Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:21][C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=1[CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[CH3:20][N:12]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([NH2:19])=[C:18]2[C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:31](=[O:32])[CH2:30][C:23]2[CH:24]=[C:25]([F:29])[CH:26]=[C:27]([F:28])[C:22]=2[F:21])[CH2:2][CH2:3]3)=[N:11]1
Reactant: O=C(O)Cc1cc(F)cc(F)c1F
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)cc(F)c2F)c2c(N)ncnc21
Yield: 49.8 %

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.330 mmol), (2,3,5-trifluorophenyl)acetic acid (69.1 mg, 0.363 mmol), HATU (151 mg, 0.396 mmol), DIEA (0.173 mL, 0.991 mmol) was stirred overnight at room temperature. At this time, LCMS analysis indicated complete conversion, so the reaction mixture was poured into water (10 mL), whereupon a beige precipitate formed. The precipitate was filtered, suspended in DCM-methanol and dry-loaded onto silica, then purified by flash chromatography (0-10% methanol in DCM) to afford 1-methyl-3-{1-[(2,3,5-trifluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (72 mg) as a white solid. LC-MS (ES) m/z=439 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 3.26-3.32 (m, 2H), 3.94 (s, 3H), 4.06 (s, 2H), 4.28-4.37 (m, 2H), 7.09-7.20 (m, 1H), 7.41-7.52 (m, 2H), 7.53-7.57 (m, 1H), 8.11-8.18 (m, 1H), 8.25 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c13)OCO2
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c[nH]c13)OCO2

Procedure:
Starting from cis-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A186) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH:14][CH2:15][C:16]1[O:20][N:19]=[CH:18][CH:17]=1.CN1CCOCC1>C(Cl)Cl>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([O:8][C:9]([O:14][CH2:15][C:16]2[O:20][N:19]=[CH:18][CH:17]=2)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCc1ccno1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(OCc1ccno1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
A 631 mg (2.65 mmol) sample of p-nitrophenoxycarbonylchloride in 2 mL of methylene chloride was added to a solution of 310 mg (3.13 mmol) of 5-hydroxymethyisoxazole and 0.344 mL of 4-methylmorpholine in 2 mL of methylene chloride cooled in an ice bath. The solution was stirred for 4 hours. The mixture was diluted with methylene chloride, which was washed with water, dried and concentrated. The crude product was chromatographed on silica gel, eluting with 2% ethyl acetate in methylene chloride. The solvent was removed and the product dried to afford 0.473 g of the title compound, which was taken directly to the next step.
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[F:8][C:9]([F:24])([F:23])[C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=1)[C:13]([OH:15])=[O:14]>C1(C)C=CC=CC=1.CO>[CH3:1][O:14][C:13](=[O:15])[C:12]1[CH:11]=[C:10]([C:9]([F:23])([F:24])[F:8])[CH:18]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:16]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Trimethylsilyldiazomethane (11.5 mL) was added drop-wise to a solution of 3,5-bis-(trifluoromethyl)-benzoic acid (2 g) in dry toluene (20 mL) and methanol (0.5 mL) previously cooled to 0° C. under a nitrogen atmosphere. The solution was stirred at r.t. for 1 hr, then concentrated in vacuo to give 3,5-bis-(trifluoromethyl)-benzoic acid methyl ester (2 g) as a colourless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[C@@H:15]([NH:23]C(OC(C)(C)C)=O)[CH2:16][CH2:17][C:18]2[N:19]=[N:20][NH:21][N:22]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:31])[C@@H:15]([NH2:23])[CH2:16][CH2:17][C:18]2[N:22]=[N:21][NH:20][N:19]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCc2nn[nH]n2)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CCc2nn[nH]n2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 730 mg 4-[(S)-2-tert-butoxycarbonylamino-4-(2H-tetrazol-5-yl)-butyryl]-piperazine-1-carboxylic acid butyl ester in 10 ml dichloromethane were added 1.2 ml TFA. After 12 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 900 mg.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>COCCOC.CCCCCCC>[F:13][C:2]([F:1])([F:12])[C:3]1[C:11]2[C:6](=[N+:7]([O-:19])[CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: FC(F)(F)c1n[nH]c2ncccc12
Solvent: CCCCCCC
Solvent: COCCOC
Product: [O-][n+]1cccc2c(C(F)(F)F)n[nH]c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
Compound (1a) was dissolved in ethylene glycol dimethyl ether (100 mL) and heptane (200 mL), and m-chloroperoxybenzoic acid (33.9 g) was added to the resulting solution at 0° C., followed by stirring at room temperature for 1 hr. The precipitate was collected by filtration to obtain compound (1b) (33.3 g, 96%) as a white solid.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23](=[O:35])(=[O:34])[NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:32])=[CH:13][CH:12]=2)=[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:7]([C:41]2[CH:46]=[C:45]([N+:47]([O-])=O)[CH:44]=[CH:43][C:42]=2[Cl:50])[N:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pt]=O.C(O)C>[NH2:47][C:45]1[CH:44]=[CH:43][C:42]([Cl:50])=[C:41]([N:7]2[C:8]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[S:23](=[O:34])(=[O:35])[NH:24][C:25](=[O:33])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:32])=[CH:15][CH:16]=3)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6]2)[CH:46]=1
Reactant: [H][H]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)OCC)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Agent: O=[Pt]
Solvent: CCO
Product: CCCCc1nn(-c2cc(N)ccc2Cl)c(C(=O)OCC)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Yield: 92.9 %

