Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:10]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:16][CH:15]([NH:31][C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([O:43]C)=[O:42])[CH:36]=3)=[O:33])[C:14]1=[O:45])=[O:11])[CH2:2]2.[OH-].[Na+]>O1CCCC1>[CH:5]12[CH2:6][CH2:7][CH:1]([CH2:9][CH2:8]1)[CH2:2][N:3]([C:10]([CH2:12][N:13]1[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[C:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])=[N:16][CH:15]([NH:31][C:32]([NH:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([OH:43])=[O:42])[CH:36]=3)=[O:33])[C:14]1=[O:45])=[O:11])[CH2:4]2
Reactant: COC(=O)c1cccc(NC(=O)NC2N=C(c3ccccc3F)c3ccccc3N(CC(=O)N3CC4CCC(CC4)C3)C2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(=O)O)c1)NC1N=C(c2ccccc2F)c2ccccc2N(CC(=O)N2CC3CCC(CC3)C2)C1=O
Reaction time: 7 h
Yield: 62.2 %

Procedure:
A mixture of N-[1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-methoxycarbonylphenyl)urea (312.5 mg) and 0.1N sodium hydroxide (7.7 ml, 1.5 eq. mol) in tetrahydrofuran (20 ml) was refluxed under stirring for 7 hours. After removal of the tetrahydrofuran, the residual aqueous mixture was extracted with ethyl acetate. After the separated aqueous layer was washed with ethyl acetate, it was acidified with diluted hydrochloric acid. The resultant precipitates were collected by filtration, washed with water and dried under reduced pressure to afford N-[1-(3-azabicyclo[3.2.2]non-3-yl)carbonylmethyl-2,3-dihydro-5-(2-fluorophenyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N'-(3-carboxyphenyl)urea (0.19 g, 62.2%) as a white crystalline powder.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:14]=[CH:13][N:12]([C@@H:15]3[O:35][C@H:34]([CH2:36][O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:25]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@@H:16]3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[N:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[N:7]=1.[CH2:45]([O:48]CC=C)[CH:46]=[CH2:47].[Na].CN(C=O)C>C(OCC)(=O)C>[CH2:45]([O:48][C:2]1[C:3]2[CH:14]=[CH:13][N:12]([C@@H:15]3[O:35][C@H:34]([CH2:36][O:37][CH2:38][C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C@@H:25]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@@H:16]3[O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[N:5]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[N:7]=1)[CH:46]=[CH2:47]
Reactant: CS(=O)(=O)c1nc(Cl)c2ccn([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@@H]3OCc3ccccc3)c2n1
Reactant: C=CCOCC=C
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1nc(S(C)(=O)=O)nc2c1ccn2[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1

Procedure:
A solution of 10 g of 4chloro-2-methylsulfonyl-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine, 1.35 g of sodium allyloxide, and 50 ml of DMF is stirred at ambient temperature for 24 hours, evaporated in vacuo and coevaporated with xylenes. The residue is distributed between a mixture of ethyl acetate and water and the dried ethyl acetate extracts are evaporated in vacuo to provide crude product. Chromatography of this material over silica gel with ethyl acetate provides pure 4-allyloxy-2-methylsulfonyl-7-(2,3,5-tri-O-benzyl-β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [CH3:1][C:2]([S:21]([CH3:24])(=[O:23])=[O:22])([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][Si](C)(C)C)=[CH:11][CH:10]=1)[C:3]([O:5][CH3:6])=[O:4].C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[C:15]([C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][C:2]([CH3:1])([S:21]([CH3:24])(=[O:22])=[O:23])[C:3]([O:5][CH3:6])=[O:4])=[CH:14][CH:13]=1)#[CH:16]
Reactant: COC(=O)C(C)(CCc1ccc(C#C[Si](C)(C)C)cc1)S(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1ccc(CCC(C)(C(=O)OC)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a stirring solution of methyl 2-methyl-2-(methylsulfonyl)-4-(4-((trimethylsilyl)ethynyl)phenyl)butanoate (9.4, 4.4 g, 12.0 mmol) in methanol (80 mL) was added K2CO3 (100 mg, 0.720 mmol) and the reaction was stirred at room temperature for 3 hr. The reaction mixture was filtered through celite, concentrated under reduced pressure to give a residue, which was dissolved in DCM, filtered and concentrated under reduced pressure to yield methyl 4-(4-ethynylphenyl)-2-methyl-2-(methylsulfonyl)butanoate (9.5, 2.49 g, 70.5%). MS: m/z calcd for C15H18O4S 294.09. found [M+H]+ 295.2.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]2[CH2:15][CH2:14][CH2:13]2)[N:1]=[C:17]([CH3:24])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OCC1CCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(cyclobutylmethoxy)benzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) and ethyl 3-oxobutanoate as an orange solid (26%). 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, J=8.0 Hz, 3H), 1.83-1.90 (m, 4H), 2.10-2.13 (m, 2H), 2.59 (s, 3H), 2.86 (m, 1H), 4.16 (d, J=4.0 Hz, 2H), 4.32 (q, J=8.0 Hz, 2H), 6.90 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 8.05 (brs, 2H). MS 315 (MH+).
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[O:11][CH:10]=[CH:9][C@@H:8]([OH:12])[C@@H:7]1[OH:13])(=[O:3])[CH3:2].[Cl:14][CH2:15][C:16](OC=C)=[O:17]>C(COC)OC>[C:1]([O:4][CH2:5][C@H:6]1[O:11][CH:10]=[CH:9][C@@H:8]([O:12][C:16](=[O:17])[CH2:15][Cl:14])[C@@H:7]1[OH:13])(=[O:3])[CH3:2]
Reactant: C=COC(=O)CCl
Reactant: CC(=O)OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Solvent: COCCOC
Product: CC(=O)OC[C@H]1OC=C[C@@H](OC(=O)CCl)[C@@H]1O
Yield: 80 %

