Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([F:23])[C:19]([NH2:20])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2].N1C=CC=CC=1.C1(C)C=CC=CC=1.Cl[C:38]([O:40][CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:39]>ClCCl>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH3:14])[O:7][C@H:6]1[N:15]1[CH:22]=[C:21]([F:23])[C:19]([NH:20][C:38]([O:40][CH2:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:39])=[N:18][C:16]1=[O:17])(=[O:3])[CH3:2]
Reactant: CC(C)(C)COC(=O)Cl
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(F)c(N)nc1=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1cc(F)c(NC(=O)OCC(C)(C)C)nc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5'-Deoxy-2',3'-di-O-acetyl-5-fluorocytidine (1.5 g) and dry pyridine (0.74 ml) were dissolved in dry dichloromethane (15 ml). To the mixture, toluene solution of neopentyl chloroformate (3 eq.) was added dropwise at 0° C., and stirred at room temperature for 1 hour. After the solvent was removed under reduced pressure, the residue was partitioned between ether and saturated aqueous solution of sodium carbonate. The organic layer was successively washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 2',3'-di-O-acetyl-5'-deoxy-5-fluoro-N4 (neopentyloxycarbonyl)cytidine as pale yellow oil. This crude product was dissolved in ethanol (15 ml) and cooled on ice-bath. Then 1N aqueous sodium hydroxide solution was added dropwise while maintaining the temperature below 15° C. After the addition was completed, the reaction mixture was neutralized with concentrated. hydrochloric acid at 0° C. The solution was concentrated under reduced pressure, and the concentrate was partitioned between water and a mixed solution of CH2Cl 2 /MeOH (95:5). The aqueous layer was back-extracted with CH2Cl2 /MeOH (95:5) ten times (20 ml each). All organic layers were combined, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using CH2Cl2 /MeOH (20:1) as an eluent to give 5'-deoxy-5-fluoro-N4 -(neopentyloxycarbonyl)cytidine (1.37 g: 84% yield) as amorphous powder: FAB-MS m/z 360 (MH+); 1H-NMR (d6 -DMSO) δ0.93 (9H, s), 1.31 (3H, d,J=6.3 Hz), 3.68 (1H,q,J=5.9 Hz), 3.81 (2H, br. s), 3.87-3.92 (1H, m), 4.04-4.09 (1H, m), 5.05 (1H,d,J=5.9 Hz), 5.41 (1H, br. d, J=5.3 Hz), 5.67 (1H,dd,J=1.3, 3.6 Hz), 8.04 (1H, br. s), 10.53 (~1H, br. s).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][CH:49]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH:67]([C:69]1[CH:83]=[CH:82][C:72]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[CH:71][CH:70]=1)=O>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][CH:49]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:67]([C:69]3[CH:83]=[CH:82][C:72]([CH2:73][NH:74][C:75](=[O:81])[O:76][C:77]([CH3:80])([CH3:78])[CH3:79])=[CH:71][CH:70]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCC(Oc3ccccc3)CC2)c1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3c(N4CCC(Oc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 26.4 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-phenoxypiperidin-1-yl)pyridin-2-amine (75 mg, 0.19 mmol), DMF (0.20 mL), ethanol (1.00 mL), 1M Na2S2O4 (3 eq, 0.58 mmol, 0.58 mL) and tert-butyl N-(4-formylbenzyl)carbamate (1.1 eq, 0.21 mmol, 49 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (29 mg, 20%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.41 (s, 9H, C(CH3)3), 1.84-1.90 (m, 2H, 2× piperidine CHAHB), 2.16-2.19 (m, 2H, 2× piperidine CHAHB), 3.59-3.64 (m, 2H, 2× piperidine NCHAHA), 3.87-3.91 (m, 2H, 2× piperidine NCHAHA), 4.19 (d, J=5.9 Hz, 2H, CH2NH), 4.70 (septet, J=3.9 Hz, 1H, piperidine CH), 6.94 (t, J=7.3 Hz, 1H, phenyl H-4), 7.04 (d, J=7.8 Hz, 2H, phenyl H-3′ & H-5′), 7.31 (dd, J=8.6, 7.4 Hz, 2H, phenyl H-3 & H-5), 7.40 (d, J=8.3 Hz, 2H, phenyl H-2 & H-6), 8.13 (d, J=8.1 Hz, 2H, phenyl H-2′ & H-6′), 8.24 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.45 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][NH:21][CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1.C(#N)C.C([O-])([O-])=O.