Procedure:
A mixture of 450 mg (0.612 mmol) of ethyl 3-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-1-(2-chloro-5-nitrophenyl)-1H-pyrazole-5-carboxylate (from Step H), 50 mg of platinum oxide and 80 mL of ethanol was shaken with hydrogen at 3-4 atm for 1.25 hours. The catalyst was removed by filtration through Celite, and the filtrate was concentrated in vacuo to yield 401 mg (93%) of the title compound as a tan solid, mp>75° C. (gradual); nearly homogeneous by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 705 (M+1)+. 400 MHz 1H NMR (DMSO-d6) δ0.81 (t, J=7.4 Hz, 3H), 0.97 (t, J=7.1 Hz, 3H), 1.25 (m, 2H), 1.48 (m, 2H), 2.49 (t, 2H, partially obscured by DMSO peak), 4.0-4.2 (m, 4H), 5.5 (v br m, 2H), 6.64 (m, 2H), 7.1-7.4 (m, 8H), 7.47 (m, 2H), 7.6-7.75 (m, 2H), 8.16 (dd, J=8.0, 1.1 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:16]3[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]3)=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]=2[CH3:22])=[O:7])=[CH:4][C:3]=1[O:25][CH3:26].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:26][O:25][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:2]=1[NH:1][S:28]([CH3:27])(=[O:30])=[O:29])[C:6]([C:8]1[N:16]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:9]=1[CH3:22])=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)c1c(C)c(C(=O)c2ccc(N)c(OC)c2)n2ccccc12
Product: CCOC(=O)c1c(C)c(C(=O)c2ccc(NS(C)(=O)=O)c(OC)c2)n2ccccc12

Procedure:
This compound was obtained according to the same procedure as that described in Example 207, by sulphonylation of ethyl 3-(4-amino-3-methoxybenzoyl)-2-methylindolizin-1-ylcarboxylate, a compound of Example 97, with methanesulphonyl chloride. The product is purified by chromatography on a silica column, eluting with a toluene/ethyl acetate (8:2) mixture. A yellow powder is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16](Br)=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][S-:28].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][N:11]2[C:12](=[O:24])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([S:28][CH3:27])=[CH:15][C:14]=3[C:20]([F:23])([F:22])[F:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(Br)cc3C(F)(F)F)[C@@H]2C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Temperature: 25 °C
Yield: 65 %

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-bromo-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (56 mg, 0.13 mmol) in dry DMF (1 mL) at 60° C. was added sodium methanethiolate (9.9 mg, 0.14 mmol). The reaction was heated to reflux for 30 min and then cooled to room temperature. The reaction was quenched with 1M aq. NaOH and extracted with EtOAc (3×5 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a yellow oil. The oil was purified by flash chromatography (silica gel, 0–33% EtOAc in hexanes) to give 34 mg of the desired product as a colorless oil. MS (ESI) 403 (M+H).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][C:7]2[N:10]=[C:11]([NH:13][C:14]([NH2:16])=[NH:15])[S:12][C:6]=2[CH2:5]1)(=O)C.[OH-].[Na+]>C(O)C>[NH:13]([C:11]1[S:12][C:6]2[CH2:5][NH:4][CH2:9][CH2:8][C:7]=2[N:10]=1)[C:14]([NH2:16])=[NH:15]
Reactant: CC(=O)N1CCc2nc(NC(=N)N)sc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N=C(N)Nc1nc2c(s1)CNCC2
Yield: 68 %

