Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[I-:26].[K+].II.[N+]([O-])(OC(C)(C)C)=O>C(#N)C.[Cu](I)I>[I:26][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(N)c3c2CNC3=O)cc1
Reactant: [I-]
Agent: I[Cu]I
Agent: CC(C)(C)O[N+](=O)[O-]
Agent: II
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(I)c3c2CNC3=O)cc1
Yield: 46.4 %

Procedure:
In a similar manner to Step 4 of Example 140, 7-amino-4-(4-tert-butyldimethylsilyloxyphenyl)isoindolinone (179 mg, 0.505 mmol) was dissolved in acetonitrile (12.5 mL), and the solution was treated with potassium iodide (133 mg, 0.808 mmol), copper iodide (152 mg, 0.808 mmol), iodine (203 mg, 0.808 mmol) and tert-butyl nitrate (0.127 mL, 1.06 mmol), followed by purification by flash column chromatography (chloroform) to obtain 7-iodo-4-(4-tert-butyldimethylsilyloxyphenyl)isoindolinone (109 mg, yield 47%).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:11]=[C:12](Br)[CH:13]=[C:14]3[C:18]=2[NH:17][N:16]=[CH:15]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+].ClCCl>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].O.COCCOC>[C:1]1([NH:7][C:8]([C:10]2[CH:11]=[C:12]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)[CH:13]=[C:14]3[C:18]=2[NH:17][N:16]=[CH:15]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Nc1ccccc1)c1cc(Br)cc2cn[nH]c12
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cc(-c2cccnc2)cc2cn[nH]c12
Temperature: 150 °C
Yield: 27.8 %

Procedure:
A mixture of N-phenyl-5-bromo-1H-indazole-7-carboxamide (Example #B.1.2, 0.05 g, 0.16 mmol) and pyridine-3-yl-boronic acid (0.11 g, 0.8 mmol), 1,2-dimethoxyethane (1.3 mL), water (0.7 mL), Cs2CO3 (0.16 g, 0.48 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.013 g, 0.016 mmol) was heated at about 150° C. in the microwave under an atmosphere of nitrogen for about 15 minutes. The crude product was filtered and the solvent was removed under reduced pressure. The residue was dissolved in DMSO then purified by reverse phase HPLC (Waters Symmetry C8 column (25×100 mm, 7 μm particle size) using a gradient of 10%-100% CH3CN/0.1% aqueous TFA over 8 min (10 min run time) at a flow rate of 40 mL/min) to yield N-phenyl-5-pyridin-3-yl-1H-indazole-7-carboxamide (0.014 g, 6%); (DMSO-d6, 400 MHz) δ 13.4 (bs, 1H), 10.5 (bs, 1H), 9.12 (d, 1H), 8.62 (d, 1H), 8.48 (s, 1H), 8.34 (s, 1H), 8.28 (m, 2H), 7.84 (d, 2H), 7.56 (m, 1H), 7.42 (m, 2H), 7.16 (m, 2H); RP-HPLC (Table 1, Method e) Rt=1.81 min; m/z: (M+H)+ 315.3.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:18]([OH:30])[CH:19]2[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]2)[CH:14]=[CH:15][C:16]=1[Cl:17].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:30][CH:18]([C:13]1[CH:14]=[CH:15][C:16]([Cl:17])=[C:11]([Cl:10])[CH:12]=1)[CH:19]1[CH2:20][N:21]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:22]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(C(O)c2ccc(Cl)c(Cl)c2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(C(OC(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Benzoyl chloride (0.1 mL, 1.20 mmol) and DMAP (5 mg, 0.03 mmol) were slowly added to 15 mL of tertiary butyl 3-((3,4-dichlorophenyl)(hydroxy)methyl)azetidine-1-carboxylate (100 mg, 0.302 mmol) and triethylamine (0.07 mL, 0.482 mmol) dissolved in the distilled methylene chloride solution at 0° C., and the mixture was stirred at room temperature for one day. The reaction mixture was extracted with methylene chloride (3*30 mL), and the organic layer was washed with a 1 N HCl aqueous solution and distilled water once, respectively and dried over anhydrous magnesium sulfate. The solvent was removed by reduced pressure evaporation to obtain a colorless liquid, which was purified by flash chromatography (n-hexane:ethyl acetate (2:1, v/v)). The product was identified as a single compound by TLC (n-hexane:ethyl acetate (2:1, v/v)).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].[C:25]1([CH2:31][C:32]([O:34][CH2:35]Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH2:35][O:34][C:32](=[O:33])[CH2:31][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Reactant: O=C(Cc1ccccc1)OCCl
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)OCOC(=O)Cc1ccccc1
Yield: 64.2 %

