Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:46])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15]([NH:29][CH2:30][CH2:31][NH:32][C:33]4[CH:38]=[CH:37][C:36]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[C:35]([NH2:45])[N:34]=4)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:8][CH2:7]1)C.O.[OH-].[Na+]>COCCOC>[NH2:45][C:35]1[N:34]=[C:33]([NH:32][CH2:31][CH2:30][NH:29][C:15]2[N:14]3[N:13]=[C:12]([CH:9]4[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:46])=[O:3])[CH2:7][CH2:8]4)[N:20]=[C:19]3[CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:16]=2)[CH:38]=[CH:37][C:36]=1[C:39](=[O:44])[C:40]([F:41])([F:43])[F:42]
Reactant: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C(=O)C(F)(F)F)c(N)n4)n3n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: Nc1nc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(CC(=O)O)CC4)nn23)ccc1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
130 mg (0.19 mmol) of ethyl(4-{5-[(2-{[6-amino-5-(trifluoroacetyl)pyridin-2-yl]amino}ethyl)-amino]-7-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-c]pyrimidin-2-yl}piperidin-1-yl)acetate (Example 56A) were dissolved in 1,2-dimethoxyethane (7.5 ml), water (5 ml) and 31 mg (0.76 mmol) of sodium hydroxide were added and the reaction mixture was stirred at RT for 16 h. The mixture was then concentrated by lyophilization. This gave, after purification of the residue by preparative HPLC (Method 11), 60 mg (48% of theory) of the product as a solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:10]([O:12]C)=O)=[N:5][C:6]([Cl:9])=[CH:7][CH:8]=1.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>CO>[Cl:9][C:6]1[N:5]=[C:4]2[C:10](=[O:12])[N:20]([CH2:19][C:18]3[CH:21]=[CH:22][C:15]([F:14])=[CH:16][CH:17]=3)[CH2:2][C:3]2=[CH:8][CH:7]=1
Reactant: COC(=O)c1nc(Cl)ccc1CBr
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: O=C1c2nc(Cl)ccc2CN1Cc1ccc(F)cc1
Yield: 71.3 %

Procedure:
A solution of methyl 3-(bromomethyl)-6-chloropicolinate (100 mg, 0.38 mmol) and 4-fluorobenzylamine (237 mg, 1.89 mmol) in MeOH (10 mL) was stirred at 15° C. overnight. After the reaction, it was filtered to afford crude 2-chloro-6-(4-fluorobenzyl)-5H-pyrrolo[3,4-b]pyridin-7(6H)-one (75 mg, yield: 72%). 1H-NMR (CDCl3, 400 MHz) δ 7.73 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.28˜7.31 (m, 2H), 7.05 (t, J=8.4 Hz, 2H), 4.82 (s, 2H), 4.25 (s, 2H). MS (M+H)+: 277/279.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[N:9])[C:3]=1[C:10]#[N:11].O.[NH2:13][NH2:14]>C(O)C>[NH2:11][C:10]1[C:3]2[C:4]([C:8]#[N:9])=[CH:5][CH:6]=[CH:7][C:2]=2[NH:14][N:13]=1
Reactant: NN
Reactant: N#Cc1cccc(F)c1C#N
Solvent: O
Solvent: CCO
Product: N#Cc1cccc2[nH]nc(N)c12
Temperature: 70 °C
Yield: 86.9 %