Procedure:
5-Acetyl-2-guanidino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (232.4 mg, 0.971 mmol) was mixed with ethanol (7 ml) and treated with an aqueous solution of sodium hydroxide (1.98 ml of a 1.46M solution, 2.9 mmol). The reaction mixture was heated to 81° for 72 hours, then concentrated in vacuo; the residue was purified by column chromatography (eluant: 89:10:1 of chloroform:methanol:concentrated ammonium hydroxide) to provide the title product as an oil (129.9 mg, 0.66 mmol, 68% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].F[C:38](F)(F)[C:39]1C=C(S(Cl)(=O)=O)C=CC=1>>[CH2:38]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=3)(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[F:1])[CH3:39]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C(Nc1ccc(C(=O)O)c(F)c1)c1ccc2c(c1)N(S(=O)(=O)c1cccc(C(F)(F)F)c1)CCC2
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCC3)cc1F

Procedure:
2-Fluoro-4-{[1-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid, m/z (ES+): 523.29 (M+H+.), was prepared in analogy to example 48, steps 1 to 5. Step 4 was performed using 3-trifluoromethyl-benzenesulfonyl chloride, yielding 2-fluoro-4-{[1-(3-trifluoromethyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [C:1]([C:3]1[C:4](Cl)=[N:5][C:6]([Cl:10])=[C:7]([F:9])[CH:8]=1)#[N:2].[CH3:12][N:13]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]1>>[Cl:10][C:6]1[C:7]([F:9])=[CH:8][C:3]([C:1]#[N:2])=[C:4]([O:18][CH:15]2[CH2:16][CH2:17][N:13]([CH3:12])[CH2:14]2)[N:5]=1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Reactant: CN1CCC(O)C1
Product: CN1CCC(Oc2nc(Cl)c(F)cc2C#N)C1

Procedure:
3-cyano-2,6-dichloro-5-fluoropyridine was reacted with 1-methyl-pyrrolidin-3ol according to the method of Example 85A to provide the title compound. MS (ESI+) m/z 256 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]2[O:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:4][C:3]=1[O:17][CH3:18].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26]>>[CH3:26][C:25]1[O:24][C:23]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:22][C:21]=1[CH2:20][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]2[O:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])=[CH:4][C:3]=1[O:17][CH3:18]
Reactant: COc1cc(CCC2OC(=O)NC2=O)ccc1O
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Product: COc1cc(CCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 9, 5-[2-(4-hydroxy-3-methoxyphenyl)ethyl]-2,4-oxazolidinedione was reacted with 4-chloromethyl-5-methyl-2-phenyloxazole to obtain 5-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-methoxyphenyl]ethyl]-2,4-oxazolidinedione, which was recrystallized from ethyl acetate-chloroform to give colorless prisms, m.p.194-195° C.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1[CH2:32]O)=[O:6])[CH:2]=[CH2:3].CS(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.C(OP([CH2:59][C:60]([NH:62][CH3:63])=[O:61])(OCC)=O)C.[H-].[Na+]>>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@@H:10]([S:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C@H:8]1/[CH:32]=[CH:59]/[C:60]([NH:62][CH3:63])=[O:61])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CO
Reactant: CCOP(=O)(CC(=O)NC)OCC
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C=CCOC(=O)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1/C=C/C(=O)NC
Yield: 89.7 %

Procedure:
The same operation as in Reference Example 4-1) was carried out by using (2S,4S)-N-allyloxycarbonyl-2-hydroxymethyl-4-tritylthiopyrrolidine (the compound obtained in the Reference Example 3-1); 4.60 g, 10.0 mmol), dimethyl sulfoxide (1.99 ml, 28.0 mmol), oxalyl chloride (1.28 ml, 15.0 mmol), triethylamine (6.98 ml, 50.0 mmol), 2-(diethylphosphono)-N-methylacetamide (2.32 g, 11.0 mmol) and 60% sodium hydride (420 mg, 10.5 mmol), followed by flash column chromatographic purification on silica gel (Wakogel® C-300, 100 ml, elution with hexaneethyl acetate 1:2) to give the title compound (4.60 g, 89.7% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:14](=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:16]=2)[NH:13][N:12]=[CH:11]3)=[CH:6][CH:5]=[CH:4][N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=1[CH3:31].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:7]([C:8]3[CH:9]=[C:10]4[C:14](=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:16]=3)[NH:13][N:12]=[CH:11]4)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:24][C:23]=1[CH3:31]
Reactant: Cc1cc(B(O)O)ccc1F
Reactant: COC(=O)c1cc(-c2cccnc2Cl)cc2cn[nH]c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cccnc2-c2ccc(F)c(C)c2)cc2cn[nH]c12
Temperature: 100 °C
Yield: 38.7 %

