Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([O:12][C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:11]=[C:10]([O:12][C:13]([N:15]([CH3:16])[CH3:17])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N+:3]=1[O-:26]
Reactant: Cc1cc(OC(=O)N(C)C)c2ccccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(OC(=O)N(C)C)c2ccccc2[n+]1[O-]
Temperature: 0 °C

Procedure:
23 g (0.1 mole) of 2-methyl-4-dimethylaminocarbonyloxyquinoline were dissolved in 150 ml of dry chloroform free of alcohol and, while stirring and externally cooling with ice-water, 25 g 3-chloroperbenzoic acid (70% strength) dissolved in 400 ml chloroform were added dropwise.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11](=[O:17])[CH2:12][CH2:13][C:14](O)=[O:15].Cl>O>[S:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11](=[O:17])[CH2:12][CH2:13][C:14](=[N:2][OH:3])[OH:15]
Reactant: O=C(O)CCC(=O)c1cccs1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCC(O)=NO)c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 22.6 g. of hydroxylamine hydrochloride and 26 g. of NaOH in 300 ml. of water is stirred and 30 g. of 4-(2-thienyl)-4-oxobutyric acid is added to afford a clear yellow solution. The mixture is stirred for two hours at room temperature and acidified with 3N HCl to pH 2 to give a white precipitate. After stirring an additional half hour, the mixture is cooled in ice and filtered. The filter cake is washed with water and dried to afford the title compound, m.p. 133°-138° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[O:8])=[C:5]([NH2:18])[NH:4][N:3]=1.[CH2:19]([O:22][CH2:23][C:24](=O)[CH2:25][CH:26]1OCCO1)[CH:20]=[CH2:21].[OH-].[K+]>CCO>[CH2:19]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][N:4]2[N:3]=[C:2]([NH2:1])[C:6]([C:7]([NH:9][C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:15]=3[O:16][CH3:17])=[O:8])=[C:5]2[N:18]=1)[CH:20]=[CH2:21]
Reactant: C=CCOCC(=O)CC1OCCO1
Reactant: COc1ccncc1NC(=O)c1c(N)n[nH]c1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCOCc1ccn2nc(N)c(C(=O)Nc3cnccc3OC)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3,5-Diamino-N-(4-methoxy-3-pyridyl)-1H-pyrazole-4-carboxamide 9 (250 mg, 1.007 mmol), 1-allyloxy-3-(1,3-dioxolan-2-yl)propan-2-one (187.5 mg, 1.007 mmol) and KOH (5.650 mg, 0.1007 mmol) were suspended in dry EtOH (5 mL) and stirred at RT for 2 hr. The light brown suspension was filtered and the collected solid was purified by column chromatography on silica (7.5% MeOH in DCM, ˜75 mL) to give the desired Compound I-O-55 as a light yellow solid (206.5 mg, 58% Yield). LC-MS (M+H)+ 355.2; 1H NMR (500 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.52 (s, 1H), 8.95 (d, J=6.9 Hz, 1H), 8.21 (d, J=5.5 Hz, 1H), 7.16 (d, J=5.5 Hz, 1H), 7.09 (d, J=6.9 Hz, 1H), 6.62 (s, 2H), 6.01 (ddt, J=17.3, 10.6, 5.4 Hz, 1H), 5.37 (dq, J=17.3, 1.8 Hz, 1H), 5.24 (ddt, J=10.5, 2.0, 1.3 Hz, 1H), 4.71 (s, 2H), 4.18 (dt, J=5.4, 1.5 Hz, 2H), 4.03 (s, 3H).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:12]=[N:13][C:14]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]([O:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[CH2:29][CH2:28]3)=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH3:43][CH:44]([NH2:51])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH3:43][CH:44]([NH:51][C:5]1[N:10]=[C:9]([C:11]2[N:12]=[N:13][C:14]([CH:27]3[CH2:28][CH2:29][N:30]([C:33]([O:35][CH2:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[O:34])[CH2:31][CH2:32]3)=[CH:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=2)[CH:8]=[CH:7][N:6]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CS(=O)(=O)c1nccc(-c2nnc(C3CCN(C(=O)OCc4ccccc4)CC3)cc2-c2cccc(C(F)(F)F)c2)n1
Reactant: CC(N)c1ccccc1
Product: CC(Nc1nccc(-c2nnc(C3CCN(C(=O)OCc4ccccc4)CC3)cc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Temperature: 120 °C
Yield: 93.9 %

