Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][N:38]=[N+]=[N-])=[CH:6][CH:5]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:41])[C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][NH2:38])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(NCCc2c(CCN=[N+]=[N-])n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reaction time: 8 h
Yield: 52.7 %

Procedure:
To 4-{2-[2-(2-azido-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethylamino}-benzoic acid methyl ester (400 mg, 0.709 mmol) in THF (4 mL) at 0 C was added Ph3P (223 mg, 0.851 mmol) in portions. The reaction mixture was stirred at rt for 11 h and 35° C. for 4 h before water (50 uL) was added and stirring continued overnight. The reaction mixture was diluted with EtOAc, dried with MgSO4 and purified by flash column chromatography (EtOAc to 20% MeOH/EtOAc with 1% Et3N) to give the desired 4-{2-[2-(2-Amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethylamino}-benzoic acid methyl ester (201 mg, 53%) as a solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Li]CCCC.I[C:12]1[CH:17]=[CH:16][C:15]([C:18]2([OH:28])[CH2:27][CH2:26][C:21]3(OCC[O:22]3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>C1COCC1.[Cl-].[Zn+2].[Cl-]>[OH:28][C:18]1([C:15]2[CH:16]=[CH:17][C:12]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:13][CH:14]=2)[CH2:19][CH2:20][C:21](=[O:22])[CH2:26][CH2:27]1
Reactant: OC1(c2ccc(I)cc2)CCC2(CC1)OCCO2
Reactant: c1cocn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Product: O=C1CCC(O)(c2ccc(-c3ncco3)cc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of oxazole (240 mg, 3.5 mmol) in THF (5 mL) at −78° C. was added n-BuLi (1.6 M, 2.6 mL). After the mixture was stirred for 1 hour, a solution of zinc chloride in THF (0.5 M, 8.2 mL) was added in and the resulting mixture was allowed to warm to 0° C. over 1 hour. To the mixture was added 8-(4-iodo-phenyl)-1,4-dioxa-spiro[4.5]decan-8-ol (1.35 g, 3.5 mmol) and the resulting mixture was degassed with N2 for 3 times. To a suspension of PdCl2(PPh3)2 (122 mg, 5%) in THF (2 mL) was added nBuLi (1.6 M, 0.26 mL) and the mixture was added into the above mixture. The resulting mixture was heated to reflux under N2 for 4 hours. The resulting mixture was diluted with ethyl acetate (50 mL). The organic layer was filtered through Celite and the filtrate was washed with saline solution (2×10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in THF (2.5 mL) and was treated with 5% HCl (22.5 mL) at rt for 24 h. The mixture was neutralized with 1 N NaOH to pH 7, concentrated on rotovap, and then extracted with EtOAc (2×50 mL). The organic extracts were combined, washed with saline solution (2×50 mL), dried over sodium sulfate, concentrated in vacuo. The resulting residue was chromatographed on silica gel, eluting with hexane/ethyl acetate (100/0 to 100/0), to provide the desired compound (0.56 g, 62% for the two steps). LCMS: 258.2 (M+H+, 100%). 1H NMR: (CDCl3) δ 8.06 (d, 2H), 7.73 (s, 1H), 7.63 (d, 2H), 2.99-2.91 (m, 2H), 2.42-2.30 (m 4H), 2.22-2.05 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:39]=[CH:38][C:27]2[N:28]([CH2:34][CH2:35][O:36][CH3:37])[C:29](=[O:33])[CH2:30][CH2:31][CH2:32][C:26]=2[CH:25]=1>>[CH3:37][O:36][CH2:35][CH2:34][N:28]1[C:29](=[O:33])[CH2:30][CH2:31][CH2:32][C:26]2[CH:25]=[C:24]([NH:23][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=4[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=3)[CH:39]=[CH:38][C:27]1=2
Reactant: COCCN1C(=O)CCCc2cc(N)ccc21
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3CCOC)ncc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(2-chloro-5-trifluoromethyl-pyrimidin-4-ylamino)-N-methyl-benzamide and 7-amino-1-(2-methoxyethyl)-1,3,4,5-tetrahydrobenzo[b]azepin-2-one in an analogous manner to Example 195 (microwave: 120° C., 90 minutes) to afford a white solid (29 mg, 47%). Mp: 73-6° C. LCMS (m/e) 529 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.90 (s, 1H), 8.44 (d, J=9 Hz, 1H), 8.39 (s, 1H), 7.50-7.40 (m, 4H), 7.24 (m, 1H), 7.15 (m, 2H), 6.20 (br s, 1H), 4.00 (br m, 2H) 3.57 (t, 2H, J=5 Hz), 3.32 (s, 3H), 3.04 (d, J=5 Hz, 3H), 2.67 (br m, 2H), 2.31 (t, J=5 Hz, 2H), 2.13 (br m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:16]=1[C:15](=[O:17])[C:14]1[C:13]([O:18]C(=O)C)=[CH:12][C:11]([CH2:22][O:23]C(=O)C)=[CH:10][C:9]=1[C:8]2=[O:27].Cl.O>CO>[OH:18][C:13]1[C:14]2[C:15](=[O:17])[C:16]3[C:7](=[CH:6][CH:5]=[CH:4][C:3]=3[O:2][CH3:1])[C:8](=[O:27])[C:9]=2[CH:10]=[C:11]([CH2:22][OH:23])[CH:12]=1
Reactant: COc1cccc2c1C(=O)c1c(OC(C)=O)cc(COC(C)=O)cc1C2=O
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cccc2c1C(=O)c1c(O)cc(CO)cc1C2=O
Yield: 70.2 %

