Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P:3]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[N+:22]([O-:24])=[O:23])(=[O:6])[O:4]C)[CH3:2].[OH-].[K+]>CO>[CH2:1]([P:3]([C:7]1[CH:12]=[C:11]([O:13][C:14]2[C:19]([Cl:20])=[CH:18][C:17]([Cl:21])=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[N+:22]([O-:24])=[O:23])(=[O:4])[OH:6])[CH3:2]
Reactant: CCP(=O)(OC)c1cc(Oc2ncc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCP(=O)(O)c1cc(Oc2ncc(Cl)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A mixture of methyl P-ethyl-2-nitro-5-(3,5-dichloro-2-pyridyloxy)phenylphosphinate (0.6 g.), methanol (10 ml.) and 5% aqueous potassium hydroxide (10 ml.) is heated to 90° for 15 min. The basic aqueous solution is acidified and extracted with ether. The combined ether extracts are washed and dried and the solvent is evaporated off to give P-ethyl-2-nitro-5-(3,5-dichloro-2-pyridyloxy)phenyl-phosphinic acid.
Reaction SMILES: [NH2:1][C:2](=[O:21])[C@@H:3]([NH:10]C(=O)OCC1C=CC=CC=1)[CH2:4][O:5][C:6]([CH3:9])([CH3:8])[CH3:7].[ClH:22].[H][H]>CO.[Pd]>[ClH:22].[NH2:10][C@@H:3]([CH2:4][O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[C:2]([NH2:1])=[O:21]
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(N)=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC[C@H](N)C(N)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of Example 31A (784 mg, 2.67 mmol) in methanol (9 mL) at ambient temperature was treated with 10% Pd/C (75 mg) and sufficient 1M HCl to solubilize the substrate (ca. 0.50 mL). The system was equipped with a hydrogen balloon and stirred for 4 hours at ambient temperature. The reaction mixture was purged with nitrogen, filtered through diatomaceous earth (Celite®), rinsed with methanol and water, and the aqueous filtrate was washed with diethyl ether (2×40 mL). The aqueous layer was lyophilized providing 467 mg of the desired product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10]C(=O)C(F)(F)F)[CH3:9])=[C:4]([N+:17]([O-:19])=[O:18])[C:3]=1[F:20].O.[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[C:4]([N+:17]([O-:19])=[O:18])[C:3]=1[F:20]
Reactant: CC(NC(=O)C(F)(F)F)c1ccc(Cl)c(F)c1[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(N)c1ccc(Cl)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
N-[1-(4-Chloro-3-fluoro-2-nitro-phenyl)-ethyl]-2,2,2-trifluoro-acetamide (286 mg, 0.909 mmol) was dissolved at room temperature in THF (10 mL). Then, a solution of lithium hydroxide monohydrate (46 mg, 1.09 mmol) in water (2 mL) was added. The reaction was followed by TLC, using ethyl acetate as solvent. After 2 h., more lithium hydroxide monohydrate (46 mg, 1.09 mmol) in water (2 mL) was added. The reaction was stirred at room temperature for three days. Then, the reaction was extracted with ethyl acetate-sodium hydroxide (1N) and brine. The organic layer was collected, dried with sodium sulfate, filtered and concentrated under vacuum to produce a crude, which it was chromatograph over silica gel to yield 148 mg of 1-(4-chloro-3-fluoro-2-nitro-phenyl)-ethylamine. 1H NMR (400 MHz, Cl3CD) δ 7.90 (d, J=6.43 Hz, 1H), 7.64 (d, J=10.07 Hz, 1H), 4.62 (m, 1H), 1.58 (br s, 2H), 1.33 (d, J=6.43, 3H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[N:8]([C@@H:11]([CH:16]([CH3:18])[CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[C:9]=[O:10]>C1COCC1>[CH3:17][CH:16]([CH3:18])[C@H:11]([NH:8][C:9]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7])=[O:10])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)[C@@H](N=C=O)C(C)C
Reactant: C=CCCCNC
Solvent: C1CCOC1
Product: C=CCCCN(C)C(=O)N[C@H](C(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An oven-dried 500 mL round bottom flask under nitrogen was charged with THF (20 mL), N-methylpent-4-en-1-amine (Org. Lett. (2005), 7(9), pp 1737-1739) (1.0 g, 10.1 mmol) and methyl (2S)-2-isocyanato-3-methylbutanoate (J.O.C. (1992), 57(26), pp 7364-7366) (1.60 g, 10.1 mmol). Contents of the reaction flask were stirred at RT for 2 hours then rotary evaporated to afford the title compound as a colorless oil. LRMS m/e [M+H]+ 257.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][Si](C)(C)C)[C:7]([F:16])=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].[OH:27]S(O)(=O)=O>CC(C)=O>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([C:10](=[O:27])[CH3:11])[C:7]([F:16])=[C:6]([F:17])[C:5]=1[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1cc(C#C[Si](C)(C)C)c(F)c(F)c1Nc1ccccc1Cl
Solvent: CC(C)=O
Product: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1Cl
Yield: 73.7 %