Procedure:
3-Fluoro-1,2-benzenedicarbonitrile (APIN) (5 g, 34.2 mmol) was dissolved in ethanol (80 mL) and hydrazine monohydrate (4.98 mL, 103 mmol) was added to the solution. The reaction was heated at 70° C. overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic layer was washed with water (100 mL). The aqueous layers were extracted with ethyl acetate (200 mL). Organic layers were combined, dried over anhydrous magnesium sulfate and evaporated in vacuo to give the title compound (4.7 g, 87%) as a yellow solid. LCMS (System A) RT=0.53 min, ES+ve m/z 159 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:22])[CH2:11][C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=[CH:6][CH:5]=1.O.C(Cl)[Cl:26]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:22])[CH:11]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[Cl:26])=[CH:8][CH:9]=1
Reactant: ClCCl
Reactant: COC(=O)c1ccc(C(=O)CC(=O)OCc2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)C(Cl)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4.0 g (12.8 mmols) of 4-benzyloxycarbonylacetyl-benzoic acid methylester, dissolved in 40 ml of toluene, are mixed with 19.2 ml of a 1 M solution of SO2Cl2 in CH2Cl2 and stirred for 30 min at RT. At 0° C., water is added and the aqueous phase is separated and extracted twice with EtOAc. The organic phases are washed twice with sat. NaHCO3 solution, H2O and brine, dried (Na2SO4) and concentrated by evaporation. Column chromatography (SiO2; hexane/EtOAc 9:1→4:1; crude product dissolved in CH2Cl2) yielded the title compound as an oil: MS: [M+1]+=347; TLC(hexane/EtOAc 4:1) Rf=0.19.
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:17])OC)[N:9]=1)[C:2]([NH2:4])=[NH:3].[NH2:18][OH:19].Cl.NO.C[O-].[Na+]>CO>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[N:18][OH:19])[NH2:17])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: N=C(N)Nc1nc(CSCCC(N)=NO)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 35 ml of methanol was dissolved 4.72 g of methyl 3-[(2-guanidinothiazol-4-yl)methylthio]propionimidate and then 25 ml of a methanol solution of free hydroxylamine prepared by treating 1.2 g of hydroxylamine hydrochloride with 0.93 g of sodium methoxide was added to the solution. After stirring the mixture for 2 hours at room temperature, the solvent was distilled off under reduced pressure and the residue formed was purified by a column chromatography using a mixed solvent of chloroform and methanol as a developing solvent and recrystallized from methanol-acetone to provide 1.3 g of 3-[(2-guanidinothiazol-4-yl)methylthio]propionamidoxime. The product has the following physicochemical properties:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([C:10]1[CH:14]=[C:13]([NH:15][C:16]([NH:18][C@@H:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:22]([O:29][C:30]3[CH:31]=[CH:32][C:33]4[N:34]([C:36]([N:39]5[C@H:44]([CH3:45])[CH2:43][CH2:42][CH2:41][C@@H:40]5[CH3:46])=[N:37][N:38]=4)[CH:35]=3)[CH2:21][CH2:20]2)=[O:17])[N:12]([C:47]2[CH:48]=[C:49]([CH:58]=[CH:59][CH:60]=2)[O:50][CH2:51][CH2:52]OS(C)(=O)=O)[N:11]=1)([CH3:9])([CH3:8])[CH3:7]>C1COCC1>[C:6]([C:10]1[CH:14]=[C:13]([NH:15][C:16]([NH:18][C@@H:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C@H:22]([O:29][C:30]3[CH:31]=[CH:32][C:33]4[N:34]([C:36]([N:39]5[C@H:40]([CH3:46])[CH2:41][CH2:42][CH2:43][C@@H:44]5[CH3:45])=[N:37][N:38]=4)[CH:35]=3)[CH2:21][CH2:20]2)=[O:17])[N:12]([C:47]2[CH:60]=[CH:59][CH:58]=[C:49]([O:50][CH2:51][CH2:52][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:48]=2)[N:11]=1)([CH3:7])([CH3:8])[CH3:9]
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN5CCCC5)c4)c4ccccc43)cn12
Temperature: 60 °C
Yield: 25.9 %

