)=[O:4]
Reactant: CN1CCCC1=O
Reactant: COC(=O)c1nc(Cl)c(Cl)c(F)c1Nc1ccccc1F
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(=O)c1nc(C#N)c(Cl)c(F)c1Nc1ccccc1F
Temperature: 120 °C

Procedure:
A mixture of 5,6-dichloro-4-fluoro-3-(2-fluorophenylamino)-pyridine-2-carboxylic acid methyl ester (1.00 equivalent) (prepared in Example 8), dppf (0.02 equivalents), Pd2dba3 (0.01 equivalents), and Zn(CN)2 (0.60 equivalents) in NMP is stirred at 120° C. in a sealed tube. After stirring for 20 hours, the reaction mixture is cooled to room temperature and quenched with a 4:1:4 (volume) mixture solution of saturated aqueous NH4Cl-conc NH4OH-water. The mixture is extracted with EtOAc. The organic layer is washed with saturated aqueous NH4Cl/conc. NH4OH/water, and brine. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by flash column chromatography to afford the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=2)[CH:5]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[NH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:18]1[CH2:19][CH2:20][N:15]([C:4]2[N:3]=[C:2]([NH:21][C:22]3[CH:23]=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:7]=[C:6]([C:8]3[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=3)[CH:5]=2)[CH2:16][CH2:17]1
Reactant: Nc1cnc2ccccc2c1
Reactant: Nc1ncc(-c2cc(N3CCOCC3)nc(Cl)n2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Nc1ncc(-c2cc(N3CCOCC3)nc(Nc3cnc4ccccc4c3)n2)cn1
Temperature: 110 °C

Procedure:
A mixture of 2-chloro-6-morpholino-4,5′-bipyrimidin-2′-amine (10 mg), 3-amino-quinoline (9.8 mg), Pd(OAc)2 (1.5 mg), BINAP (6.3 mg), and cesium carbonate (15.5 mg) in THF (1 mL) was heated in a microwave at 110° C. for 10 minutes. The crude product was filtered and concentrated under reduced pressure. The product was purified by preparative HPLC to give 6-morpholino-N2-(quinolin-3-yl)-4,5′-bipyrimidine-2,2′-diamine. LCMS (m/z): 401.0 (MH+). Rt=1.83 min.
Reaction SMILES: Cl[C:2]1[C:3]2[S:18][C:17]([NH2:19])=[N:16][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]=1.[NH2:20][C@@H:21]([CH2:23][OH:24])[CH3:22].C(N(C(C)C)CC)(C)C.O>CN1CCCC1=O>[NH2:19][C:17]1[S:18][C:3]2[C:2]([NH:20][C@H:21]([CH3:22])[CH2:23][OH:24])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:5][C:4]=2[N:16]=1
Reactant: Nc1nc2nc(SCc3ccccc3)nc(Cl)c2s1
Reactant: C[C@@H](N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@H](CO)Nc1nc(SCc2ccccc2)nc2nc(N)sc12
Temperature: 100 °C
Reaction time: 24 h
Yield: 32 %

Procedure:
The product of example 1 step c) (25.0 g), D-Alaninol (12.3 g) and diisopropylethylamine (26.0 g) were diluted in N-methylpyrrolidinone (250 ml) and stirred at 100° C. for 24 h before cooling and pouring the reaction mixture into H2O (2.5 l). The precipitate was filtered and dried in vacuo before being preabsorped onto silica gel. Chromatography using EtOAc. 4% MeOH/EtOAc as eluents afforded the desired product as a yellow solid (9.0 g. 32%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:33])[CH2:7][C:8]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:24]=[CH:23][C:22]([S:25](=[O:31])(=[O:30])[NH:26][CH2:27][CH2:28][OH:29])=[CH:21][CH:20]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([Cl:32])[CH:14]=2)[CH:9]=1.C1COCC1.O>CCCCCC>[Cl:32][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:7][C:6]([OH:33])=[O:5])[C:17]([CH3:18])=[C:16]2[C:19]1[CH:24]=[CH:23][C:22]([S:25](=[O:30])(=[O:31])[NH:26][CH2:27][CH2:28][OH:29])=[CH:21][CH:20]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(S(=O)(=O)NCCO)cc2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(CC(=O)O)cc2ccc(Cl)cc2c1-c1ccc(S(=O)(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
Lithium hydroxide monohydrate (0.019 g, 0.45 mmol) was added to a solution of {6-chloro-4-[4-(2-hydroxyethylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.05 g, 0.11 mmol) in a 3:1 mixture of THF—H2O mixture (5 mL). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was concentrated to remove the THF, and the crude material was diluted with water, acidified [pH˜2] with a 6 N aqueous solution of hydrochloric acid. The mixture was extracted twice with ethyl acetate. The collected organic layers were washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give the crude product. Trituration with hexane gave {6-chloro-4-[4-(2-hydroxyethylsulfamoyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid (0.03 g, 62%) as a solid. 1H NMR (DMSO-d6) δ: 12.48 (br. s, 1H), 7.98 (d, J=7.8 Hz, 3H), 7.91 (s, 1H), 7.73 (t, J=5.6 Hz, 1H), 7.49 (d, J=7.8 Hz, 3H), 7.03 (s, 1H), 4.73 (br. s, 1H), 3.86 (s, 2H), 3.44 (d, J=5.4 Hz, 2H), 2.93 (q, J=5.9 Hz, 2H), 2.08 (s, 3H). MS calcd. for C21H21ClNO5S [(M+H)+] 434, obsd. 434.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=1)[C:20]([O:22][CH3:23])=[O:21]>C(Cl)Cl>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][CH:26]=[C:17]([NH:16][S:10]([C:8]2[S:9][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:15][C:6]=3[C:7]=2[CH3:14])(=[O:12])=[O:11])[CH:18]=1
Reactant: COC(=O)c1cccc(N)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Br)cc12
Solvent: ClCCl
Product: COC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Br)cc3c2C)c1
Yield: 56.1 %

