Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11](I)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:16][CH:17]([CH:22]=[CH2:23])[C:18]([O:20][CH3:21])=[O:19]>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:23][CH2:22][C:17](=[O:16])[C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(I)c1
Reactant: C=CC(O)C(=O)OC
Product: COC(=O)C(=O)CCc1cccc(O[Si](C)(C)C(C)(C)C)c1

Procedure:
Methyl 4-[3-(tert-butyldimethylsilyloxy)phenyl]-2-oxo-butyrate was prepared as a yellow oil from 3-(tert-butyldimethylsilyloxy) iodobenzene and methyl 2-hydroxy-3-butenoate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](B2OC(C)(C)C(C)(C)O2)=[N:22]1>O>[NH:21]1[C:29]2[C:24](=[C:25]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=4)[N:3]=3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[N:22]1
Reactant: COc1cccc(Oc2nc(Cl)nc3c2cnn3C)c1
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Solvent: O
Product: COc1cccc(Oc2nc(-c3cccc4[nH]ncc34)nc3c2cnn3C)c1

Procedure:
6-Chloro-4-(3-methoxy-phenoxy)-1-methyl-1H-pyrazolo[3,4-d]pyrimidine was reacted with indazole boronic acid pinacol ester in General Procedure A. Addition of water gave a solid which was purified by preparative HPLC to give 114. NMR: (CDCl3): 3.81 (s, 3H, CH3), 4.18 (s, 3H, CH3), 7.02-7.04 (m, 2H, 2×ArH), 7.09 (m, H, ArH), 7.44-7.52 (m, 2H, 2×ArH), 7.70 (d, H, ArH, J=9 Hz), 8.16 (s, H, ArH), 8.22 (d, H, ArH, J=6.9 Hz), 8.34 (s, H, ArH), 13.17 (sbr, H, NH). MS: (ESI+) MH+=373.24
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][C:7]([OH:16])=[CH:6][C:5]2=1.[CH:17]1([CH2:20][CH2:21]O)[CH2:19][CH2:18]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]=[CH:11][C:10]3[C:5]([C:4]=2[CH:3]=1)=[CH:6][C:7]([O:16][CH2:21][CH2:20][CH:17]1[CH2:19][CH2:18]1)=[CH:8][CH:9]=3
Reactant: Oc1ccc2ccc3ccc(Br)cc3c2c1
Reactant: OCCC1CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Brc1ccc2ccc3ccc(OCCC4CC4)cc3c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 6-bromophenanthren-3-ol (3 g, 11 mmol) from Step 1 of Route A of Example 168, 2-cyclopropylethanol (2.85 g, 33 mmol) and triphenylphosphine (5.78 g, 22 mmol) in THF (50 mL) was added di-tert-butylazodicarboxylate (5.08 g, 22 mmol). The reaction mixture was stirred at room temperature overnight, then quenched with water. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The material was purified by flash chromatography on silica (100% hexanes) to afford 3-bromo-6-(2-cyclopropylethoxy)phenanthrene.
Reaction SMILES: C([O:5][C:6](=[O:45])[CH2:7][O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)=[CH:13][C:12]([C:22](=[O:37])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:11][C:10]=1[C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=1)(C)(C)C>C(O)=O>[CH3:21][C:17]1[CH:16]=[C:15]([C:14]2[CH:13]=[C:12]([C:22](=[O:37])[NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:11]=[C:10]([C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([CH3:44])[CH:39]=3)[C:9]=2[O:8][CH2:7][C:6]([OH:45])=[O:5])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cccc(-c2cc(C(=O)NCCCCCCCc3ccccc3)cc(-c3cccc(C)c3)c2OCC(=O)OC(C)(C)C)c1
Solvent: O=CO
Product: Cc1cccc(-c2cc(C(=O)NCCCCCCCc3ccccc3)cc(-c3cccc(C)c3)c2OCC(=O)O)c1
Yield: 99.4 %