Procedure:
The 8-methoxy-3-acetoxymethyl-1-acetoxy anthraquinone (120 mg) of Example 22 was refluxed in methanol (30 ml) with concentrated hydrochloric acid (10 ml) and water (10 ml) for three hours. The solvents and acid were evaporated off in vacuum and the residue crystallized from chloroform to obtain reddish yellow crystals (65 mg) of 1-hydroxy-3-hydroxymethyl-8-methoxy anthraquinone (formula 19). m.p. 215°-216°, ir (KBr) 3520-3460, 1670, 1635, 1585 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH2:21]1[CH2:28][O:27][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22]1>C(C(C)=O)C(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:15]2[CH2:16][CH2:17][N:18]([CH2:28][CH2:21][CH2:22][CH2:23][S:24]([OH:27])(=[O:26])=[O:25])[CH2:19][CH2:20]2)=[CH:4][CH:3]=1
Reactant: O=S1(=O)CCCCO1
Reactant: Fc1ccc(C(c2ccccn2)N2CCNCC2)cc1
Solvent: CC(=O)CC(C)C
Product: O=S(=O)(O)CCCCN1CCN(C(c2ccc(F)cc2)c2ccccn2)CC1
Yield: 71.5 %

Procedure:
After a mixture of [4-fluorophenyl-(2-pyridyl)methyl]piperazine (2.71 g), 1,4-butanesultone (4.08 g) and isobutylmethylketone (60 ml) is heated at reflux temperature for 20 hours, precipitated crystals are collected by filtration and recrystallized from ethanol-acetone to give the title compound (2.91 g, 71.5%). mp. 231°-232° C.
Reaction SMILES: [CH:1]1[C:10]2[C@H:11]3[CH2:16][NH:15][CH2:14][CH2:13][C@H:12]3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][CH:2]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][C@H:12]3[N:8]4[C:9]5[C:4](=[CH:3][CH:2]=[CH:1][C:10]=5[C@H:11]3[CH2:16]2)[CH2:5][CH2:6][CH2:7]4)=[CH:23][CH:24]=1
Reactant: c1cc2c3c(c1)[C@H]1CNCC[C@H]1N3CCC2
Reactant: Fc1ccc(OCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(OCCCN2CC[C@@H]3[C@H](C2)c2cccc4c2N3CCC4)cc1
Yield: 31.8 %

