Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1.Cl.[Cl:15][C:16]1[CH:17]=[N:18][C:19](=[O:22])[NH:20][CH:21]=1>ClCCl>[F:11][C:10]([F:13])([F:12])[C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[O:3][CH2:2][N:20]1[CH:21]=[C:16]([Cl:15])[CH:17]=[N:18][C:19]1=[O:22]
Reactant: FC(F)(F)c1cccc(OCCl)c1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: ClCCl
Product: O=c1ncc(Cl)cn1COc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 1-chloromethoxy-3-trifluoromethylbenzene [see Preparation 4) (7 mmol) in dichloromethane (10 ml) was added to a solution of 5-chloropyrimidin-2-one hydrochloride (70 mmol) in dichloromethane (30 ml) and the mixture stirred at room temperature for 18 h. The solvent was then distilled off, the mixture triturated with water, the residual solid extracted with chloroform and the dried (MgSO4) chloroform solution evaporated; yield 1.88 g (94%). The product was a mixture of the N- and O-isomer in the ratio 3:1. The isomers were separated by the difference in their solutilities in tetrachloromethane, the O-isomer being the more solunble. The title compound, the N-isomer was isolated in a non-crystalline form. 1H NMR (CDCl3) δ 5.82 (CH2), 7.1-7.3 (Ph), 7.85 (H-4, J4,6 3 Hz), 8.45 (H-6).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)=O.CCOC(C)=O.CCCCCC.[N+:24]([CH3:27])([O-:26])=[O:25]>>[N+:24]([CH:27]=[CH:1][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2)([O-:26])=[O:25]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc2[nH]ccc2c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])C=Cc1ccc2[nH]ccc2c1
Yield: 11 %

Procedure:
5-Formyl indole (14.5 g) was refluxed with NH4OAc (10.0 g) in nitromethane ((100 mL) for 3 hours. The mixture was cooled and evaporated under reduced pressure. The residue was recrystallized from isopropanol to give the first portion of intermediate and the mother liquid was purified by chromatograph (EtOAc:hexane=1:4 to 2:3) to the second portion intermediate of 5-(2-nitro-vinyl)-1H-indole (2.09 g combined, in 11% yield), which was treated with NaBH4 (1.85 g) in methanol (150 mL) at room temperature for 35 min then quenched with acetic acid (4 mL), concentrated and followed by chromatography purification (EtOAc:hexane=1:9) to afford 5-(2-nitro-ethyl)-1H-indole (1.37 g) in 65% yield. This nitro compound was hydrogenated with Pd—C (10%) under atmosphere hydrogen in methanol overnight to afford 2-(1H-indol-5-yl)-ethylamine in 99% yield. LC-MS showed the product had the expected M+H+ of 161.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2Cl)=[N:13][C:12]([Cl:17])=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]2)=[N:23][CH:24]=1>>[Cl:17][C:12]1[N:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])=[C:15]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(N)cn2)C1
Reactant: O=C(c1cnc2ccc(Cl)nc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Cl)nc34)cn2)C1
Yield: 62.9 %