Procedure:
A solution of [3,3″-Dimethyl-5′-(7-phenyl-heptylcarbamoyl)-[1,1′:3′,1″]terphenyl-2′-yloxy]acetic acid tert-butyl ester (180 mg, 0.311 mmol) in 3.5 mL HCOOH was stirred at room temperature until all of the ester was consumed by TLC (1:1 EtOAc:Hexanes). The excess HCOOH was removed in vacuo (first on a rotoevaporator then pumping under high vacuum) then crystallized from CH2Cl2/Hexanes to yield 170 mg, 100% of the acid as a yellow foam. mp 58-62° C.; 1H NMR (DMSO-d6) δ 1.21-1.28 (m, 6H); 1.44-1.57 (m, 4H); 2.35 (s, 6H); 2.53 (t, J=7.69 Hz, 2H); 3.23 (quartet, J=6.37 Hz, 2H); 3.82 (s, 2H); 7.10-7.24 (m, 7H); 7.30-7.41 (m, 6H); 7.80 (s, 2H); 8.51 (t, J=5.49 Hz, 1H); 12.60 (bs, 1H); —IR 3375, 3025, 2925, 2865, 1730, 1630, 1600, 1550, 1450, 1350, 1210, 1195, 1080, and 700 cm−1; mass spectrum [(−)ESI], m/z 548 [M−H]−; Anal Calcd. for C36H39NO4: C, 78.66; H, 7.15; N, 2.55; Found: C, 77.39; H, 7.42; N, 2.37.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[C:2]=[O:3].[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1>>[CH2:4]([NH:1][C:2]([NH:11][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:22]=[C:23]([NH:27][C:28](=[O:32])[CH:29]([CH3:30])[CH3:31])[CH:24]=[CH:25][CH:26]=2)[CH2:17][CH2:16]1)=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C=NCc1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)NCc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure P and Scheme AB using (isocyanatomethyl)benzene and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 437.2 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[N:11]=2)=[CH:8][N:7]=[C:6](SC)[N:5]=1)([CH3:3])[CH3:2].[NH2:27][CH:28](O)[CH:29]([CH3:31])[CH3:30].C1C[O:36]CC1>CN1C(=O)CCC1>[OH:36][C:29]([CH3:31])([CH3:30])[CH2:28][NH:27][C:6]1[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[N:11]=2)=[CH:8][N:7]=1
Reactant: CSc1ncc(-c2ccnc(Nc3ccc(C#N)cc3)n2)c(C(C)C)n1
Reactant: C1CCOC1
Reactant: CC(C)C(N)O
Solvent: CN1CCCC1=O
Product: CC(C)c1nc(NCC(C)(C)O)ncc1-c1ccnc(Nc2ccc(C#N)cc2)n1

Procedure:
4-(4′-Isopropyl-2′-(methylthio)-4,5′-bipyrimidin-2-ylamino)benzonitrile (36b) (51.1 mg, 0.141 mmol) and 1-amino-2-methylpropanol (126 mg, 1.410 mmol) were dissolved in THF (513 μl) and NMP (51.3 μl), then the reaction mixture was microwaved at 200° C. for 2 hours. The reaction was approximately 10% complete. Additional 1-amino-2-methylpropanol (126 mg, 1.410 mmol) was added, and the reaction mixture was microwaved at 200° C. for an additional 2 hours. The reaction mixture was microwaved at 200° C. for additional 3.5 hours. The crude reaction mixture was purified by reverse-phase HPLC [30-100% organic phase over 15 minutes using 0.1% TFA modified mobile phase] to obtain the desired product as a yellow foamy solid. 1H NMR (400 MHz, MeOD) δ ppm 1.27 (d, J=6.57 Hz, 6 H) 1.30 (s, 6 H) 3.43-3.65 (m, 2 H) 3.71 (ddd, J=13.52, 6.69, 6.57 Hz, 1 H) 7.08 (d, J=5.05 Hz, 1 H) 7.63 (m, J=9.09 Hz, 2 H) 7.95 (m, J=8.59 Hz, 2 H) 8.45 (s, 1 H) 8.61 (d, J=5.05 Hz, 1 H). HRMS (ES+) for C22H25N7O.H+ [MH+]: calcd, 404.2199. found, 404.2201. UV-LC: 95.41/100% UV purity at 214/254 nm; tR=5.73 minutes over 7.75 minutes.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH:10](Br)[CH3:11].[OH-].[Na+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: CC(Br)Br
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: BrCCOc1ccc(Br)cc1
Yield: 82.8 %

