Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[OH-].[K+].[I:15]I.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>CN(C=O)C>[I:15][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: II
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 97.2 %

Procedure:
To a solution of 5-nitro-1H-indazole (10.0 g, 62.3 mmol) in DMF (120 ml) was added potassium hydroxide (12.9 g, 230.4 mmol) followed by iodine (31.1 g, 122.6 mmol) portion wise over 5 minutes. The resulting mixture was stirred at room temperature for 14 hours and then poured onto 10% sodium metabisulfite (100 ml) and extracted into ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (50 ml), dried (Na2SO4) and concentrated in vacuo to afford the title compounds as a pale orange solid (17.5 g). 1H NMR (400 MHz, DMSO-d6) δ 7.77 (1H, d), 8.26 (1H, d), 8.34 (1H, s), 14.15 (1H, s). MS (ES+) m/e=290.
Reaction SMILES: C([O:5][C:6](=[O:26])[NH:7][C@H:8]([C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Br:25])[CH:24]=1)[C@@H:9]([C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[F:18])O)(C)(C)C.C(OC(=O)N[C@H](C1C=C(F)C=CC=1F)[C@@H](C1C=NC=C(Br)C=1)O)(C)(C)C.CC(C)([O-])C.[K+].C(OCC)(=O)C>O1CCCC1.O>[Br:25][C:23]1[CH:24]=[C:19]([C@@H:8]2[C@@H:9]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[F:18])[O:26][C:6](=[O:5])[NH:7]2)[CH:20]=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cncc(Br)c1)[C@H](O)c1cc(F)ccc1F
Agent: CC(C)(C)OC(=O)N[C@H](c1cc(F)ccc1F)[C@H](O)c1cncc(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1N[C@H](c2cncc(Br)c2)[C@@H](c2cc(F)ccc2F)O1
Temperature: -7 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
A mixture of tert-butyl((1R,2R)-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)-2-hydroxyethyl)carbamate and tert-butyl((1R,2R)-2-(5-bromopyridin-3-yl)-1-(2,5-difluorophenyl)-2-hydroxyethyl)carbamate (about 6:1 ratio) (101 g, 236 mmol) in tetrahydrofuran (590 mL) was cooled to −7° C. with a methanol/ice bath. To this mixture was added a solution of 1 M potassium tert-butoxide in tetrahydrofuran (590 mL, 590 mmol) via an addition funnel while maintaining the internal temperature <3° C. The reaction mixture was stirred with a cooling bath for 30 min and then allowed to warm up to room temperature. After 20 h, the reaction was deemed complete by LC/MS. The reaction mixture was concentrated to dryness to give crude product. Another identical scale reaction was performed. The crude products of the two batches were combined to work up together. They were treated with ethyl acetate (1.75 L) and water (1.75 L). The layers were separated. The organic layer was washed with brine (1.75 L), dried (sodium sulfate), and evaporated to give 161.5 g of crude product as a brown solid. This was purified by ISCO to give 67.1 g (42% yield). LC/MS (ES+) 355/357 (M+H, 100; Br isotope pattern); 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J=2.2 Hz, 1H), 8.53 (d, J=1.8 Hz, 1H), 7.97 (t, J=2.0 Hz, 1H), 7.29-7.23 (m, 1H), 7.18-7.09 (m, 2H), 6.40 (s, 1H), 5.56 (d, J=5.7 Hz, 1H), 4.84 (d, J=5.5 Hz, 1H); Calcd for C14H9N2BrF2O2: C, 47.34; H, 2.55; N, 7.86; Br, 22.50; F, 10.69. Found: C, 47.29; H, 2.61; N, 7.87; Br, 22.40; F, 10.37. Note: Chiral HPLC of the above sample showed 4.7% of the enantiomer. The (4S,5S) enantiomer can be purged by recrystallization from methanol to give >99.9 ee with 67% recovery.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][C:14]3[C:17]([I:20])=[N:18][NH:19][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.CS(O)(=O)=O.C(N(CC)CC)C>O1CCCC1.C(Cl)Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[N:16]=[CH:15][C:14]3[C:17]([I:20])=[N:18][N:19]([CH:22]4[CH2:23][CH2:24][CH2:25][CH2:26][O:21]4)[C:13]=3[CH:12]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: C1=COCCC1
Reactant: COc1cc(OC)cc(-c2cc3[nH]nc(I)c3cn2)c1
Agent: CS(=O)(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(OC)cc(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 90.9 %