Procedure:
A mixture of 2-(2-chlorophenylamino)-3,4-difluoro-5-trimethylsilanylethynylbenzoic acid methyl ester (5) (79.4 mg, 0.20 mmol), HgSO4 (59.8 mg, 2.0 mmol), and conc. H2SO4 (0.02 mL, 0.40 mmol) in 80% aqueous acetone (2.5 mL), were refluxed for 48 hours. The reaction was concentrated under reduced pressure, and diluted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4 and concentrated to give 50.1 mg (73%) of the desired product (6).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].CN(C)C=O.[CH2:25](Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[CH2:25]([N:8]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1cc(-c2n[nH]c(-c3ccncc3)n2)ccn1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: c1ccc(Cn2nc(-c3ccncc3)nc2-c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3,5-bis(4-pyridyl)-1,2,4-triazole (4.4 g., 0.02 mol) in dry tetrahydrofuran (200 ml.) is added 57% sodium hydride in mineral oil (1 g., 0.024 mol.) and the mixture is heated 45 minutes at reflux. The suspension is concentrated to a solid, N,N-dimethylformamide (70 ml.) and benzyl chloride (2.8 g., 0.022 mol.) are added. The mixture is stirred 0.5 hour at ambient temperature followed by 4 hours at steam bath temperature. The solution is concentrated to a gum, water is added and the material solidifies. After recrystallization from methylcyclohexane 1.4 g. of 1-benzyl-3,5-bis(4-pyridyl)-1,2,4-triazole, melting at 136°-138°C. is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]2[N:9]=[C:10]([NH2:12])[N:11]=[C:7]2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.[F:19][C:20]1[CH:21]=[C:22]([C:26](Cl)=[O:27])[CH:23]=[CH:24][CH:25]=1.CCN(CC)CC>O1CCOCC1>[F:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[C:26]([NH:12][C:10]1[N:11]=[C:7]2[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]2[N:9]=1)=[O:27]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: COc1ccc(-c2ccccc2)c2nc(N)nn12
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1ccc(-c2ccccc2)c2nc(NC(=O)c3cccc(F)c3)nn12
Temperature: 90 °C

Procedure:
A mixture of 15 mg (0.062 mmol) 5-methoxy-8-phenyl-[1,2,4]triazolo[1,5-a]-pyridin-2-yl-amine, 11 mg (0.068 mmol) 3-fluorophenyl carboxylic acid chloride, and 31.5 μl (0.312 mmol) NEt3 in 1 ml dioxane was heated to 90° C. for 16 h. The mixture was purified by preparative HPLC on reversed phase eluting with an acetonitrile/water gradient. Evaporation yielded the title compound. MS m/e (%): 281.7 ((M+CH3CN)+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:34]([OH:35])=[C:33]([C:36]([F:39])([F:38])[F:37])[CH:32]=[CH:31][C:9]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][C:19]=2[N+:28]([O-])=O)=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO>[NH2:28][C:19]1[CH:20]=[C:21]([CH2:24][C:25]([OH:27])=[O:26])[CH:22]=[CH:23][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][C:9]2[CH:31]=[CH:32][C:33]([C:36]([F:38])([F:39])[F:37])=[C:34]([OH:35])[C:8]=2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3[N+](=O)[O-])cc2)ccc(C(F)(F)F)c1O
Solvent: CO
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3ccc(CC(=O)O)cc3N)cc2)ccc(C(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Rhodium-alumina (Rh 5%) (100 mg) was added to a solution of (4′-{[2-(tert-butoxycarbonyl)-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-2-nitro-1,1′-biphenyl-4-yl)acetic acid (130 mg, 0.237 mmol) obtained in Example (37-2) in methanol (4 ml), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 days. The insolubles were removed by filtration through Celite and the filtrate was concentrated. The obtained residue was purified by silica gel preparative thin layer chromatography (developing solvent: methylene chloride/methanol=20/1) to give the title compound as a yellow amorphous compound (63 mg, yield: 51%).
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][C:12]=1[CH2:22][CH2:23][CH3:24])=[O:10].[CH2:25]([N:27]([CH3:35])[C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][N:29]=1)[CH3:26]>>[CH2:25]([N:27]([CH3:35])[C:28]1[N:29]=[CH:30][C:31]([NH:34][C:9]([C:11]2[O:15][C:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:13][C:12]=2[CH2:22][CH2:23][CH3:24])=[O:10])=[CH:32][CH:33]=1)[CH3:26]
Reactant: CCCc1nc(-c2ccccc2)oc1C(=O)ON1C(=O)CCC1=O
Reactant: CCN(C)c1ccc(N)cn1
Product: CCCc1nc(-c2ccccc2)oc1C(=O)Nc1ccc(N(C)CC)nc1