Procedure:
Pyrrolidine (36 μL, 0.43 mmol) was added to a solution of Intermediate 96f (111 mg, 0.14 mmol) in THF (2 mL). The reaction was heated to 60° C. in a sealed vial overnight. The mixture was cooled, evaporated in vacuo and the residue was purified by FCC, using 0-15% MeOH in DCM, then triturated with Et2O to give the title compound (27 mg, 25%) as an off-white solid. LCMS (Method 5): Rt 3.87 min, m/z 746.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.55 (3H, d, J=6.0 Hz), 0.58 (3H, d, J 6.0 Hz), 1.23 (9H, s), 1.32-1.54 (3H, m), 1.53-1.78 (7H, m), 1.79-1.95 (2H, m), 1.96-2.10 (2H, m), 2.49-2.60 (2H, m), 2.68-2.94 (2H, m), 3.06-3.20 (3H, m), 3.27 (1H, m, obscured by water), 4.03-4.14 (2H, m), 4.74-4.83 (1H, m), 5.49 (1H, t, J=4.0 Hz), 6.29 (1H, s), 6.90-6.96 (1H, m), 7.01-7.09 (3H, m), 7.16 (1H, dd, J=9.7, 2.0 Hz), 7.19-7.25 (2H, m), 7.26-7.32 (2H, m), 7.33-7.39 (1H, m), 7.62 (1H, d, J=9.7 Hz), 7.84 (1H, m), 8.06 (1H, s).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:6]2.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:45]I>C1COCC1>[I:45][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[NH:8][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:6]2
Reactant: O=[N+]([O-])c1cc(CO)cc2cc(-c3ccccc3)[nH]c12
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(CI)cc2cc(-c3ccccc3)[nH]c12
Reaction time: 2 h

Procedure:
5-Hydroxymethyl-2-phenyl-7-nitro-1H-indole (804 mg, 3 mmol) prepared in Step A of Example 29 was dissolved in THF (10 mL), and imidazole (408 mg, 6 mmol) and triphenylphosphine (1.52 g, 6 mmol) were added thereto. Iodine (453 mg, 3.9 mmol) was added to the mixture, which was then stirred for 2 h. After completion of the reaction, the reaction mixture was filtered through a cellite, and the product was used in the next reaction without further purification.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)=[C:8]([CH:11]=1)[C:9]#[N:10])([CH3:3])[CH3:2].[Sn](Cl)[Cl:23]>Cl.C(O)C>[ClH:23].[CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:19]=[C:9]([NH2:10])[C:8]=2[CH:11]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(Nc2ccccc2[N+](=O)[O-])c(C#N)c1
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Product: CC(C)c1ccc2c(c1)C(N)=Nc1ccccc1N2
Temperature: 86 °C

Procedure:
Combine 5-isopropyl-2-(2-nitro-phenylamino)-benzonitrile (4.54 g, 16.1 mmol) and tin (II) chloride (10.92 g, 48.4 mmol) in 65.0 mL of 5N HCl solution and 65.0 mL of ethanol. Heat this mixture at 86° C. for 18 hours. Chilling the mixture precipitates the title compound as 4.22 g of a yellow solid: mp>250° C.; mass spectrum (ion spray): m/z=252 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9](Br)[S:8][CH:7]=1)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)CCC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[S:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1csc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1csc(-c2ccsc2)c1
Yield: 44.7 %

Procedure:
The same reaction as in Referential Example 37 was carried out except using 380 mg of 5-bromo-3-thiophenecarboxylic acid ethyl ester [see J. Am. Chem. Soc., 26, 2446 (1954)], 730 mg of tributyl(3-thienyl)stannane and 10 mg of tetrakis(triphenylphosphine) palladium to give 172 mg (yield 51%) of 5-(3-thienyl)-3-thiophenecarboxylic acid ethyl ester.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]=2)=[CH:5][CH:4]=1)=O.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29]>>[O:29]=[C:24]1[NH:25][C:26](=[O:28])[C:27](=[CH:1][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:10]=3)=[CH:5][CH:4]=2)[S:23]1
Reactant: O=C1CSC(=O)N1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C=O)cc2)c1
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1
Yield: 100.1 %

