Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])=[O:5])#[N:2].[CH:16]([CH:18]=[CH2:19])=O.COC(=O)C(C)=C>[Cl-].[Zn+2].[Cl-].O1CCOCC1>[C:1]([C:3](=[CH:19][CH:18]=[CH2:16])[C:4]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11](=[O:15])[C:12]([CH3:14])=[CH2:13])=[O:5])#[N:2]
Reactant: C=C(C)C(=O)OCCCOC(=O)CC#N
Reactant: C=CC=O
Agent: C=C(C)C(=O)OC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1COCCO1
Product: C=CC=C(C#N)C(=O)OCCCOC(=O)C(=C)C
Reaction time: 8 h
Yield: 60.2 %

Procedure:
35.2 g of methacryloyloxypropyl cyanoacetate is mixed with 50 ml of dioxane. 13.5 g of zinc chloride is added during mixing. 13,25 g of acrolein are added dropwise over 10 minutes, taking care the reaction temperature not to exceed 20° C. The stirring is continued for a further 8 hours at room temperature yielding a clear yellow solution. 100 ml of methylmethacrylate are mixed in and then three consecutive extractions with 150 ml of 2N hydrochloric aced are performed. The organic layer is filtered and stripped under reduced pressure (0.7 mm Hg). The pot temperature is not to exceed 90° C. and a steady stream of air through the product is maintained during stripping. 25 g of methacryloyloxypropyl 2-cyanopenta-2,4-dienoate are obtained with nD20=1,5045. The IR spectrum (FIG. 3) confirms the chemical structure. The product possesses the same adhesive properties as described in Example 1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].C1(C)C=CC(S(O[CH2:18][CH:19]2[CH2:23][S:22][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:20]2)(=O)=O)=CC=1>CN(C)C=O.C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:18][CH:19]1[CH2:23][S:22][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:20]1
Reactant: c1c[nH]cn1
Reactant: Cc1ccc(S(=O)(=O)OCC2CSC(NC(=O)OC(C)(C)C)=N2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1=NC(Cc2ncc[nH]2)CS1
Temperature: 70 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
0.21 g of imidazole predissolved in 10 cm3 of dimethylformamide is added to a solution of 0.085 g of sodium hydride in 20 cm3 of dimethylformamide. After the sodium hydride has disappeared, a solution of 1 g of tert-butyl N-[(4RS)-4-(p-toluenesulfonyloxymethyl)-4,5-dihydro-2-thiazolyl]carbamate in 10 cm3 of dimethylformamide is added and the mixture is then stirred at a temperature in the region of 70° C. for 3 hours. The reaction medium is diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue obtained is chromatographed on a column of alumina, eluting with ethyl acetate and a mixture of ethyl acetate/methanol (80/20 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions to give 0.25 g of tert-butyl N-[(4RS)-4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazolyl]carbamate in the form of a sticky yellow mass [mass spectrum: DCI m/z=283 MH+ m/z=183 (M-C5H7O2)+].
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C[Si]([C:17]#[N:18])(C)C>[I-].[Zn+2].[I-]>[OH:10][CH:9]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:12][CH:11]=1)[C:17]#[N:18]
Reactant: CC(C)Cc1ccc(C=O)cc1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Product: CC(C)Cc1ccc(C(O)C#N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.5 %

Procedure:
Zinc iodide (0.21 g) was added to a mixture of 4-isobutylbenzaldehyde (6.5 g) and trimethylsilylcyanide (5.0 g). The mixture was stirred at room temperature for 30 minutes and partitioned between ethyl acetate and 7% hydrochloric acid. The organic layer was washed with 7% hydrochloric acid and water and dried over magnesium sulfate. The solvent was removed in vacuo to give 2-hydroxy-2-(4-isobutylphenyl)acetonitrile as a yellow oil (8.15 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])[CH2:6][CH3:7].[C:16]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][CH2:18][CH2:17]1.ClCC(Cl)(Cl)Cl.Cl>[N+](C1C=CC=CC=1)([O-])=O>[O:23]=[C:16]([C:12]1[CH:11]=[CH:10][C:9]([O:14][CH3:15])=[C:8]([CH2:5][CH2:6][CH3:7])[CH:13]=1)[CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]
Reactant: O=C1CCCC(=O)O1
Reactant: CCCc1ccccc1OC
Agent: Cl
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCCc1cc(C(=O)CCCC(=O)O)ccc1OC
Reaction time: 48 h
Yield: 66.3 %