Procedure:
Following general procedure I, cyclopropyl(4,6-dichloro-1,5-naphthyridin-3-yl)-methanone (267 mg, 1.0 mmol) was reacted with (S)-tert-butyl 1-(5-aminopyridin-2-yl)-piperidin-3-ylcarbamate (340 mg, 1.2 mmol) to afford the desired product (329 mg, 63%) as a brown solid: 1H NMR (500 MHz, CDCl3) δ 10.19 (br s, 1H), 9.03 (s, 1H), 8.17 (d, J=8.8 Hz, 1H), 8.04 (d, J=2.8 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 7.31-7.25 (m, 1H), 6.70 (d, J=9.1 Hz, 1H), 4.78 (br s, 1H), 3.83-3.62 (m, 3H), 3.47-3.25 (m, 2H), 2.55-2.47 (m, 1H), 1.97-1.83 (m, 2H), 1.73-1.58 (m, 1H), 1.45 (s, 9H), 1.12-1.04 (m, 2H), 1.00-0.90 (m, 2H); ESI MS m/z 523 [M+H]+
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[CH2:15]([C:18]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[C:21]([CH2:28][CH2:29][CH3:30])=[C:20]([C:31]([O:33][CH3:34])=[O:32])[C:19]=1[C:35]([O:37][CH3:38])=[O:36])[CH2:16][CH3:17]>C1C=CC=CC=1>[CH2:15]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][CH2:29][CH3:30])=[C:20]([C:31]([O:33][CH3:34])=[O:32])[C:19]=1[C:35]([O:37][CH3:38])=[O:36])[CH2:16][CH3:17]
Reactant: CCCc1c2c(c(CCC)c(C(=O)OC)c1C(=O)OC)CCCC2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: CCCc1c(C(=O)OC)c(C(=O)OC)c(CCC)c2ccccc12
Yield: 70.6 %

Procedure:
2,3-Dichloro-5,6-dicyanobenzoquinone (1.362 g, 6.0 mmols) was added to a solution of dimethyl 1,4-dipropyl-5,6,7,8-tetrahydronaphthalene-2,3-dicarboxylate (0.665 g, 2.0 mmols) in benzene (20 ml). The mixture was then refluxed for 24 hours. After filtration, the solvent in the mixture was removed in vacuum. Column chromatography was performed using silica gel as the packing material to give the title compound (0.464 g ) as colorless crystals. The GC yield was 87% and the isolation yield was 71%.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][NH:18][CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:22][C:23]1[N:24]=[CH:25][C:26]([CH:29]=O)=[N:27][CH:28]=1>>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([C@H:16]4[C@H:20]([CH3:21])[CH2:19][N:18]([CH2:22][C:23]5[CH:28]=[N:27][C:26]([CH3:29])=[CH:25][N:24]=5)[CH2:17]4)[NH:13][C:14](=[O:15])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H]1CNC[C@H]1c1nc2c(cnn2C2CCCC2)c(=O)[nH]1
Reactant: Cc1cnc(C=O)cn1
Product: Cc1cnc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCCC4)c(=O)[nH]3)C2)cn1

Procedure:
Following the procedure for the preparation of 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(pyridin-3-ylmethyl)pyrrolidin-3-yl]-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting 1-cyclopentyl-6-[(3S,4S)-4-methylpyrrolidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one and 5-methylpyrazine-2-carbaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.53 (s, 1H), 8.53 (s, 1H), 8.01 (s, 1H), 5.16-5.05 (m, 1H), 4.02 (d, J=14.1 Hz, 1H), 3.74 (d, J=14.1 Hz, 1H), 3.45-3.41 (m, 1H), 3.38 (t, J=8.3 Hz, 1 Hz, 1H), 3.08 (d, J=9.9 Hz, 1H), 2.84-2.83 (m, 1H), 2.62-2.54 (m, 1H), 2.52 (s, 3H), 2.47-2.40 (m, 1H), 2.14-1.89 (m, 6H), 1.71-1.64 (m, 2H), 1.24-1.16 (m, 3H). MS: (M+H m/z=394.1).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:41][CH:42]([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:43]1[CH:48]=[CH:47][C:46]([P:49](=[O:56])([O:53][CH2:54][CH3:55])[O:50][CH2:51][CH3:52])=[CH:45][CH:44]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:41][CH:42]([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:43]2[CH:48]=[CH:47][C:46]([P:49](=[O:56])([O:50][CH2:51][CH3:52])[O:53][CH2:54][CH3:55])=[CH:45][CH:44]=2)=[O:10])=[CH:6][N:5]=[C:4]([C:11]2[N:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: O=C(O)c1cnc(-c2cccnn2)nc1O
Reactant: CCOP(=O)(OCC)c1ccc(C(N)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Product: CCOP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-c3cccnn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-hydroxy-2-(pyridazin-3-yl)pyrimidine-5-carboxylic acid, 30-ie, (137 mg, 0.63 mmol) in MeCN (10 mL) was added HATU (357 mg, 0.94 mmol), TEA (190 mg, 1.88 mmol) and diethyl 4-(amino(phenyl)methyl)phenylphosphonate, 2-c, (200 mg, 0.63 mmol). The solution was stirred at room temperature for 1 h. The product was precipitated from ice water (50 mL, crush ice). The product was collected by vacuum filtration and dried in a vacuum to afford a syrup, which was purified by pre-HPLC to yield title crude, 8-5, product as pale yellow (100 mg, 31%) 1H NMR (300 MHz, DMSO-d6) δ1.19-1.24 (t, J=7.5 Hz, 6H), 3.96-4.01 (q, J=7.5 Hz, 4H), 6.34-6.36 (d, J=6.0 Hz, 1H), 7.37-7.70 (m, 11H), 7.70 (m, 1H), 8.50 (m, 2H), 9.494 (d, J=3.0 Hz, 1H), 10.52 (s, 1H); LC-MS: (M+H)+ 520.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17].C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[O:35]>C1COCC1>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34](=[O:35])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: COc1ccccc1N=C=O
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1NC(=O)Nc1ccc(CC(=O)OC(C)(C)C)cc1OC
Reaction time: 96 h
Yield: 89.7 %