Procedure:
Under Ar, a mixture of 28 (0.62 g, 1.0 mmol) and (S) (−)-α-methylbenzylamine (1.5 mL, 11.6 mmol) was heated at 120 ° C. for 3 h. The reaction was chromatographed on a Still column (40 mm) and the product eluted with 80% EtOAc-hexanes to yield 0.6 g of 29.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2/[CH:16]=[CH:17]/[CH:18]([OH:27])[CH2:19][CH:20]([OH:26])[CH2:21][C:22](OC)=[O:23])=[CH:4][C:3]=1[CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=2/[CH:16]=[CH:17]/[C@@H:18]2[O:27][C:22](=[O:23])[CH2:21][C@@H:20]([OH:26])[CH2:19]2)=[CH:4][C:3]=1[CH2:28][O:29][Si:30]([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:31])[CH3:32]
Reactant: COC(=O)CC(O)CC(O)/C=C/c1c(C)cc(C)cc1-c1ccc(F)c(CO[Si](C)(C)C(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)c(/C=C/[C@H]2C[C@H](O)CC(=O)O2)c(-c2ccc(F)c(CO[Si](C)(C)C(C)(C)C)c2)c1

Procedure:
A solution of the compound (1h) (900 mg 1.7 mmol), 1 N NaOH (2.5 mL, 2.5 mmol) and MeOH (15 mL) was stirred at 25° C. for 1 hour. The reaction mixture was evaporated in vacuo at 25° C. and the residue was dissolved in H2O (100 mL). The reaction solvent was acidified with 12 N HCl (1 mL) and extracted with Et2O (100 mL). The organic extract was washed with H2O (2×100 mL), dried over MgSO4, filtered, evaporated and the residual crude dihydroxy acid was dissolved in toluene (75 mL) and heated at reflux in a Dean-Stark apparatus. After 3 hours the toluene was removed in vacuo leaving the crude compound (1i) as a thick yellow oil. The oil was chromatographed on silica gel. Elution with CH2Cl2 -acetone (19:1, v=v) to provide the compound (1i) as a pale yellow oil, homogenous by HPLC [time of elution was 3.72 minutes with a flow rate of 4 mL/minutes using 10% isopropanol/hexane on a Whatman Partisil PXS 10/25 PAC column]; NMR 0.139 (6H, s), 0.946 (9H, s), 1.61-1.84 (2H, m), 2.345 (6H, s), 2.45-2.75 (2H, m), 3.947-3.994 (H, m), 4.81 (2H, m), 5.096-5.134 (H, m), 5.30 (H, dd, J=7 and 16 Hz), 6.50 (H, d, J=16 Hz), 6.938-7.338 (6H, m).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH2:16])=[N:6][CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:9]=2)[CH2:3][CH2:2]1.[OH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[C:26](O)=[O:27])=[CH:20][CH:19]=1>>[CH:1]1([C:4]2[NH:9][C:8]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:7][N:6]3[C:26](=[O:27])[C:25]([CH2:24][C:21]4[CH:22]=[CH:23][C:18]([OH:17])=[CH:19][CH:20]=4)=[N:16][C:5]=23)[CH2:3][CH2:2]1
Reactant: O=C(O)C(=O)Cc1ccc(O)cc1
Reactant: Nc1ncc(-c2ccccc2)nc1C1CC1
Product: O=c1c(Cc2ccc(O)cc2)nc2c(C3CC3)[nH]c(-c3ccccc3)cn1-2

Procedure:
Synthesized using method A with 3-cyclopropyl-5-phenylpyrazin-2-amine and 3-(4-hydroxyphenyl)-2-oxopropanoic acid as starting materials. Exact mass calculated for C22H18N3O2+ m/z−356.14, found m/z−356.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2O[C:13](=O)[C:12]([C:16]([O:18][CH3:19])=[O:17])=[C:11]([S:20][CH3:21])[CH:10]=2)=[CH:5][CH:4]=1.[C:22]1([N:28]2[CH:36]=[C:35]3[C:30]([CH2:31][CH2:32][CH2:33]C3=O)=[N:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[K+].Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:33]3[CH2:32][CH2:31][C:30]4[C:35](=[CH:36][N:28]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:29]=4)[C:13]=3[C:12]([C:16]([O:18][CH3:19])=[O:17])=[C:11]([S:20][CH3:21])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C1CCCc2nn(-c3ccccc3)cc21
Reactant: COC(=O)c1c(SC)cc(-c2ccc(OC)cc2)oc1=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1c(SC)cc(-c2ccc(OC)cc2)c2c1-c1cn(-c3ccccc3)nc1CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
A mixture of methyl 6-(4-methoxyphenyl)-4-(methylthio)-2-oxo-2H-pyran-3-carboxylate (306 mg, 1 mmol), 2-phenyl-6,7-dihydro-2H-indazol-4(5H)-one (212 mg, 1 mmol) and powdered KOH (84 mg, 1.5 mmol) in dry DMF (5 mL) was stirred at 25° C. for 8 hr. At the end the reaction mixture was poured into ice water with vigorous stirring and finally neutralized with dilute HCl. The solid thus obtained was filtered and purified on a neutral alumina column using 15% chloroform in hexane as eluent to yield 269 mg (59%) of methyl 6-(4-methoxyphenyl)-8-(methylthio)-2-phenyl-4,5-dihydro-2H-benzo[e]indazole-9-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:26]=[CH:25][C:8]([CH2:9][N:10]([CH2:22][CH2:23][OH:24])[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[CH:32][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH2:22][CH2:23][O:24][C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([F:27])[CH:33]=2)[C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:21]=2[NH:20][CH:19]=[CH:18]3)=[O:12])=[CH:25][CH:26]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Oc1cccc(F)c1
Reactant: CC(C)(C)c1ccc(CN(CCO)C(=O)c2cccc3cc[nH]c23)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CN(CCOc2cccc(F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 40.5 %