Procedure:
In a manner similar to that of Example 1(f), by reacting 9.5 g (32 mmol) of tert-butyl (4′-formyl-biphenyl-3-yl)carbamate with 3.8 g (32 mmol) of 2,4-thiazolidine dione, 12.7 g (91%) of the expected product are obtained.
Reaction SMILES: [C:1]([N:4]([CH2:13][C:14]([OH:16])=O)[C:5]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH:20]=1>>[C:1]([N:4]([CH2:13][C:14]([N:25]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)=[O:16])[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Reactant: COc1ccc(N(CC(=O)O)C(C)=O)cc1
Product: COC(=O)CCCN(C(=O)CN(C(C)=O)c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(acetyl)-2-(p-anisidino)acetic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(acetyl)-2-(p-anisidino)acetyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-acetyl-2-(p-anisidino)acetyl]-4-(p-anisidino)butyric acid (M.P. 97° to 100°).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1/[CH:15]=[CH:16]/[C:17](=[O:25])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[C:12]([Cl:26])[CH:11]=[C:10]([Cl:27])[CH:9]=2)=[O:5])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:38][Si:39]([CH2:42][CH2:43][O:44][CH2:45]Cl)([CH3:41])[CH3:40]>CN(C=O)C.O>[C:19]1([NH:18][C:17](/[CH:16]=[CH:15]/[C:14]2[C:13]3[C:8](=[CH:9][C:10]([Cl:27])=[CH:11][C:12]=3[Cl:26])[N:7]([CH2:45][O:44][CH2:43][CH2:42][Si:39]([CH3:41])([CH3:40])[CH3:38])[C:6]=2[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:25])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1/C=C/C(=O)Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(/C=C/C(=O)Nc2ccccc2)c2c(Cl)cc(Cl)cc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
To a cooled (0°) solution of (E)-Ethyl-3-[2-(phenylcarbamoyl)ethenyl]-4,6-dichloroindole-2-carboxylate (300 mg) in dry DMF (25 ml) a solution of sodium bis-(trimethylsilyl)amide (1M;0.0814 ml) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes then cooled to 0°. Trimethylsilylethoxymethylchloride (185 mg) was added, and the reaction was stirred for one hour at room temperature. The resulting solution was poured in H2O (20 ml) and extracted with diethylether (15 ml×3). The organic layers were dried, concentrated under vacuum and the product isolated by chromatography on silica gel(CH/EA:83/15) to give the title compound (311 mg). Rf =0.35 CH/EA:85/15
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[C:22](OC(C)(C)C)=O)[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C@@H:17]3[CH2:21][CH2:20][CH2:19][N:18]3[CH3:22])[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccnc(Nc2cccc(Cl)c2)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1CNc1ccnc(Nc2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.3 %

