Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([O:24]C)[C:11](=[O:23])[N:12]([CH3:22])[C:13]=3[N:17]([CH3:21])[C:18](=[O:20])[CH3:19])[C:8]2=[O:26])=[CH:4][CH:3]=1.Br.O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:9](=[C:10]([OH:24])[C:11](=[O:23])[N:12]([CH3:22])[C:13]=3[N:17]([CH3:21])[C:18](=[O:20])[CH3:19])[C:8]2=[O:26])=[CH:27][CH:28]=1
Reactant: COc1c2c(c(N(C)C(C)=O)n(C)c1=O)CCN(Cc1ccc(F)cc1)C2=O
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N(C)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 1.5 h

Procedure:
To N-[6-(4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridin-1-yl]-N-methylacetamide (0.070 g, 0.181 mmol) was dissolved in 1 mL glacial acetic acid and 0.75 mL 30% by weight HBr in acetic acid solution was added. The reaction was stirred for 1.5 hours, water was added and the reaction evaporated to dryness under vacuum. The residue was purified on reverse phase and the fractions collected and evaporated. The residue was dissolved in dioxane, from which crystals formed and were collected. The crystals were dried under vacuum with heat to give the product.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>CN(C=O)C>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)[CH2:2][CH2:3]2)=[CH:28][CH:27]=1
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2CCN(c3ccc4c(c3)CCC(=O)N4)CC2)cc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 58.8 %

Procedure:
To a mixture of 1.2 g of 6-(1-piperazinyl)-3,4-dihydrocarbostyril, 1.17 g of potassium carbonate and 20 ml of DMF was added 720 mg of 4-methoxybenzyl chloride and the mixture was stirred at 80° C. for 2.5 hours. The reaction mixture was poured into a large amount of saturated saline solution and extracted with chloroform. After washing with water the extract was dried over anhydrous sodium sulfate. Chloroform was distilled off and the residue was purified through silica gel column chromatography. Recrystallization from ethanol gave 950 mg of 6-[4-(4-methoxybenzyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 196°-198° C., colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1Cl.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[N:16]1[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]1
Reactant: CN1CCNCC1
Reactant: CC(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)c1ccc(N2CCN(C)CC2)c(Cl)c1

Procedure:
3',4'-Dichloroacetophenone (9.65 g., 0.05 mole) and N-methylpiperazine (10 g., 0.1 mole) are refluxed (165° C.) for 24 hours. The solution is cooled and 100 ml. water containing 2 g. of sodium hydroxide is added. The oil is decanted and diluted with 200 ml. of toluene and washed first with dilute alkali then several times with water. The toluene layer is dried with magnesium sulfate and evaporated in vacuo to an oil. The residue is distilled 146°-150° at 0.1-0.3 mm., yield 3.0 g. This product is dissolved in ethyl ether and converted to the hydrochloride using isopropanolic hydrogen chloride and the salt crystallized from acetonitrile. The purified salt is reconverted to the base with dilute sodium hydroxide. The product is extracted using ethyl ether, separated, dried, evaporated to dryness to give 3'-chloro-4'-(4-methyl-1-piperazinyl)acetophenone as a yellow oil.
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2.Cl[CH:19]([O:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>C(O)(C)(C)C.[I-].[K+]>[N:14]1[C:15]2[C:10](=[CH:9][C:8]([O:7][CH:19]([O:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(Cl)OCC
Reactant: Oc1ccc2ncccc2c1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)C(OCC)Oc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
Potassium t-butoxide (3.15 g) was dissolved in t-butyl alcohol (20 ml) and stirred for 10 minutes at ambient temperature. 6-Hydroxyquinoline (3.0 g) was added, the resulting dark green solution was stirred for 15 minutes, and then ethyl 2-chloro-2-ethoxyacetate (4.22 g, 90% pure) added, followed by a catalytic amount of potassium iodide (0.005 g). The mixture was stirred for 18 hours, poured into water and extracted with chloroform. The organic fraction was washed with brine, water, and dried over magnesium sulphate. The solvent was evaporated to give a brown oil, which was purified by flash chromatography on silica gel, eluting with a gradient of ethyl acetate:hexane (1:2 to 4:1) to give ethyl 2-(6-quinolinyloxy)-2-(ethoxy)acetate as a pale brown oil (3.68 g).
Reaction SMILES: I[C:2]1[N:11]=[C:10]2[N:4]([CH2:5][CH2:6][C:7]3[CH:23]=[CH:22][CH:21]=[CH:20][C:8]=3[CH:9]2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[C:3]=1[CH3:24].C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1)CCC.[K].[Li+].[Cl-]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:24][C:3]1[N:4]2[C:10]([CH:9]([O:12][CH:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)[C:8]3[CH:20]=[CH:21][CH:22]=[CH:23][C:7]=3[CH2:6][CH2:5]2)=[N:11][C:2]=1[C:30]1[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: Cc1c(I)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [K]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccncc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 110 °C