Procedure:
To a solution of 175 mg (0.5 mmol) of 1H-indole-7-carboxylic acid (4-tert-butyl-benzyl)-(2-hydroxy-ethyl)-amide, 62 mg (0.55 mmol) of 3-fluorophenol and 144 mg (0.55 mmol) of triphenyl phosphine in 5 ml THF were added dropwise 88 μl (0.55 mmol) of azodicarboxylic acid diethyl ester at 0° C. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was dissolved in diethyl ether. The organic layer was washed twice with 2N aqueous NaOH solution, once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (silica gel; diethyl ether/heptane 1:1) to yield 90 mg (40%) product as a white solid. MS (ISP) 445.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([NH:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])[CH:5]=[C:4]([N:17]2[CH2:22][CH:21]=[CH:20][CH2:19][CH2:18]2)[N:3]=1.C(Cl)(Cl)Cl.[C:27](Cl)(Cl)=[O:28].Cl>C1(C)C=CC=CC=1.C(N(CC)CC)C>[N:17]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])[N:7]3[O:8][C:27](=[O:28])[N:1]=[C:2]3[N:3]=2)[CH2:18][CH:19]=[CH:20][CH2:21][CH2:22]1
Reactant: COCCOC(=O)Nc1cc(N2CC=CCC2)nc(N)[n+]1[O-]
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCCOC(=O)Nc1cc(N2CC=CCC2)nc2nc(=O)on12

Procedure:
2 G. of 2-methoxyethyl 2-amino-6-[3,6-dihydro-1(2H)-pyridyl]-4-pyrimidinecarbamate-3-oxide are dissolved at 0° C. in 15 ml. of chloroform and 3.7 ml. of triethylamine. The cold stirred mixture is treated with 3.2 ml. of 20% phosgene in toluene. The mixture is then stirred for 4 hours, acidified with hydrochloric acid, washed with water and extracted with methylene chloride. The organic phase is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The residue obtained is crystallized from methylene chloride and ether, there being obtained pure 2-methoxyethyl 5-[3,6-dihydro-1(2H)-pyridyl]-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-pyrimidine-7-carbamate having a melting point of 195°-196° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([O:18]C)=[O:17])[CH:10]=2)=[CH:5][CH:4]=1>Cl.C(O)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=3[C:16]([OH:18])=[O:17])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccccc1-c1cc(-c2ccc(OC)cc2)on1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2cc(-c3ccccc3C(=O)O)no2)cc1
Yield: 99 %

Procedure:
A solution of 1.81 g of methyl 2-[5-(4-methoxyphenyl)-3-isoxazolyl]benzoate in 8 ml concentrated HCl and 8 ml of acetic acid was held at reflux for 4 hours, cooled, diluted with water, and filtered to give 1.71 g (99%) of white solid, mp 182°-185° C. Recrystallization of the solid from CH3CN gave 1.27 g (73%) of solid, mp 186°-187.5° C.
Reaction SMILES: C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:54]1[N:59]=[C:58]([N:60]2[CH2:65][CH2:64][O:63][CH2:62][CH2:61]2)[N:57]=[C:56]([C:66]2[CH:67]=[N:68][C:69]([NH2:72])=[N:70][CH:71]=2)[CH:55]=1.[N:73]1[C:82]2[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=2)[CH:76]=[C:75]([NH2:83])[CH:74]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C1COCC1>[NH2:72][C:69]1[N:68]=[CH:67][C:66]([C:56]2[N:57]=[C:58]([N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)[N:59]=[C:54]([NH:83][C:75]3[CH:74]=[N:73][C:82]4[C:77]([CH:76]=3)=[CH:78][CH:79]=[CH:80][CH:81]=4)[CH:55]=2)=[CH:71][N:70]=1
Reactant: Nc1cnc2ccccc2c1
Reactant: Nc1ncc(-c2cc(Cl)nc(N3CCOCC3)n2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: Nc1ncc(-c2cc(Nc3cnc4ccccc4c3)nc(N3CCOCC3)n2)cn1
Temperature: 110 °C