[K+].[K+].FC(F)(F)S(O[CH2:44][C:45]([F:48])([F:47])[F:46])(=O)=O>O>[CH3:2][N:3]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([C:19]4([CH2:23][C:24]#[N:25])[CH2:22][N:21]([CH2:44][C:45]([F:48])([F:47])[F:46])[CH2:20]4)[CH:18]=3)[N:11]3[CH:26]=[CH:27][N:28]=[C:10]3[CH:9]=2)[CH:5]=[N:4]1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(CC(F)(F)F)C4)c3)n2)cn1
Temperature: 45 °C
Yield: 45.3 %

Procedure:
To a solution of 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (Example 62; 50 mg, 0.12 mmol) in acetonitrile (1.2 mL, 0.12 mmol) was added K2CO3 (48 mg, 0.35 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (30 mg, 0.13 mmol). The reaction mixture was heated to 45° C. for 15 hours, then cooled. After diluting in water, the mixture was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. Purification of the crude material by reverse phase HPLC using a 0-100% acetonitrile/water gradient afforded 2-(3-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoro ethyl)azetidin-3-yl)acetonitrile (24 mg, 48.0% yield). MS (apci) m/z=442.2 (M+H).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].N1C=CC=CC=1.C(Cl)Cl.[C:20]([O:24][C:25](=[O:34])[NH:26][CH:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1)([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[C:5]1([O:4][C:2](=[O:3])[NH:33][CH:30]2[CH2:31][CH2:32][CH:27]([NH:26][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:34])[CH2:28][CH2:29]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(N)CC1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NC1CCC(NC(=O)Oc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Phenyl chloroformate (1 eq.) is added dropwise to a solution of pyridine/DCM. The reaction mixture is cooled to 0° C. and a solution of (4-amino-cyclohexyl)-carbamic acid tert-butyl ester (1 eq.) in DCM is added dropwise. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is partitioned between (0.2 M) HCl(aq) and DCM. The organics are washed with water, saturated sodium hydrogen carbonate solution and brine. The combined organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound.
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([S:16](Cl)(=[O:18])=[O:17])[CH:11]=3)[C:6](=[O:20])[C:5]=2[CH:4]=[CH:3][C:2]=1[S:21](Cl)(=[O:23])=[O:22].C([N:28]([CH:31]([CH3:33])C)[CH2:29][CH3:30])(C)C>C(Cl)Cl>[N:28]1([S:21]([C:2]2[CH:3]=[CH:4][C:5]3[C:6](=[O:20])[C:7]4[C:12](=[CH:11][C:10]([S:16]([N:28]5[CH2:29][CH2:30][CH2:5][CH2:4][CH2:3][CH2:33][CH2:31]5)(=[O:18])=[O:17])=[CH:9][CH:8]=4)[C:13](=[O:15])[C:14]=3[CH:1]=2)(=[O:23])=[O:22])[CH2:31][CH2:33][CH2:14][CH2:1][CH2:2][CH2:30][CH2:29]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C1c2ccc(S(=O)(=O)Cl)cc2C(=O)c2cc(S(=O)(=O)Cl)ccc21
Solvent: ClCCl
Product: O=C1c2ccc(S(=O)(=O)N3CCCCCCC3)cc2C(=O)c2cc(S(=O)(=O)N3CCCCCCC3)ccc21
Temperature: -50 °C
Reaction time: 4 h
Yield: 91 %

Procedure:
Anthraquinone-2,7-disulfonylchloride (1215 mg, 3 mmole) was dissolved in 100 mL DCM. The solution was cooled to −50° C. To this solution was added 1 mL (8 mmole) of heptamethyleneimine, followed by 1 mL of diisopropylethylamine. The reaction mixture was stirred at room temperature for 4 hrs. Solvent was evaporated and the residue was treated with 1N HCl, filtered off, washed with water and dried. Crude material was crystallized from chloroform-hexane to give 1.014 g (91%) of yellow compound 1-27. H1-NMR (CDCl3): 8.70 (2H, d, C1 and C8), 8.47 (2H, d, C4 and C5), 8.22 (2H, dd, C3 and C6), 3.22 (8H, m), 1.70 (20H, m).