Procedure:
To a stirred solution of tert-butyl 4-amino-3-methoxylphenylacetate (1.41 g, 5.94 mmol) and triethylamine (165 ml, 1.19 mmol) in THF (20 ml) was added 2-methoxyphenyl isocyanate (790 ml, 5.94 mmol), and the resulting mixture was stirred for 4 days. The mixture was concentrated to a small volume in vacuo, and hexane was added to the residue to give precipitate, which was collected to give tert-butyl 4-[N′-(2-methoxyphenyl)ureido]-3-methoxylphenylacetate (2.06 g, 90%) as a white crystalline material. mp 132–134° C.; 1H-NMR (CDCl3) δ 1.46 (s, 9 H), 3.50 (s, 2 H), 3.87 (s, 3 H), 3.88 (s, 3 H), 6.84 (s, 1 H), 6.87–6.90 (m, 2 H), 6.98–7.03 (m, 2 H), 7.12 (s, 1 H), 7.16 (s, 1 H), 8.06 (d, J=8.4 Hz, 1 H), 8.13 (dd, J=7.2, 2.0 Hz, 1 H); MS (ESI) m/z 387 (N++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CCN(C(C)C)C(C)C.[NH2:46][CH2:47][CH2:48][C:49]1[CH:60]=[CH:59][C:52]([CH2:53][NH:54][CH2:55][CH:56]([CH3:58])[CH3:57])=[CH:51][CH:50]=1>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([NH:46][CH2:47][CH2:48][C:49]3[CH:60]=[CH:59][C:52]([CH2:53][NH:54][CH2:55][CH:56]([CH3:58])[CH3:57])=[CH:51][CH:50]=3)=[O:22])[CH:17]=2)[CH3:14])(=[O:11])=[O:12])=[C:5]([CH3:24])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: CC(C)CNCc1ccc(CCN)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCCc3ccc(CNCC(C)C)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (60 mg, 0.15 mmol), CDI (46 mg, 0.27 mmol), DIPEA (0.134 mL, 0.76 mmol) and N-[4-(2-aminoethyl)benzyl]-2-methylpropan-1-amine (40 mg, 0.14 mmol) in DCE (1 mL). A portion of the crude product was purified using prep method A.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:10](Cl)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1.[C:13]1([S:19][CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH:5]1([C:10]([C:16]2[CH:17]=[CH:18][C:13]([S:19][CH3:20])=[CH:14][CH:15]=2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CSc1ccccc1
Reactant: O=C(Cl)C1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: CSc1ccc(C(=O)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
To a suspension of anhydrous aluminum chloride (9.3 g, 69.6 mmol) in 58 mL CHCl3 at 0° C. was added dropwise cyclopentanecarbonyl chloride (10.0 g, 75.4 mmol), followed by thioanisole (7.21 g, 58.0 mmol). The ice bath was removed and the mixture was stirred at room temperature for 2 h. Water (200 ml) was added with cooling, the layers were separated and the aqueous layer was extracted with CHCl3 (3×50 mL). The combined aqueous layers were dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel (4% EtOAc/hexane) to give 11.9 g of the title ketone (93%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[NH:28][CH2:29][CH2:30][NH2:31]>>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH:2]([OH:4])[CH2:3][NH:31][CH2:30][CH2:29][NH:28][C:22]2[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=2[CH3:20])=[CH:7][CH:8]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Reactant: Cc1cccc(C)c1NCCN
Product: Cc1cccc(C)c1NCCNCC(O)COc1ccc(OCc2ccccc2)cc1