Procedure:
Pd(OAc)2, BINAP, cesium carbonate, THF (0.8 mL) were mixed with 5-(6-chloro-2-morpholinopyrimidin-4-yl)pyrimidin-2-amine (1 eq) and quinolin-3-amine (2 eq). The mixture was heated under microwave irradiation for 10 minutes at 110° C. The solution was filtered and concentrated under reduced pressure. LC/MS (m/z): 401.4 (MH+).
Reaction SMILES: [CH2:1]([O:3][P:4](/[CH:9]=[CH:10]\[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([O:41]C)=[O:40])[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH2:7]([O:6][P:4](/[CH:9]=[CH:10]\[C:11]1[C:12]([O:22][CH2:23][C:24]2[CH:47]=[CH:46][C:27]([O:28][CH2:29][C:30]3[N:31]=[C:32]([C:36]4[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=4)[C:39]([OH:41])=[O:40])[O:33][C:34]=3[CH3:35])=[C:26]([O:48][CH3:49])[CH:25]=2)=[N:13][N:14]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:15]=1)([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOP(=O)(/C=C\c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C(=O)OC)c3)oc2C)c(OC)c1)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOP(=O)(/C=C\c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3cccc(C(=O)O)c3)oc2C)c(OC)c1)OCC
Temperature: 50 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
To a mixture of methyl 3-[4-({4-[({4-[(Z)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate (1.38 g), tetrahydrofuran (10 mL) and methanol (10 mL) was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (5 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 3-[4-({4-[({4-[(Z)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoic acid as colorless crystals (1.26 g, yield 93%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 158-159° C.
Reaction SMILES: [CH2:1]([C:5]1[O:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][CH2:3][CH3:4].[Li]CCCC.[CH2:15]1[O:17][CH2:16]1>C1COCC1>[CH2:1]([C:5]1[O:6][C:7]([CH2:15][CH2:16][OH:17])=[CH:8][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccco1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCc1ccc(CCO)o1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
To a solution of 2-butylfuran (3.00 g, 24.2 mmol) in THF (24 mL) at −78° C. was added n-BuLi (11.6 mL, 2.5 M, 29.0 mmol) dropwise over 10 min. The reaction was warmed to rt and stirred for 3.5 h. After cooling to 0° C., ethylene oxide (1.81 mL, 36.2 mmol) was added, the reaction was warmed to rt and stirring was continued for 19 h. The reaction was then cooled to 0° C. and quenched with sat. NH4Cl (20 mL), followed by extraction with diethyl ether (2×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 4.07 g (100%) compound 502A as a bright orange oil. This material was used without further purification. HPLC: 96% at 3.23 min (retention time) (YMC Combiscreen ODS-A column, 4.6×50 mm, eluting with 10-90% aqueous methanol containing 0.2% phosphoric acid over 4 min, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 169.22 [M+H]+.
Reaction SMILES: C([O:9][C@H:10]1[CH2:14][O:13][C@@H:12]2[C@@H:15]([O:18]C(=O)C3C=CC=CC=3)[CH2:16][O:17][C@H:11]12)(=O)C1C=CC=CC=1.[OH-].[Na+].CO>O1CCCC1>[O:13]1[CH2:14][C@H:10]([OH:9])[C@H:11]2[O:17][CH2:16][C@H:15]([OH:18])[C@@H:12]12
Reactant: O=C(O[C@H]1CO[C@H]2[C@@H]1OC[C@@H]2OC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O[C@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To (3S,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diyl dibenzoate (6.30 g, 17.8 mmol), a mix of NaOH 10%:MeOH=1:1 (60 mL) was added. After stirring at room temperature for 24 hrs, the solvent was evaporated under reduced pressure. Water (30 mL) was added and extraction with EtOAc (30 mL) was carried out. The aqueous layer (pH adjusted to 6 with H3PO4 5%) was evaporated under reduced pressure to leave a white residue. Tetrahydrofuran was added in a large amount, then the suspension was filtered and the filtrate was concentrated to give the title product as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][C:8]#[N:9].[BH4-].[Na+].O>C(O)C.[Ni](Cl)Cl>[CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH2:8][NH2:9]
Reactant: Cc1ccsc1CC#N
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccsc1CCN
Temperature: 25 °C
Yield: 49.5 %