Procedure:
A single necked round bottom flask (100 mL) equipped with a magnetic stirring bar was charged with methyl 5-(2-chloropyridin-3-yl)-1H-indazole-7-carboxylate (0.88 g, 3.0 mmol), 4-fluoro-3-methylphenyl boronic acid (0.56 g, 3.63 mmol), PdCl2(PPh3)4 (214 mg g, 1.0 mmol), 1,4-dioxane (75 mL) and 2M aq. Na2CO3 (4.2 mL, 8.4 mmol mL) under argon atmosphere. The rubber septum was replaced with reflux condenser containing three-way stopcock. The system was then evacuated three times and back filled with argon and externally heated at 100° C. (oil bath) for 48 h. The heterogeneous reaction mixture was allowed to cool to room temperature and concentrated under vacuum to remove the volatiles by rotary evaporator. The crude concentrate flask was charged with chloroform (100 mL)/water (30 mL) and stirred. Organic layer was separated and the aqueous layer further extracted with chloroform (75 mL). Combined organic layers were stirred over MgSO4/Celite® for 20 min, suction filtered and filter cake washed with chloroform (30 mL). The filtrate collected was concentrated and purified by silica gel flash chromatography [Combiflash® companion System® with RediSep® silica gel column (24g), solvent eluent gradient 30-50% EtOAc/hexanes] to obtain methyl 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-1H-indazole-7-carboxylate (420 mg, 39%) as a white solid. 1H NMR (DMSO-d6): δ 13.1 (s, 1H), 8.62 (dd, 1H, J=0.5 and 4.7 Hz), 8.04 (s, 1H), 7.83 (d, 1H, J=7.6 Hz), 7.66 (s, 1H), 7.45-7.34 (app m, 3H), 7.02 (d, 1H, J=8.5 Hz), 6.96-6.85 (m, 2H), 2.11 (s, 3H). 19F NMR (DMSO-d6): δ −118.91. LCMS: rt 5.23 min (A), purity 93%,MS (m/e) 362 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([NH2:15])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1.N([O-])=[O:20].[Na+].Cl>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([NH:15][OH:20])=[C:10]([N+:16]([O-:18])=[O:17])[CH:9]=1
Reactant: Cc1cc(-c2ccccc2F)cc([N+](=O)[O-])c1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(-c2ccccc2F)cc([N+](=O)[O-])c1NO

Procedure:
Reflux of a combination of starting compounds 4-Bromo-2-methyl-6-nitro-phenylamine 160 and aromatic boronic acid 161 in the presence of Pd(Ph3P)4, K3PO4, Benzene, dimethylformamide gives rise to intermediate 2′-Fluoro-5-methyl-3-nitro-biphenyl-4-ylamine 162. Tricyclic intermediate 5-(2-Fluoro-phenyl)-7-nitro-2H-indazole 165 is formed from intermediate 162 by using one of two reactions. One reaction involves treating intermediate 162 with sodium nitrite, acetic acid, and hydrochloric acid to form intermediate N-(2′-Fluoro-5-methyl-3-nitro-biphenyl-4-yl)-hydroxylamine 163 then refluxing intermediate 163 in benzene to form intermediate 165. The second reaction involves treating intermediate 162 with HBF4 and sodium nitrite forming intermediate 2′-Fluoro-5-methyl-3-nitro-biphenyl-4-diazonium+ BF4− 164 then treating intermediate 164 with potassium acetate and 18-Crown-6 in chloroform to form intermediate 165. Intermediate 165 is treated with Pd—C in ethanol and hydrogen, which reduces the nitro substituent of intermediate 165 to an amine forming intermediate 5-(2-Fluoro-phenyl)-2H-indazol-7-ylamine 166. Treatment of intermediate 166 with Bu4NBr3 (TBATB) and DMF-H2O brominated intermediate 166 to form intermediate 4-Bromo-5-(2-fluoro-phenyl)-2H-indazol-7-ylamine 167. The bromine of intermediate 167 is replaced with a carbonitrile group by refluxing in coppercyanide in pyridine forming intermediate 7-Amino-5-(2-fluoro-phenyl)-2H-indazole-4-carbonitrile 168. Reductive alkylation of intermediate 168 is accomplished by treating intermediate 168 with the appropriate aldehyde in the presence of zinc chloride and sodium cyano borohydride forming intermediate 169, which is brominated by treatment with Bu4NBr3 (TBATB) in DMF-H2O forming target compound 7-Amino-3-bromo-5-(2-fluoro-phenyl)-2H-indazole-4-carbonitrile derivative 170
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([S:17][C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1.[CH3:25][N:26]=[C:27]=[O:28]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH:10]([S:17][C:18]2[CH:19]=[CH:20][C:21]([NH:24][C:27]([NH:26][CH3:25])=[O:28])=[CH:22][CH:23]=2)[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: CN=C=O
Reactant: Nc1ccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(SC(CCc2ccc(Cl)cc2)Cn2ccnc2)cc1