Procedure:
Aluminium chloride (112 g) was slowly added over one hour to a stirred mixture of o-propylanisole (60 g), glutaric anhydride (50.5 g), tetrachloroethane (880 ml) and nitrobenzene (200 ml) maintained between 3°-4°. The mixture was stirred for two days and then poured into dilute hydrochloric acid. The organic phase was steam distilled, and the residue remaining was extracted with ether, which was then extracted with sodium bicarbonate solution. Acidification and crystallisation from ethylacetate-light petroleum (bp 60°-80°) gave 5-oxo-5-(4-methoxy-3-propylphenyl)pentanoic acid (70 g), mp 105°-106°. This acid was refluxed with zinc amalgam (270 g), dioxan (300 ml), toluene (300 ml), and concentrated hydrochloric acid (100 ml) for two days. Extraction with ether and subsequent evaporation gave an oil, which crystallised from cyclohexane to give 5-(4-methoxy-3-propylphenyl)pentanoic acid (36 g), mp 84°. This acid was esterified with methanol and concentrated sulphuric acid, and the methyl ester so obtained (26 g) was added to a stirred suspension of lithium aluminium hydride (3 g) in tetrahydrofuran at 0°. The mixture was refluxed for 3 hours, cooled, treated with water, and extracted with ether, which on evaporation gave the title alcohol (16 g), mp 34.5°-35° .
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[C:28]1([C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.S(=O)(=O)(O)O.C(OC(=O)C)(=O)C>C(O)(=O)C>[NH:1]([C:11]([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH:6][C:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
A mixture of 7.4 g of Fmoc-Gln-OH (20 mmol) and 10.4 g of triphenylmethanol (40 mmol) in 300 ml of acetic acid is stirred at 100° for 10 minutes. After the addition of 0.1 ml of concentrated sulfuric acid the whole is stirred at 100° for a further 15 minutes, a clear yellow solution forming. This is concentrated by evaporation under reduced pressure at 60°, and the residue is dried under reduced pressure for 10 minutes. The solid residue is dissolved in 60 ml of acetic acid at 60°, left at 60° for 20 minutes, then 2 ml of acetic anhydride (20 mmol) are added and after 1 hour at 60° the whole is concentrated by evaporation under reduced pressure. The oily residue is dried for 10 minutes at 60°, then dissolved in 100 ml of acetic acid and introduced dropwise into 500 ml of ice-cold water. The precipitate is isolated by filtration, washed well with water and dissolved in ethyl acetate; the aqueous phase is separated off and the organic phase is washed with a saturated aqueous sodium chloride solution. After drying over sodium sulfate, the organic solution is concentrated to dryness by evaporation, the residue is dissolved in 50 ml of 1,2-dichloroethane and applied to 100 g of silica gel; elution is carried out with 1,2-dichloroethane and with 1,2-dichloroethane containing 2%, then 4%, methanol. The fractions containing the Fmoc-Gln(Trt)-OH are concentrated by evaporation under reduced pressure, and the product is crystallised from a mixture of ethyl acetate and diisopropyl ether, m.p. from 125°.
Reaction SMILES: [SH:1][C:2]1SC=[C:5]([C:7]2C=CC=[CH:9][CH:8]=2)[N:6]=1.F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N:6]1[CH:5]=[CH:7][CH:8]=[CH:9][C:2]=1[S:1][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1
Reactant: Sc1nc(-c2ccccc2)cs1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(Sc2ccccn2)cc1
Temperature: 65 °C
Yield: 145.7 %