Procedure:
5.12 g. 4-Benzyloxyphenyl glycidyl ether and 6.56 g. N-(2,6-dimethylphenyl)-ethylenediamine are heated for 20 hours at 70° C., while stirring. The reaction mixture is worked up by ion exchanger chromatography, using "Amberlite" CG 50 II pract. (Serva) in the manner described in Example 5. There are obtained 6.8 g. (81% of theory) of the desired product in the form of a light colored, viscous oil.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:28])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[NH:19][C:18]2=[O:27])[CH:11]=1.CO.[Li+].[OH-].Cl>O>[F:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:27])[C:17]2=[CH:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([NH:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:29])=[O:2])=[O:28]
Reactant: COC(=O)CCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCNC(=O)c1cccc(C=C2C(=O)Nc3ccc(F)cc32)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.9 %

Procedure:
5-(3-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)pentanoic acid methyl ester (396 mg, 1 mmol) and 300 ml of CH3OH were stirred at room temperature while 25 ml of 4 N solution of LiOH in H2O was added. The mixture was stirred for 24 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid to pH 7 and evaporated under vacuum to remove methanol. The residue was adjusted to pH 3 with concentrated hydrochloric acid. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (294 mg, 77% yield) as a brown solid. LC-MS (m/z) 383 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=O)=[CH:14][CH:13]=1)#[N:10]>N1C=CC=CC=1>[C:9]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[O:8][C:3]3[C:2]([N:1]=2)=[CH:7][CH:6]=[CH:5][N:4]=3)=[CH:14][CH:13]=1)#[N:10]
Reactant: Nc1cccnc1O
Reactant: N#CCc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: N#CCc1ccc(-c2nc3cccnc3o2)cc1
Reaction time: 8 h

Procedure:
Ten grams of 4-(cyanomethyl)benzoic acid is refluxed in 70 mls. of thionyl chloride for four hours. The solvents are removed leaving a residue of 4-cyanomethylbenzoyl chloride. To a solution of 5.5 g. of 3-amino-2-hydroxy pyridine in cold pyridine there is added slowly, with cooling, 8 g. of 4-cyanomethyl benzoyl chloride. The mixture is allowed to come to room temperature and stirred overnight. The mixture is added to 300 ml. of ice and the solid amide separated by filtration and recrystallized from methanol. A mixture of 3 g. of the above amide in 50 mls. of phsophorus oxychloride is heated under reflux for 5 hours. The solvents are removed in vacuo and the residue is crystallized from ethyl acetate to give 2-(4-cyanomethylphenyl)oxazolo[5,4-b]pyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][CH2:20][C:21]([NH2:23])=[O:22].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:19][CH2:20][C:21](=[O:22])[NH2:23])=[O:15])=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(OCc2ccccc2)nc1
Reactant: NCC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: NC(=O)CNC(=O)c1ccc(OCc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of 6-benzyloxy-nicotinic acid (500 mg, 2.18 mmol), glycinamide HCI (265 mg, 2.4 mmol), 4-dimethylamino pyridine (133 mg; 1.09 mmol), N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide HCl (460 mg; 2.4 mmol) and methylene chloride (10 ml) was stirred at 0° C. for 1 h then at r.t. overnight. The precipitate was filtered off and washed with methylene chloride and water. The title compound was obtained as a white solid (328 mg; 53%). MS: m/e=286.2 (M+H+).
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[CH2:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH2:30][CH3:31]>C1COCC1>[CH2:29]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:2]#[N:3])=[CH:34][CH:33]=1)[CH2:30][CH3:31]
Reactant: N#CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCc1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCc1ccc(C=CCCCCCC#N)cc1
Yield: 67.3 %