Procedure:
Nickel chloride (0.95 g, 0.73 mmol) was slowly added dropwise to the solution of 2-(3-methylthiophen-2-yl) acetonitrile obtained in step (45-2) (0.10 g 0.73 mmol) in ethanol (3 mL). To a reaction mixture was added portion wise sodium borohydride (0.83 g, 2.19 mmol), and was stirred at room temperature. Water (30 mL) was sequentially added to the mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography (dichloro methane:methanol=8:2), to obtain the title compound (51 mg, 50%).
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:25][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([C:22]([OH:24])=O)[CH:17]=[CH:16]3.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:25][C:13]1[CH:14]=[C:15]3[C:20](=[CH:21][C:12]=1[CH2:11]2)[N:19]=[C:18]([C:22]([NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])[CH:17]=[CH:16]3
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)c1ccc2cc3c(cc2n1)C[C@]1(C3)C(=O)Nc2ncccc21

Procedure:
A mixture of (S)-2′-oxo-1′,2′,6,8-tetrahydrospiro[cyclopenta[g]quinoline-7,3′-pyrrolo[2,3-b]pyridine]-2-carboxylic acid (15 mg, 0.045 mmol, described in Intermediate 14), aniline (4 mg, 0.045 mmol), EDC (26 mg, 0.136 mmol), HOBT (21 mg, 0.136 mmol), and N,N-diisopropylethylamine (0.039 mL, 0.226 mmol) was stirred in DMF (1 mL) at ambient temperature for 18 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=407 (M+1). MS: m/z=407.1500; calculated m/z=407.1503 for C25H19N4O2.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=[N:3]1.[I:16]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>S(=O)(=O)(O)O>[I:16][C:9]1[CH:10]=[C:11]2[C:6](=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=1)[NH:5][CH:4]=[N:3][C:2]2=[O:1]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cccc2c(=O)nc[nH]c12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc(I)cc2c(=O)nc[nH]c12
Temperature: 40 °C
Reaction time: 192 h
Yield: 56 %

Procedure:
To a solution of Methyl 4-oxo-1,4-dihydroquinazoline-8-carboxylate (6.0 g, 0.0294 mol) in sulphuric acid (48 mL) was added N-Iodosuccinimide (53 g, 0.2382 mol; 4 equiv of NIS was added at the beginning of reaction and the remaining NIS was added at day-2, day-3 and day-4 of the reaction in equal portions). The reaction mixture was stirred at 40° C. for 8 days and cooled to room temperature. (The completion of reaction was monitored by LCMS). The reaction mixture was carefully poured on-to ice cold solution of saturated potassium carbonate and maintained a basic pH. The precipitate was filtered, washed with water and dried. This solid was further suspended in saturated sodium bicarbonate (100 mL) containing methanol (20 mL). After stirring for 30 min, the insoluble solid was collected by filtration. This material was further slurred in a mixture of chloroform and methanol (1:1) and filtered and dried under vacuum to afford (5.5 g, 56%) of the title compound as an off white solid. TLC-: Chloroform/Methanol: (9/1): Rf=0.25. LCMS: Mass found (M+1, 331.0).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.[Rh]>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=[O:18])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Rh]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Yield: 102.9 %

Procedure:
A solution of 30.0 g (0.11 mole) of t-butoxycarbonylphenylalanine in 750 ml of tetrahydrofuran was hydrogenated at 60° for 24 hours using 50 psi hydrogen gas and 5% rhodium on carbon. The mixture was filtered and the filtrate concentrated to give the title compound (30.7 g) as a colorless oil. The oil was used without further purification. Structure assignment was supported by the nmr spectrum (loss of aromatic protons and appearance of cyclohexyl protons).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.Br.[C:21]([NH:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][NH:30][CH2:29]2)(=[O:23])[CH3:22].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:21]([NH:24][CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[CH2:31][N:30]([C:11]1[CH:12]=[C:13]3[C:8]([C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:15])[CH2:29]2)(=[O:23])[CH3:22]
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CC(=O)NCc1ccc2c(c1)CNC2
Agent: Br
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)NCc1ccc2c(c1)CN(c1cc3c(cc1F)c(=O)c(C(=O)O)cn3C1CC1)C2
Yield: 74.2 %

Procedure:
398 mg of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 490 mg of 5-acetamidomethylisoindoline hydrobromide, 795 mg of DBU, and 3 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 485 mg of 7-(5-acetamidomethyl-2-isoindolinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.