Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25]Cl)=[N:23][N:24]=2)[CH:3]=1.[I-].[Na+].[N:29]12[CH2:37][CH2:36][CH2:35][C@H:34]1[CH2:33][NH:32][CH2:31][CH2:30]2.CCN(C(C)C)C(C)C>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:32]3[CH2:31][CH2:30][N:29]4[CH2:37][CH2:36][CH2:35][C@H:34]4[CH2:33]3)=[N:23][N:24]=2)[CH:3]=1
Reactant: C1C[C@H]2CNCCN2C1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(Br)cc21
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CN4CCN5CCC[C@H]5C4)o3)cc(Br)cc21
Temperature: 70 °C
Yield: 61.2 %

Procedure:
6-Bromo-4-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]-1-(phenylsulfonyl)-1H-indazole (300 mg, 0.661 mmol) and sodium iodide (99 mg, 0.661 mmol) were weighed into a round-bottomed flask and dissolved in acetonitrile (2 ml) before (S)-1,4-diazabicyclo[4.3.0]nonane (167 mg, 1.322 mmol, available from ABCR GmbH & CO.KG) and DIPEA (0.231 ml, 1.322 mmol) were added. The mixture was heated to 70° C. for 2 h. The mixture was cooled, diluted with DCM and washed with 2 M aqueous HCl (2 ml). The organic layer was separated by hydrophobic frit. The aqueous extracts were combined and neutralised to pH 7 with NaOH then extracted with more DCM (2×10 ml) which was combined with the other organic extracts and evaporated under a stream of nitrogen to give an orange oil. This was dissolved in DCM and loaded onto the top of a 10 g silica cartridge that was subsequently eluted with 0-15% MeOH(+1% triethylamine)/DCM over 15 mins. The appropriate fractions were combined and the solvent removed in vacuo to give the title compound as a cream solid (220 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]2=[O:19])=[N:5][N:4]=1.[C:20]1(C)C(S(O)(=O)=O)=CC=C[CH:25]=1>C(O)C>[CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][CH2:20][CH3:25])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]2=[O:19])=[N:5][N:4]=1
Reactant: C=CCCN1CCC(O)N(c2nnc(OC)s2)C1=O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: CCO
Product: C=CCCN1CCC(OCC)N(c2nnc(OC)s2)C1=O

Procedure:
Tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-but-3-enyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), ethyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermomater and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-but-3-enyl-6-ethoxy-2(1H)-pyrimidinone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:21]([C:22]([N:24]2[CH2:28][CH2:27][S:26][C:25]2=[S:29])=[O:23])=[CH:20][C:12]([C:13]([NH:15][CH2:16][CH2:17][O:18][CH3:19])=[O:14])=[CH:11][C:10]=1[C:30]([N:32]1CCS[C:33]1=S)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN.CO>ClCCl>[CH2:1]([O:8][C:9]1[C:21]([C:22]([N:24]2[CH2:28][CH2:27][S:26][C:25]2=[S:29])=[O:23])=[CH:20][C:12]([C:13]([NH:15][CH2:16][CH2:17][O:18][CH3:19])=[O:14])=[CH:11][C:10]=1[C:30]([NH:32][CH3:33])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCNC(=O)c1cc(C(=O)N2CCSC2=S)c(OCc2ccccc2)c(C(=O)N2CCSC2=S)c1
Agent: CN
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)c1cc(C(=O)NCCOC)cc(C(=O)N2CCSC2=S)c1OCc1ccccc1

Procedure:
To a solution of compound 18A (2.1 g, 3.65 mmol) in dichloromethane (100 mL), a solution of 0.1 mL methylamine solution (40% wt in water, d=0.902) and 50 mL dichloromethane was added dropwise over 24 h. The reaction progress was monitored by TLC chromatography. When the reaction was judged complete, the reaction mixture was directly applied to a gradient flash silica column (1-5% methanol in dicholoromethane). The desired product was obtained as yellow, thick oil; yield 1.22 g, (69% based on compound 18A).
Reaction SMILES: N1([C:6]23[CH2:21][CH2:20][CH2:19][CH2:18][CH:7]2[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Br:17])=[N:9][O:10]3)CCCC1.Cl.[OH-].[K+]>CO>[O:10]1[C:6]2[CH2:21][CH2:20][CH2:19][CH2:18][C:7]=2[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Br:17])=[N:9]1
Reactant: Brc1ccccc1C1=NOC2(N3CCCC3)CCCCC12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Brc1ccccc1-c1noc2c1CCCC2
Yield: 97.4 %