Procedure:
A mixture of 4-bromophenol (30 g, 173 mmol), dibromoethane (40 mL, 464 mmol), NaOH (11.0 g, 275 mmol) and water (430 mL) was refluxed for 11 h. The phases were separated and the organic phase was further purified by distillation, yielding the sub-title compound (40.1 g 83%).
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[CH2:12]([N:16]1[C:20]([C:21](SC)=[O:22])=[C:19]([CH:25]=O)[N:18]=[C:17]1[N:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1)[C:13]#[C:14][CH3:15].[CH2:40]([O:47][C:48]([NH:50][CH:51](P(OC)(OC)=O)[C:52]([O:54][CH3:55])=[O:53])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>ClCCl>[CH3:55][O:54][C:52]([C:51]1[N:50]([C:48]([O:47][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)=[O:49])[C:21](=[O:22])[C:20]2[N:16]([CH2:12][C:13]#[C:14][CH3:15])[C:17]([N:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:29][CH2:28]3)=[N:18][C:19]=2[CH:25]=1)=[O:53]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C(=O)SC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(C(=O)OC)n(C(=O)OCc3ccccc3)c(=O)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.079 g of 1,8-diazabicyclo[5.4.0]-7-undecene and then 5 ml of dichloromethane containing 0.194 g of t-butyl 4-[1-(2-butynyl)-4-formyl-5-methylsulfanylcarbonyl-1H-imidazol-2-yl]piperazine-1-carboxylate were added to a 2 ml dichloromethane solution of 0.174 g of methyl benzyloxycarbonylamino-(dimethoxyphosphoryl)-acetate, and the mixture was stirred at room temperature for 16 hours. The solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 0.147 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (3:2).
Reaction SMILES: [CH2:1]([O:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:11][O:12][C:13]12[O:19][C:16]([S:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:22])=[O:21])([CH:17]=[CH:18]1)[CH:15]([C:29](O)=[O:30])[CH2:14]2.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][NH:9][C:29]([CH:15]1[CH2:14][C:13]2([O:12][CH3:11])[O:19][C:16]1([S:20]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)(=[O:21])=[O:22])[CH2:17][CH2:18]2)=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NOCc1ccccc1
Reactant: COC12C=CC(S(=O)(=O)c3ccccc3)(O1)C(C(=O)O)C2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC12CCC(S(=O)(=O)c3ccccc3)(O1)C(C(=O)NOCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Added the O-benzylhydroxylamine·hydrochloric acid (0.387 grams, 2.43 mmol) to a stirred solution of 3-(4-methoxy-phenylsulfonyl-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid in methylene chloride (5 ml). Added 4-dimethylaminopyridine (0.306 grams, 2.51 mmol) and stirred approximately one-half hour (until solids dissolved), then added the 1,3-dicyclohexylcarbodiimide (0.250 grams, 1.21 mmol) and stirred at room temperature overnight. The reaction was filtered through a pad of Celite and the filtrate concentrated in vacuo to give 1.06 grams of 3-(4-Methoxyphenylsulfonyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid benzyloxyamide. Took this up in methanol and decanted filtrate from fine needle crystals. Concentration of filtrate gave 0.82 grams of 3-(4-Methoxyphenylsulfonyl-7-oxabicyclo[2.2.1]heptane-2-carboxylic acid benzyloxyamide.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:7]=[CH:8][C:9]([C:20]([F:23])([F:22])[F:21])=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11]2)[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.O1CCCC1.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>O>[CH3:1][N:2]([C:6]1[CH:7]=[CH:8][C:9]([C:20]([F:23])([F:22])[F:21])=[C:10]2[C:14]=1[NH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11]2)[CH2:3][CH2:4][O:5][S:37]([CH3:36])(=[O:39])=[O:38]
Reactant: CCOC(=O)c1cc2c(C(F)(F)F)ccc(N(C)CCO)c2[nH]1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1cc2c(C(F)(F)F)ccc(N(C)CCOS(C)(=O)=O)c2[nH]1