Reaction SMILES: S(Cl)(Cl)=O.COC1C=CC=CC=1CCC(O)=O.C1(CCCC(Cl)=O)C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][C:41]=1[O:42][CH3:43])[N:38]=[CH:37][N:36]=[C:35]2[O:44][C:45]1[CH:51]=[CH:50][C:48]([NH2:49])=[CH:47][CH:46]=1.[CH3:52][O:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=1[CH2:60][CH2:61][C:62]([N:64]=[C:65]=[S:66])=[O:63]>C1(C)C=CC=CC=1.C(O)C>[CH3:30][O:31][C:32]1[CH:33]=[C:34]2[C:39](=[CH:40][C:41]=1[O:42][CH3:43])[N:38]=[CH:37][N:36]=[C:35]2[O:44][C:45]1[CH:51]=[CH:50][C:48]([NH:49][C:65]([NH:64][C:62](=[O:63])[CH2:61][CH2:60][C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][C:54]=2[O:53][CH3:52])=[S:66])=[CH:47][CH:46]=1
Reactant: COc1ccccc1CCC(=O)N=C=S
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: COc1ccccc1CCC(=O)O
Agent: O=C(Cl)CCCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccccc1CCC(=O)NC(=S)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 3-(2-methoxyphenyl)propanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 3-(2-methoxyphenyl)propanoyl isothiocyanate was prepared using the resultant 4-phenylbutanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(2-methoxyphenyl)propanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (37 mg, yield 43%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH3:16])=[O:10])=[CH:4][C:3]=1[CH:17]=O.[NH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(Cl)Cl.CCOCC>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:15]=[CH:14][O:13][C:12]=2[CH3:16])=[O:10])=[CH:4][C:3]=1[CH:17]=[N:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: Cc1occc1C(=O)Nc1ccc(Cl)c(C=O)c1
Reactant: NN1CCOCC1
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: Cc1occc1C(=O)Nc1ccc(Cl)c(C=NN2CCOCC2)c1
Reaction time: 8 h
Yield: 87.2 %

Procedure:
To a chilled suspension of N-(4-chloro-3-formylphenyl)-2-methyl-3-furancarboxamide (2.0 g) in methanol (30 ml) was added 4-aminomorpholine (0.8 g). The resultant reaction mixture was stirred overnight. TLC analysis (methlyenechloride:ether, 5:1) of the reaction mixture showed a new spot and traces of substrate. The reaction mixture was stirred for another hour at 30° C. and then the reaction mixture was poured into water and extracted into ether/ethyl acetate. The extract was washed with water, dried (MgSO4), filtered, and evaporated to leave a solid. The solid was then covered with ether/ligroin and stirred for several hours and then collected on a filter to give 2.3 g of N-[4-chloro-3-[(4-morpholinylimino)methyl]phenyl]-2-methyl-3-furancarboxamide as an off-white solid, mp 121-123° C.
Reaction SMILES: [N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:4][CH:3]=[N:2]1.C([BH3-])#N.[Na+]>C(O)(=O)C.CCOC(C)=O.C([O-])([O-])=O.[Na+].[Na+]>[N:1]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:5]([C:6]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7])[CH2:4][CH2:3][NH:2]1
Reactant: CC(C)(C)OC(=O)C1CC=NN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)C1CCNN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
Di-tert-butyl 4,5-dihydropyrazole-1,5-dicarboxylate (12.65 g, 46.8 mmol) was dissolved in acetic acid (69.2 ml), and the solution was cooled in a water bath. Sodium cyanoborohydride (5.88 g, 94 mmol) was added portionwise under N2. The reaction was stirred at 25° C. for 5 hrs. The solvent was then removed under reduced pressure to give a residue. The residue was diluted with EtOAc (150 mL), and Na2CO3 (sat.) (100 mL) was cautiously added to the solution. The layers were separated and the aq. solution was extracted with EtOAc (2×30 mL), and the organics were dried over Na2SO4. The solvent was removed under reduced pressure to give the crude product di-tert-butyl pyrazolidine-1,5-dicarboxylate (12.74 g) as light yellow oil, which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[F:26])[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[S:12][C:8]=2[C:7]=1[C:21]#[N:22].[N:27]([C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)=[C:28]=[O:29]>CN(C)C=O.C(OCC)(=O)C>[C:21]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14]([CH:16]3[CH2:17][CH2:18]3)=[O:15])=[N:10][C:9]=2[CH:19]=[CH:20][C:6]=1[O:5][C:4]1[CH:23]=[CH:24][C:25]([F:26])=[C:2]([NH:1][C:28](=[O:29])[NH:27][C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:39])[F:38])=[CH:32][CH:31]=2)[CH:3]=1)#[N:22]