Procedure:
To a stirred solution of 5.8 g of 2-(3a,4,5,6,7,7a-hexahydro-7a-pyrrolidino-1,2-benzisoxazol-3-yl)-bromobenzene in 60 ml of methanol was added 100 ml of concentrated hydrochloric acid and the solution was refluxed for 20 min. The solution was cooled to room temperature and neutralised with 10M potassium hydroxide solution. The solution was extracted with 400 ml then 200 ml of methylene chloride and the combined organic layers were dried over sodium sulfate and evaporated to yield 4.5 g of 2-(4,5,6,7-tetrahydro-1,2-benzisoxazol-3-yl)-bromobenzene as a gum, GC-M.S. (E.I.) (M/Z): 277 [M]+.
Reaction SMILES: Cl[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+].[CH:53]1([NH2:56])[CH2:55][CH2:54]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].O.O1CCOCC1>[CH:53]1([NH:56][C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=2)[CH2:55][CH2:54]1
Reactant: Nc1nccnc1Cl
Reactant: NC1CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: C1COCCO1
Solvent: O
Product: Nc1nccnc1NC1CC1
Temperature: 45 °C

Procedure:
A glass microwave reaction vessel (20 mL) was charged with 3-chloropyrazin-2-amine (0.500 g, 3.86 mmol, FSSI), tris(dibenzylideneacetone)dipalladium(o) (0.070 g, 0.076 mmol, Strem Chemicals, Inc.) and BrettPhos (0.100 g, 0.186 mmol, Strem Chemicals, Inc.). The vessel was transferred to the glove-box where sodium tert-butoxide (0.700 g, 7.28 mmol, Sigma-Aldrich Chemical Company) was added. The vessel was capped and placed under an atmosphere of argon using 3 evacuation/backfill cycles. Dioxane (5 mL) and cyclopropylamine (0.410 mL, 5.85 mmol, Alfa Aesar) were added and the reaction mixture was heated at 45° C. for 1 h. The reaction was poured into water (100 mL, 0° C.) and the extracted with DCM (4×).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH3:12][CH:13]1[CH2:18][NH:17][CH2:16][CH:15]([CH3:19])[NH:14]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:17]1[CH2:16][CH:15]([CH3:19])[NH:14][CH:13]([CH3:12])[CH2:18]1)(=[O:10])=[O:9]
Reactant: CC1CNCC(C)N1
Reactant: O=S(=O)(Cl)c1ccccc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(S(=O)(=O)c2ccccc2Br)CC(C)N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
A solution of 2-bromobenzene-1-sulfonyl chloride (100 mg, 0.39 mmol), 2,6-dimethylpiperazine (56 mg, 0.49 mmol), and diisopropylethyl amine (0.202 mL, 1.17 mmol) in CH2Cl2 (2.5 mL) was allowed to stir for 15 min at rt. The reaction mixture was then directly subjected to FCC purification to give the title compound (0.105 g, 81%). 1H NMR (600 MHz, CDCl3) δ 8.09-8.07 (m, 1H), 7.76-7.73 (m, 1H), 7.47-7.44 (m, 1H), 7.43-7.37 (m, 1H), 3.70-3.66 (m, 2H), 2.97-2.91 (m, 2H), 2.38-2.33 (m, 2H), 1.06-1.04 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:11])[NH:8][NH:9][CH:10]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH:20](Br)[CH3:21]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]2[CH2:21][CH2:20][CH2:19][O:11][C:7]=12)=[O:5])[CH3:2]
Reactant: CC(Br)CBr
Reactant: CCOC(=O)c1c[nH][nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2c1OCCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
3-Oxo-2,3-dihydro-1H-pyrazole-4-carboxylic acid ethyl ester (13.2 g, 84.5 mmol), potassium carbonate (50 g, 0.3 mol) and N,N-dimethylformamide (500 mL) were combined in a 250 mL round bottom flask, and the mixture was heated to 130° C. 1,2-Dibromo-propane (10.4 mL, 0.10 mol) was added. After 30 minutes, the mixture was partitioned between DCM and water. The aqueous layer was extracted with DCM and the combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The yellow solid was purified by column chromatography (DCM/MeOH) to afford the ester (9.67 g, 58%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ7.62 (s, 1H), 4.41-4.38 (m, 2H), 4.13 (q, 2H), 4.08 (t, 2H, J=6.03 Hz), 2.21-2.15 (m, 2H), 1.21 (t, 3H, J=7.09 Hz).
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[C:9]([F:27])=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])(=[O:18])=[O:17])[CH:11]=[CH:12][C:13]=2[F:14])=[N:4][N:5]([CH3:7])[CH:6]=1.CC1(C)C(C)(C)OB([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[CH3:7][N:5]1[CH:6]=[C:2]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[C:3]([C:8]2[C:9]([F:27])=[C:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[F:26])(=[O:18])=[O:17])[CH:11]=[CH:12][C:13]=2[F:14])=[N:4]1
Reactant: Cn1cc(Br)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
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: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccncc2)c(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 110 °C
Reaction time: 0.08 h