Procedure:
The title compound (0.14 g, 32%) was prepared by the general method of Example 402 from (±)-cis-5,6,7a,8,9,10,11,11a-octahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline (0.25 g, 1.2 mmol), 1-(3-chloropropoxy)-4-fluorobezene (0.37 g, 2.0 mmol), KI (catalytic) and K2CO3 (0.28 g, 2.0 mmol) after chromatographic purification as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ1.78-2.08 (m, 7H), 2.10-2.30 (m, 1H), 2.32-2.50 (m, 3H), 2.51-2.72 (m, 3H), 2.75-2.82 (m, 1H), 3.00-3.12 (m, 1H), 3.12-3.25 (m, 2H), 3.89 (t, J=6.3 Hz, 2H), 6.55 (t, J=7.5 Hz, 1H), 6.70-6.92 (m, 6H) ppm.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[Cl:27][C:28]1[CH:45]=[CH:44][C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])=[CH:30][CH:29]=1.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.CO.C(OCC)(=O)C>[Cl:27][C:28]1[CH:45]=[CH:44][C:31]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([C:1]2[C:6](=[O:7])[O:5][CH2:4][C:2]=2[OH:3])=[O:42])=[CH:30][CH:29]=1
Reactant: O=C(O)CCCCCCCCOc1ccc(Cl)cc1
Reactant: O=C1COC(=O)C1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CCCCCCCCOc1ccc(Cl)cc1)C1=C(O)COC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.6 %

Procedure:
To a stirring solution of 736 mg (7.36 mmol) of tetronic acid in 30 mL of dimethylformamide is added 1.2 mL (8.09 mmol) of triethylamine and 300 mg of 4-dimethylaminopyridine at 0° C. Next, 1.7 g (8.86 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 2.6 g (8.06 mmol) of 9-(4-chlorophenoxy)nonanoic acid are added and the reaction is stirred overnight at room temperature. The reaction is acidified with 1.0N HCl and extracted with four 50 mL portions of ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo affording crude compound. Pure material is obtained by flash chromatography with 10% methanol/ethyl acetate as eluant affording 800 mg (30%) of 3-[9-(4-chlorophenoxy)-1-oxononyl]-4-hydroxy-2(5H)-furanone.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([C:10]1[CH:15]=[C:14](C(C)(C)C)[CH:13]=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>>[C:6]([C:10]1[CH:15]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:13]=[C:12]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CC(C)(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1
Product: CC(C)(C)c1cc(C(C)(C)C)cc(S(=O)(=O)Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Chlorosulfonic acid (4 mL) was added to 1,3,5-tri-tert-butyl-benzene (1.5 g, 6.1 mmol) which had been cooled to 0° C. After being stirred at 0° C. for 30 minutes, the mixture was warmed to room temperature and stirred for 1 hour. Then the mixture was poured into ice water (50 mL) and extracted with dichloromethane (20 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (gradient elution: 0-20% ethyl acetate in petroleum ether) to afford 3,5-di-tert-butyl-benzenesulfonyl chloride (880 mg, 50%) as a yellow solid (reference: Guthrie, R. D. et al. Aust. J. Chem. 40 (1987) 2133).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:20])=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[CH:10]=2)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.[OH-].[Na+]>C1COCC1.CC(C)=O>[CH3:17][O:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:18][CH3:19])[N:8]=[C:7]([CH3:20])[C:6]([CH2:4][OH:3])=[CH:15]2
Reactant: CCOC(=O)c1cc2cc(OC)c(OC)cc2nc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2cc(CO)c(C)nc2cc1OC
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A solution of 6,7-dimethoxy-2-methylquinoline-3-carboxylic acid ethyl ester (2.83 g, 10.3 mmol) in dry THF (75 ml) was added dropwise over 20 min to a stirred, ice-cooled suspension of lithium aluminiumhydride (0.39 g, 10.3 mmol) in dry THF (50 ml). The mixture was allowed to come to room temperature over 2 h and the excess lithium aluminiumhydride was decomposed by sequential careful addition of ethyl acetate, acetone and 2M NaOH. The mixture was filtered and the white gummy material was extracted twice with acetone. The filtrate and the extracts were combined and concentrated to give 2.31 g of 6,7-dimethoxy-2-methylquinoline-3-methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]([OH:20])[CH3:19])[CH:5]=[C:6]([F:17])[C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.F[C:22]1C=C(C2(O)CCC2)C=C(F)[CH:27]=1>>[F:17][C:6]1[CH:5]=[C:4]([C:18]2([OH:20])[CH2:27][CH2:22][CH2:19]2)[CH:3]=[C:2]([F:1])[C:7]=1[B:8]1[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:15])([CH3:16])[O:9]1
Reactant: CC(O)c1cc(F)c(B2OC(C)(C)C(C)(C)O2)c(F)c1
Reactant: OC1(c2cc(F)cc(F)c2)CCC1
Product: CC1(C)OB(c2c(F)cc(C3(O)CCC3)cc2F)OC1(C)C