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: N#Cc1c(Oc2ccc(F)c(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1c(Oc2ccc(F)c(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.5 %

Procedure:
N-[6-(3-Amino-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (150 mg, 0.402 mmol) produced in Example 30(vi) was dissolved in N,N-dimethylformamide (2 mL), 1-isocyanato-4-(trifluoromethyl)benzene (75 μL, 0.522 mmol) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (10 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (5 mL) and saturated brine (5 ml), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=60/40→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from acetone/n-hexane to give the title compound (115 mg, 51%) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:5]2=[CH:6][N:7]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[F:18])=[N:9][N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)[C:5]2=[CH:6][N:7]=1
Reactant: Brc1cc2c(I)nn(C3CCCCO3)c2cn1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: Fc1ccccc1-c1nn(C2CCCCO2)c2cnc(Br)cc12
Temperature: 145 °C
Yield: 37.7 %

Procedure:
To a microwave tube was added 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (300 mg, 0.74 mmol), 2-fluorophenylboronic acid (134 mg, 0.96 mmol), Pd(dppf)Cl2(60 mg, 0.07 mmol), sodium carbonate (314 mg, 2.96 mmol), 1,2-dimethoxyethane (3 mL), ethanol (0.3 mL) and water (0.3 mL). The tube was flushed with nitrogen for 2 minutes and heated in a Biotage microwave at 145° C. for 1 hour. The solvent was distilled off and the crude product was purified via flash chromatography eluting with 20% to 95% ethyl acetate in petroleum to afford 5-bromo-3-(2-fluorophenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine as a yellow oil (105 mg, 38%). ESI MS m/z=377 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([C:11](=O)/[CH:12]=[CH:13]/[N:14](C)C)[CH:8]=[CH:7][C:6]=1[S:18]([CH3:21])(=[O:20])=[O:19])(=O)C.[NH:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][N:31]=1)[C:27]#[N:28])N>CCO.CC(O)=O>[CH3:1][O:4][C:5]1[CH:10]=[C:9]([C:11]2[N:22]([C:24]3[CH:25]=[C:26]([C:27]#[N:28])[CH:29]=[CH:30][N:31]=3)[N:14]=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:6]=1[S:18]([CH3:21])(=[O:20])=[O:19]
Reactant: N#Cc1ccnc(NN)c1
Reactant: CC(=O)Oc1cc(C(=O)/C=C/N(C)C)ccc1S(C)(=O)=O
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(-c2ccnn2-c2cc(C#N)ccn2)ccc1S(C)(=O)=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
A mixture of 5-[(2E)-3-(dimethylamino)prop-2-enoyl]-2-(methylsulfonyl)phenyl acetate (1.5 g, 5.3 mmol) and 2-hydrazinylisonicotinonitrile (0.8 g, 6 mmol, PREPARATION 2) in EtOH (15 mL) and AcOH (3 mL) was stirred at 90° C. overnight. The reaction mixture was cooled, concentrated, and purified by prep-HPLC to afford the title compound (270 mg, 14%). 1H NMR (400 MHz, CDCl3): δ 3.26 (3H, s), 3.96 (3H, s), 6.58 (1H, d, J=1.6 Hz), 6.96 (1H, dd, J=8.4, 1.2 Hz), 7.05 (1H, d, J=1.2 Hz), 7.41 (1H, dd, J=4.8, 1.2 Hz), 7.81 (1H, d, J=2.0 Hz), 7.93 (1H, d, J=8.4 Hz), 8.18 (1H, s), 8.35 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H14N4O3S, 355. Found, 355.
Reaction SMILES: [CH2:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH2:17][OH:18])[CH2:2][CH3:3].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>ClCCl>[CH2:1]([C:4]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([F:15])([F:16])[F:14])=[CH:12][C:7]=2[S:6][C:5]=1[CH:17]=[O:18])[CH2:2][CH3:3]
Reactant: CCCc1c(CO)sc2cc(C(F)(F)F)ccc12
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCc1c(C=O)sc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89.6 %

Procedure:
To a suspension of [3-propyl-6-(trifluoromethyl)-benzothiophen-2-yl]methanol (126 mg, 0.459 mmol) and powdered Molecular sieves 3A (250 mg) in dichloromethane (2.3 mL) was added pyridinium chlorochromate (198 mg, 0.919 mmol). The mixture was stirred for 40 minutes at room temperature, to which was added ether (20 mL) and silica gel (Wakogel C-300HG, 2 g). The mixture was stirred for 10 minutes at room temperature, and filtered. The filtered cake was washed out with ether. The filtrate and washings were combined, and concentrated to give the titled compound as a brown crystal (112 mg, yield 90%).