Procedure:
Following the general procedure for the preparation of acyloxyalkyl/alkoxycarbonyloxyalkyl carboxylic esters from carboxylic acids of Description 22, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (0.5 g, 1.3 mmol) dissolved in 10 mL of anhydrous toluene was reacted with 1.1 g (4.0 mmol) of chloromethyl 2-phenylacetate in the presence of 0.44 g (1.6 mmol) of silver carbonate (Ag2CO3). After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.44 g (64% yield) of the title compound (28a) as a colorless oil. Rf=0.47 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=0.97 (s, 3H), 0.99 (s, 3H), 2.24-2.30 (m, 2H), 3.20-3.24 (m, 2H), 3.62-3.65 (m, 2H), 3.68 (s, 2H), 3.84 (s, 1H), 3.91 (d, J=9.2 Hz, 1H), 4.15 (d, J=9.6 Hz, 1H), 4.28 (d, J=10.8 Hz, 1H), 4.53 (d, J=11.2 Hz, 1H), 5.78 (d, J=5.6 Hz, 1H), 5.87 (d, J=5.6 Hz, 1H), 7.25-7.38 (m, 10H) ppm. MS (ESI) m/z 548.99 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][C:11]3[C:13]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:14]=4[S:15][C:10]=3[C:9](=[O:21])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2NC3C4C=CC=CC=4SC=3C(=O)C2)C=CC=CC=1>>[C:1]1([C:7]2[N:12]=[C:11]3[C:13]4[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:14]=4[S:15][C:10]3=[C:9]([OH:21])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CC(c2ccccc2)Nc2c1sc1cc(F)ccc21
Agent: O=C1CC(c2ccccc2)Nc2c1sc1ccccc21
Product: Oc1cc(-c2ccccc2)nc2c1sc1cc(F)ccc12

Procedure:
The procedure was similar to step S3E, while the starting material was 17D in stead of 3D.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][CH2:12][O:13][C:6]=2[CH:5]=1.[N+:15]([O-])([OH:17])=[O:16]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[C:9]([N+:15]([O-:17])=[O:16])=[CH:8][C:7]2[O:10][CH2:11][CH2:12][O:13][C:6]=2[CH:5]=1
Reactant: COC(=O)c1ccc2c(c1)OCCO2
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COC(=O)c1cc2c(cc1[N+](=O)[O-])OCCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 5.0 g. of 3,4-ethylenedioxybenzoic acid methyl ester in 5.0 mls. of glacial acetic acid is added dropwise 5.0 mls. of 70% nitric acid at 50°-60°C. After addition the reaction mixture is kept at 55°C. for one hour, then cooled and 50 mls. of ice water added. The resulting precipitate is recovered by filtering, water washed and dried to obtain 6-nitro-3,4-ethylenedioxybenzoic acid methyl ester, m.p. 115°-118°C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:32][CH3:33])[CH2:14][CH2:13][CH:12]([O:15][C:16]2[C:27]3[C:26]4[C@@H:25]([CH2:28][C:29]([OH:31])=O)[CH2:24][CH2:23][C:22]=4[S:21][C:20]=3[N:19]=[CH:18][N:17]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=[N:40]C=2C=1.CCN=C=NCCCN(C)C.[NH4+].[Cl-]>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:29]([CH2:28][C@H:25]1[CH2:24][CH2:23][C:22]2[S:21][C:20]3[N:19]=[CH:18][N:17]=[C:16]([O:15][CH:12]4[CH2:13][CH2:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])([CH2:32][CH3:33])[CH2:10][CH2:11]4)[C:27]=3[C:26]1=2)(=[O:31])[NH2:40]
Reactant: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(=O)O)CC4)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 60.2 %