Procedure:
4-(2-(4-Phenyl)thiazolyl)thio-1-nitrobenzene: A solution of 2-mercapto-4-phenylthiazole (4.0 g, 20.7 mmoles) in DMF (40 mL) was treated with 1-fluoro-4-nitrobenzene (2.3 mL, 21.7 mmoles) followed by K2CO3 (3.18 g, 23 mmol), and the mixture was heated at approximately 65° C. overnight. The reaction mixture was then diluted with EtOAc (100 mL), sequentially washed with water (100 mL) and a saturated NaCl solution (100 mL), dried (MgSO4) and concentrated under reduced pressure. The solid residue was triturated with a Et2O/hexane solution to afford the desired product (6.1 g): TLC (25% EtOAc/75% hexane) Rf 0.49; 1H-NMR (CDCl3) δ 7.35-7.47 (m, 3H), 7.58-7.63 (m, 3H), 7.90 (d, J=6.9 Hz, 2H), 8.19 (d, J=9.0 Hz, 2H).
Reaction SMILES: [C:1]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1.C(O)(=O)C>O>[CH:13](=[C:9]1[CH:10]=[CH:11][C:3]2[CH2:2][C:1]([NH:6][C:5](=[O:7])[C:4]=2[CH2:8]1)=[O:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1Cc2ccccc2C(=O)N1
Reactant: O=Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCNCC1
Product: O=C1CC2=C(CC(=Cc3ccccc3)C=C2)C(=O)N1
Temperature: 25 °C
Yield: 79.2 %

Procedure:
A stirred mixture of homophthalimide (15 g, 93 mmol), benzaldehyde (9.9 g, 93 mmol), piperidine (9 ml) and acetic acid (465 ml) was heated under reflux for 1 hour, cooled to ambient temperature and diluted with water (500 ml). The resulting solid was collected by filtration, washed with water and dried in vacuo to give 4-benzylidenehomophthalimide (18.5 g, 82%) as a solid; m.pt. 173-177° C. Used crude for the next step.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:20]3[CH:25]=[CH:24][N:23]=[C:22](S(C)=O)[N:21]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13](S(C)=O)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1>>[CH:29]1([NH:32][C:2]2[N:7]3[N:8]=[C:9]([C:20]4[CH:25]=[CH:24][N:23]=[C:22]([NH:32][CH:29]5[CH2:31][CH2:30]5)[N:21]=4)[C:10]([C:11]4[CH:16]=[CH:15][N:14]=[C:13]([NH:32][CH:29]5[CH2:31][CH2:30]5)[N:12]=4)=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:31][CH2:30]1
Reactant: CS(=O)c1nccc(-c2nn3c(Cl)cccc3c2-c2ccnc(S(C)=O)n2)n1
Reactant: NC1CC1
Product: c1cc(NC2CC2)n2nc(-c3ccnc(NC4CC4)n3)c(-c3ccnc(NC4CC4)n3)c2c1

Procedure:
N-Cyclopropyl-2,3-bis[2-(cyclopropylamino)pyrimidin-4-yl]pyrazolo[1,5-a]pyridin-7-amine was prepared by treating 7-chloro-2,3-bis[2-(methylsulfinyl)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine with cyclopropylamine as described in Example 7. 1H NMR, (CDCl3): δ 8.47 (d, 1H), 8.19 (d, 1H), 7.86 (d, 1H), 7.37 (t, 1H), 7.04 (d, 1H), 6.71 (d, 1H), 6.44 (d, 1H), 6.36 (s, 1H), 5.53 (s, 1H), 5.39 (s, 1H), 2.62–290 (m, 3H), 0.77–0.96 (m, 8H), 0.56–0.70 (m, 4H); MS m/z 440 (M+1).
Reaction SMILES: [CH3:1][N:2]([S:22]([CH3:25])(=[O:24])=[O:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.Cl.CCN(C(C)C)C(C)C.[NH:36]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C@@H:37]([C:46](O)=[O:47])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=1.CCN=C=NCCCN(C)C.CI.C1C=NC2N(O)N=NC=2C=1>CCOC(C)=O.CN(C=O)C>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][C@@H:37]([NH:36][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C:46]([N:12]2[CH2:13][CH2:14][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[N:2]([CH3:1])[S:22]([CH3:25])(=[O:24])=[O:23])[CH2:10][CH2:11]2)=[O:47])=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CN(c1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CI
Product: CN(c1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Yield: 31.2 %