Procedure:
A mixture of 6-(3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[4,3-c]pyridine (0.50 g, 1.3 mmol), dihydropyran (360 μL, 3.9 mmol), and methanesulfonic acid (17 μL, 0.26 mmol) in tetrahydrofuran (3 mL) and methylene chloride (7.5 mL) was stirred at 80° C. for 2 days. After cooling, to the mixture was added some triethylamine, and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford the desired product (0.55 g). LCMS (M+H)+=466.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18].C(N(CC)CC)C>C(Cl)Cl>[Cl:14][CH2:15][CH2:16][C:17]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)CCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=O)CCCl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.8 %

Procedure:
4-(t-butoxycarbonyl)piperazine (3 g, 16 mmol) was suspended in 10 mL of methylene chloride and cooled in an ice/water bath. 3-Chloropropionyl chloride (2.04 g, 16 mmol) was dissolved in 10 mL of methylene chloride and added slowly, while maintaining the internal temperature below 50° C. Triethylamine (1.63 g, 16 mmol) was then added to the cold (50° C.) solution. The solution was slowly warmed to room temperature and then stirred at room temperature overnight. The reaction mixture was diluted with 150 mL of methylene chloride and washed with 5% aqueous NaHCO3 (2×100 mL), brine (2×100 mL), dried over MgSO4, filtered, concentrated and dried under vacuum to give 3.71 g of crude product. The crude material was purified by flash chromatography on silica gel eluting with ethyl acetate to give 1.85 g (41.8%) of 1-(3-chloropropionyl)-4-(t-butoxycarbonyl)piperazine as a pale yellow solid. 1H NMR (300 MHz/CDCl3): δ 1.47 (s, 9H), 2.82 (t, 2H, J=6.95 Hz), 3.40-3.46 (m, 6H), 3.60-3.63 (m, 2H), 3.84 (t, 2 H, J=6.95 Hz); mass spectrum, m/z=283.1 (M+Li); high-resolution FAB-MS calcd for C12H21N2O3Cl1 276.1240 (M+), found 276.1227.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34](=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37])=[N:32][CH:33]=1)(C(C)(C)C)(C)C>C1COCC1>[OH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34](=[O:39])[CH2:35][CH:36]([CH3:37])[CH3:38])=[N:32][CH:33]=1
Reactant: CC(C)CC(=O)c1ccc(CO[Si](C)(C)C(C)(C)C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)CC(=O)c1ccc(CO)cn1
Reaction time: 2 h
Yield: 84.5 %

Procedure:
Add tetrabutylammonium fluoride (5.853 mL, 5.853 mmol, 1M solution in THF) to a solution of 5-(tert-butyldimethylsilyloxymethyl)-2-(3-methyl-butyryl)-pyridine (900 mg, 2.927 mmol) in anhydrous THF (30 mL) at 0° C. and stir at this temperature for 2 h. Concentrate the solvent in vacuo and purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (3:2) to provide the desired intermediate (478 mg, 84%). MS (ES+) m/z: 194 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][NH:23][CH3:24])=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26].[C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[N:38]=[C:39](OCC)[CH3:40])#[N:31].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:18])[NH:11][C:10]([CH2:19][O:20][CH2:21][CH2:22][N:23]([CH3:24])[C:39](=[N:38][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[C:30]#[N:31])[CH3:40])=[C:9]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(C)=Nc1ccccc1C#N
Reactant: CCOC(=O)C1=C(COCCNC)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(COCCN(C)C(C)=Nc2ccccc2C#N)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 150 °C
Yield: 28.8 %

