Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9](I)[CH:8]=1.B(F)(F)F.CCOCC.[N:24]1[O:25][CH2:26][CH:27]2[CH2:31][N:30]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH2:29][C:28]=12>O1CCCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([C:28]23[CH2:29][N:30]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:31][CH:27]2[CH2:26][O:25][NH:24]3)[CH:8]=1
Reactant: Fc1ccc(Br)cc1I
Reactant: O=C(OCc1ccccc1)N1CC2=NOCC2C1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC2CONC2(c2cc(Br)ccc2F)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 26.5 %

Procedure:
A 1.6 M hexanes solution of n-butyl lithium (25.4 mL, 40.6 mmol) is added drop wise to a −78° C. solution of 4-bromo-1-fluoro-2-iodobenzene (12.22 g, 40.6 mmol) in tetrahydrofuran (60 mL) to give a yellow solution that is stirred at −78° C. for 15 minutes. Boron trifluoride etherate (5.14 mL, 40.6 mmol) is added to a separate −78° C. solution of benzyl 3,3a,4,6-tetrahydropyrrolo[3,4-c]isoxazole-5-carboxylate (5 g, 20.3 mmol) in tetrahydrofuran (60 mL) and the mixture is stirred at −78° C. for 5 minutes. This solution is added to the previously prepared −78° C. organolithium mixture via cannula. The combined mixture is stirred for 30 minutes at −78° C. The mixture is quenched with saturated aqueous ammonium chloride and warmed to room temperature. The mixture is extracted with ethyl acetate (3×) and the organic extracts are combined, dried over sodium sulfate, filtered and the solvent removed in vacuo. The crude product is purified over silica gel with a 35 minute 5% to 100% ethyl acetate in hexanes gradient to give the title compound (2.27 g, 27%). ES/MS (m/e): (79Br/81Br) 421/423 (M+H).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[Br:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:37]=1[N:36]=[C:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)[CH:34]=[CH:33]2>>[F:1][C:2]([F:25])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:41]2[CH2:42][CH2:43][N:38]([C:35]3[CH:34]=[CH:33][C:32]4[C:37](=[C:28]([Br:27])[CH:29]=[CH:30][CH:31]=4)[N:36]=3)[CH2:39][CH2:40]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: Brc1cccc2ccc(N3CCNCC3)nc12
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3ccc4cccc(Br)c4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 8-bromo-2-piperazin-1-yl-quinoline.
Reaction SMILES: C(OC([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.F[C:25]1[C:34]([O:35][CH3:36])=[C:33]2[C:28]([C:29](=[O:44])[C:30]([C:41]([OH:43])=[O:42])=[CH:31][N:32]2[C@@H:37]2[CH2:39][C@@H:38]2[F:40])=[CH:27][CH:26]=1>CS(C)=O>[NH2:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C:25]3[C:34]([O:35][CH3:36])=[C:33]4[C:28]([C:29](=[O:44])[C:30]([C:41]([OH:43])=[O:42])=[CH:31][N:32]4[C@@H:37]4[CH2:39][C@@H:38]4[F:40])=[CH:27][CH:26]=3)[CH2:13]2)[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Reactant: COc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(N2CC[C@@H](C3(N)CC3)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
After adding 3-(R)-[1-tert-butoxycarbonylaminocyclopropyl]pyrrolidine (165 mg, 731 μmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (2 ml), 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (180 mg, 609 μmol) was added thereto and it was heated under reflux for 13 hours under a nitrogen atmosphere. After concentrating the reaction solution under reduced pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (50 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (5 ml) to the residue while cooling with ice, stirring was performed at room temperature for 30 minutes. 1 mol/l Hydrochloric acid (5 ml) was then added to the reaction solution, and after washing the yellow acidic aqueous solution with chloroform (50 ml×4), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution and the insolubles were removed by filtration. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×4) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was purified by preparative chromatography (development at the lower layer of a 7:3:1 mixture of chloroform methanol:water), recrystallized in isopropyl alcohol, and dried under a reduced pressure. 146 mg (60%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28](=O)[C:29]#[C:30][CH3:31])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.C(OC([N:40]1[CH2:45][CH2:44][O:43][C@H:42]([CH2:46][O:47][NH2:48])[CH2:41]1)=O)(C)(C)C.CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28](=[N:48][O:47][CH2:46][C@H:42]4[O:43][CH2:44][CH2:45][NH:40][CH2:41]4)[C:29]#[C:30][CH3:31])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CC#CC(=O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](CON)C1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC#CC(=NOC[C@@H]1CNCCO1)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Product: Cl
Temperature: 80 °C
Reaction time: 22 h
Yield: 225.6 %