Procedure:
To a solution of 2-[(3R)-12-[(4-[[(tert-butoxy)carbonyl]amino]-4-ethylcyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]acetic acid (100 mg, 0.21 mmol, 1.00 equiv) in 5 mL of distilled DMF was added HOBt (42.6 mg), EDCI (60 mg), 4-dimethylaminopyridine (38.2 mg) and NH4Cl (56 mg, 1.05 mmol, 4.98 equiv) successively and the resulting solution was stirred for 14 hr at 25° C. under nitrogen. The reaction was then quenched with water and extracted with 3×50 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1) to give tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-ethylcyclohexyl)carbamate (60 mg, 60%) as colorless oil. MS (ES): m/z 476 [M+H]+.
Reaction SMILES: FC(F)(F)[C:3]1[CH:12]=[CH:11][C:10](OC)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.Br>C(O)(=O)C>[N:8]1[C:9]2[C:4](=[CH:3][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(F)(F)F)c2cccnc12
Agent: Br
Solvent: CC(=O)O
Product: c1ccc2ncccc2c1
Yield: 29.2 %

Procedure:
The 5-trifluoromethyl-8-methoxyquinoline 8.50 g was dissolved in 100 mL glacial acetic acid and added to 20 ml HBr in a 100 mL flask. The solution was heated to reflux for 20 hrs. The reaction mixture was allowed to come to room temperature. The reaction mixture was concentrated by removal of 55 mL of solvent under vacuum. The solution was then poured into 100 mL cold water and neutralized with 2N NaOH to pH 7.0. The resulting solution was extracted with 2×100 ml ether, dried with NaSO4, filtered and concentrated to an oil, which solidified upon standing (5.0 g). The crude material was purified by filtration through a short silica gel column where the silica was first washed with 2% TEA in methylene chloride. The column was then dried under N2 pressure and re-solvated with neat methylene chloride. Elution with 2% EtOH/methylene chloride gave 1.41 g of the desired product as a white crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[N:27]1([C:33]([C:35]2[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:40][CH2:39][C:38]1[CH:37]=[CH:36][C:35]([C:33]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:34])=[CH:42][CH:41]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(C(=O)N2CCCCC2)cc1
Product: O=C(c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)N1CCCCC1

Procedure:
Using a method similar to the General Procedure 5-2, react 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 mg, 1.17 mmol) with 4-(piperidin-1-ylcarbonyl)-benzylamine (308 mg, 1.41 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (20:1, 10:1, 7:1 and 5:1) to give 7-chloro-6-[4-(piperidine-1-carbonyl)-benzylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[CH:13][C:14](=[O:16])[N:15]=[C:10]3[CH:9]([OH:17])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.[C:25]1(=[O:31])[O:30][C:28](=[O:29])[CH2:27][CH2:26]1>N1C=CC=CC=1>[C:25]([OH:30])(=[O:31])[CH2:26][CH2:27][C:28]([OH:16])=[O:29].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[CH:13][C:14](=[O:16])[N:15]=[C:10]3[CH:9]([OH:17])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[CH:13][C:14](=[O:16])[N:15]=[C:10]3[CH:9]([OH:17])[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:6]=2[CH:24]=1
Reactant: O=C1CCC(=O)O1
Agent: O=c1ccn2c(n1)C(O)N=C(c1ccccc1)c1cc(Cl)ccc1-2
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)O
Temperature: 0 °C

Procedure:
A suspension of 9-chloro-5-hydroxy-7-phenylpyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one in pyridine was stirred for 3 hours with succinic anhydride. The mixture was then poured in ice water, the solid collected on filter and recrystallized from methanol-water to give 9-chloro-5-hydroxy-7-phenylpyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one hemisuccinate.
Reaction SMILES: C(N(CC)CC)C.C(O[C:13]([NH:15][N:16]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=1[F:25])C)=O)(C)(C)C.[CH3:26][C@:27]12[C:33]([CH3:35])([CH3:34])[C@H:30]([CH2:31][CH2:32]1)[CH:29]([C:36](Cl)=[O:37])[C:28]2=O.Cl.O1CCOCC1>ClCCCl>[F:25][C:19]1[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:18]=1[N:16]1[C:36](=[O:37])[C:29]2[C@@H:30]3[C:33]([CH3:35])([CH3:34])[C@@:27]([CH3:26])([CH2:32][CH2:31]3)[C:28]=2[N:15]1[CH3:13]
Reactant: CN(NC(=O)OC(C)(C)C)c1cccc(F)c1F
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClCCCl
Product: Cn1c2c(c(=O)n1-c1cccc(F)c1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 28.9 %