Procedure:
1.03 g (5.5 mmol) of 6-O-acetylglucal are taken up in about 2-5 ml of dimethoxyethane and 10 ml of vinyl chloroacetate and stirred with 1 g of lipase P (Amano) at room temperature for about 2-3 h. Filtering off the enzyme, concentration of the solution and chromatography on silica gel (ether/hexane 1:2) result in 6-O-acetyl-3-O-chloroacetyl-glucal in 80-85% yield.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:47][CH:48]1[CH2:52][N:51]([CH2:53][CH3:54])[N:50]([CH2:55][CH3:56])[CH2:49]1>>[CH2:55]([N:50]1[CH2:49][CH:48]([NH:47][C:19](=[O:21])[CH2:18][C:15]2[CH:14]=[CH:13][C:12]([O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])=[CH:17][CH:16]=2)[CH2:52][N:51]1[CH2:53][CH3:54])[CH3:56]
Reactant: CCN1CC(N)CN1CC
Reactant: CC(C)=CCC/C(C)=C/COc1ccc(CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Product: CCN1CC(NC(=O)Cc2ccc(OC/C=C(\C)CCC=C(C)C)cc2)CN1CC
Temperature: 25 °C
Reaction time: 6 h
Yield: 95.3 %

Procedure:
To a solution of 4-geranyloxyphenylacetic acid (1.50 g) in tetrahydrofuran anhydride (30 ml) were added 1- hydroxybenzotriazole (0.85 g), N,N'- dicyclohexyl carbodiimide (1.29 g), and 4-amino-1,2- diethylpyrazolidine (0.75 g) while being cooled with ice and then the mixture was stirred for 6 hours at room temperature. The reaction solution was filtered so as to filter out the deposited product and the filtrate was concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1), thereby yielding 2.05 g (95%) of the aimed compound.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15]C)=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1.[OH-].[Na+]>O1CCCC1>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[NH:3]1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1NC2=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)Sc1ccccc1NC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dissolve 1.49 gm of the ester of Example 2 in 50 cc of tetrahydrofuran. Add 40 cc of 10% sodium hydroxide and stir at room temperature for 3 hours. Evaporate the tetrahydrofuran and extract the aqueous residue with ethyl acetate. Acidify and separate the precipitate by filtration. Wash the precipitate well with water and dry in vacuo to obtain the title product (m.p. 362°-364° C.).
Reaction SMILES: [ClH:1].C[O:3][C:4]([CH2:6][C:7]1[CH:37]=[CH:36][C:10]([C:11]([NH:13][CH2:14][C:15]2[O:19][C:18]([C:20]([O:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:33](=[NH:35])[NH2:34])[CH:29]=4)[CH:24]=3)=[O:21])=[CH:17][CH:16]=2)=[O:12])=[CH:9][CH:8]=1)=[O:5].Cl>C(O)(=O)C>[ClH:1].[C:4]([CH2:6][C:7]1[CH:37]=[CH:36][C:10]([C:11]([NH:13][CH2:14][C:15]2[O:19][C:18]([C:20]([O:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:33](=[NH:34])[NH2:35])[CH:29]=4)[CH:24]=3)=[O:21])=[CH:17][CH:16]=2)=[O:12])=[CH:9][CH:8]=1)([OH:5])=[O:3]
Reactant: COC(=O)Cc1ccc(C(=O)NCc2ccc(C(=O)Oc3ccc4cc(C(=N)N)ccc4c3)o2)cc1
Agent: Cl
Solvent: CC(=O)O
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(CNC(=O)c4ccc(CC(=O)O)cc4)o3)ccc2c1
Yield: 44.5 %