Procedure:
With a procedure similar to example 50 above, 2-phenyl-4-propyl-oxazole-5-carboxylic acid [6-(ethyl-methyl-amino)-pyridin-3-yl]-amide was prepared from 2-phenyl-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N2-ethyl-N2-methyl-pyridine-2,5-diamine. LCMS calcd for C21H24N4O2 (m/e) 364, obsd 365 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].C([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])(C)(C)C>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:19]1[CH2:20][CH2:21][N:16]([C:14]([OH:15])=[O:13])[CH2:17][CH2:18]1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(O)N1CCN(C(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.7 %

Procedure:
2-Thiophenecarbonylchloride (2.04 g, 1.49 mL) was added to a solution of tert-butyl-1-piperazinecarboxylate (2.5 g, 13.4 mmol) and DMAP (20 mg) in pyridine (15 mL) at 0° C. under N2 atmosphere and stirred at room temperature for overnight. The mixture was poured into ice water, the precipitate was filtered, washed several times with water, and dried to yield white solids (3.5 g, 88%). Mp 76° C. 1H NMR (DMSO-d6): δ 1.42 (s, 12H), 3.40 (m, 4H), 3.61 (m, 4H), 7.12 (m, 1H), 7.43 (d, J=4.1 Hz, 1H), 7.77 (d, J=4.8 Hz, 1H). EIMS m/z 297 (M+1), 319 (M+23). Anal. (C14H20N2O3S) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=1)(=[O:14])=[O:13].[C:31](N1C=CN=C1)(N1C=CN=C1)=[O:32]>ClCCCl>[Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[S:12](=[O:14])(=[O:13])[N:15]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:31]1=[O:32]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(NS(=O)(=O)c2cnccc2NCc2c(F)cccc2Cl)cc1OC
Solvent: ClCCCl
Product: COc1ccc(N2C(=O)N(Cc3c(F)cccc3Cl)c3ccncc3S2(=O)=O)cc1OC
Yield: 22.2 %

Procedure:
A solution of 4-[(2-chloro-6-fluorobenzyl)amino]-N-(3,4-di methoxyphenyl)pyridine-3-sulfonamide (0.04 g, 0.09 mmol) and 1,1′-carbonyldiimidazole (56 mg, 0.34 mmol) in 1,2-dichloroethane (10 mL) was heated for 30 min at 100° C., then cooled and concentrated in vacuo. Purification by gradient column chromatography eluting with 0-30% EtOAc in hexane yielded the title compound (10 mg, 0.02 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2C)[CH2:4][O:3]1.[Cl:22]C1C=C(C=C(C)C=1O)C#N>>[Cl:22][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:19])[C:9]=1[O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:21])([CH3:1])[O:6]1)[C:13]([NH:15][OH:16])=[NH:14]
Reactant: Cc1cc(C#N)cc(Cl)c1O
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Product: Cc1cc(C(=N)NO)cc(Cl)c1OC[C@@H]1COC(C)(C)O1