Procedure:
The intermediate methyl 3-{[(5-bromo-3-methyl-1-benzothiophen-2-yl)sulfonyl]amino}benzoate was prepared according to General Procedure 1, described in Example 1, starting from 5-bromo-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 10) (870 mg, 2.67 mmol) and methyl 3-aminobenzoate (367 mg, 2.43 mmol). The reaction mixture was diluted with CH2Cl2 (20 mL) and washed with 1M HCl (30 mL). The organic phase was dried (Na2SO4). Evaporation of the solvents afforded 600 mg of crude methyl-3-{[(5-bromo-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoate, which was used without further purification.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].C(S)CCCCCCCCCCC.[CH3:18][O:19][C:20](=[O:34])[CH2:21][C:22]1[C:26]2[C:27]([F:33])=[CH:28][C:29]([O:31]C)=[CH:30][C:25]=2[S:24][CH:23]=1.Cl>C1(C)C=CC=CC=1>[CH3:18][O:19][C:20](=[O:34])[CH2:21][C:22]1[C:26]2[C:27]([F:33])=[CH:28][C:29]([OH:31])=[CH:30][C:25]=2[S:24][CH:23]=1
Reactant: COC(=O)Cc1csc2cc(OC)cc(F)c12
Agent: CCCCCCCCCCCCS
Agent: Cl
Agent: [Al+3]
Solvent: Cc1ccccc1
Product: COC(=O)Cc1csc2cc(O)cc(F)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 41.1 %

Procedure:
To a suspension of aluminum chloride (713 mg) in toluene (10 mL) was added dodecane-1-thiol (4.00 mL) at 0° C. After stirring at 0° C. for 30 min, a solution of methyl(4-fluoro-6-methoxy-1-benzothiophen-3-yl)acetate (850 mg) in toluene (10 mL) was added dropwise to the mixture. The mixture was stirred at room temperature for 45 h. To the mixture was added aluminum chloride (713 mg) again, and the mixture was stirred at room temperature for 4 h. The mixture was poured into ice water. To the mixture was added 6N HCl, and the mixture was extracted with EtOAc. The EtOAc extract was washed successively with 1N HCl and brine, dried over MgSO4, and concentrated in vacuo. A mixture of the residue, conc. H2SO4 (0.5 mL) and MeOH (50 mL) was stirred at 75° C. for 4 h then concentrated in vacuo. To the residue was added saturated aqueous NaHCO3 and the mixture was extracted with EtOAc. The EtOAc extract was washed with brine, dried over MgSO4, and concentrated in vacuo. The residual crystals were washed with toluene and IPE to give the title compound (330 mg). The mother liquid was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (180 mg). Total yield, 510 mg. The crystals were recrystallized from acetone-hexane.
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14]([NH:16][C@H:17]3[CH2:22][CH2:21][O:20][CH2:19][C@H:18]3[CH3:23])[C:13]([N+:24]([O-])=O)=[CH:12][N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].CO>C1COCC1.O.CCOC(C)=O>[N:1]1([C:10]2[N:15]=[C:14]([NH:16][C@H:17]3[CH2:22][CH2:21][O:20][CH2:19][C@H:18]3[CH3:23])[C:13]([NH2:24])=[CH:12][N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C[C@@H]1COCC[C@@H]1Nc1nc(-n2cnc3ccccc32)ncc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H]1COCC[C@@H]1Nc1nc(-n2cnc3ccccc32)ncc1N