Procedure:
To a solution of tert-butyl (2S)-2-[({2-[(3-chlorophenyl)amino]pyrimidin-4-yl}amino)methyl]pyrrolidine-1-carboxylate (160 mg, 0.40 mmol) in THF (3 mL) is added lithium aluminum hydride (2 M in THF, 0.6 mL, 1.19 mmol). The reaction is stirred at room temperature for 24 hours and then quenched with NaOH (1 N, 2 mL) and stirred for an additional hour. The reaction solution is partitioned between EtOAc and sat. NaHCO3. The organic layer is dried (MgSO4), concentrated in vacuo, and purified over silica (MeOH/CH2Cl2) to afford 22 mg (17% yield) of the desired compound: 1H NMR (CDCl3, 300 MHz) δ 1.58-1.68 (m, 1H), 1.70-1.83 (m, 2H), 1.99-2.11 (m, 1H), 2.29 (q, J=8.7 Hz, 1H), 2.43 (s, 3H), 2.48-2.58 (m, 1H), 3.04-3.12 (m, 1H), 3.29 (t, J=6.3 Hz, 1H), 3.77 (d, J=11.7 Hz, 1H), 6.01 (d, J=6.0 Hz, 1H), 6.94 (ddd, J=8.1, 2.4, 0.9 Hz, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.49 (ddd, J=8.4, 2.1, 0.9 Hz, 1H), 7.78 (d, J=6.0 Hz, 1H), 7.89 (t, J=2.1 Hz, 1H); HRMS calcd for C16H20ClN5, 318.1485 m/z (M+H)+; observed 318.1491 m/z.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][CH:7]=1.C([Li])CCC.CN([CH:19]=[O:20])C.[Cl-].[NH4+]>C1COCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:10]=[CH:9][S:8][C:7]=1[CH:19]=[O:20]
Reactant: c1cc(C2OCCO2)cs1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1sccc1C1OCCO1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
5.00 g (32.0 mmol) of 3-(1,3-dioxolan-2-yl)thiophene was dissolved in 100 ml of THF. 24.5 ml (1.5 mol/l) of n-butyllithium was added dropwise thereinto. After stirring for 0.5 hour, the mixture was cooled to −70° C., 3.10 ml (40.0 mmol) of DMF was added, and then the mixture was transferred to an ice bath. After stirring for about 2 hours, an aqueous saturated ammonium chloride was added, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, to give a crude product. The crude product was subjected to silica gel (ethyl acetate:hexane=1:2), to give 3.68 g (20.0 mmol, 62.4%) of the title compound as a yellow oil.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[CH2:5].[Br:13]N1C(=O)CCC1=O>C(Cl)Cl.C(OCC)(=O)C>[Br:13][CH2:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: C=C(O[Si](C)(C)C)c1ccc[nH]1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CBr)c1ccc[nH]1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
Crude 2-[1 -(trimethyl-silanyloxy)-vinyl]-1H-pyrrole was diluted with CH2Cl2 (10 ml), cooled to 0° C., and treated with N-bromosuccinimide (1.94 mmol, 0.35 g). The resulting mixture was put in a −20° C. freezer overnight. After warming to room temperature, the mixture was diluted with ethyl acetate (75 ml), washed with saturated aqueous sodium bicarbonate (2×20 ml), brine (2×20 ml), and the organics concentrated under reduced pressure. Purification of the residue by silica gel chromatography provided 0.29 g (80%) of 2-bromo-1-(1H-pyrrol-2-yl)-ethanone. 1H NMR (CDCl3) δ7.12 (1H, dt, J=2.7, 1.3), 7.02 (1H, ddd, J=3.8, 2.4, 1.3), 6.36-6.31 (1H, m), 4.27 (2H, s).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11]([O:17][C@H:18]([CH3:22])[C:19](Cl)=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>C(Cl)Cl.N1C=CC=CC=1.Cl>[CH2:11]([O:17][C@H:18]([CH3:22])[C:19]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCO[C@H](C)C(=O)Cl
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCO[C@H](C)C(=O)Oc1ccc(C(=O)O)cc1
Yield: 46.4 %