Procedure:
To a solution of 2-iodo-1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 133) (110 mg, 0.251 mmole) in DMF (4 mL) are added potassium 4-tributylstannylpyridine (354 mg, 1 mmole), Pd(PPh3)4 (28 mg, 0.025 mmole), LiCl (50 mg, 1.25 mmole). The flask is evacuated and filled with argon. The reaction mixture is heated at 110° C. for 5 hours. AcOEt and water are added, as well as a 10% KF solution. The aqueous phase is extracted with AcOEt. The organic phase is washed with 0.5N HCl. The HCl phase is made alkaline with 1H NaOH and the aqueous phase is extracted with AcOEt. The organic phase is dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH) (98:2) then (CH2Cl2:MeOH:NH4OH) (95:5:0.5). The residue is the re-purified to afford by silica gel chromatography eluting with (toluene:acetone:NEt3) (10:90:2) to (5:95:5) to give 1-methyl-4-(1-methylpiperidin-4-yloxy)-2-pyridin-4-yl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](O)=[O:19])[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:62][O:63][C:64](=[O:82])[C@@H:65]([NH2:81])[CH2:66][C:67]1[CH:72]=[CH:71][C:70]([C:73]2[CH:78]=[CH:77][N:76]=[C:75]([CH3:79])[C:74]=2[CH3:80])=[CH:69][CH:68]=1.CN1CCOCC1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:19])[NH:81][C@H:65]([C:64]([O:63][CH3:62])=[O:82])[CH2:66][C:67]2[CH:68]=[CH:69][C:70]([C:73]3[CH:78]=[CH:77][N:76]=[C:75]([CH3:79])[C:74]=3[CH3:80])=[CH:71][CH:72]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[CH:27][CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCC2CCCCC2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (72 mg), EDCI (33 mg), HOBt (24 mg), and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (59 mg) were suspended in 3 mL DCM and NMM (0.067 mL) added. The mixture was stirred at room temperature for 3 hours and the mixture was directly purified over silica (hexanes to 1:1 hexanes/EtOAc to 1:1 hexanes/EtOAc+1% MeOH) to give (3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (86 mg). LCMS: (m/z) 791.
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([CH2:12][C@@H:13]([NH3+:25])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([C:22]#[N:23])[CH:19]=[CH:18][C:17]=1[I:24])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:26][N:27]([CH3:39])[C:28]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)=[O:29].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl.O>[C:22]([C:20]1[CH:19]=[CH:18][C:17]([I:24])=[C:16]([CH:21]=1)[O:15][CH2:14][C@H:13]([NH:25][C:34](=[O:35])[C:33]1[CH:32]=[CH:31][C:30]([C:28](=[O:29])[N:27]([CH3:39])[CH3:26])=[CH:38][CH:37]=1)[CH2:12][C:10]([O:9][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[O:11])#[N:23]
Reactant: CN(C)C(=O)c1ccc(C(=O)O)cc1
Reactant: N#Cc1ccc(I)c(OC[C@H]([NH3+])CC(=O)OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C)C(=O)c1ccc(C(=O)N[C@@H](COc2cc(C#N)ccc2I)CC(=O)OCc2ccccc2)cc1
Reaction time: 18 h