Procedure:
tert-Butyl 4-{2-[methyl(methylsulfonyl)amino]phenyl}piperazinecarboxylate (Step 1) (700 mg, 1.9 mmol) was stirred with 25 mL of HCl satd EtOAc. The resulting crude material was diluted with EtOAc and washed with a satd NaHCO3 soln. The organic layer was separated, dried over Na2SO4, filtered and concentrated in vacuo. This material was treated with DIEA (400 μl, 2.295 mmol), Boc-p-Cl-D-Phe-OH (672 mg, 2.241 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide methiodide (1.25 g, 4.206 mmol), HOAT (345 mg, 2.535 mmol), and DMF (15 mL) according to the procedure for preparation XIX. The crude material was purified by flash chromatography (SiO2, 1.5:1 hexane:EtOAc) to yield N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[methyl-(methylsulfonyl)amino]phenyl}piperazinyl)-2-oxoethyl]-(tert-butoxy)carboxamide (327 mg). MS (ESI, pos. ion) m/z: 551 (M+H), (ESI, neg. ion) m/z: 549 (M−H). Calc'd for C26H35ClN4O5S: 551.10.
Reaction SMILES: [Br-:1].[CH:2]1([C:8]([OH:33])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH2:18][C:19](=[O:26])[NH:20][C:21]2[CH:25]=[CH:24][O:23][N:22]=2)[CH3:17])=[O:10])C[CH2:6][CH2:5][CH2:4][CH2:3]1.C1(C(C2C=CC=CC=2)(O)C(O)=O)CCCC1>>[Br-:1].[CH:2]1([C:8]([OH:33])([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:9]([O:11][CH:12]2[CH2:16][CH2:15][CH2:14][N+:13]2([CH2:18][C:19](=[O:26])[NH:20][C:21]2[CH:25]=[CH:24][O:23][N:22]=2)[CH3:17])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[N+]1(CC(=O)Nc2ccon2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCCC1
Agent: O=C(O)C(O)(c1ccccc1)C1CCCC1
Agent: [Br-]
Product: C[N+]1(CC(=O)Nc2ccon2)CCCC1OC(=O)C(O)(c1ccccc1)C1CCCC1

Procedure:
This compound is prepared by an analogous method to (1R/S,3R)-3((R/S)-(2-cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-1-(isoxazol-3-ylcarbamoylmethyl)-1-methyl-pyrrolidinium bromide (QAX003) (Example 2) by replacing cyclohexyl-hydroxy-phenyl-acetic acid with cyclopentyl-mandelic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6](Br)[CH:7]=1.[C:16]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[C:6]([C:23]3[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=3)[CH:7]=2)=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CCOC(=O)/C=C/c1cc(Br)cc(Br)c1
Product: CCOC(=O)/C=C/c1cc(-c2ccc(C(C)(C)C)cc2)cc(-c2ccc(C(C)(C)C)cc2)c1