Procedure:
Triethylamine (1 mL, 7.2 mmol) was added dropwise to a solution of N′-(2,3-difluoro-phenyl)-N′-methyl-hydrazinecarboxylic acid tert-butyl ester (360 mg, 1.4 mmol) in 1,2-dichloroethane (6 mL) over 1 min. The reaction mixture was stirred for 5 min and then a solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo[2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 800 mg, 3.72 mmol) in 1,2-dichloroethane (14 mL) was added over 2 min. The reaction mixture was heated in an oil bath at 50° C. for 1 h. The solution was allowed to cool and a solution of HCl in dioxane (4 M; 6 mL, 24 mmol) was added and the mixture was heated at reflux for 1.5 h and then allowed to cool to room temperature. The solvent was evaporated and the residue was purified by preparative HPLC and dried under high vacuum to give (4S,7R)-2-(2,3-difluoro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (129 mg, 29%) as a white solid. ES(+)-MS (M+H) 319.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[NH:14][C:13]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=4)=[N:12][C:11]=3[N:10]([CH3:30])[C:9]2=[O:31])=[CH:5][CH:4]=1.Cl[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16](=[O:17])[C:15]3[N:14]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][N:37]=4)[C:13]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:27])([F:29])[F:28])[CH:20]=4)=[N:12][C:11]=3[N:10]([CH3:30])[C:9]2=[O:31])=[CH:32][CH:33]=1
Reactant: Cc1ccc(CCl)nc1
Reactant: COc1ccc(Cn2c(=O)c3[nH]c(Cc4cccc(OC(F)(F)F)c4)nc3n(C)c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)c3c(nc(Cc4cccc(OC(F)(F)F)c4)n3Cc3ccc(C)cn3)n(C)c2=O)cc1
Temperature: 55 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a solution of 1-(4-methoxybenzyl)-3-methyl-8-(3-(trifluoromethoxy)benzyl)-1H-purine-2,6(3H,7H)— dione (110 mg, 0.238 mmol, intermediate 48) in DMF (4 mL) was added 2-(chloromethyl)-5-methylpyridine (33.8 mg, 0.238 mmol, intermediate 50), followed by potassium carbonate (49.5 mg, 0.358 mmol). The reaction was stirred at 55° C. for 2 h. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a white solid product (120 mg, 88.8% yield) which was used without purification. LCMS MH+ 566.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[CH:4][C:3]=1[O:13][CH2:14][O:15][CH3:16].[Li]CCCC.[I:22]I>C1COCC1.CC(OC)(C)C>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][O:9]2)=[C:4]([I:22])[C:3]=1[O:13][CH2:14][O:15][CH3:16]
Reactant: II
Reactant: COCOc1cc2c(c(F)c1F)OCCC2
Agent: [Li]CCCC
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: COCOc1c(F)c(F)c2c(c1I)CCCO2
Temperature: 20 °C
Reaction time: 1 h

Procedure:
16.6 g (72.1 mmol) of 7,8-difluoro-6-methoxymethoxychroman are initially introduced in 350 ml of THF, and 54.3 ml (86.5 mmol) of n-BuLi (15% soln. in hexane) are added dropwise at −78° C. When the addition is complete, the mixture is stirred at this temperature for 30 min and subsequently at 20° C. for 1 h. The solution is re-cooled to −78° C., and a solution of 22.0 g (86.5 mol) of iodine in 100 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 1.5 h and subsequently diluted with MTBE. The solution is washed with water and sat. sodium chloride soln. and dried using sodium sulfate. The crude product remaining after removal of the solvents is purified by column chromatography (SiO2, n-heptane:MTBE=2:1), giving 7,8-difluoro-5-iodo-6-methoxymethoxychroman as a brownish oil.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[C:16]([C:15]1[C:14]([F:13])=[CH:21][CH:20]=[CH:19][C:18]=1[O:12][C:4]1[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])#[N:17]
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: N#Cc1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(F)cc1Oc1cccc(F)c1C#N
Temperature: 90 °C