Procedure:
2.05 g (4.33 mmol) of (1R)-1-benzyloxycarbonylmethyl-2-(5-cyano-2-iodophenoxy)ethyl ammonium chloride, 1.25 g (6.49 mmol) of 4-dimethylcarbamoylbenzoic acid, 994 mg (7.35 mmol) of 1-hydroxybenzotriazole, and 2.71 ml (19.46 mmol) of triethylamine were dissolved in 25 ml of dichloromethane, and 1.41 g (7.35 mmol) of 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride was added thereto and stirred under cooling with ice for 10 minutes and then at room temperature for 18 hours. The reaction was stopped by adding water, and the title compound was obtained in an ordinary manner by treatment with dichloromethane as the extractant to obtain the crude product. It was purified by silica gel column chromatography (hexane:ethyl acetate=3:1, v/v) to obtain the title compound.
Reaction SMILES: Br[C:2]1[C:3]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:4][N:5]2[C:10]=1[CH:9]=[CH:8][C:7]([O:11]C)=[N:6]2.Cl.N1C=CC=CC=1.[H-].[Na+].Br[CH:30]([F:32])[F:31]>CN(C=O)C.C(OCC)(=O)C>[F:31][CH:30]([F:32])[O:11][C:7]1[CH:8]=[CH:9][C:10]2[N:5]([N:4]=[C:3]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[CH:2]=2)[N:6]=1
Reactant: COc1ccc2c(Br)c(-c3cccc(F)c3)nn2n1
Reactant: FC(F)Br
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cccc(-c2cc3ccc(OC(F)F)nn3n2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
Portions of 3-bromo-2-(3-fluoro-phenyl)-6-methoxy-pyrazolo[1,5-b]pyridazine (400 mg, 2.1 g total) were placed in individual Reactivials equipped with a magnetic stirrer bar. Pyridine hydrochloride (10 eq) was added to each vial, the vials sealed, and heated to 2000 for 3 hours. The vials were allowed to cool to ˜140° before opening and the contents poured into ice/water. The resulting mixture was extracted into ethyl acetate (3×100 ml) and the combined organic extracts washed with water (7×75 ml), dried (Na2SO4) and evaporated to give the des-bromo phenol as a brown solid (1.0 g, MH+ 230). This solid was dissolved in anhydrous DMF (10 ml) and sodium hydride (60% dispersion in mineral oil, 200 mg) added portionwise. After stirring for 20 minutes at ambient temperature the solution was transferred to a small cooled autoclave and bromodifluoromethane (5 ml, xs, condensed at −30°) added. The autoclave was then sealed, allowed to warm to ambient temperature and stirred for 36 hours. The resulting solution was diluted with ethyl acetate (200 ml), washed with water (10×20 ml), dried (Na2SO4), concentrated and the residual gum purified by flash column chromatography with cyclohexane:ethyl acetate (4:1) as eluant. This gave the title compound as a solid (652 mg, 60%).
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:12]/[C:13]1[C:20]([Cl:21])=[CH:19][C:18]([F:22])=[CH:17][C:14]=1[C:15]#[N:16])=[N+]=[N-]>C1(C)C=CC=CC=1>[Cl:21][C:20]1[C:13]([N:12]2[CH:11]=[C:5]3[CH:6]=[N:7][CH:8]=[C:9]([F:10])[C:4]3=[N:1]2)=[C:14]([CH:17]=[C:18]([F:22])[CH:19]=1)[C:15]#[N:16]
Reactant: N#Cc1cc(F)cc(Cl)c1/N=C/c1cncc(F)c1N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: N#Cc1cc(F)cc(Cl)c1-n1cc2cncc(F)c2n1
Temperature: 25 °C
Yield: 92.4 %