Procedure:
A mixture of ethyl 7-[N-methyl-N-(2-hydroxyethyl)amino]-4-trifluoromethyl-1H-indole-2-carboxylate (0.37 g, 1.12 mmol)., triethylamine (0.25 g, 2.46 mmol) and tetrahydrofuran (20 ml) was cooled to -19° C., after which methanesulfonyl chloride (0.14 g, 1.23 mmol) was added dropwise with stirring. The reaction mixture was stirred at -18° C. to -13° C. for 1 hour, poured into cold water, and then extracted three times with ethyl acetate. The extract solution was washed with a 5% aqueous sodium hydrogencarbonate solution and a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain an oil of ethyl 7-[N-methyl-N-(2-methanesulfonyloxyethyl)amino]-4-trifluoromethyl-1H-indole-2-carboxylate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:15]3=[C:16]([C:18](=[O:21])[CH:19]=[CH:20][N:14]3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH:17]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.CO.O>C(Cl)Cl>[OH:2][CH2:3][C:5]1[CH:6]=[C:7]2[C:15]3=[C:16]([C:18](=[O:21])[CH:19]=[CH:20][N:14]3[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH:17]=1
Reactant: COC(=O)c1cc2c(=O)ccn3c4ccccc4c(c1)c23
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: O=c1ccn2c3ccccc3c3cc(CO)cc1c32
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
2-methoxycarbonyl-4H-pyrido[3,2,1-jk]carbazole-4-one (300 mg) produced in Example 176 was suspended in anhydrous methylene chloride (100 ml), and diisobutylaluminium hydride (1M solution in methylene chloride, 4.3 ml) was added dropwise to the suspension in an acetone-dry ice bath. The mixture was stirred at room temperature for 1 hour, and methanol and water was added to the reaction mixture. The floating materials formed were separated by filtration, and the filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by silica gel flash column chromatography (eluent: ethyl acetate) to obtain the title compound (70 mg, 26%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[CH3:14][N:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]#[N:21].CC1C=C(C2N(C)C=CN=2)C2C(=C(O)C=CC=2)N=1.[Li+].CC([N-]C(C)C)C>CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:13])[CH:3]=[C:2]2[C:19]1[N:15]([CH3:14])[C:16]([C:20]#[N:21])=[CH:17][CH:18]=1
Reactant: Cc1cc(Br)c2cccc(O)c2n1
Reactant: Cn1cccc1C#N
Agent: CC(C)[N-]C(C)C
Agent: Cc1cc(-c2nccn2C)c2cccc(O)c2n1
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C#N)n2C)c2cccc(O)c2n1

Procedure:
Coupling of 4-bromo-2-methyl-quinolin-8-ol (75 mg. 0.32 mmol) with 1-methyl-1H-pyrrole-2-carbonitrile (84 mg. 0.79 mmol) according to the synthesis of of 2-methyl-4-(1-methyl-1H-imidazol-2-yl)-quinolin-8-ol using LDA as the base (1.8 M in Heptan/THF/Ethylbenzol. 0.44 mL. 0.79 mmol) yielded the title compound. MS (m/z): 264.2 [M+H+].
Reaction SMILES: [CH:1]([O:14][C:15]1[C:24]2[N:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:18]([C:25](O)=[O:26])=[C:17]2[CH2:28][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[C:30](=[O:31])[C:16]=12)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:40]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:43]([O:42][C:40]([N:47]1[CH2:48][CH2:49][N:50]([C:25]([C:18]2[C:19]3[CH:20]=[CH:21][CH:22]=[N:23][C:24]=3[C:15]([O:14][CH:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:16]3[C:30](=[O:31])[N:29]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=4)[CH2:28][C:17]=23)=[O:26])[CH2:51][CH2:52]1)=[O:41])([CH3:46])([CH3:45])[CH3:44]
Reactant: O=C(O)c1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2c3c(c(OC(c4ccccc4)c4ccccc4)c4ncccc24)C(=O)N(Cc2ccc(F)cc2)C3)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.8 %