Procedure:
A solution of 1-[4-(4-chlorophenyl)-2-(4-aminophenylthio)-n-butyl]imidazole (360 mg) in dry tetrahydrofuran (10 ml) was treated with 0.16 ml of methyl isocyanate. The solution was warmed at gentle reflux overnight and the solvent evaporated. The residue was chromatographed on silica gel eluting with 2.2% water in ethyl acetate to give 1-[4-(4-chlorophenyl)-2-(4-methylaminocarbonylaminophenylthio)-n-butyl]imidazole.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH2:13]OC1C=CC(B(O)O)=CC=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[B:24]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33]CCCC(O)=O)=[CH:29][CH:28]=1)([OH:26])[OH:25].C(Br)C1C=CC=CC=1>>[CH2:1]([O:8][C:9](=[O:10])[CH2:11][CH2:12][CH2:13][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([B:24]([OH:26])[OH:25])=[CH:28][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCOc1ccc(B(O)O)cc1)OCc1ccccc1
Reactant: O=C(O)CCCCc1ccc(B(O)O)cc1
Agent: BrCc1ccccc1
Product: O=C(CCCCc1ccc(B(O)O)cc1)OCc1ccccc1
Yield: 79 %

Procedure:
Using a procedure analogous to that used to prepare 1B, 5B (250 mg, 1.13 mmol) was reacted with benzyl bromide to afford 5C (226 mg, 79%) as a clear oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1.[S:23](Cl)([CH3:26])(=[O:25])=[O:24]>>[S:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH2:20][CH2:21][CH3:22])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]([CH2:15][CH3:16])=[C:10]([CH2:17][CH3:18])[N:9]=2)[CH:7]=1)(=[O:25])(=[O:24])[CH3:26]
Reactant: CS(=O)(=O)Cl
Reactant: CCCOc1ccc(O)cc1-c1nc(CC)c(CC)c(=O)[nH]1
Product: CCCOc1ccc(OS(C)(=O)=O)cc1-c1nc(CC)c(CC)c(=O)[nH]1

Procedure:
The title compound was prepared by reacting the compound of example 81 with mesyl chloride in the same manner as that of example 50. 1H NMR (CDCl3) δ: 8.39 (1H, d), 7.43 (1H, dd), 7.06 (1H, d), 4.18 (2H, t), 3.20 (3H, s), 2.68 (2H, q), 2.58 (2H, q), 2.00 (2H, m), 1.28 (3H, t), 1.14 (6H, t).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][OH:9]>C(Cl)(Cl)Cl.O>[O:9]1[CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:1][CH3:7])[CH2:8]1
Reactant: Cc1ccccc1
Reactant: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCC1CO1

Procedure:
To a solution of 0.50 g of sixth generation PAMAM in 5 ml of methanol was added 0.56 g of epoxyoctane. After 6 days at room temperature, the solvent was evaporated in vacuo to give 0.80 g of colorless oil. The material was soluble in chloroform, toluene or methanol, but not soluble in water. The 13C-NMR spectrum was in accord with a dendrimer with C-8 alkyl groups attached to its terminal amines.