Procedure:
A solution of 2-{[1-(4-azido-5-fluoropyridin-3-yl)-meth-(E)-ylidene]-amino}-3-chloro-5-fluorobenzonitrile (1.67 g, 5.25 mmol) in anhydrous toluene (25 mL) was heated under reflux for 4.5 hours. The resultant mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-5% methanol in DCM) to afford the title compound as a yellow solid (1.41 g, 93% yield). LCMS (Method C): RT=2.71 min, m/z: 291 [M+H+].
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH2:16][O:15][C:14]2[CH:13]=[C:12]3[C:7]([C:8]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:9][C:10](=[O:17])[NH:11]3)=[CH:6][C:5]=2[O:4]1.I[CH:25]([CH3:27])[CH3:26]>CN(C=O)C>[CH2:3]1[CH2:16][O:15][C:14]2[CH:13]=[C:12]3[C:7]([C:8]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[N:9][C:10]([O:17][CH:25]([CH3:27])[CH3:26])=[N:11]3)=[CH:6][C:5]=2[O:4]1
Reactant: CC(C)I
Reactant: O=c1nc(-c2ccccc2)c2cc3c(cc2[nH]1)OCCO3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1nc(-c2ccccc2)c2cc3c(cc2n1)OCCO3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a suspension of sodium hydride (60% dispersion, 44 mg, 1.07 mmol) in 1 mL of DMF was added a suspension of 6,7-ethylenedioxy-4-phenylquinazolin-2(1H)-one (100 mg, 0.36 mmol) in 4 mL of DMF and stirred at rt for 15 min. 2-Iodopropane (150 μL, 1.45 mmol) was then added and the mixture was heated to ˜60-70° C. for 1.5 h. Excess sodium hydride was quenched with water and the solution extracted with 25 mL of 9:1 EtOAc:hexane. The extract was washed with 2×25 mL water and brine, then dried with MgSO4 and concentrated in vacuo. The crude solid was subjected to flash column chromatography eluting with acetone:hexane to give the title compound 6,7-ethylenedioxy-2-isopropoxy-4-phenylquinazolin (95 mg, 83%). 1H NMR (CDCl3): 7.75 (d, 2H), 7.52 (m, 3H), 7.44 (s, 1H), 7.29 (s, 1H), 5.49 (m, 1H), 4.43-4.30 (m, 4H), 1.46 (d, 6H), followed by the title compound 6,7-ethylenedioxy-1-isopropyl-4-phenylquinazolin-2(1H)-one (9 mg, 8%). 1H NMR (CDCl3): 7.70 (d, 2H), 7.50 (m, 3H), 7.30 (s, 1H), 7.05 (s, 1H), 5.15 (m, 1H), 4.41-4.26 (m, 4H), 1.68 (d, 6H).
Reaction SMILES: N1C=CN=C1.[OH:6][C:7]1[C:8](=[O:13])[C:9](=[O:12])[C:10]=1[CH3:11].[C:14]([Si:18]([CH3:21])([CH3:20])Cl)([CH3:17])([CH3:16])[CH3:15].O>CN(C=O)C>[O:12]([C:9]1[C:8](=[O:13])[C:7](=[O:6])[C:10]=1[CH3:11])[Si:18]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:21])[CH3:20]
Reactant: Cc1c(O)c(=O)c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(O[Si](C)(C)C(C)(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Imidazole (11 mmol) is added to a solution of compound 93 (5 mmol) and tert-butyldimethylchlorosilane (5.5 mmol) in 5 mL of DMF cooled by an ice bath. The mixture is allowed to warm to room temperature. After 16 hours, the mixture is poured into water (50 mL) and extracted with ether (3×50 mL), the organic phases are washed with brine (50 mL) and dried over anhydrous MgSO4, and the solvent is evaporated in vacuo. The residue is purified by flash chromatography to give the product as a colorless oil.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=[CH:18][N:17]=2)=[O:15])[CH:10]=[CH:9][C:8]=1[CH2:25][N:26]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[CH2:28][O:27]1>C(OC(=O)C)(=O)C>[Cl:6][C:7]1[CH:12]=[C:11]([N:13]2[C:22](=[O:24])[C:21]3[C:16](=[N:17][CH:18]=[CH:19][CH:20]=3)[C:14]2=[O:15])[CH:10]=[CH:9][C:8]=1[CH2:25][N:26]1[C:30](=[O:31])[C:29]([CH3:33])([CH3:32])[CH2:28][O:27]1
Reactant: CC1(C)CON(Cc2ccc(NC(=O)c3ncccc3C(=O)O)cc2Cl)C1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CC1(C)CON(Cc2ccc(N3C(=O)c4cccnc4C3=O)cc2Cl)C1=O
Temperature: 0 °C
Yield: 29.2 %

Procedure:
Using a method analogous to that of M. P. Cava et al., supra, a solution of 5.0 grams (0.061 mole) of sodium acetate in 50 mL of acetic anhydride was stirred while heating with a steam bath, and 1.5 grams (0.004 mole) of 2-[[2-chloro-4-[(3-carboxy-2-pyridinyl)carbonylamino]phenyl]methyl]-4,4-dimethyl-3-isoxazolidinone was added in one portion. Upon completion of addition the reaction mixture was heated with the steam bath for an additional 30 minutes. The reaction mixture was poured into 500 mL of ice-water, and the resultant solid was collected by filtration. The solid was recrystallized from acetone-water to yield 0.45 gram of 2-[[2-chloro-4-(pyrrolo[3,4-b]pyridine-5,7-dione-6-yl)phenyl]-methyl]-4,4-dimethyl-3-isoxazolidinone; m.p. 139°-141° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][N:5]([CH3:7])[CH:6]=1.O.[C:10]([OH:18])(=[O:17])[C:11]([CH2:13][C:14](O)=[O:15])=[CH2:12]>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([N:8]2[C:14](=[O:15])[CH2:13][CH:11]([C:10]([OH:18])=[O:17])[CH2:12]2)=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Cn1cc(Br)c(N)n1
Solvent: Cc1ccccc1
Solvent: O
Product: Cn1cc(Br)c(N2CC(C(=O)O)CC2=O)n1
Temperature: 120 °C
Reaction time: 5 h