Procedure:
This compound was synthesized from 6-cyanohexyltriphenylphosphonium bromide (9.05 g, 20 mmol) and p-propylbenzaldehyde (2.96 g, 20 mmol) in THF (100 mL) by a Wittig reaction. Kugelrohr distillation afforded the product (3.25 g, 67%) as a colorless liquid (bp 144°-148° C./0.05 torr). IR 2290 cm-1 ; 1H-NMR: 0.95 (t, 3H), 1.55 (m, 8H), 2.40 (m, 6H), 5.60 (m, 1H), 6.40 (d, 1H), 7.10 (s, 4H).
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[CH:20][C:21]2[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[CH:18]=O)=[CH:13][CH:12]=1>Cl.CO>[C:7]([NH:6][N:5]=[CH:18][C:17]([C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)=[CH:20][C:21]1[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)(=[NH:9])[NH2:8]
Reactant: O=CC(=Cc1ccc([N+](=O)[O-])s1)c1ccc(Cl)cc1
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: CO
Product: N=C(N)NN=CC(=Cc1ccc([N+](=O)[O-])s1)c1ccc(Cl)cc1

Procedure:
A solution of 0.46 g of aminoguanidine hydrogen carbonate in 5 cc of 10% hydrochloric acid is added to 1.0 g of 2-(4-chlorophenyl)-3-(5-nitro-2-thienyl)acrolein in 20 cc of methanol, and the mixture is heated to 50° for one hour. Upon cooling, the hydrochloride of the title compound is obtained as yellow crystals having a M.P. of 225°-227°.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:28](=[O:29])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[CH3:30])[C:21]3=[O:31])[CH2:16][C:17](O)=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:45][OH:46]>C1COCC1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([N:20]3[C:28](=[O:29])[C:27]4=[C:26]([CH3:30])[CH:25]=[CH:24][CH:23]=[C:22]4[C:21]3=[O:31])[CH2:16][C:17]([NH:45][OH:46])=[O:18])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3cccc(C)c3C2=O)cc1OC1CCCC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2C(=O)c3cccc(C)c3C2=O)cc1OC1CCCC1
Yield: 94.2 %