Procedure:
The title compound is obtained as a colorless oil (1.39 g) in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 3-chloro-4-hydroxy-5-methyl-benzonitrile and L-alpha-beta-isopropyliden glycerol; LC-MS: tR=0.66 min, [M+H]+=314.96.
Reaction SMILES: [CH2:1]([S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:17]=[O:18])(=[O:15])=[O:14])(=[O:6])=[O:5])[CH2:2][CH3:3].[NH2:19][C:20]1[N:25]=[C:24]([Cl:26])[CH:23]=[C:22]([O:27][CH2:28][CH3:29])[N:21]=1>C(#N)C>[Cl:26][C:24]1[CH:23]=[C:22]([O:27][CH2:28][CH3:29])[N:21]=[C:20]([NH:19][C:17]([NH:16][S:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:4]([CH2:1][CH2:2][CH3:3])(=[O:6])=[O:5])(=[O:15])=[O:14])=[O:18])[N:25]=1
Reactant: CCCS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: CCOc1cc(Cl)nc(N)n1
Solvent: CC#N
Product: CCCS(=O)(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(Cl)cc(OCC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 2-propylsulfonylbenzenesulfonyl isocyanate (1.67 g, 5.76 mmol) in dry acetonitrile was added 2-amino-4-chloro-6-ethoxypyrimidine (1.00 g, 5.76 mmol). After stirring at room temperature overnight, the reaction mixture was filtered and the solid washed with 1-chlorobutane to give the product as a white powder melting at 220°-222° C.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:8])(=O)C.C(SCC(C)C(NC1N=CC=CC=1C(OC)=O)=O)(=O)C>C(Cl)Cl.CO>[SH:4][CH2:5][CH:6]([CH3:20])[C:7]([NH:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16])=[O:8]
Reactant: COC(=O)c1cncc(NC(=O)C(C)CSC(C)=O)c1
Agent: COC(=O)c1cccnc1NC(=O)C(C)CSC(C)=O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cncc(NC(=O)C(C)CS)c1

Procedure:
Following the procedure of Example 2, but substituting an equivalent amount of methyl 5-(2-acetylthiomethyl-propionamido)-nicotinate, obtained as disclosed in Example 12, for methyl 2-(2-acetylthiomethyl-propionamido)-nicotinate and using a mixture of methylene chloride/methanol 99:1 as eluent for the chromatographic column, methyl 5-(2-mercaptomethyl-propionamido)-nicotinate is obtained: m.p. 96°-97° C., from ethyl acetate.
Reaction SMILES: CO.[CH:3]1([NH:13][C:14]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[N:25]=3)=[CH:17][C:15]=2[NH2:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.Cl.[C:31](=N)(OC)[CH3:32]>O>[O:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[C:18]1[CH:19]=[CH:20][C:14]2[N:13]([CH:3]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH2:6][CH2:5][CH2:4]3)[C:31]([CH3:32])=[N:16][C:15]=2[CH:17]=1
Reactant: COC(C)=N
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCCc2ccccc21
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1C1CCCc2ccccc21
Yield: 49.4 %

Procedure:
To a methanol (5 mL) solution of 2-(2-(1,2,3,4-tetrahydronaphthalen-1-yl)aminoanilin-5-yl)benzoxazole (see Working Example 87-1) (0.30 g, 0.8 mmol) was added methyl acetimidate hydrochloride (0.10 g, 0.9 mmol), and this was heated to reflux for 3 hours. After the reaction solution was cooled, water was added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The residue obtained was purified by silica gel column chromatography to yield the title compound (0.15 g, 47% yield) as a colorless amorphous mass.
Reaction SMILES: [NH:1]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:2]([C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:34]([O:36]C)=[O:35])[CH2:30][CH:31]([CH3:33])[CH3:32])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(C)=O.O>[NH:1]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:2]([C:18]([NH:20][C@H:21]([C:26]([NH:28][C@H:29]([C:34]([OH:36])=[O:35])[CH2:30][CH:31]([CH3:32])[CH3:33])=[O:27])[CH2:22][CH:23]([CH3:24])[CH3:25])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.67 h

Procedure:
Boc-Lys(Z)-Leu-Leu-OMe (12.0 g, 19.33 mmol) was dissolved in acetone (41.0 g, 52 mL) at 22-23° C. A solution of NaOH (1.94 g, 48.5 mmol) in water (18.0 g) was added over 5 min. After stirring for 40 min., the reaction was quenched with a solution of citric acid (10.2 g, 53.0 mmol) in water (18.0 g). The acetone was removed on a rotary evaporator at 40° C. The remaining mixture was extracted with ethyl acetate (2×65 mL). The EtOAc extract was washed with water (50 g) then with aqueous saturated sodium chloride solution (50 g). The EtOAc extract was dried over anhydrous MgSO4 (10 g). The EtOAc solution was filtered and diluted with DMF (40. g). The ethyl acetate was evaporated at 40° C. under reduced pressure to give the solution of the product in DMF. Weight of solution ˜52 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Cl[C:29]1[CH:30]=[CH:31][C:32]2[N:33]=[CH:34][N:35]=[C:36]([O:39][CH:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[C:37]=2[N:38]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.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.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:1][C:2]1[C:7]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:6][C:5]([C:29]2[CH:30]=[CH:31][C:32]3[N:33]=[CH:34][N:35]=[C:36]([O:39][CH:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[C:37]=3[N:38]=2)=[CH:4][N:3]=1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Reactant: CC1(C)OB(c2cnc(Cl)c(NC(=O)c3ccc(F)cc3F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccc3ncnc(OC4CCOCC4)c3n2)cnc1Cl)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 15.9 %