Procedure:
To a solution of 2-(1H-benzo[d]imidazol-1-yl)-N-(cis-3-methyl-tetrahydro-2H-pyran-4-yl)-5-nitropyrimidin-4-amine (51 mg) in THF (10 mL) was added a solution of sodium hydrosulfite (300 mg) and sodium bicarbonate (150 mg) in water (10 mL). The mixture briefly became blue followed by colorless. Methanol (1 mL) was added to maintain the homogeneity of the solution. The mixture was diluted with 70 mL EtOAc and washed twice with brine. The aqueous washes were extracted with another 50 mL of EtOAc and then the combined organic layers were dried over sodium sulfate and concentrated in vacuo to provide 2-(1H-benzo[d]imidazol-1-yl)-N4-(cis-3-methyl-tetrahydro-2H-pyran-4-yl)pyrimidine-4,5-diamine. The diamine intermediate was dissolved in THF (5 mL) and treated with 1,1′-carbonyldiimidazole (80 mg) at 50° C. for 16 hours. The mixture was diluted with 50 mL EtOAc and washed 3 times with brine. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. Column chromatography (2→4% MeOH/DCM) provided 19.3 mg of the title compound. 1H-NMR (300 MHz, 5% CD3OD in CDCl3) δ 8.9 (s, 1H), 8.5 (d, 1H), 8.2 (s, 1H), 7.8 (d, 1H), 7.4 (t, 1H), 7.3 (t, 1H), 4.7 (m, 1H), 4.2 (d(br), 1H), 3.9 (d, 1H), 3.7 (d, 1H), 3.5 (m, 2H), 2.3 (t(br), 1H), 1.8 (d(br), 1H), 1.2 (d, 3H).
Reaction SMILES: [CH:1]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]1[OH:3].C(=O)([O-])O.[Na+].[CH2:23]([O:30][C:31](Cl)=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(Cl)(Cl)Cl.C(#N)C>CC(N(C)C)=O>[CH2:23]([O:30][C:31]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:1]2[O:7][C@H:6]([CH2:8][OH:9])[C@@H:4]([OH:5])[C@@H:2]2[OH:3])[C:11](=[O:12])[N:13]=1)=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: Nc1ccn(C2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Reactant: CCCCCCCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCCCCCCOC(=O)Nc1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
To a solution of 4.0 g of arabinofuranosylcytosine dissolved in 50 ml of dimethylacetamide, there are added 4.15 g of sodium hydrogen carbonate and 4.41 g of heptylchloroformate. The resultant mixture is allowed to react under stirring at room temperature for 3 hours. After the reaction, dimethylacetamide is removed under reduced pressure and 150 ml of cold water is added to the residue. After the mixture is stirred for 2 hours, the solids are collected by filtration and dried. Recrystallization of the white powders obtained is performed twice, using 200 ml and 150 ml of a mixture of chloroform-acetonitrile (1:1), to give 2.5 g of N4 -heptyloxycarbonyl-1-β-D-arabinofuranosylcytosine (Yield:40%).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3B(O)O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1C=C1c2ccccc2CCc2ccccc21
Reactant: Brc1cccnc1
Product: C(=C1c2ccccc2CCc2ccccc21)c1ccccc1-c1cccnc1

Procedure:
Following procedures essentially as described in Example 225 and using 2-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylboronic acid (100 mg, 0.307 mmol) and 3-bromopyridine (73 mg, 0.460 mmol) provides the title compound. Purify further via silica gel chromatography to obtain 14.9 mg (14%) of material that is 98% pure by HPLC. MS (ES) 360 (M+H).
Reaction SMILES: O[C:2]1([C:32]2C=CC=CC=2)[CH2:7][CH2:6][N:5]([C:8]2N=C[C:11]([NH:14][C:15]([C:17]3[O:21][C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[N:19][C:18]=3[C:28]([F:31])([F:30])[F:29])=[O:16])=[CH:10][CH:9]=2)CC1.N[C:39]1C=C2C(=CC=1)NC=C2>>[NH:5]1[C:8]2[C:2](=[CH:32][C:11]([NH:14][C:15]([C:17]3[O:21][C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH:24]([CH3:39])[CH2:23]4)=[N:19][C:18]=3[C:28]([F:31])([F:29])[F:30])=[O:16])=[CH:10][CH:9]=2)[CH:7]=[CH:6]1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C(Nc1ccc(N2CCC(O)(c3ccccc3)CC2)nc1)c1oc(N2CCCCC2)nc1C(F)(F)F
Product: CC1CCCN(c2nc(C(F)(F)F)c(C(=O)Nc3ccc4[nH]ccc4c3)o2)C1