Procedure:
3-(3-Cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-(3-methylphthalimido)propionamide was prepared by the procedure of Example 1 from 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-(4-methyl-1,3-dioxoisoindolin-2-yl)propanoic acid (5.44 g, 12.9 mmol), carbonyldiimidazole (2.19 g, 13.5 mmol) and hydroxylamine hydrochloride (1.16 g, 16.7 mmol) in THF (32 mL) to afford 3-(3-cyclopentyloxy-4-methoxyphenyl)-N-hydroxy-3-(3-methylphthalimido)propionamide as a white solid (5.33 g, 94.6%): mp, 187.5–189.5° C.; 1H NMR (DMSO-d6) δ 1.55–1.87 (m, 8H, C5H8), 2.61 (s, 3H, CH3), 3.12 (d, J=7.8 Hz, 2H, CH2), 3.70 (s, 3H, OCH3), 4.62–4.83 (m, 1H, OCH), 5.66 (t, J=7.8 Hz, 1H, CH), 6.90–7.10 (m, 3H, Ar), 7.52–7.80 (m, 3H, Ar), 8.79 (s, 1H, OH), 10.59 (s, 1H, NH); 13C NMR (DMSO-d6) δ 16.9, 23.5, 32.1, 34.2, 49.9, 55.5, 79.6, 112.1, 114.2, 119.7, 120.7, 127.8, 131.3, 131.6, 137.2, 146.7, 149.1, 166.0, 167.5, 168.3; Anal. Calcd. for C24H26N2O6: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.63; H, 5.86; N, 6.24.
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([F:23])[C:21]=1[F:22])[NH2:18]>C(#N)C>[CH3:6][O:5][C:3](=[O:4])[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[NH:18][C:17]1[CH:16]=[C:15]([F:14])[C:21]([F:22])=[C:20]([F:23])[CH:19]=1
Reactant: COC(=O)C(Br)c1cccc(F)c1
Reactant: Nc1cc(F)c(F)c(F)c1
Solvent: CC#N
Product: COC(=O)C(Nc1cc(F)c(F)c(F)c1)c1cccc(F)c1
Temperature: 120 °C
Yield: 53.3 %

Procedure:
Methyl 2-bromo-2-(3-fluorophenyl)acetate (300 mg, 1.21 mmol) and 3,4,5-trifluoroaniline (268 mg, 1.82 mmol) were dissolved in acetonitrile (4 ml) and stirred under microwave heating into a sealed vial at 120° C. for 1 hours. Some crystals of KI were added, and the resulting mixture was stirred under the same conditions for 1 hour (UPLC-MS: conversion complete). Solvent was evaporated, and the crude residue was purified by flash chromatography (Petroleum ether/EtOAc=9/1) to obtain (3-fluoro-phenyl)-(3,4,5-trifluoro-phenylamino)-acetic acid methyl ester (202 mg, 53% yield).
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.C([Mg]Cl)(C)C.[CH2:18]([Sn:22]([CH2:28][CH2:29][CH2:30][CH3:31])([CH2:24][CH2:25][CH2:26][CH3:27])Cl)[CH2:19][CH2:20][CH3:21]>C1COCC1>[S:9]1[CH:10]=[CH:11][CH:12]=[C:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Sn:22]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:18][CH2:19][CH2:20][CH3:21])[CH:7]=1
Reactant: Ic1cc(-c2cccs2)ccn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cc(-c2cccs2)ccn1
Temperature: -16 °C
Reaction time: 0.33 h

Procedure:
In a round-bottomed flask, 2-iodo-4-thiophen-2-yl-pyridine (150 mg, 0.52 mmol) was dissolved in THF (3.2 mL). The light yellow solution was cooled to −16° C. (NaCl/ice bath) and isopropylmagnesium chloride (2.0M solution in THF, 0.30 mL, 0.60 mmol) was added dropwise. The reaction mixture was stirred at −16° C. for 20 min then tributylchlorostannane (0.17 mL, 0.63 mmol) was slowly added. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched with saturated NH4Cl solution and then extracted with 50 mL EtOAc (2×). The combined organic layers were washed with 5 mL water and once with 5 mL brine then dried over sodium sulfate, filtered and concentrated to afford 4-thiophen-2-yl-2-(tributylstannanyl)pyridine a light brown oil which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[C:4]([CH2:11]Br)[CH:3]=1.[NH2:13][CH2:14][CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[N:13]([CH2:14][CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21])[CH2:11]2
Reactant: CN1CCCC1CCN
Reactant: O=C([O-])c1ccc(Br)cc1CBr
Product: CN1CCCC1CCN1Cc2cc(Br)ccc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 6 starting from 4-bromo-2-(bromomethyl)benzoate and 2-(2-aminoethyl)-1-methylpyrrolidine (Aldrich Cat No. D139505). LCMS (M+H)+=323.0.