Procedure:
A mixture of N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2,4-difluorobenzamide (Intermediate 14) (0.100 g, 0.253 mmol), 6-chloro-4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidine (Intermediate 1) (0.074 g, 0.279 mmol), 1N aq. sodium bicarbonate (0.043 g, 0.507 mmol) and PdCl2(dppf)-CH2Cl2 (0.021 g, 0.025 mmol) in dioxane (1.26 ml) was subjected to microwave irradiation for 1 hour at 110° C., and cooled to room temperature. The reaction mixture was filtered through a Celite pad and washed with DCM. The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=1:1) to give N-(2-chloro-5-(4-(tetrahydro-2H-pyran-4-yloxy)pyrido[3,2-d]pyrimidin-6-yl)pyridin-3-yl)-2,4-difluorobenzamide (0.020 g, 16%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 2.05-2.13 (2H, m), 2.23-2.27 (2H, m), 3.70-3.76 (2H, m), 4.11-4.18 (2H, m), 5.65-5.71 (1H, m), 7.00-7.05 (1H, m), 7.10-7.15 (1H, m), 8.25-8.38 (3H, m), 8.84 (1H, s), 8.03 (1H, d, J=2.4 Hz), 9.19-9.24 (1H, m), 9.71 (1H, d, J=2.4 Hz). m/z=498.0 [M+1]+.
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:12][C:13](=[O:15])[CH3:14]>>[O:15]=[C:13]([CH3:14])[CH2:12][S:1][C:2]1[CH:3]=[C:4]([B:8]([OH:10])[OH:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CCl
Reactant: OB(O)c1cccc(S)c1
Product: CC(=O)CSc1cccc(B(O)O)c1

Procedure:
Prepared according to the procedure described in Example 1, Step 1, using the following starting materials: 3-mercaptophenylboronic acid and chloroacetone.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][N:16]2[CH:22]=1.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=3)=[CH:17][N:16]2[CH:22]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(N)ccc2n1
Reactant: O=C(O)c1cccnc1
Product: Cc1onc(-c2ccccc2)c1-c1cn2cc(NC(=O)c3cccnc3)ccc2n1
Yield: 80 %

Procedure:
As described for Example 56, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridin-6-ylamine (71 mg, 0.22 mmol) was converted, using nicotinic acid instead of cyclopropylacetic acid, to the title compound (63 mg, 80%) which was obtained as an off-white solid. MS: m/e=396.3 [M+H]+.
Reaction SMILES: [CH:1]1([C:7]2[C:12]3[O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[I:25]I>C1COCC1>[CH:1]1([C:7]2[C:12]3[O:13][C:14]4[C:19]([I:25])=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: c1ccc2c(c1)oc1c(C3CCCCC3)cccc12
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Ic1cccc2c1oc1c(C3CCCCC3)cccc12
Temperature: -90 °C
Reaction time: 6 h
Yield: 57.9 %

Procedure:
4-Cyclohexyldibenzo[b,d]furan (11.3 g, 45.0 mmol) and THF (1000 mL) were cooled down to −90° C. After that, n-BuLi (56.2 mL, 90.0 mmol, 1.6 M in THF) was added at −90° C. The mixture was stirred for 6 h and allowed to warm from −90° C. to room temperature. The mixture was then cooled to −90° C., and iodine (22.9 g, 90.0 mmol) was added at −90° C. The resultant mixture was stirred for 17 h and allowed to warm from −90° C. to room temperature. The reaction mixture was then quenched by the addition of saturated Na2S2O3 solution and extracted with DCM. The extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was purified by flash chromatography using 5% DCM/hexane to yield 4-cyclohexyl-6-iododibenzo[b,d]furan (9.8 g, 58% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Br:35])[CH2:25][CH2:24]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[Br:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[N:26]1[CH2:25][CH2:24][N:23]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([NH:13][C:2]3[C:11]4[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:28][CH2:27]1
Reactant: Nc1ccc(S(=O)(=O)N2CCN(c3ccccc3Br)CC2)cc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Product: O=S(=O)(c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1)N1CCN(c2ccccc2Br)CC1

Procedure:
In the manner given in Example 1C, 4,7-dichloroquinoline is heated with 1-[(p-aminophenyl)-sulfonyl]-4-(o-bromophenyl)piperazine to give 1-(o-bromophenyl)-4-[[4-[[7-chloro-4-quinolinyl]-amino]phenyl]sulfonyl]piperazine.