Procedure:
To a suspension of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline (VII-4, 786 mg) and 614 mg of (S)-2-aminooxymethyl-morpholine-4-carboxylic acid tert-butyl ester in 31 ml of 1,4-dioxane was added 2.21 ml of 2 mol/L methanesulfonic acid aqueous solution, followed by stirring at 80° C. for 22 hours. And, 1.32 ml of 2 mol/L methanesulfonic acid aqueous solution was additionally added, followed by further stirring for 5.5 hours. After completion of the reaction, the reaction mixture was poured into aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate. After an aqueous layer was re-extracted with ethyl acetate, all organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. After the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluting with chloroform: methanol=9:1) to obtain a yellow oil. This oil was dissolved in 50 ml of ethyl acetate, and filtered, and 0.95 ml of 4 mol/L hydrochloric acid-ethyl acetate solution was added with stirring, followed by stirring at room temperature for 1 hour. A precipitate was filtered, and washed with ethyl acetate and hexane in this order. A substance collected by filtration was recrystallized with methanol-ethyl acetate to obtain 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholin-2-ylmethoxyimino)-2-butyn-1-yl)quinazoline dihydrochloride (VIII-32, 839 mg) as a yellow crystal.
Reaction SMILES: [CH3:1][C:2]([CH3:12])=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.O>[Ru].C(O)(C)C>[CH2:4]([C@@H:5]1[CH2:6][CH2:7][C@H:8]([OH:11])[CH2:9][CH2:10]1)[CH2:3][CH:2]([CH3:12])[CH3:1].[CH2:4]([C@H:5]1[CH2:6][CH2:7][C@H:8]([OH:11])[CH2:9][CH2:10]1)[CH2:3][CH:2]([CH3:12])[CH3:1]
Reactant: CC(C)=CCc1ccc(O)cc1
Agent: [Ru]
Solvent: CC(C)O
Solvent: O
Product: CC(C)CC[C@H]1CC[C@@H](O)CC1
Product: CC(C)CC[C@H]1CC[C@H](O)CC1
Reaction time: 5 h

Procedure:
330 g 4-(3-methyl-but-2-enyl)-phenol, 3 wt. % ruthenium-on-active charcoal (Ru content, based on the weight of the dry catalyst: 5%; water content about 50%) are initially introduced into 570 ml isopropanol in a stirred autoclave with a gassing stirrer. Hydrogenation is carried out for 5 hours at 100° C. under a hydrogen pressure of 130 bar. After filtration, 329 g 4-isoamylcyclohexanol are obtained as a crude product. After distillation, 316 g 4-isoamylcyclohexanol, which has the following composition: 53.8% cis-4-isoamylcyclohexanol and 44.9% trans-4-isoamylcyclohexanol, are obtained.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[Cl:12][CH2:13][CH2:14]O>>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([O:5][CH2:14][CH2:13][Cl:12])=[O:4]
Reactant: OCCCl
Reactant: O=C(O)C(O)c1ccccc1
Product: O=C(OCCCl)C(O)c1ccccc1