Procedure:
To a solution of 4-bromo-1-methyl-1H-pyrazol-3-amine (312 mg) in a mixed solvent of water (2.0 mL) and toluene (2.0 mL) was added itaconic acid (245 mg). The reaction mixture was stirred at 120° C. for 5 hr, and the solvent was evaporated under reduced pressure. The residue was used for the next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[N:24]=[C:23]([O:25][CH:26]3[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]3)[CH:22]=[CH:21][N:20]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]3([OH:17])[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1.[C:39](Cl)(=[O:41])[CH3:40].C(N(CC)CC)C>C(Cl)Cl>[C:39]([NH:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[N:24]=[C:23]([O:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)[CH:22]=[CH:21][N:20]=2)[CH:5]=[C:6]([C:8]2[S:12][C:11]([C:13]3([OH:17])[CH2:16][CH2:15][CH2:14]3)=[N:10][CH:9]=2)[CH:7]=1)(=[O:41])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Nc3cc(N)cc(-c4cnc(C5(O)CCC5)s4)c3)n2)CC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc(Nc2nccc(OC3CCN(C(=O)OC(C)(C)C)CC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Reaction time: 1 h
Yield: 65.2 %

Procedure:
At 0° C., the product from Step 3 (40 mg, 0.074 mmol) in DCM (0.4 mL) was added to acetyl chloride (6.34 μl, 0.089 mmol) and triethylamine (15.53 μL, 0.111 mmol) and the reaction was aged for 1 h. The mixture was then purified directly by column chromatography on silica gel (30-100%, ethyl acetate: 10:1 methanol in hexanes) to afford tert-butyl 4-{[2-({3-(acetylamino)-5-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}piperidine-1-carboxylate (28 mg, 65% yield). Example 109(1). MS ESI: [M+H]+ m/z 581.3. 1H NMR (600 MHz, CDCl3): δ 8.10 (d, J=6.0 Hz, 1H); 7.90 (s, 1H); 7.76 (s, 1H); 7.65 (br s, 1H); 7.53 (s, 1H); 7.11 (s, 1H); 6.14 (d, J=6.0 Hz, 1H); 5.25 (m, 1H); 3.67 (m, 2H); 3.12 (br s, 2H); 2.64 (m, 2H); 2.43 (m, 2H); 2.13 (s, 3H); 1.92 (m, 4H); 1.66 (m, 2H); 1.43 (s, 9H). rhSYK activity=++
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[N:2]1.[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[NH:27][C:26]2[CH:28]=[CH:29][C:30]([NH2:32])=[CH:31][C:25]=2[N:24]=1)([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]1[NH:24][C:25]2[CH:31]=[C:30]([NH:32][C:10]([C:7]3[CH:8]=[C:9]4[C:4]([CH:3]=[N:2][NH:1]4)=[CH:5][CH:6]=3)=[O:12])[CH:29]=[CH:28][C:26]=2[N:27]=1)([CH3:15])[CH3:14]
Reactant: CC(C)c1ccccc1Nc1nc2cc(N)ccc2[nH]1
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(C)c1ccccc1Nc1nc2ccc(NC(=O)c3ccc4cn[nH]c4c3)cc2[nH]1

Procedure:
Methyl Indazole-6-carboxylate (4 mmol; Batt et al., J. Med. Chem. 2000, 43, 41-58) was hydrolyzed as in general procedure C to obtain 1H-Indazole-6-carboxylic acid. The carboxylic acid (0.5 mmol) was coupled with aforementioned N2-(2-isopropylphenyl)-1H-benzimidazole-2,5-diamine (0.5 mmol) using HBTU as described in general procedure D to yield 1H-indazole-6-carboxylic acid [2-(2-isopropylphenylamino)-3H-benzimidazol-5-yl]-amide as an off-white solid. MS: m/z 411 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH2:13][CH2:14]Br)[CH:8]=2)[CH:3]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:13][CH2:14][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:6]=[CH:5]2
Reactant: BrCCOc1ccc2cc(Br)ccc2c1
Reactant: C1CCNC1
Product: Brc1ccc2cc(OCCN3CCCC3)ccc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
In a flask containing 0.5 g (1.5 mmol) the product from Example 37A, 10 mL of pyrrolidine was added. After stirring at 80° C. for 3 h, the reaction mixture was concentrated under vacuum. The residue was diluted with 100 mL of CH2Cl2 and washed sequentially with water, sodium bicarbonate and brine, dried and evaporated under reduced pressure. Silica gel chromatography (MeOH:CH2Cl2, 95:5) gave the desired material in 98% yield. 1HNMR (300 MHz, CDCl3) δ 1.80 (m, 4H), 2.6 (m, 4H), 2.97 (t, 2H), 4.20 (t, 2H), 2.49 (m, 2H) 7.10–7.90 (m, 6H); MS (ESI) m/z 321 (M+H)+.