Procedure:
The colourless glass, (E)-ethyl 3-(4,4″-di-tert-butyl-[1,1′;3′,1″]terphenyl-5′-yl)-acrylate was prepared from (E)-ethyl 3-(3,5-dibromophenyl)-acrylate (example 109a) and 4-tert-butylphenylboronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.[C:29]1([S:35]([O:38][C:39]2[CH:40]=[CH:41][C:42]([CH2:45]Br)=[N:43][CH:44]=2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH:9]([CH2:45][C:42]2[CH:41]=[CH:40][C:39]([O:38][S:35]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)(=[O:37])=[O:36])=[CH:44][N:43]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: O=S(=O)(Oc1ccc(CBr)nc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OS(=O)(=O)c2ccccc2)cn1)N=C(c1ccccc1)c1ccccc1
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
A solution of ethyl N-(diphenylmethylene)glycinate (1.71 g, 6.40 mmol) in dry THF (10 ml) was added to a stirred solution of LDA (2M in heptane/THF/ethylbenzene, 3.20 ml, 6.40 mmol) in dry THF (10 ml) at -70° under nitrogen. After stirring at this temperature for 0.75 h, a solution of 5-benzenesulphonyloxy-2-bromomethyl-pyridine [2.00 g, 6.01 mmol; prepared as described by Myers et al, J. Org. Chem. (1996), 61, 813] in dry THF (10 ml) was added. The reaction mixture was stirred at -70° for 1 h then at room temperature for 18 h. The reaction was quenched with water (10 ml) then partitioned between EtOAc (70 ml) and brine (30 ml). The phases were separated and the aqueous phase re-extracted with EtOAc (2×40 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford the crude product as a dark oil. Purification by flash chromatography (silica, 60% to 75% Et2O/hexane; applied as DCM solution) afforded the title compound as a tan-coloured solid (2.25 g, 72%). δH (CDCl3) 8.02 (1H, d, J 2.8 Hz, pyr-H (6), 7.72 (2H, d, J~8 Hz, ortho-Ar-H), 7.59 (1H, t, J~8 Hz, para-Ar-H), 7.50 (2H, dd, J 8.4, 1.4 Hz, phenyl-H), 7.40-7.27 (8H, ms, Ar and phenyl-H), 7.19 (1H, dd, J 8.5, 2.8 Hz, pyr-H (4)), 7.11 (1H, d, J 8.5 Hz, pyr-H (3)), 6.67 (2H, br d, J~8 Hz, phenyl-H), 4.50 (1H, dd, J 9, 4.6 Hz, CH-α), 4.24-4.10 (2H, sym.m. CH2CH3), 3.50-3.33 (2H, m, pyr--CH2), 1.24 (3H, t, J 7.2 Hz, CH2CH3); m/z (ESI) 515 (MH+).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]([CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:11]3[CH:24]=[CH:25][CH:26]=[CH:27][C:10]=3[CH2:9][O:8][C:7]=2[CH:28]=1.[CH3:29][C:30]1[N:35]=[C:34]2[NH:36][C:37]([CH2:39][CH3:40])=[N:38][C:33]2=[C:32]([CH3:41])[CH:31]=1>>[CH3:29][C:30]1[N:35]=[C:34]2[N:36]([CH2:2][C:3]3[CH:4]=[CH:5][C:6]4[CH:12]([CH:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:11]5[CH:24]=[CH:25][CH:26]=[CH:27][C:10]=5[CH2:9][O:8][C:7]=4[CH:28]=3)[C:37]([CH2:39][CH3:40])=[N:38][C:33]2=[C:32]([CH3:41])[CH:31]=1
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)C1c2ccccc2COc2cc(CO)ccc21
Product: CCOC(=O)C(C(=O)OCC)C1c2ccccc2COc2cc(Cn3c(CC)nc4c(C)cc(C)nc43)ccc21
Yield: 31 %