Procedure:
2-Chloroethyl 2-hydroxy-2-phenylacetate was prepared from 2-hydroxy-2-phenylacetic acid and excess 2-chloroethanol essentially by the method described in Step 1 of Example 1; however, the distillate solidified after standing at 4° C.: b.p. 119° C./0.35 mm Hg; m.p. 43°-45° C.; 1H NMR δ 3.50 (d, 1H, J=6.0 Hz), δ 3.58-3.62 (m, 2H), δ 4.28-4.46 (m, 2H),δ 5.22 (d, 1H, J=5.9 Hz), δ 7.3-7.4 (5H); HRMS calcd for C9H7ClO3Tms (M--CH3) 271.0557, obsd 271.0598.
Reaction SMILES: Br[CH2:2][C:3]([C@@H:5]1[CH2:7][C@@H:6]1[C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=O.[Cl:18][C:19]1[N:24]=[N:23][C:22]([NH2:25])=[C:21]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:20]=1>CN(C=O)C.C(Cl)Cl>[Cl:18][C:19]1[CH:20]=[C:21]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:22]2[N:23]([CH:2]=[C:3]([C@@H:5]3[CH2:7][C@@H:6]3[C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[N:25]=2)[N:24]=1
Reactant: Nc1nnc(Cl)cc1N1CCOCC1
Reactant: O=C(CBr)[C@@H]1C[C@@H]1c1ccc2ccccc2n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Clc1cc(N2CCOCC2)c2nc([C@@H]3C[C@@H]3c3ccc4ccccc4n3)cn2n1
Reaction time: 48 h

Procedure:
Compound 79c (67 mg, 0.23 mmol) was dissolved in DMF (2 mL) and compound 19a (50 mg, 0.23 mmol) was added in one portion. The reaction was allowed to stir for 48 h under an argon atmosphere, at which time it was diluted with DCM (50 mL) and washed with saturated sodium bicarbonate (50 mL). The organic layer was concentrated under reduced pressure and then purified by preparative TLC (5% MeOH/DCM) to afford compound 79d. Mass spectrum (LCMS, ESI pos.) Calcd. For C22H20ClN5O 406.1 (M+H). found 406.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23]([C:25]3[S:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:24])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34].[CH3:45][N:46]([CH3:51])[CH2:47][CH2:48][NH:49][CH3:50]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:45][N:46]([CH3:51])[CH2:47][CH2:48][N:49]([C:33]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][O:22][C:23]([C:25]3[S:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[O:24])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:18])([CH3:19])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:31][CH3:32])[CH:3]=1)=[O:34])[CH3:50]
Reactant: CNCCN(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(OC(=O)N(C)CCN(C)C)ccc1-c1ccc2c(c1COC(=O)c1ccc(C)s1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.5 %

Procedure:
A mixture of 6-(4-hydroxy-2-methoxyphenyl)-5-(5-methylthiophen-2-ylcarbonyloxymethyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-2, 42.8 mg, 0.0952 mmol), 1,1′-carbonyldiimidazole (47.7 mg, 0.294 mmol) and 4-dimethylaminopyridine (1.7 mg, 0.014 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL), and then the mixture was stirred at room temperature for 1 hour. N,N,N′-trimethylethylenediamine (25 μL, 0.192 mmol) was added thereto, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (5.8 mg) as a colorless amorphous product. (Yield 11%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([C:7]1[C:8]([OH:18])=[C:9]2[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:10]2=[N:11][CH:12]=1)=O.Cl.[NH2:23]O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[C:8](=[C:9]4[CH:15]=[N:14][N:13]([CH2:16][CH3:17])[C:10]4=[N:11][CH:12]=3)[O:18][N:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: NO
Reactant: CCn1ncc2c(O)c(C(=O)c3cccc(Cl)c3)cnc21
Agent: Cl
Solvent: c1ccncc1
Product: CCn1ncc2c3onc(-c4cccc(Cl)c4)c3cnc21