Procedure:
To a solution of tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.1 mmol) in dimethoxyethane (3 mL), N-[3-(4-bromo-1-methyl-1H-pyrazol-3-yl)-2,4-difluoro-phenyl]-2,5-difluorobenzenesulfonamide (0.14 g, 0.3 mmol) in dimethoxyethane (3 mL) was added and the mixture was insufflated with nitrogen for 5 min. A solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.63 mmol) in dimethoxyethane (3 mL) was added and the mixture was insufflated with nitrogen for 10 min, then 2 M sodium carbonate solution (2.5 mL) was added and the mixture was heated at 110° C. in a microwave cavity for 3 h. The mixture was cooled and the organic phase was concentrated. The crude oil was purified by flash chromatography (eluant: dichloromethane/ethyl acetate 1:1). The title compound was obtained as a white solid (0.05 g, 36%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:11][C:12]2[CH:20]=[C:16]([C:17]([OH:19])=O)[C:15]([OH:21])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:22][C:23]([F:36])([F:35])[C:24]1[CH:25]=[C:26]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[NH2:27]>>[F:22][C:23]([F:35])([F:36])[C:24]1[CH:25]=[C:26]([NH:27][C:17](=[O:19])[C:16]2[CH:20]=[C:12]([N:11]=[N:10][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[CH:13]=[CH:14][C:15]=2[OH:21])[CH:28]=[C:29]([C:31]([F:32])([F:34])[F:33])[CH:30]=1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(N=Nc2ccc([N+](=O)[O-])cc2)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(N=Nc2ccc([N+](=O)[O-])cc2)ccc1O
Yield: 11.3 %

Procedure:
Using 5-[(4-nitrophenyl)diazenyl]salicylic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:24])[C:19]([O:21]CC)=[O:20])[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:13][CH2:14][N:15]([C:18](=[O:24])[C:19]([OH:21])=[O:20])[CH2:16][CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N1CCN(c2ccc(C)cc2C(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(N2CCN(C(=O)C(=O)O)CC2)c(C(C)(C)C)c1
Yield: 89.2 %