Procedure:
Carboxylic acid 213 (0.015 g, 0.029 mmol) was dissolved in 0.8 mL of dimethylformamide. To this was added BOC-piperazine (0.0116 g, 0.058 mmol), triethylamine (0.012 mL, 0.087 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.011 g, 0.058 mmol), 1-Hydroxybenzotriazole hydrate (0.0059 g, 0.0435 mmol) and stirred at room temperature. After 15 hours, starting material was consumed. Dilute with dichloromethane, washed with 1M HCl solution, saturated brine solution, dried (Na2SO4), concentrated to give crude product. Chromatographed (10 to 50% ethyl acetate/hexanes) to give 4-[9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinoline-5-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester 229 (0.009 g, 0.013 mmol, 45%.) 1H NMR (CDCl3) 9.075 (s, 1H), 8.15 (s, 1H), 8.03 (d, 1H), 7.74 (dd, 4H), 7.53 (dd, 1H), 7.27 (m, 8H), 7.04 (dd, 2H), 4.91 (d, J=17 Hz, 1H), 4.69 (d, J=17 Hz, 1H), 4.41 (d, J=17 Hz, 1H), 4.055 (d, J=17 Hz, 1H), 3.55-2.96 (br m, 8H), 1.44 (s, 9H.) MS: 687 (M+1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[N:8]([CH2:14][C:15]2[CH:19]=[C:18]([C:20]3[S:21][C:22]([Cl:25])=[CH:23][CH:24]=3)[O:17][N:16]=2)[N:7]=1)=O)C>C1COCC1>[Cl:25][C:22]1[S:21][C:20]([C:18]2[O:17][N:16]=[C:15]([CH2:14][N:8]3[C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:6]([CH2:4][OH:3])=[N:7]3)[CH:19]=2)=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1cc(C(=O)O)n(Cc2cc(-c3ccc(Cl)s3)on2)n1
Solvent: C1CCOC1
Product: O=C(O)c1cc(CO)nn1Cc1cc(-c2ccc(Cl)s2)on1
Reaction time: 16 h