Procedure:
A mixture of methyl 4-fluoro-2-hydroxybenzoate (10.5 g), 2,6-difluorobenzonitrile (17.17 g) and Cs2CO3 (22.12 g) in dimethyl sulfoxide (150 mL) was heated at 90° C. for 2 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate three times. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The solid was triturated with 7:3 hexanes/ethyl acetate (300 mL). The filtrate was concentrated, and the residue was purified by flash chromatography on silica gel eluting from 15%-25% ethyl acetate in hexanes to give the title compound.
Reaction SMILES: [ClH:1].[N:2]1[O:6][N:5]=[C:4]2[CH:7]=[C:8]([C:11]([CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[O:12])[CH:9]=[CH:10][C:3]=12.Br[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]2[C:26]([CH:30]=1)=[N:27][O:28][N:29]=2.C(=O)(O)[O-].[Na+].Cl>C(O)C.C(OCC)(=O)C.[I-].[Li+]>[ClH:1].[N:29]1[O:28][N:27]=[C:26]2[CH:30]=[C:22]([CH2:21][CH2:20][N:16]3[CH2:17][CH2:18][CH:13]([C:11]([C:8]4[CH:9]=[CH:10][C:3]5[C:4]([CH:7]=4)=[N:5][O:6][N:2]=5)=[O:12])[CH2:14][CH2:15]3)[CH:23]=[CH:24][C:25]=12
Reactant: BrCCc1ccc2nonc2c1
Reactant: O=C(c1ccc2nonc2c1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(c1ccc2nonc2c1)C1CCN(CCc2ccc3nonc3c2)CC1
Yield: 40.3 %

Procedure:
4-(Benzofurazan-5-carbonyl)piperidine hydrochloride (80 mg, 0.3 mmol), 5-(2-bromoethyl)benzofurazan (170 mg, 0.75 mmol), sodium bicarbonate (101 mg, 1.2 mmol) and lithium iodide (1 mg) in ethanol were heated under reflux for 19 hours, cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /CH3OH/NH3 (Aq.); 98:2:0.2 to give a yellow solid. This was dissolved in ethyl acetate (2 ml), and ethanolic HCl (Ca. 1M, 1 ml) was added. The resulting solid was collected and dried in vacuo to give the hydrochloride as a white solid (50 mg, 40%), mp 226°-228° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][OH:18])[C:10](=[O:19])[N:9]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][CH2:16][CH:17]=[O:18])[C:10](=[O:19])[N:9]=1
Reactant: O=c1nc(-c2ccccc2F)ccn1CCCCO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=CCCCn1ccc(-c2ccccc2F)nc1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 4-(2-fluoro-phenyl)-1-(4-hydroxy-butyl)-1H-pyrimidin-2-one (80 mg, 0.30 mmol) in DCM (8 ml), the solution at 0° C., solid Dess Martin periodinane (380 mg, 0.61 mmol) was added portionwise. The mixture was stirred at room temperature for 1 hour. Na2S2O3 was added and the mixture was extracted with DCM; the organic layer was dried (Na2SO4), filtered and evaporated. The crude was purified by flash chromatography with ethyl acetate to give 50 mg of the title compound as a green solid (64% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([S:25]([CH2:28][CH2:29][CH2:30][C:31]([O:33]C(C)(C)C)=[O:32])(=[O:27])=[O:26])[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]3[O:22][CH:23]=[CH:24][C:13]=23)=[O:11])=[CH:5][CH:4]=1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([S:25]([CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:26])=[O:27])[C:10]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]3[O:22][CH:23]=[CH:24][C:13]=23)=[O:11])=[CH:7][CH:8]=1
Reactant: COc1ccc(N(C(=O)c2c3ccccc3nc3occc23)S(=O)(=O)CCCC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(N(C(=O)c2c3ccccc3nc3occc23)S(=O)(=O)CCCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
200 mg (0.34 mmol) N-(4-Methoxy-phenyl)-N-(tert-butyl-oxycarbonylpropyl-sulfonyl)-furo[2,3-b]quinoline-4-carboxamide 9 were dissolved in 3.0 mL trifluoroacetic acid and stirred for 15 minutes at room temperature. The solvent was removed under reduced pressure to give an yellow oil. The residue was purified by silica gel chromatography (eluent: methylene chloride/diethylether 6:4+0.1% acetic acid). Evaporation of the appropriate fractions gave 140 mg of the desired product 10.