Procedure:
To 3 g of 6-amidino-2-naphthyl 5-(4-methoxycarbonylmethylbenzoylaminomethyl)furan-2-carboxylate hydrochloride was added 60 ml of acetic acid, and hydrogen chloride gas was passed into the mixture until saturation while cooling with ice and stirring. Thereafter the mixture was stirred for 48 hours at 50° C. and then cooled with ice. The precipitate was collected by filtration and washed with 100 ml of acetone. The crystals were dissolved in 40 ml of DMF, then 1 g of active carbon was added to the solution and stirred for 1 hour while cooling with ice. Thereafter, the insolubles were removed by filtration, 90 ml of acetone was added to the filtrate and stirred for 18 hours at room temperature. The precipitate was collected by filtration and washed with 50 ml of acetone to obtain 1.3 g of the intended product.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=1.[Li+].CC([N-]C(C)C)C.Br[CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)Cc1ccc(Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(CC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
n-BuLi (1.60M in hexanes, 35.6 mL, 56.9 mmol) was added to a 0° C. solution of diisopropylamine (8.35 mL, 59.6 mmol) in THF (200 mL). The mixture was allowed to stir at 0° C. for 30 minutes, and was then cooled to −78° C. A solution of methyl 2-(4-chlorophenyl)acetate (10.0 g, 54.2 mmol) in THF (10 mL) was added to the −78° C. LDA solution by syringe, which was then stirred for 45 minutes. Neat tert-butyl bromoacetate (9.60 mL, 65.0 mmol) was added by syringe, and the reaction was stirred for 15 minutes at −78° C. The bath was removed, and the reaction was allowed to warm to room temperature. After stirring an additional 5 hours, the reaction mixture was quenched with saturated NH4Cl solution, and the solvent(s) were removed in vacuo. The oily mixture was extracted with ethyl acetate, and the organics were combined. The organic portion was dried over MgSO4, filtered, and concentrated in vacuo. The crude oil was purified on silica gel (95:5 hexanes:EtOAc) to afford the 4-tert-butyl 1-methyl 2-(4-chlorophenyl)succinate as a pale yellow oil (14.3 g, 88%). 1H NMR (CDCl3, 400 MHz) δ 7.29 (d, J=7.2 Hz, 2H), 7.22 (d, J=7.2 Hz, 2H), 4.00 (dd, J=9.6, 5.6 Hz, 1H), 3.67 (s, 3H), 3.07 (dd, J=16.4, 9.6 Hz, 1H), 2.58 (dd, J=16.8, 6.0 Hz, 1H), 1.40 (m, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]2[C:7]([C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)=[O:11])=[CH:8][O:9][C:5]=2[C:4]=1[N+:26]([O-])=O.C([O-])=O.[NH4+].COCCOC>[Pd].CO>[NH2:26][C:4]1[C:5]2[O:9][CH:8]=[C:7]([C:10]([C:12]3[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=3)=[O:11])[C:6]=2[CH:24]=[CH:25][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C(=O)c2coc3c([N+](=O)[O-])c(OC)ccc23)cc(OC)c1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: CO
Product: COc1cc(C(=O)c2coc3c(N)c(OC)ccc23)cc(OC)c1OC
Temperature: 25 °C
Yield: 54 %