Procedure:
A mixture of 4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2-(2-methylaminoethoxymethyl)-1,4-dihydropyridine (2.5 g.), ethyl N-(2-cyanophenyl)acetimidate (1.1 g.) and p-toluenesulphonic acid (0.1 g.) was heated at 150° C. for 4 hours, cooled, and then dissolved in chloroform. The solution was washed with sodium bicarbonate solution, water and dried over sodium sulphate. Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with chloroform/hexane (1:1) gave the product as an oil (0.95 g.) which was used directly in the next stage.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21].BrC1C=CC=CC=1>CCOCC>[F:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[O:21][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: Clc1ncnc2[nH]ccc12
Solvent: CCOCC
Solvent: Brc1ccccc1
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]ccc23)c(F)c1
Temperature: 130 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
To a sealed tube equipped with a magnetic stir bar was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 6.5 mmol, 1.0 eq.), 2-Fluoro-4-nitro-phenol (1.5 g, 9.5 mmol, 1.5 eq) and bromobenzene (5 ml). The mixture was stirred at 130° C. for 4 hours. The reaction mixture was then cooled to room temperature and ether was added (5 ml). After addition of ether the resulting precipitate was filtered and washed with ether. The product was recrystallized from methanol to give 4-(2-fluoro-4-nitro-phenoxy)-7H-pyrrolo[2,3-d]pyrimidine as an off white solid. (1.6 g, 89% yield). 1H NMR (400 MHz, DMSO): 12.44 (s, 1H), 8.41(dd, 1H), 8.34 (s, 1H), 8.24 (m, 1H), 7.80 (m, 1H), 7.61 (m, 1H), 6.69 (d, 1H); MS (ESI) for C12H7FN4O3: 275 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH2:10]([N:13]1[C:22](=[O:23])[C:21]2[NH:20][C:19]([C:24]3[N:28]([CH3:29])[N:27]=[C:26]([O:30][CH2:31][C:32](O)=[O:33])[CH:25]=3)=[N:18][C:17]=2[N:16]([CH2:35][CH2:36][CH3:37])[C:14]1=[O:15])[CH2:11][CH3:12]>>[CH3:37][CH2:36][CH2:35][N:16]1[C:14](=[O:15])[N:13]([CH2:10][CH2:11][CH3:12])[C:22](=[O:23])[C:21]2[C:17]1=[N:18][C:19]([N:20]=2)=[C:24]1[N:28]([CH3:29])[NH:27][C:26]([O:30][CH2:31][C:32]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)=[O:33])=[CH:25]1
Reactant: CCCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CCC)c1=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: CCCn1c(=O)c2c(n(CCC)c1=O)=NC(=C1C=C(OCC(=O)Nc3ccc(Cl)c(Cl)c3)NN1C)N=2

Procedure:
Using 3,4-dichloroaniline and 2-[5-(1,3-dipropyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid (Example 36), according to the method described in Example 36.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:15]=[C:14]([O:16][CH:17]2[CH2:35][CH:34]3[N:19]([C:20](=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][CH:29]4[C:31]([C:37]([OH:39])=O)([NH:32][C:33]3=[O:36])[CH2:30]4)[CH2:18]2)[C:13]2[C:8](=[C:9]([CH3:43])[C:10]([O:41][CH3:42])=[CH:11][CH:12]=2)[N:7]=1.C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:85][S:86]([CH:89]6[CH2:91][CH2:90]6)(=[O:88])=[O:87])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:15]=[C:14]([O:16][CH:17]2[CH2:35][CH:34]3[N:19]([C:20](=[O:40])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH:28][CH:29]4[C:31]([C:37]([NH:85][S:86]([CH:89]5[CH2:91][CH2:90]5)(=[O:88])=[O:87])=[O:39])([NH:32][C:33]3=[O:36])[CH2:30]4)[CH2:18]2)[C:13]2[C:8](=[C:9]([CH3:43])[C:10]([O:41][CH3:42])=[CH:11][CH:12]=2)[N:7]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nccs3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nccs3)nc2c1C

Procedure:
The title compound was prepared from 18-[2-(thiazol-2-yl)-7-methoxy-8-methyl-quinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid 25 following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo-[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=708 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH2:21][OH:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6]>C(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH:21]=[O:22])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=1)=[O:6]
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)c1ccc(CO)c(Br)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
MnO2 (8.0 equiv.) was added into a solution of 3-bromo-4-(hydroxymethyl)-N-(3-(trifluoromethyl)phenyl)benzamide (1.0 equiv.) in DCM (0.14 M). The suspension was stirred at rt for 1 hr. The mixture was filtered over celite and concentrated to yield 3-bromo-4-formyl-N-(3-(trifluoromethyl)phenyl)benzamide in 100% yield. LC/MS (m/z)=373.9 (MH+), Rt=0.0.94 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH2:23])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[C:32]1([C:38](Cl)=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:38](=[O:39])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c(-c3ccnc(N)n3)cc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2[nH]c(-c3ccnc(NC(=O)c4ccccc4)n3)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-(2-Amino-pyrimidin-4-yl)-4-oxo-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester and Et3N (4 eq.) in dry THF, PhCOCl (2 eq.) was added and the mixture was stirred at room temperature under argon overnight. Thus NaOH(1N) was added; after 30′ the solvent was evaporated and the residue was dissolved in water and the aqueous phase was extracted with AcOEt (2×). The organic phase was then washed with aq. NH4Cl and dried over Na2SO4. After solvent evaporation the crude product was purified by flash chromatography (CH2Cl2:MeOH 97:3) to give the pure product as a solid.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1O.CN(C)C=O.C1(OC(=O)OC2C=CC=CC=2)C=CC=CC=1.C(=O)=O>C(=O)(O)[O-].[Na+].CCOCC>[CH:16]1[C:14](=[O:15])[N:13]=[C:11]2[N:10]([CH:1]3[O:9][CH:6]([CH2:7][OH:8])[CH:4]([OH:5])[CH:2]3[O:12]2)[CH:17]=1
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: O=C(Oc1ccccc1)Oc1ccccc1
Agent: O=C([O-])O
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=c1ccn2c(n1)OC1C(O)C(CO)OC12
Yield: 79.6 %