Procedure:
5-(3-Chlorobenzoyl)-1-ethyl-4-hydroxy-1H-pyrazolo[3,4-b]pyridine (4.25 g) was refluxed overnight in 100 ml of pyridine containing 4.5 g of hydroxylamine hydrochloride. The reaction mixture was then evaporated and the residue triturated with 5% hydrochloric acid. The resulting product was then filtered off and washed with methanol. Recrystallization from ethyl acetate gave analytically pure product (1.91 g), mp 178°-179° C.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[C:13]([C:15]1[S:16][C:17]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:18]=2[N:19]=1)#[N:14].N[C@@H:26]([C:29]([OH:31])=[O:30])[CH2:27][SH:28]>>[OH:12][C:10]1[CH:9]=[CH:8][C:6]2[N:7]=[C:3]([CH:1]3[N:2]=[C:26]([C:29]([OH:31])=[O:30])[CH2:27][S:28]3)[S:4][C:5]=2[CH:11]=1.[NH2:24][C:22]1[CH:21]=[CH:20][C:18]2[N:19]=[C:15]([CH:13]3[N:14]=[C:26]([C:29]([OH:31])=[O:30])[CH2:27][S:28]3)[S:16][C:17]=2[CH:23]=1
Reactant: N[C@H](CS)C(=O)O
Reactant: N#Cc1nc2ccc(N)cc2s1
Reactant: N#Cc1nc2ccc(O)cc2s1
Product: Nc1ccc2nc(C3N=C(C(=O)O)CS3)sc2c1
Product: O=C(O)C1=NC(c2nc3ccc(O)cc3s2)SC1

Procedure:
While 2-cyano-6-hydroxybenzothiazole or 2-cyano-6-aminobenzothiazole do not react with luciferase to generate light, both compounds readily cyclize with D-cysteine to form 2-(6-hydroxybenzo[d]thiazol-2-yl)-2,5-dihydrothiazole-4-carboxylic acid (D-luciferin) or 2-(6-aminobenzo[d]thiazol-2-yl)-2,5-dihydrothiazole-4-carboxylic acid (aminoluciferin), respectively, which do generate light when reacted with luciferase, e.g., at thermostable firefly luciferase. The assays can be performed at a pH of 4-9 with 1-100 μM derivative. Numerous non-luciferase enzymes may be detected and/or their activity measured in a bioluminescent assay using these derivatives.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]2[N:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.Cl.Cl.[F:54][C:55]1[CH:56]=[C:57]([C@H:62]2[CH2:66][CH2:65][CH2:64][NH:63]2)[C:58]([CH3:61])=[N:59][CH:60]=1>CN(C=O)C>[F:54][C:55]1[CH:56]=[C:57]([C@H:62]2[CH2:66][CH2:65][CH2:64][N:63]2[C:2]2[CH:7]=[CH:6][N:5]3[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]3[N:3]=2)[C:58]([CH3:61])=[N:59][CH:60]=1
Reactant: Cc1ncc(F)cc1[C@H]1CCCN1
Reactant: CCOC(=O)c1cnn2ccc(O)nc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3C)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
To a solution of ethyl 5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (Preparation B, Step A, 372 mg, 1.8 mmol) in DMF (10 mL) was added (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (874 mg, 1.98 mmol). The mixture was stirred at ambient temperature for 10 minutes then treated with DIEA (1.57 mL, 8.99 mmol) and (R)-5-fluoro-2-methyl-3-(pyrrolidin-2-yl)pyridine dihydrochloride (455 mg, 1.80 mmol). After stirring at ambient temperature for 4 hours the mixture was partitioned between 10% citric acid (50 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×30 mL). The combined organic phases were washed successively with water (30 mL), saturated NaHCO3 (30 mL), water (30 mL) and brine (2×30 mL), then dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 1% MeOH/DCM to afford the product as white foam (480 mg, 72% yield). MS (apci) m/z=370.0 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[N:27]1([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(#N)C>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([N:7]2[C:3]([CH2:2][N:30]3[CH2:29][CH2:28][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:32][CH2:31]3)=[N:4][N:5]=[N:6]2)=[CH:9][C:10]=1[C:16]([F:19])([F:18])[F:17])#[N:13]
Reactant: N#Cc1ccc(-n2nnnc2CCl)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2nnnn2-c2ccc(C#N)c(C(F)(F)F)c2)CC1
Temperature: 120 °C
Yield: 60.8 %