Procedure:
Compound 44 was prepared by the general procedure for compound 1, by using intermediates A-10 and 5-aminoindole as starting materials. 1H NMR (500 MHz, DMSO-d6) δ 11.10 (br s, 1H), 10.01 (s, 1H), 7.36 (m, 2H), 7.30 (br d, 1H, J=6.8 Hz), 6.41 (s, 1H), 4.12 (m, 2H), 3.29 (br s, 1H), 3.05 (t, 1H, J=12.3 Hz), 2.74 (t, 1H, J=12.2 Hz), 1.70 (m, 3H), 1.53 (m, 1H), 1.15 (m, 1H), 0.94 (d, 3H, J=6.0 Hz). MS (M+1): 393.
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11][NH:12][C:13](=[O:17])[CH2:14][CH:15]=[CH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.[Br:25]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([O:11][N:12]1[CH:15]([CH2:16][Br:25])[CH2:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(=O)NOC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)ON1C(=O)CC1CBr
Reaction time: 0.02 h
Yield: 116.5 %

Procedure:
To a solution of 0.3 g (1.28 mmole) of N-benzyloxycarbonyloxy but-3-eneoic acid amide in 20 ml of acetonitrile was added 0.1857 g (1.36 mmole) of potassium carbonate followed by 2 ml of water. The mixture was stirred vigorously for one minute and a solution of 0.2383 g (1.34 mmole) of N-bromosuccinimide in 5 ml of acetonitrile was added dropwise over 5 minutes with continued vigorous stirring. Stirring was continued for 10 minutes post addition and then the mixture was diluted with 200 ml of ethyl acetate. The solution was washed with water, aqueous 10% sodium bisulfite and brine and was dried over magnesium sulfate. The solvent was evaporated to provide 0.4686 g of the title compound as a pale yellow oil. The product was contaminated with minor amounts of succinimide and N-hydroxy-4-bromomethylazetidinone.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=1>>[CH:16]1([C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][CH2:13][CH:12]=[CH:11]1
Reactant: C1=CCCCC1
Reactant: O=C(O)c1ccc(I)cc1
Product: O=C(O)c1ccc(C2C=CCCC2)cc1

Procedure:
The title compound is prepared by following a procedure analogous to Example 114, Step 1, and using 4-iodobenzoic acid (3.0 g, 12.10 mmol), and cyclohexene (12.3 mL) to give the product (0.40 g, 1.98 mmol, 16%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][C:3]=1[CH3:19].CCN(C(C)C)C(C)C.Cl.[C:30]([O:34][NH2:35])([CH3:33])([CH3:32])[CH3:31].CCN=C=NCCCN(C)C.Cl.C(Cl)CCl>C(Cl)Cl>[C:30]([O:34][NH:35][C:13](=[O:15])[C@H:12]([NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=1)(=[O:9])=[O:10])[CH:16]([CH3:18])[CH3:17])([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1cc(S(=O)(=O)N[C@@H](C(=O)O)C(C)C)ccc1F
Reactant: CC(C)(C)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(S(=O)(=O)N[C@@H](C(=O)NOC(C)(C)C)C(C)C)ccc1F
Reaction time: 0.5 h