Procedure:
Uridine (10 g, 0.04 mole) was dissolved in 20 ml of warm, dry dimethylformamide, and 11.4 g of diphenylcarbonate (0.06 m) and 0.2 g of sodium bicarbonate were added. The solution was stirred and heated at 150° C. until evolution of carbon dioxide ceased (30 min approx). After cooling the solution was poured into 200 ml of ether with rapid stirring. The resulting solid was filtered off, washed with ether, and recrystallised from methanol to give 7.2 g (80%) of the title compound, as white crystals, melting at 235°-40° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12](Cl)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2.C1(O)C=CC=CC=1.[CH2:26]([N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)[CH3:27]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]([NH:34][CH:31]1[CH2:32][CH2:33][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30]1)=[C:11]1[C:6]([CH:7]=[CH:8][C:9]([O:17][CH3:18])=[CH:10]1)=[N:5]2
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2c1
Reactant: CCN1CCC(N)CC1
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: CCN1CCC(Nc2c3ccc(Cl)cc3nc3ccc(OC)cc23)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 6,9-dichloro-2-methoxyacridine (100 mg, 0.36 mmol) and phenol (approximately 1.5 g) was heated to 100° C. under nitrogen atmosphere and stirred for 1 hour. 1-Ethylpiperidin-4-amine (92 mg, 0.72 mmol) was added to the mixture. The reaction was stirred at 100° C. for 5 hours, cooled to 20-25° C., and diluted with dichloromethane. The mixture was washed twice with sodium hydroxide solution (1 N) and twice with ammonium chloride solution. The phases were separated, and the organic layer was dried and concentrated. The residue was purified by Biotage column chromatography using triethylamine (5%) and methanol (5 to 15%) in dichloromethane to give the title compound; MS (Found: M+1=370).
Reaction SMILES: C(OC([CH2:8][NH:9][C:10]1[CH:15]=[C:14]([C:16]2[C:17]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:18][N:19]([C:21]3[N:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=3)[CH:20]=2)[CH:13]=[CH:12][N:11]=1)=O)(C)(C)C.C([O:39]C(NC1C=C(C2C(C3C=CC(F)=CC=3)=NN(C3N=NC(Cl)=CC=3)C=2)C=CN=1)=O)(C)(C)C>>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:17]2[C:16]([C:14]3[CH:13]=[CH:12][N:11]=[C:10]([NH:9][CH3:8])[CH:15]=3)=[CH:20][N:19]([C:21]3[CH:26]=[CH:25][C:24](=[O:39])[NH:23][N:22]=3)[N:18]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)CNc1cc(-c2cn(-c3ccc(Cl)nn3)nc2-c2ccc(F)cc2)ccn1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc(Cl)nn3)nc2-c2ccc(F)cc2)ccn1
Product: CNc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccc(F)cc2)ccn1
Yield: 89 %

Procedure:
The reaction was carried out in the same manner as in Example 2-4) except for using 330 mg (0.69 mmol) of 4-{2-[(t-butoxycarbonyl)methylamino]pyridin-4-yl}-1-(6-chloropyridazin-3-yl)-3-(4-fluorophenyl)-1H-pyrazole obtained in Example 3-1) in place of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-1-(6-chloropyridazin-3-yl)-3-(4-fluorophenyl)-1H-pyrazole to obtain 222 mg of the title compound as a pale beige powder. (Yield: 89%)
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([O:6]C)=O.[CH3:10][O:11][CH2:12][CH2:13][NH2:14]>>[OH:1][CH2:2][C:3]([CH3:9])([CH3:8])[C:4]([NH:14][CH2:13][CH2:12][O:11][CH3:10])=[O:6]
Reactant: COC(=O)C(C)(C)CO
Reactant: COCCN
Product: COCCNC(=O)C(C)(C)CO
Yield: 100 %

Procedure:
Prepared as in Example 215d (Method A) from methyl 3-hydroxy-2,2-dimethylpropanoate and 2-methoxyethanamine in 100% yield. MS 176 (MH+).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:12])([F:11])[C:5]([O:7][CH2:8][CH2:9]Cl)=[O:6]>CS(C)=O>[F:3][C:4]([F:12])([F:11])[CH:5]1[O:7][CH2:8][CH2:9][O:6]1
Reactant: O=C(OCCCl)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: FC(F)(F)C1OCCO1
Reaction time: 8 h
Yield: 29.9 %