Procedure:
To a solution of p-hydroxybenzoic acid (2.15 g, 15.6 mmol) in methylene chloride (30 ml) and pyridine (10 ml), a solution of (R)-2-n-hexyloxypropanoyl chloride (3.0 g, 15.6 mmol) in methylene chloride (20 ml) was added dropwise and then the mixture was refluxed for 7 hours. After cooling, the resultant mixture was taken up in dilute hydrochloric acid, extracted with ethyl ether; the organic extract was washed twice with dilute hydrochloric acid and with H2O for four times, and dried over anhydrous Na2SO4. The solvent was evaporated and the residue was recrystallized from n-hexane to afford 2.13 g of the title compound as white crystals; mp. 67.0°-72.0° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.O.C(Cl)[Cl:16]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([Cl:16])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: ClCCl
Solvent: CO
Solvent: O
Product: CC(C)(C)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 4-tert-butyl-phenol (40.0 g, 0.27 mol) and SO2Cl2 (37.5 g, 0.28 mol) in CH2Cl2 was added MeOH (9.0 g, 0.28 mol) at 0° C. After addition was complete, the mixture was stirred overnight at room temperature and then water (200 mL) was added. The resulting solution was extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography (Pet. Ether/EtOAc, 50:1) to give 4-tert-butyl-2-chloro-phenol (47.0 g, 95%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH:17]=O)[CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:17]/[CH2:16][CH:13]1[CH2:14][CH2:15][O:10][CH2:11][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=CCC1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/CC1CCOCC1
Yield: 35.6 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.65 g, 5 mmol) was reacted with (tetrahydro-pyran-4-yl)-acetaldehyde (Pharmacore) (0.64 g, 5 mmol) in CH2Cl2 at room temperature for 5 h to give [2-(tetrahydro-pyran-4-yl)-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.43 g, 33%).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[C:12](OCC)(=[O:14])C.CCCCCC>>[OH:9][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:8][C:7]=1[CH:12]=[O:14]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CCOC(C)=O
Solvent: CCCCCC
Product: O=Cc1cc(C(F)(F)F)ccc1O
Yield: 34 %

Procedure:
Following the general procedure and FCC purification with 30% ethyl acetate-hexane, 4-trifluoromethyl phenol (10.0 g, 61.7 mmol) gave 2-hydroxy-5-trifluoromethyl-benzaldehyde 27 (3.9 g, 34%) as a pink solid.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C(C)C>[O:18]1[CH2:17][CH:16]1[CH2:14][O:1][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCc2c(O)cccc2N1
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Product: O=C1CCCc2c(cccc2OCC2CO2)N1
Yield: 60 %

Procedure:
5.3 g (0.03 mole) of 6-hydroxy-2,3,4,5-tetrahydro-1H-benzazepin-2-one, 5 ml of epibromohydrin and 4.5 g of potassium carbonate in 250 ml of methyl isobutyl ketone are refluxed for 48 hours. After the mixture has cooled, it is filtered and the filtrate is concentrated under reduced pressure on a rotary evaporator. The residue is recrystallized from cyclohexane in the presence of animal charcoal. 4.2 g (60% yield) of 6-(2,3-epoxy-propoxy)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one, of melting point 121°-123° C., are obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:8]=1)(=O)=O.F[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:9]1[CH:10]=[CH:11][C:7]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[N:8]1
Reactant: O=S(=O)(Oc1ccn(-c2ccccn2)n1)C(F)(F)F
Reactant: N#Cc1cccc(F)c1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1cccc(-c2ccn(-c3ccccn3)n2)c1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
1-Pyridin-2-yl-1H-pyrazol-3-yl trifluoromethanesulfonate (0.211 g, 0.72 mmol), 3-fluorobenzonitrile (0.111 g, 0.76 mmol) and potassium carbonate (0.209 g, 1.51 mmol) in a mixture of ethyleneglycol dimethyl ether (20 mL) and water (4 mL) was degassed by argon bubbling for 15 min., then tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) was added the resulting solution degassed for a further 15 min. The solution was stirred at 65° C. for 12 h. The reaction mixture was quenched with water (30 mL), then extracted with EtOAc (3×30 mL) and washed with brine. The combined organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was chromagraphed on silica gel eluting with EtOAc:hexane (2:3) to afford a white solid which was recrystallized from EtOAc-hexane to give 3-(1-pyridin-2-yl-1H-pyrazol-3-yl)benzonitrile as a white solid. 1H NMR (CD3Cl, 300 MHz) δ 8.64 (d, 1H), 8.44 (d, 1H), 8.25 (s, 1H), 8.14 (d, 1H), 8.10 (d, 1H), 7.87 (t, 1H), 7.64 (d, 1H), 7.55 (t, 1H), 7.24 (dd, 1H), 6.80 (d, 1H). MS (ESI) 247 (M++H).