Procedure:
Following the procedure of Intermediate 106, replacing 1-(3,5-difluorophenyl)ethanol with 1-(3,5-difluorophenyl)cyclobutanol (see US2012/225062) provided the title compound.
Reaction SMILES: O=C1N(C)C(=O)N(C)[CH:4]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[OH:21])N1C.[OH-:23].[Na+]>O>[OH:21][C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[CH:4]=[O:23]
Reactant: CN1C(=O)N(C)C(c2c(O)ccc3ccccc23)N(C)C1=O
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=Cc1c(O)ccc2ccccc12

Procedure:
29.7 g (0.1 mol) of 2,4-dioxo-hexahydro-1,3,5-trimethyl-6-(2-hydroxy-naphthyl)-s-triazine and 20 g (0.5 mol) of sodium hydroxide in 50 ml of water are stirred for 8 hours at 95° C. The solution is then acidified and 2-hydroxy-naphthaldehyde of melting point 82° C is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[CH:8]([OH:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10].Cl(O)(=O)(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(O[C:30]([CH3:33])([CH3:32])[CH3:31])(=O)C>>[C:30]([O:14][CH:8]([C:3]1[S:4][C:5]([Br:7])=[CH:6][C:2]=1[Br:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:33])([CH3:32])[CH3:31]
Reactant: CCOC(=O)C(O)c1sc(Br)cc1Br
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCOC(=O)C(OC(C)(C)C)c1sc(Br)cc1Br
Temperature: 0 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
Ethyl 2-(3,5-dibromothiophen-2-yl)-2-hydroxyacetate (7b) (100 mg, 0.29 mmol) was dissolved in tert-butyl acetate (5.4 mL) at −20° C. and 70% perchloric acid (0.7 mL) was rapidly added. The mixture was stirred at 0° C. for 3 hours then poured in a saturated solution of potassium carbonate. Layers were separated. The aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to provide ethyl 2-(tert-butoxy)-2-(3,5-dibromothiophen-2-yl)acetate (100 mg, 0.40 mmol, 86%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4](N)[CH:3]=1.N(OCCC(C)C)=O.[I:20]CI>>[I:20][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1
Reactant: Cc1cc(N)ncc1[N+](=O)[O-]
Reactant: ICI
Agent: CC(C)CCON=O
Product: Cc1cc(I)ncc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 28 %