Reaction SMILES: [N+:1]([C:4]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]2[CH:11]3[CH2:18][CH:7]([CH2:8][N:9](C(=O)C(F)(F)F)[CH2:10]3)[C:6]=2[CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Na+].[Na+].O.CO.C(Cl)Cl>CO>[N+:15]([C:14]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]2[CH:7]3[CH2:18][CH:11]([CH2:10][NH:9][CH2:8]3)[C:12]=2[CH:13]=1)([O-:17])=[O:16]
Reactant: O=C(N1CC2CC(C1)c1cc([N+](=O)[O-])c([N+](=O)[O-])cc12)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1cc2c(cc1[N+](=O)[O-])C1CNCC2C1

Procedure:
1-(4,5-Dinitro-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-2,2,2-trifluoro-ethanone (3.7 g, 10.7 mmol) and Na2CO3 (2.3 g, 21.4 mmol) were combined in methanol (50 mL) and H2O (20 mL) then warmed to reflux for 18 hours. The reaction was cooled, concentrated, treated with H2O and extracted with CH2Cl2 (3×50 mL) then dried through a cotton plug. After concentration, the residue was chromatographed to provide brown solids. (1.9 g, 71%). (TLC 5% methanol/CH2Cl2 (NH3) Rf 0.36). 1H NMR (400 MHz, CDCl3)7.69 (s, 2H), 3.17 (br s, 2H), 3.11 (d, J=12.6 Hz, 2H), 2.53 (m, 1H), 2.07 (d, J=11.0 Hz, 1H). GCMS m/e 249 (M+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([C:15](OCC)=[O:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Li+].[BH4-].C1COCC1.Cl>CCOC(C)=O>[CH3:1][S:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([CH2:15][OH:16])[O:12]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCOC(=O)C1CCc2ccc(S(C)(=O)=O)cc2O1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2c(c1)OC(CO)CC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 7-(methylsulfonyl)chromane-2-carboxylate (0.6 g, 2.1 mmol), LiBH4 (0.18 g, 8.5 mmol) and THF (8 ml) was stirred at 0° C. for 15 min and 2 h at room temperature. HCl (10%) and EtOAc was added, the organic phase was dried (Na2SO4), filtered and concentrated to give the title compound. Yield 0.66 g. MS m/z (rel. intensity, 70 eV) 507 (20), 485 (25), 265 (23), 244 (13), 243 (M+1, bp).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Br:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35]Br>CN(C=O)C>[Br:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][C@@:9]([CH3:10])([C:11]([O:13][CH3:14])=[O:12])[N:8]=[C:7]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1cccc(Br)c1
Reactant: COC(=O)[C@H](C)N=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@](C)(Cc1cccc(Br)c1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of methyl N-(diphenylmethylene)alaninate (2.6 g, 9.7 mmol) in DMF (20 mL) cooled to 0° C. was added NaHMDS (12.2 mL, 12.2 mmol, 1M in THF) slowly via syringe and the reaction mixture was stirred at 0° C. for 15 min at which point 3-bromo-benzyl bromide (2.55 g, 10.2 mmol) in DMF (10 mL) was added slowly via syringe. The reaction mixture was allowed to warm to rt over 16 h, quenched with aq NH4Cl and water, extracted with EtOAc, washed with aq LiCl (×3), dried over Na2SO4, concentrated in vacuo, and purified by flash chromatography (120 g silica, 0-15% EtOAc in hexanes) to provide methyl 3-bromo-N-(diphenylmethylene)-α-methylphenylalaninate.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([C:17](=[O:28])[C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Cl>CCOCC.[Cl-].[Zn+2].[Cl-]>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([CH:17]([OH:28])[C:18]2[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1
Reactant: CCOC(=O)C(Cc1ccc(F)cc1)C(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
To a solution of zinc chloride (21.54 g, 158 mmol) in ether (500 ml) was added sodium borohydride (11.96 g, 316 mmol), and the mixture was stirred at room temperature for 30 min. Precipitated sodium chloride was filtered off. To the filtrate was gradually added a solution of ethyl 2-((4-fluorophenyl)methyl)-3-oxo-3-(4-(trifluoromethyl)phenyl)propionate (28 g, 79 mmol) in ether (200 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 min. The reaction solution was poured into 1N aqueous hydrochloric acid solution (500 ml), and extracted with ethyl acetate (500 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl(2RS,3RS)-2-((4-fluorophenyl)methyl)-3-hydroxy-3-(4-(trifluoromethyl)phenyl)propionate (28 g, 100%) as a colorless oil.