Procedure:
To a solution of 1 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-pyrazole-3,5-dicarboxylic acid 3-ethyl ester in 15 ml THF 314 mg LiBH4 were added cautiously. Then the reaction mixture was stirred for 16 h, quenched with diluted HCl and filtered through a Chem Elut® cartridge by elution with ethyl acetate and DCM. After concentration under reduced pressure the crude residue was directly subjected to the next reaction step.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][OH:15].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:15][CH2:14][C:13]([O:17][CH2:18][CH3:19])=[O:16])[N:3]=1
Reactant: CCOC(=O)CO
Reactant: Cc1cc(C)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1nc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution containing 4,6-dimethyl-2-methylsulfonylpyrimidine (10.0 g, 53.8 mmol), ethyl glycolate (5.60 g, 53.8 mmol), and 30 mL of N,N -dimethylformamide was prepared and to this was added with stirring potassium carbonate (8.0 g, 60 mmol). The mixture was allowed to stir at ambient temperature overnight. It was then poured into water and the resulting mixture was extracted 3 times with ethyl acetate. The combined organic extracts were extracted with water. The aqueous extract was saturated with sodium chloride and extracted twice more with ethyl acetate. All of the ethyl acetate layers were combined, dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 8.20 g (72.6 percent of theory) of the title compound as a yellow oil. This oil was filtration chromatographed on silica gel, eluting with a 30:70 mixture of ethyl acetate and hexane. The product containing eluate was concentrated by evaporation under reduced pressure to obtain 7.9 g (70 percent of theory) of the title compound as a colorless oil which solidified on standing to a white solid melting at 57°-59° C.
Reaction SMILES: [CH:1]([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)=[O:2].C(O)(=[O:15])C>>[CH:1]([NH:3][CH:4]1[C:12]2[CH:11]=[CH:10][S:9][C:8]=2[C:7](=[O:15])[CH2:6][CH2:5]1)=[O:2]
Reactant: CC(=O)O
Reactant: O=CNC1CCCc2sccc21
Product: O=CNC1CCC(=O)c2sccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 22.4 g of ceric sulfate in 50% aqueous acetic acid is stirred overnight at room temperature and 2 g of N-formyl-4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine is added. After 6 hours, the mixture is filtered, and the filter cake is washed with 50% aqueous acetic acid. The work-up procedure of Example 1 is then followed with the filtrate to give 1.1 g of the title compound, m.p. 102° to 114° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[C:35]([O:38]CC)(=[O:37])[CH3:36].Cl.[C:42]([O:45]CC)(=[O:44])[CH3:43]>CC(O)C>[C:42]([OH:45])(=[O:44])/[CH:43]=[CH:36]/[C:35]([OH:38])=[O:37].[C:35]([O:24][CH2:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([S:14]([N:5]2[CH:4]=[C:3]([CH2:25][NH:26][CH3:27])[C:2]([F:1])=[C:6]2[C:7]2[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=2)(=[O:16])=[O:15])[CH:18]=1)(=[O:37])[CH3:36]
Reactant: CCOC(C)=O
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(CO)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(COC(C)=O)c2)c(-c2cccnc2F)c1F
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl [(4-fluoro-5-(2-fluoropyridin-3-yl)-1-{[3-(hydroxymethyl)phenyl]sulfonyl}-1H-pyrrol-3-yl)methyl]methylcarbamate (207 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 2 hr. The solvent was concentrated under reduced pressure, diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate solution. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→ethyl acetate:methanol=32:1) (basic TLC:Rf=0.4 (ethyl acetate)) to give a free base of the title compound as a pale-yellow oil (yield 61.1 mg). A solution of the obtained free base in ethyl acetate (1 mL) was added dropwise to a solution of fumaric acid (16 mg) in ethanol (1 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate and ethanol to give the title compound as a white solid (yield 58 mg, 25%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:19][CH2:18]1)[C:10]([F:17])([F:16])[C:11]([O:13]CC)=[O:12].[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:19][CH2:18]1)[C:10]([F:17])([F:16])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)C(F)(F)C1(c2ccc(F)cc2F)CO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)C(F)(F)C1(c2ccc(F)cc2F)CO1
Yield: 100.1 %

Procedure:
In 11 ml of ethanol was dissolved 1.1 g of ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2,2-difluorobutyrate. To the resulting solution was dropwise added 4.7 ml of a 1N aqueous sodium hydroxide solution at 5°-10° C. The solution was subjected to reaction at the same temperature for 10 minutes. The reaction mixture was introduced into a mixed solvent consisting of 50 ml of ethyl acetate and 50 ml of water. The resulting solution was adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 0.99 g of oily 3-(2,4-difluorophenyl)-3,4-epoxy-2,2-difluorobutyric acid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][OH:6])[CH3:3].[CH2:7]([Cl:10])[CH:8]=[CH2:9]>O>[Cl-:10].[CH2:7]([N+:2]([CH3:3])([CH3:1])[CH2:4][CH2:5][OH:6])[CH:8]=[CH2:9]
Reactant: CN(C)CCO
Reactant: C=CCCl
Solvent: O
Product: C=CC[N+](C)(C)CCO
Product: [Cl-]
Reaction time: 1 h

Procedure:
89 grams of N-dimethylaminoethanol were dissolved in 244.7 grams of water, to which 76.5 grams of allyl chloride were added slowly and with cooling, keeping the temperature below 35° C. The reaction was essentially complete within one hour. A clear solution was obtained.