Procedure:
To a stirred solution of ethyl [4-(2-tert-butyl-4-methylphenyl)piperazin-1-yl](oxo)acetate (Example 81, 0.210 g, 0.63 mmol) in THF (5 mL) stirring at 0° C. was added 1 M lithium hydroxide solution (5 mL, 5 mmol). After 2 h the reaction mixture was acidified with 1 M hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated in vacuum to provide [4-(2-tert-butyl-4-methylphenyl)piperazin-1-yl](oxo)acetic acid (0.171 g, 89%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl.C(#N)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: Cc1ccc(C(O)(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: Cc1ccc(C(c2ccc(C)cc2)(c2ccc(C)cc2)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Compound 22 described above (0.17 g, 0.562 mmol) was dissolved in chloroform (4 mL) (Wako Pure Chemical Industries, Ltd.), and thionyl chloride (0.5 mL) (Wako Pure Chemical Industries, Ltd.) was added dropwise while cooling with ice. The mixture was returned to room temperature and stirred for 2 hours, and then the solvent was distilled off under reduced pressure, to thereby obtain a residue. The residue was dissolved in acetonitrile (4 mL) (Wako Pure Chemical Industries, Ltd.), and piperidine (0.19 g, 2.23 mmol) (Wako Pure Chemical Industries, Ltd.) was added thereto. The mixture was refluxed for 1 hour and allowed to cool to room temperature. The solvent was distilled off under reduced pressure, and then a saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the concentrated residue, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was washed with water and brine. After that, the organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to alumina column chromatography (n-hexane (Wako Pure Chemical Industries, Ltd.) as an eluent), to thereby obtain the title compound (0.19 g, 92% yield).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12]([NH:13][C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]5[CH:29]=[CH:28][C:27]([NH:30]C(OC(C)(C)C)=O)=[CH:26][CH:25]=5)=[CH:19][N:18]=4)=[O:15])[C@H:7]3[C:6]=2[C:5]([F:38])=[CH:4][CH:3]=1.Cl.CC(O)=O.CCO.C(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12]([NH:13][C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]5[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=5)=[CH:19][N:18]=4)=[O:15])[C@H:7]3[C:6]=2[C:5]([F:38])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccc(NC(=O)N[C@@H]3[C@@H]4COc5c(F)ccc(F)c5[C@@H]43)nc2)cc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1ccc(Oc2ccc(NC(=O)N[C@@H]3[C@@H]4COc5c(F)ccc(F)c5[C@@H]43)nc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
Dried N-[(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-yl]-N′-[5-(4-(N-t-butoxycarbonylamino)phenoxy)-2-pyridinyl]urea (242 mg, 0.46 mmol) was dissolved in methylene chloride (2 ml) and then 1M HCl/AcOH (4.6 ml) was added and the reaction solution was stirred for 60 minutes at room temperature. The volatile matters were removed by evaporation. The residue was worked up by extractions between methylene chloride and sat. aq. NaHCO3. The organic phase was dried through sodium sulfate and evaporated. Silica gel column chromatography (1-3% EtOH/methylene chloride gradient) gave 139 mg of pure product as white powder (71% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH:19]([CH3:21])[CH3:20])[CH:13]=2)=[N:10]O)=[CH:4][CH:3]=1.Cl.NC(C1C=CN=C([Cl:41])C=1)C(C1C=CC(F)=CC=1)=O>>[ClH:41].[NH2:10][CH:9]([C:12]1[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH:19]([CH3:21])[CH3:20])[CH:13]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)=[O:22]
Reactant: CC(C)Oc1cc(C(=NO)C(=O)c2ccc(F)cc2)ccn1
Reactant: NC(C(=O)c1ccc(F)cc1)c1ccnc(Cl)c1
Agent: Cl
Product: CC(C)Oc1cc(C(N)C(=O)c2ccc(F)cc2)ccn1

Procedure:
23c was prepared from 22c (2.0 g; 7.6 mmol) using the method described in the synthesis of 23a.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][CH2:11][C:12]([O:14]CC1C=CC=CC=1)=[O:13])=[O:7])([CH3:4])[CH3:3].O.ON1[C:31]2C=CC=C[C:30]=2N=N1.C(O)C>C(Cl)Cl>[NH:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C@H:9]([C:22]([O:24][CH2:30][CH3:31])=[O:23])[CH2:10][CH2:11][C:12](=[O:13])[OH:14]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Reactant: On1nnc2ccccc21
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Boc-Glu (OBzl)-OH, 1.01 g (3.0 mmol), 620 mg (3.1 mmol) of N,N-dicyclohexylcarbodiimide (DCC) and 475 mg (3.1 mmol) of 1-hydroxybenzotriazole monohydrate (HOBt.H2O) were suspended in 12 ml of methylene chloride. The suspension was cooled to 0° C. and 175 μl of ethyl alcohol was added thereto. After reverting to room temperature, stirring was continued overnight. The mixture was extracted with ethyl acetate/water. After the organic layer was washed with aqueous saturated sodium chloride solution (brine), sodium sulfate was added thereto and dried. The organic layer was concentrated under reduced pressure. The resulting residue was dissolved in 12 ml of methanol, and 100 mg of 10% Pd/C was added to the solution. The mixture was stirred in a hydrogen atmosphere overnight and purified in accordance with the purification step A to give the crude product of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13]([C:21]#[N:22])=[CH:12]1.ClC1C=C(C=CC=1)C(OO)=[O:28].ClCCl.CO>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13]([C:21]#[N:22])=[CH:12]1.[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[N+:18]=2[O-:28])[C:13]([C:21]#[N:22])=[CH:12]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: Cc1ccc2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2[n+]1[O-]
Yield: 142 %