Procedure:
The same procedures as in Steps C and D of Example 1 were repeated using 367 mg of Compound 23-a and mg of 5,7-dimethyl-2-ethyl-3H-imidazo[4,5-b]pyridine to give 150 mg (31%) of the product as an oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:9]=2)[CH:5]=[C:4]([CH2:19]O)[CH:3]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCCCC>[Br:22][CH2:19][C:4]1[CH:3]=[C:2]([CH3:1])[C:10]2[C:6](=[CH:7][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:9]=2)[CH:5]=1
Reactant: Cc1cc(CO)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCC
Product: Cc1cc(CBr)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)methanol (138 mg, 0.472 mmol) and carbon tetrabromide (235 mg, 0.708 mmol) in tetrahydrofuran (1 mL) at 0° C. was added triphenylphosphine (186 mg, 0.708 mmol). The resulting solution was stirred at room temperature for 30 min. The reaction was diluted with several volumes of pentane and filtered to remove undissolved solids. The organics were concentrated and purified by column chromatography (5→12% EtOAc/Hex) to give 114 mg (68%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 8.03 (s, 1H), 7.48 (s, 1H), 7.06 (s, 1H), 5.68 (s, 2H), 4.55 (s, 2H), 3.61 (m, 2H), 2.59 (s, 3H), 0.91 (m, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 148.8, 131.6, 129.0, 126.6, 123.3, 121.6, 118.1, 81.7, 67.3, 35.4, 17.7, 17.1, −1.5.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:15][OH:16]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCN(Cc2ccccc2)C1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: ON=C1CCN(Cc2ccccc2)C1
Temperature: 90 °C
Reaction time: 5 h
Yield: 102.2 %

Procedure:
To a solution of 1-benzylpyrrolidin-3-one (1.0 g, 5.71 mmol) in pyridine (5 mL) is added hydroxylamine hydrochloride (0.59 g, 8.57 mmol). After stirring at 90° C. for 5 hours, the reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate, water, and brine. The organic layer is dried over MgSO4, filtered, and filtrate concentrated to afford 1-benzylpyrrolidin-3-one oxime (1.11 g) as an oil. MS CI: m/z 191 (MH+).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[C:17]([O:18][CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[C:16]2[C:11]([CH:12]=[N:13][C:14]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([S:39](=[O:42])(=[O:41])[NH2:40])=[CH:35][CH:34]=3)=[N:15]2)=[CH:10][CH:9]=1.[CH3:43][N:44]1[CH:48]=[CH:47][C:46](B2OC(C)(C)C(C)(C)O2)=[CH:45]1>COCCOC.[Pd]>[CH3:43][N:44]1[CH:48]=[CH:47][C:46]([C:8]2[C:17]([O:18][CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)=[C:16]3[C:11]([CH:12]=[N:13][C:14]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([NH2:40])(=[O:41])=[O:42])=[CH:37][CH:38]=4)=[N:15]3)=[CH:10][CH:9]=2)=[CH:45]1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2c(Br)ccc3cnc(Nc4ccc(S(N)(=O)=O)cc4)nc23)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: Cn1ccc(-c2ccc3cnc(Nc4ccc(S(N)(=O)=O)cc4)nc3c2OC2CCNCC2)c1
Temperature: 92.5 °C
Reaction time: 1.5 h
Yield: 22.9 %

Procedure:
A 2M solution of K2CO3 (180 μL) was added to a mixture of tert-butyl 4-(7-bromo-2-(4-sulfamoylphenylamino)quinazolin-8-yloxy)piperidine-1-carboxylate (18 mg, 0.031 mmole), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole (20 mg, 0.093 mmole) and palladium (4 mg, 0.005 mmole) in DME (0.6 mL). The reaction was sparged with argon, sealed and heated at 90-95° C. with stirring. After 90 minutes, LCMS showed that the reaction had reached completion. The Boc group was removed by adding 4M HCl (1.5 mL) in dioxane to the cooled reaction mixture. After 2 hours, the reaction was complete by LCMS. The reaction was filtered, evaporated, dissolved in DMSO (1 mL) and purified by prep. HPLC to give 3.4 mg of the pure product as a TFA salt.