Procedure:
To a solution of 4-methyl-5-nitro-2-pyridinamine (12 g, 78.35 mmol) in diiodomethane (100 mL) was added isoamyl nitrite (22 mL, 160.4 mmol) at rt. After stirring for 30 min, the reaction was kept at 80° C. for 2 hr. The reaction was cooled and concentrated; but most of the diiodomethane remained. The crude mixture was loaded into column directly and eluted with 10% of EtOAc in hexane, and 2-iodo-4-methyl-5-nitropyridine (5.7 g, 28%) was obtained as a yellow solid after the removal of solvents under reduced pressure.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH:12]=[C:13]1[NH:17][C:16](=[O:18])[CH2:15][S:14]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[C:15]3[S:14][C:13](=[NH:12])[NH:17][C:16]3=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N=C1NC(=O)CS1
Reactant: O=Cc1ccc2c(c1)OCO2
Product: N=C1NC(=O)C(=Cc2ccc3c(c2)OCO3)S1

Procedure:
Following the general method as outlined in Example 1, starting from 1,3-benzodioxol-5-carbaldehyde and 2-imino-1,3-thiazolidin-4-one, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:8]=1)[NH2:5].Cl[C:15]1[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=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.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:15]2[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][N:16]=2)[CH:6]=[C:7]([C:9]2[S:13][CH:12]=[N:11][CH:10]=2)[CH:8]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Nc1cc(F)cc(-c2cncs2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Product: Fc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cncs2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
The product of Step 2 (0.93 g, 4.79 mmol), 2-chloro-4-(trifluoromethyl)pyrimidine (0.874 g, 4.79 mmol), palladium(II) acetate (0.107 g, 0.479 mmol), xantphos (0.416 g, 0.718 mmol), and cesium carbonate (3.12 g, 9.58 mmol) were added to a dry flask. The flask was degassed with argon, and then dioxane (20 ml) was added. The reaction mixture was degassed with argon for five minutes, and then heated to 90° C. After 2 hours, the reaction mixture was cooled, diluted with ethyl acetate, filtered through celite, and concentrated. The residue was purified by column chromatography on silica gel (EtOAc/hexane gradient) to afford solids. The solids were dissolved in hot ethyl acetate (25 mL) and then triturated with hexanes (50 mL) while cooling. After 2 hours, the mixture was filtered to afford N-[3-fluoro-5-(1,3-thiazol-5-yl)phenyl]-4-(trifluoromethyl)pyrimidin-2-amine (1.18 g, 3.47 mmol, 72% yield). MS ESI: [M+H]+ m/z 341.1. 1H NMR (500 MHz, DMSO-d6) δ 10.52 (s, 1H); 9.10 (s, 1H); 8.87 (d, J=4.0 Hz, 1H); 8.31 (s, 1H); 7.93 (s, 1H); 7.66-7.62 (m, 1H); 7.35 (d, J=4.5 Hz, 1H); 7.28 (dt, J=8.0 Hz, 1.5 Hz, 1H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:26])[C:22]([O:24]C)=[O:23])[CH:9]=1)(=[O:3])[CH3:2].C1(N2CCNCC2)C=CC=CC=1.ClCCl>CS(C)=O>[C:1]([NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[C:10]([NH:20][C:21](=[O:26])[C:22]([OH:24])=[O:23])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)C(=O)Nc1cc(NCCNC(C)=O)nc(-c2ccccc2)n1
Agent: c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(=O)NCCNc1cc(NC(=O)C(=O)O)nc(-c2ccccc2)n1
Reaction time: 16 h

Procedure:
To a well of a 96 well microtitre plate were added methyl [(6-{[2-(acetylamino)ethyl]amino}-2-phenylpyrimidin-4-yl)amino](oxo)acetate (30 μl of a 0.3M solution in anhydrous DMSO) and 4-phenylpiperazine (30 μl of a 1.5M solution). This solution was left to shake on a plate shaker for 16 hrs. After this time 800 μl of dichloromethane were added, then 100 mg of PS-NCO. The plate was sealed, then mixed for 48 hrs. The slurry was filtered and the solvents removed in vacuo, to furnish the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:6]=[CH:5]2
Reactant: Fc1ccc2[nH]ncc2c1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)Cn1ncc2cc(F)ccc21