Procedure:
A mixture of 0.022 g (0.057 mmol) of (6-methoxy-7-nitrobenzofuran-3-yl)(3,4,5-trimethoxyphenyl)methanone, 0.1 g of ammonium formate and 0.1 g of 10% palladium on carbon in 5 ml of a mixture of 1,2-dimethoxyethane and methanol (4:1) was refluxed for 30 minutes (TLC controlled reaction). After cooling to room temperature the mixture was filtered through a pad of Celite and washed with methylene chloride. The filtrates were evaporated to dryness under reduced pressure and the residue was purified by flash column chromatography to give 0.011 g (55% yield) of pure title compound as a colorless solid; 1H NMR (CDCl3) δ 3.89 (s, 6H, OMe); 3.92 (s, 6H, OMe); 4.01 (broad s, 2H, NH2); 6.95 (d, 1H, CH aromatic, J=8.54 Hz); 7.14 (s, 2H, CH aromatic); 7.46 (d, 1H, CH aromatic, J=8.54 Hz); 8.0 (s, 1H, CH furan).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]1([CH2:47][CH2:48][CH2:49][NH2:50])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:50][CH2:49][CH2:48][CH2:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCCCc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCCc1ccccc1

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 3-phenylpropylamine (41 uL) according to Method A to give the title compound (48 mg). 1H-NMR (400 MHz, CD3OD) d 7.79 (s, 1H), 7.40 (d, J=8.5 Hz, 1H), 7.26-7.13 (m, 10H), 6.99 (d, J=8.5 Hz, 1H), 4.72 (s, 2H), 4.52 (t, J=6.8 Hz, 1H), 4.25 (dd, J=5.3 Hz, J=9.2 Hz, 1H), 3.18 (m, 1H), 3.09-2.92 (m, 4H), 2.77 (dd, J=9.5 Hz, J=13.5 Hz, 1H), 2.50 (t, J=7.7 Hz, 2H), 1.69 (m, 2H), 1.34 (s, 9H); IR (KBr) 3302, 2926, 1736, 1686, 1646 cm−1; HRMS m/z 647.2823 (calc. of monoisotopic mass for C35H41N3O9 gives 647.2823).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[N:17]=[C:16]([N:18]4[CH2:22][CH2:21][CH2:20][C:19]4=[O:23])[CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(=O)([O-])O.[Na+].O1CCOCC1.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>[NH2:1][C:2]1[N:3]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:5]2[N:10]=[N:9][N:8]([CH2:11][C:12]3[N:17]=[C:16]([N:18]4[CH2:22][CH2:21][CH2:20][C:19]4=[O:23])[CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1nc(Cl)c2nnn(Cc3cccc(N4CCCC4=O)n3)c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1nc(-c2ccccc2)c2nnn(Cc3cccc(N4CCCC4=O)n3)c2n1
Yield: 178.5 %

Procedure:
A mixture of 1-[6-(5-amino-7-chloro[1,2,3]triazolo[4,5-d]pyrimidin-3-ylmethyl)pyridin-2-yl]pyrrolidin-2-one (0.50 g, 1.45 mmol) and phenylboronic acid (0.354 g, 2.90 mmol) in saturated aqueous sodium hydrogen carbonate (5 mL) and 1,4-dioxane (20 mL) was degassed with a stream of nitrogen for 10 min then treated with tetrakis(triphenylphosphine)palladium(0) (0.083 g, 0.0725 mmol), refluxed for 2 h then partitioned between EtOAc and water. The organic phase was separated and the aqueous phase re-extracted with EtOAc (×2). The combined organic extracts were dried (MgSO4), concentrated in vacuo to give a yellow solid (1.00 g) which was purified by column chromatography [SiO2; EtOAc-hexane (1:1) then EtOAc]. The resulting yellow solid (0.68 g) was triturated with diethyl ether to give the title compound (0.38 g, 68%) as an off-white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35]>>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:31][CH2:30][N:29]([C:34]([N:33]([CH3:37])[CH3:32])=[O:35])[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)C(=O)Cl
Product: CN(C)C(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Yield: 34.1 %