Procedure:
2(R)-[(4-Fluoro-3-methylphenylsulfonyl)]amino-3-methylbutyric acid (2.64 g, 9.12 mmol) was dissolved in DCM (30 ml), followed by addition of DIEA (3.18 ml, 2 eq.) and O-t-butylhydroxylamine hydrochloride (2.3 g, 2 eq.). EDC.HCl (2.1 g, 1.2 eq.) was then added portionwise as solid. More EDC (0.6, 0.5 eq.) was added after 40 min and the reaction was stirred for another 30 min. The solvent was removed on a rotavap at room temperature, and residue was partitioned with ethylacetate (80 ml), 1N HCl (50 ml). The organic layer was washed with 1N HCl, brine, and dried over Na2SO4. The crude product was flash column purified with 5% to 12% ethylacetate in DCM gradient solvent to give product N-t-butoxy-2(R)-[(4-fluoro-3-methylphenylsulfonyl)]amino-3-methylbutyramide as a white foam. TLC (1:10 ethylaceate:DCM) Rf 0.16. NMR (500 MHz, CD3OD) δ: 0.89 (d, 3H), 0.90 (d, 3H), 1.08 (s, 9H), 1.86 (m, 1H), 2.30 (d, 3H), 3.44 (d, 1H), 7.18 (t, 1H), 7.70 (m, 1H), 7.77 (m, 1H).
Reaction SMILES: [CH2:1]([N:4]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[N:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH3:27][N:28]=[C:29]=[O:30]>O1CCCC1>[CH3:27][NH:28][C:29](=[O:30])[O:14][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[N:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)[CH:6]=[CH:7]2
Reactant: CN=C=O
Reactant: CCCN(c1ccncc1)n1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(c1ccncc1)n1ccc2cc(OC(=O)NC)ccc21

Procedure:
To 2.5 g of 1-(propyl-4-pyridinylamino)-1H-indol-5-ol in 30 ml of tetrahydrofuran was added potassium carbonate (milled, 1.3 g) followed by methyl isocyanate (0.56 ml). The reaction was allowed to proceed for half an hour. The reaction mixture was then filtered and the filtrate concentrated to yield a solid (2.9 g) which was eluted with 5% methanol in dichloromethane on a silica gel column via HPLC. The desired fractions were concentrated to yield a solid (2.7 g) which was recrystallized from isopropyl ether to yield a solid 1.8 g, m.p. 158°-159° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:16][C:17](=[O:31])[CH:18]([NH2:30])[C:19]([NH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Br:32][C@H:33]([CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[C:45](=[O:46])[C:44]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:43]2[C:42]1=[O:51])[C:34](O)=[O:35]>>[CH2:22]([NH:21][C:19](=[O:20])[CH:18]([NH:30][C:34](=[O:35])[C@@H:33]([Br:32])[CH2:37][CH2:38][CH2:39][CH2:40][N:41]1[C:45](=[O:46])[C:44]2=[CH:47][CH:48]=[CH:49][CH:50]=[C:43]2[C:42]1=[O:51])[C:17]([NH:16][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1
Reactant: O=C(O)[C@H](Br)CCCCN1C(=O)c2ccccc2C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCc1ccccc1)C(NC(=O)[C@@H](Br)CCCCN1C(=O)c2ccccc2C1=O)C(=O)NCCc1ccccc1

Procedure:
Prepare by the method of Example 3.3 using N,N′-diphenethyl-2-aminomalonamide trifluoroacetic acid salt (20 mmol) and (R)-2-bromo-6-phthalimidohexanoic acid (25 mmol) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:11][OH:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: ON=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.8 %

Procedure:
To a solution of 4-chlorobenzaldehyde (10.0 g) in chloroform (350 mL), hydroxylamine hydrochloride (10.2 g) was added and the mixture was stirred at room temperature for 18 hours in an argon atmosphere. After adding 2 mol/L hydrochloric acid (200 mL), three extractions were conducted with chloroform. The combined organic layers were washed with saturated brine and thereafter dried over anhydrous magnesium sulfate. After removing the desiccant by filtration, the filtrate was concentrated under reduced pressure. The resulting residue was crystallized with a liquid mixture of n-hexane and chloroform to give 1-(4-chlorophenyl)-N-hydroxymethaneimine as a colorless solid (9.27 g).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][CH2:25][C:24]3[N:23]=[C:22]([CH3:27])[NH:21][C:20]=3[C:19]3[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[CH3:33].CCN(C(C)C)C(C)C>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:18]2[N:17]([C:15]([C:12]3[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[C:10]([CH3:33])[CH:11]=3)=[O:16])[CH2:26][CH2:25][C:24]3[N:23]=[C:22]([CH3:27])[NH:21][C:20]=3[C:19]=2[CH:28]=1
Reactant: Cc1nc2c([nH]1)-c1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(C)c1)CC2
Reactant: CC(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc2c([nH]1)-c1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)C(C)C)c(C)c1)CC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 85 %

Procedure:
Isobutyryl chloride (0.07 ml, 0.07 mmol) was added to a solution of (4-aminomethyl-3-methyl-phenyl)-(9-chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone from Example E125.3 (24 mg, 0.07 mmol) in dichloromethane (3 ml) and DIEA (0.10 ml, 0.57 mmol) at 0° C. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane to 10% methanol:90% di-chloromethane) to give a colourless oil identified as the title compound 24 mg, 85%).