Procedure:
To a solution of 4-[5-(chloromethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Intermediate 24, 575 mg, 2.00 mmol) in acetonitrile (10 mL) was added triethylamine (0.558 mL, 4.00 mmol) and 1,1-dimethylethyl 1-piperazinecarboxylate (410 mg, 2.20 mmol). The mixture was then heated to 120° C. for 20 min in a microwave reactor. The crude product was purified by silica chromatography (Biotage SP4, 40+S), eluting with 30% ethyl acetate in hexane (2 column volumes) then a gradient from 30-60% ethyl acetate in hexane (10 CV) then 60% ethyl acetate in hexane (2 column volumes). The relevant fractions were evaporated under vacuum to leave a white solid, 1,1-dimethylethyl 4-({1-[4-cyano-3-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl)-1-piperazinecarboxylate (532 mg).
Reaction SMILES: [C:1](=[O:4])([OH:3])[O-:2].[Na+:5]>O>[C:1](=[O:3])=[O:2].[C:1](=[O:2])([O-:4])[O-:3].[Na+:5].[Na+:5]
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C([O-])[O-]
Product: O=C=O

Procedure:
U.S. Pat. No. 3,113,834 to Beecher et al. discloses a process for producing dense soda ash which includes the steps of decomposing a sodium bicarbonate solution by heating it to its boiling point while it is under pressure in excess of atmospheric. Beecher et al. discloses temperatures for decomposing sodium bicarbonate solutions between 150° C. to about 250° C. at super atmospheric pressure. U.S. Pat. No. 3,451,767 to Saeman et al. also discloses a method of making dense soda ash by decomposing a sodium bicarbonate solution at 150° to 250° C. and at 80 to 500 psia (pounds per square inch absolute) to form water, carbon dioxide, and anhydrous sodium carbonate. According to the Saeman process, sodium bicarbonate is mixed with a recycle stream containing suspended sodium carbonate seed crystals, a step not disclosed in Beecher. Similarly, Fujita et al. discloses a process for preparing sodium carbonate anhydride by countercurrent contacting of high pressure steam and a suspension of sodium bicarbonate or sodium sesquicarbonate in a concentrated solution of sodium carbonate at temperatures above 150° C.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]([F:13])[C:5]([F:12])=[C:6]([C:10]#[N:11])[C:7]=1[C:8]#[N:9].[F:15][C:16]1[C:21]([OH:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([OH:25])[C:17]=1[F:26].[Na][Na].C[N:30]([CH3:32])C>>[C:8]([C:7]1[C:2]([F:1])=[C:3]([C:4]([F:13])=[C:5]([F:12])[C:6]=1[C:10]#[N:11])[O:22][C:21]1[C:16]([F:15])=[C:17]([F:26])[C:18]([O:25][C:3]2[C:4]([F:13])=[C:5]([F:12])[C:6]([C:10]#[N:11])=[C:7]([C:32]#[N:30])[C:2]=2[F:1])=[C:19]([F:24])[C:20]=1[F:23])#[N:9]
Reactant: CN(C)C
Reactant: Oc1c(F)c(F)c(O)c(F)c1F
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1C#N
Agent: [Na][Na]
Product: N#Cc1c(F)c(F)c(Oc2c(F)c(F)c(Oc3c(F)c(F)c(C#N)c(C#N)c3F)c(F)c2F)c(F)c1C#N