Procedure:
This example illustrates a process of the invention only. A suspension of 9.6 g (0.20 mol) of 50% NaH in mineral oil in 150 mL of DMSO was stirred at 15°-20° while 35.4 g (0.20 mol) of 2-chloroethyl trifluoroacetate were added dropwise. The resulting mixture was stirred overnight while the reaction temperature was maintained below 30°. The reaction mixture was then heated to 50° at 0.33 kPa (2.5 mm) to drive off volatile products which were recovered. Fractionation of the volatiles gave 8.5 g (30% yield) of 2-trifluoromethyl-1,3-dioxolane, b.p. 87°-93°. IR (CCl4): 3300 and 2910 (sat'd CH), 1200-1100 cm-1 (CF, C--O). NMR (CCl4): 1H 5.13 (q, JHF 4 Hz, 1H, CH) and 4.07 ppm (s, 4H, ring OCH2).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:14]([NH2:15])=[CH:13][C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([F:34])=[CH:30][C:31]=2[F:33])[N:26]=[C:25]([C:35]2[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=2)[C:24]=1[CH3:42].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[F:33][C:31]1[CH:30]=[C:29]([F:34])[CH:28]=[C:27]2[C:32]=1[C:23]([NH:15][C:14]1[C:9]([C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:10][CH:11]=[C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=1)=[C:24]([CH3:42])[C:25]([C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1)=[N:26]2
Reactant: COc1ccc(-c2ncc(N3CCOCC3)cc2N)cn1
Reactant: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ncc(N3CCOCC3)cc2Nc2c(C)c(-c3cc(C)ccn3)nc3cc(F)cc(F)c23)cn1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
A mixture of 6′-methoxy-5-morpholino-2,3′-bipyridin-3-amine (51.7 mg, 0.18 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (45.2 mg, 0.15 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (12.6 mg, 0.026 mmol), tris(dibenzylideneacetone)dipalladium (0) (6.4 mg, 6.99 μmol), and sodium tert-butoxide (36.6 mg, 0.38 mmol) in dry toluene (1.5 mL) was degassed by nitrogen. The resulting reaction was heated to 100° C. and monitored with TLC and LC-MS. After 18 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (5-50% EtOAc in hexanes) to afford an impure orange residue. The light orange film was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 5,7-difluoro-N-(6′-methoxy-5-morpholino-2,3′-bipyridin-3-yl)-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.65 (1H, dd, J=2.4, 0.7 Hz), 8.54 (1H, dd, J=4.9, 0.6 Hz), 8.08 (2H, m), 7.71 (1H, m), 7.61 (1H, ddd, J=9.7, 2.4, 1.4 Hz), 7.20 (1H, ddd, J=5.0, 1.6, 0.8 Hz), 7.00 (3H, m), 6.53 (1H, d, J=2.5 Hz), 4.00 (3H, s), 3.92 (4H, m), 3.25 (4H, m), 2.49 (3H, s), 2.21 (3H, s). Mass Spectrum (pos.) m/e: 555.2 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[C:12]([O:17][CH2:18][CH2:19][N:20]=[C:21]=[O:22])(=[O:16])[C:13]([CH3:15])=[CH2:14].[N-]=C=O>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1(C)C=CC=CC=1>[CH3:15][C:13](=[CH2:14])[C:12]([O:17][CH2:18][CH2:19][NH:20][C:21]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2])=[O:22])=[O:16]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: C=C(C)C(=O)OCCN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: [N-]=C=O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OCCNC(=O)OCc1ccccc1[N+](=O)[O-]

Procedure:
A monomer was prepared by adding 14.4 g 2-nitrobenzyl alcohol (Alfa Aesar, Ward Hill, Mass.), 14.6 g isocyanatoethyl methacrylate (Aldrich, Milwaukee, Wis.), and 1 drop of dibutyltin dilaurate (Alfa Aesar, Ward Hill, Mass.) to a 4-ounce jar. The jar was sealed and placed in a 70° C. oven for 2 hours. The resulting reaction mixture was analyzed by infrared spectroscopy (Nexus 670 FT-IR E.S.P.; Thermo Nicolet Corporation; Madison, Wis.) which showed no absorbance at 2250 cm−1, indicating substantially no remaining isocyanate functionality. The reaction mixture was cooled and 40 mL of toluene were added to it. The jar was then capped and refrigerated overnight. The next day, the white crystals that had separated were filtered off and dried to produce 26.9 g of NBMA. NMR and IR spectral analyses confirmed the structure of the product.