Procedure:
The title compound was prepared according to the method described for Preparation 93 using 5-fluoro-1H-indazole and ethyl bromoacetate to afford the title compound as an off-white solid in 53% yield, 260 mg.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:5])[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](Cl)=[O:21])=[CH:15][CH:14]=1>ClCCCl>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH3:11])=[C:9]([C:20](=[O:21])[CH2:19][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(C)[nH]1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Solvent: ClCCCl
Product: CCOC(=O)c1cc(C(=O)Cc2ccc(F)cc2)c(C)[nH]1
Yield: 76 %

Procedure:
4-[2-(4-Fluorophenyl)-acetyl]-5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (111) was synthesized from 5-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (107) and (4-Fluorophenyl)-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloroethane/RT. Purification: recrystallization from ether/pentane. Yield: 76%. 1H (CDCl3, 400 MHz): δ 10.5 (NH, broad s), 7.31 (1H, s), 7.22 (2H, dd), 6.99 (2H, dd), 4.36 (2H, q), 4.06 (2H, s), 2.58 (3H, s), 1.39 (3H, t) ppm. 13C (CDCl3, 100 MHz): δ 194.1, 163.0, 161.5, 160.6, 141.0, 131.1, 130.7, 121.5, 120.5, 116.9, 115.4, 115.2, 61.0, 45.9, 14.4, 14.0 ppm. LC/MS: 100%.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([NH:21][C:22]([C@H:24]3[CH2:29][CH2:28][C@H:27]([N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])[CH2:26][CH2:25]3)=[O:23])=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>N1C=CC=CC=1>[CH3:36][S:37]([NH:1][C:2]1[C:7]2[C:8]([NH:21][C:22]([C@H:24]3[CH2:25][CH2:26][C@H:27]([N:30]4[CH2:34][CH2:33][CH2:32][C:31]4=[O:35])[CH2:28][CH2:29]3)=[O:23])=[C:9]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)=[O:12])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)(=[O:39])=[O:38]
Reactant: Nc1cccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c12
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N4CCCC4=O)CC3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-4-amino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (27 mg) obtained in Example 426 is dissolved in pyridine (2 ml), and thereto is added methanesulfonyl chloride (7 μl) under ice-cooling. The mixture is stirred at room temperature overnight, and thereto are further added pyridine (3 ml) and methanesulfonyl chloride (500 μl) under ice-cooling. The mixture is stirred at room temperature for 6 hours. Water is added to the reaction solution, and the mixture is extracted with chloroform. The solvent is evaporated under reduced pressure, and the resulting residue is purified by silica gel column chromatography (eluent: chloroform, then chloroform/methanol=9/1) to give the title compound (21.2 mg).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.O>C(O)(=O)C>[OH:15][C:10]1[C:11]2[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: NNc1ccc(I)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: O=c1c2ccccc2c(O)nn1-c1ccc(I)cc1
Temperature: 125 °C
Yield: 8.3 %

Procedure:
4-Iodo phenyl hydrazine (8.97 g, 36.4 mmol) was added in one portion to a stirred mixture of phthalic anhydride (5.0 g, 33 mmol) in acetic acid (40 ml) at room temperature. The reaction mixture was heated to 125° C. for 2 hours, and then allowed to cool to room temperature. The suspension was poured into H2O (100 ml) and the resulting solid was removed by filtration. The mother liquor was acidified with conc. HCl. The resulting solid was collected by filtration and dried in vacuum to give the title compound (1.0 g, 8% yield) as a white solid. 1H-NMR: (400 MHz, D6-DMSO) 11.91 (1H, br. s), 8.30 (1H, d), 7.91–8.03 (3H, m), 7.83 (2H, d), 7.51 (2H, d); MS (ESI+)=365.0 (M+H)+.