Procedure:
(5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (75 mg, 0.183 mmol) was reacted with dimethylcarbamoyl chloride (14 uL, 0.192 mmol), according to the procedure of Example 126. The crude product was triturated with 1:1 ether-hexanes to yield (30 mg, 34%) desired product. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.91 (s, 1 H), 7.81 (d, 1 H), 7.59 (s, 1H), 7.45-7.32 (m, 6 H), 7.13 (d, 1 H), 6.65 (s, 1 H), 5.64 (s, 2 H), 3.76 (m, 2 H), 3.42 (m, 3 H), 3.29 (m, 1 H), 2.73 (s, 6 H), 2.31-1.95 (m, 2 H); ES-MS m/z 481.2 [M+H]+, HPLC RT (min) 2.57.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7](OC)=[C:5](O)[CH:4]=1.C[C:13]([CH3:16])([O-:15])[CH3:14].[K+].[CH2:18](O)[CH2:19]C>>[CH:13]1([O:15][C:4]2[CH:5]=[CH:7][CH:10]=[CH:11][C:3]=2[CH:2]=[O:1])[CH2:16][CH2:19][CH2:18][CH2:14]1
Reactant: COc1ccc(C=O)cc1O
Reactant: CCCO
Reactant: CC(C)(C)[O-]
Agent: [K+]
Product: O=Cc1ccccc1OC1CCCC1
Reaction time: 3 h
Yield: 77.5 %

Procedure:
77.70 g (500 mmoles) of isovanillin and 69.40 g (600 mmoles) of 97% potassium t-butoxide (t-BuOK) dissolved in 800 ml of 1-propanol, 69.0 ml 630 mmoles), and the solution refluxed. After 3 hours another 9.25 g (80 mmoles) of t-BuOK were added at 80° C. and the suspension refined for another 3 hours. The solid was filtered off and the filtrate evaporated in vacuo to dryness. The residue was dissolved in ether and extracted with 1N NaOH. The ether phase was evaporated to dryness: 85.40 g (77.5%) of cyclopentyloxybenzaldehyde was isolated.
Reaction SMILES: [CH:1]1([C:4]2[C:9]([C:10]#N)=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.Cl.[OH-:22].[Na+]>C1(C)C=CC=CC=1>[CH:1]1([C:4]2[C:9]([CH:10]=[O:22])=[CH:8][CH:7]=[CH:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: N#Cc1cccnc1C1CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=Cc1cccnc1C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-cyclopropyl-3-cyano-pyridine (18.5 g, 128 mmol) was dissolved in toluene (400 ml) and DIBAL (1.01M in toluene, 153 ml) was added thereto at 0° C. After stirred at 0° C. for 1 h, the reaction mixture was poured into 2N HCl aq (90 ml); and 5N NaOH aq. (40 ml) was added thereto. The mixture was extracted with EtOAc and the organic layer was washed with brine, dried over MgSO4. The desiccant was removed through filtration, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane/EtOAc=10/0 to 7/3) to obtain the intended compound as a pale yellow solid.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[NH2:26][C:27]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:29][N:28]=1.NC1C=CNN=1>O1CCCC1>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:13])[C:3]2=[CH:2][NH:26][C:27]1[CH:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:29][N:28]=1
Reactant: O=C1Nc2ccc(Cl)cc2/C1=C/O
Reactant: Nc1cc(-c2ccccc2)[nH]n1
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: O=C1Nc2ccc(Cl)cc2C1=CNc1cc(-c2ccccc2)[nH]n1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-5-chloro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 3-amino-5-phenylpyrazole for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-5-chloro-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.1668 gms. of 3-amino-5-phenylpyrazole by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[NH:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)=O)[CH2:6][CH2:5]2>P(Cl)(Cl)(Cl)=O>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:5][CH2:6][N:7]3[C:8]2=[C:9]([CH:10]=1)[C:19]([N:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1)=[N:18][C:12]1[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=13
Reactant: Cc1ccc(N2CCc3cc(Br)ccc32)c(NC(=O)N2CCN(C)CC2)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc2c(c1)N=C(N1CCN(C)CC1)c1cc(Br)cc3c1N2CC3
Yield: 53.8 %

Procedure:
A solution of N-[2-(5-bromo-1-indolinyl)-5-methylphenyl]-4-methyl-1-piperazinecarboxamide (3.3 g, 7.68 mmoles) and phosphorus oxychloride (30 ml) was heated at reflux for 25 minutes under nitrogen. The solution was cooled and excess phosphorus oxychloride was removed at 55°-60° C. under vacuum. Ice-chilled 2N-sodium hydroxide solution (100 ml) and dichloromethane (250 ml) were added to the residue. The organic phase was separated and washed with brine (2 times, 100 ml), dried over anhydrous magnesium sulfate, and concentrated. Purification was accomplished by flash chromatography over aluminum oxide (Grade III, 100 g), eluted with dichloromethane (21). The fractions containing pure material were pooled and concentrated. Recrystallization from isopropanol (30 ml) yielded 1.7 g (53.9%) of product, mp 187°-189° C.