Procedure:
Part A: A solution of 1.24 g of 1-(2-bromo-4-isopropyl-phenyl)-3-cyano-6-methyl-7-azaindole (Example 72) and 1.42 g of 85% 3-chloro-peroxybenzoic acid in 20 mL of chloroform was refluxed for 6 hrs. The mixture was cooled and washed first with 10% sodium bicarbonate solution, then with brine. The solution was dried (Na2SO4) and evaporated to give a residue. TLC on silica gel with 95:5 dichloromethane-methanol showed a trace spot at Rf 0.88 and a major spot at Rf 0.34. The material was purified by chromatography on silica gel with dichoromethane, followed by 1% methanol in dichloromethane, to give a trace of unchanged 1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-7-azaindole (Rf 0.88) and 0.92 g of 1-(2-bromo-4-isopropylphenyl)-3-cyano-6-methyl-7-azaindole 7-oxide (Rf0.34); mp 179.2°. Mass spec. (m+H)+=370.0559; calcd., 370.0555 (79Br).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[F:21].[C:22](=[O:24])=[O:23]>C1COCC1>[Br:13][C:14]1[C:15]([F:21])=[C:16]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:22]([OH:24])=[O:23]
Reactant: Cc1ccc(F)c(Br)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(Br)c(F)c(C(=O)O)c1
Temperature: -10 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of diisopropylamine (1.8 mL, 12.7 mmol) in THF (20 mL) at −10° C., n-BuLi (0.68 g, 10.6 mmol) was added and the reaction was stirred for 1 hour at −10° C. and was then cooled to −78° C. A solution of 2-bromo-1-fluoro-4-methylbenzene (2.0 g, 10.6 mmol) in THF (10 mL) was added in dropwise and the reaction was stirred for 1 hour after which excess solid carbon dioxide (4.76 g, 106 mmol) was added. After 30 minutes the reaction mixture was allowed to warm to room temperature, allowing for pressure release, and was quenched with water. The resulting layers were separated and the aqueous portion was extracted with Et2O. The aqueous layer was then acidified with aqueous 6.0 M HCl solution and the resulting white precipitate was extracted into Et2O. The combined organic portions were dried (MgSO4), and concentrated in vacuo to afford 3-bromo-2-fluoro-5-methylbenzoic acid (2.1 g, 9.0 mmol, 85%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 2.37 (s, 3H) 7.60 (dd, J=5.9, 1.8 Hz, 1H) 7.75 (dd, J=6.2, 1.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([O:15]C)=[O:14].C[O-].[Na+].CO.Cl>O>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)[S:4][C:3]=1[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1sc(-c2ccncc2)cc1N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cc(-c2ccncc2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A mixture of methyl 3-amino-5-(pyridin-4-yl)thiophene-2-carboxylate (2.34 g, 10 mmol), sodium methoxide (1.62 g, 30 mmol), methanol (40 mL) and water (10 mL) was refluxed for 4 h. The mixture was allowed to cool to room temperature and stirring was continued overnight. The mixture was cooled under ice-bath, then conc. HCl (2.48 mL, 30 mmol) was added (pH was approx. 4). The resultant yellow precipitate was collected by filtration and washed with water and methanol to afford the title compound (2.02 g, 92%) as a yellow solid:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]2[S:20][C:19]3[S:21][C:22]([CH:24]=[O:25])=[CH:23][C:18]=3[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O-:26]Cl=O.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][C:16]2[S:20][C:19]3[S:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:18]=3[CH:17]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CCc2cc3cc(C=O)sc3s2)CC1
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(CCc2cc3cc(C(=O)O)sc3s2)CC1

Procedure:
3-3 (2.0 g, 5.27 mmol) was treated with NaClO2 (5.27 g, 58.3 mmol) as described for 1-7 to provide 3-4 as a white solid.