Procedure:
More specifically, in Reaction Scheme-7, tetrafluorophthalonitrile and tetrafluorohydroquinone (or its metal salts, e.g., disodium salt) are reacted usually in the presence of a base (for example, trimethylamine, etc.) in a polar solvent at 0 to 5° C. for 30 minutes to obtain 1,4-bis(3,4-dicyanotrifluorophenoxy)tetrafluorobenzene, which is then hydrolyzed, for example, in an aqueous 60% sulfuric acid solution at 150° C. for 15 hours to obtain 1,4-bis(3,4-dicarboxytrifluorophenoxy)tetrafluorobenzene. Refluxing the product in acetic anhydride for 2 hours results in dehydration to give 1,4-bis(3,4-dicarboxytrifluorophenoxytetrafluorobenzene dianhydride. Also, 1,4-bis(3,4-dicyanotrifluorophenoxy)tetrafluorobenzene may be heated, for example, in an aqueous 80% sulfuric acid solution at 200° C. for 2 hours to effect hydrolysis and dehydration in one step to obtain 1,4-bis(3,4-dicarboxytrifluorophenoxytetrafluorobenzene dianhydride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[N:12]1C2C(=CC=CC=2)C=C(B(O)O)C=1.Br[C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[C:28]1([C:60]3[C:51](=[CH:52][C:53]4[O:58][CH2:57][CH2:56][O:55][C:54]=4[CH:59]=3)[O:50][CH2:49]1)[C:29](=[O:48])[N:30]2[CH:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44]C=1)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:26]2[CH:34]=[CH:33][CH:32]=[C:31]3[C:27]=2[C:28]2([C:60]4=[CH:59][C:54]5[O:55][CH2:56][CH2:57][O:58][C:53]=5[CH:52]=[C:51]4[O:50][CH2:49]2)[C:29](=[O:48])[N:30]3[CH2:35][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][N:12]=2)=[CH:5][CH:4]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Reactant: OB(O)c1cnc2ccccc2c1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cccc3c2C2(COc4cc5c(cc42)OCCO5)C(=O)N3Cc2ccccn2)cc1

Procedure:
Following the procedure as described in EXAMPLE 2.46 and making non-critical variations using 4-methoxyphenyl boronic acid to replace quinolin-3-ylboronic acid, and 4′-bromo-1-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 4′-(4-methoxyphenyl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one was obtained (68%) as a colorless solid: mp 205-206° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.59 (d, J=4.7 Hz, 1H), 7.65-7.68 (m, 1H), 7.32-7.17 (m, 3H), 6.91-6.84 (m, 2H), 6.78-6.61 (m, 4H), 6.41 (s, 1H), 6.25 (s, 1H), 5.26 (d, J=15.8 Hz, 1H), 4.92 (d, J=15.8 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.36 (d, J=9.0 Hz, 1H), 4.27-4.08 (m, 4H), 3.77 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.3, 158.9, 155.6, 155.5, 149.5, 144.6, 142.6, 140.0, 137.9, 137.1, 130.9, 129.8, 129.0, 128.7, 125.7, 122.9, 122.8, 121.7, 113.2, 111.1, 108.5, 99.4, 64.6, 64.0, 58.5, 55.3, 46.2; MS (ES+) m/z 493.0 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH:9][CH:10]=[O:11])=[C:4]([Cl:12])[N:3]=1.[NH2:13][CH2:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:25][CH2:24][CH2:23][C:22]2=[O:26])[CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CC(O)C>[NH2:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]([NH:9][CH:10]=[O:11])=[C:6]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]([N:21]3[CH2:25][CH2:24][CH2:23][C:22]3=[O:26])[N:20]=2)[N:7]=1
Reactant: Nc1nc(Cl)c(NC=O)c(Cl)n1
Reactant: NCc1cccc(N2CCCC2=O)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Nc1nc(Cl)c(NC=O)c(NCc2cccc(N3CCCC3=O)n2)n1
Yield: 54.1 %

Procedure:
A mixture of N-(2-amino-4,6-dichloropyrimidin-5-yl)formamide (3.61 g, 17.43 mmol) and 1-(6-aminomethylpyridin-2-yl)pyrrolidin-2-one (containing triphenylphosphine oxide) (10.00 g, ca. 50 mmol) and triethylamine (4.86 mL, 34.86 mmol) in propan-2-ol (100 mL) was heated at reflux for 18 h, cooled and the resulting precipitate filtered to give the title compound (3.41 g) as an off-white solid; NMR δH (400 MHz, d6-DMSO) 9.21 (1H, s), 8.20 (1H, d, J 1 Hz), 8.12 (1H, d, J 8.5 Hz), 7.73 (1H, t, J 7.5 Hz), 7.38 (1H, t, J 6 Hz), 7.02 (1H, d, J 7.5 Hz), 6.45 (2H, br s), 4.53 (2H, d, J 6.0 Hz), 4.00-3.95 (2H, m), 2.57 (2H, t, J 8.0 Hz) and 2.08-2.00 (2H, m).