Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][NH:4][C:5]([C:7]1([NH:10]C(=O)OC(C)(C)C)[CH2:9][CH2:8]1)=[O:6].[ClH:20]>C(Cl)Cl.O1CCOCC1>[ClH:20].[C:7]([CH:9]1[CH2:8][C:7]1([NH2:10])[C:5]([NH:4][CH2:3][C:2]([F:1])([F:18])[F:19])=[O:6])([CH3:9])([CH3:8])[CH3:5]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NCC(F)(F)F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(C)C1CC1(N)C(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
To tert-butyl (1-((2,2,2-trifluoroethyl)carbamoyl)cyclopropyl)carbamate (3.2 g, 11 mmol) in CH2Cl2 (20 mL) was added 4 M HCl in dioxane (20 mL). The solution was stirred for 18 h at ambient temperature. The reaction mixture was concentrated in vacuo and the residue placed in a 60° C. vacuum oven (24 h) to afforded the title compound as an off-white solid (2.3 g, 93%): 1H NMR (400 MHz, DMSO-d6) δ 8.77 (bs, 3H), 8.50 (t, J=6.3 Hz, 1H), 3.90 (qd, J=9.7, 6.1 Hz, 2H), 1.52-1.15 (m, 4H); 19F NMR (376 MHz, DMSO-d6) δ −70.54; 13C NMR (101 MHz, DMSO-d6) δ 175.33, 132.46 (q, J=280.8 Hz), 45.13 (q, J=34.34 Hz), 40.06, 17.57.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH2:27])[CH3:26])=[N:23][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([C@@H:25]([NH:27][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([CH:14]4[CH2:16][CH2:15]4)[NH:11][N:10]=3)[C:5]([Cl:17])=[CH:4][N:3]=2)[CH3:26])=[N:23][CH:24]=1
Reactant: C[C@H](N)c1ccc(Br)cn1
Reactant: Clc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: C[C@H](Nc1ncc(Cl)c(Nc2cc(C3CC3)[nH]n2)n1)c1ccc(Br)cn1
Temperature: 180 °C
Yield: 68.6 %

Procedure:
A mixture of 2,5-dichloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 7; 0.15 g, 0.553 mmol), (S)-1-(5-bromopyridin-2-yl)ethanamine (Method 26; 0.245 g, 0.611 mmol), and DIEA (0.145 ml, 0.833 mmol) in n-BuOH (2 ml) was heated in a sealed tube at 180° C. in a microwave for 1 hour. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:1) to give the title compound as a white solid (0.165 g, 68%). 1H NMR (400 MHz) δ 12.48, 12.38 and 12.07 (s, 1H), 9.66 (br s, 1H), 8.62 (s, 1H), 8.33 and 7.57 (br s, 1H), 7.96 (d, J=8.2 Hz, 1H), 7.92 (br s, 1H), 7.32 (br s, 1H), 5.81 (bs, 1H), 4.99 (br s, 1H), 1.84 (br s, 1H), 1.45 (d, J=6.8 Hz, 3H), 0.94 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 435. Found: [M+11]+ 436.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:34])[CH2:24][O:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:36][S:37](O)(=[O:39])=[O:38]>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH2:13][CH2:14][O:15][C:16](=[O:35])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:34])[CH2:24][O:25][C:26]2[CH:31]=[C:30]([CH3:32])[C:29]([S:37]([Cl:36])(=[O:39])=[O:38])=[C:28]([CH3:33])[CH:27]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cc(C)cc(OCC(=O)NCCCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1
Solvent: ClCCl
Product: Cc1cc(OCC(=O)NCCCCCC(=O)OCCS(=O)(=O)c2cccc([N+](=O)[O-])c2)cc(C)c1S(=O)(=O)Cl
Reaction time: 0.5 h
Yield: 40 %

Procedure:
To a cooled solution of 6-[2-(3,5-dimethyl-phenoxy)acetylamino]hexanoic acid 2-(3-nitrobenzenesulfonyl)ethyl ester (Intermediate 16, 4.6 g, 9.1 mmol) in 3 mL of CH2Cl2 was added drop-wise ClSO3H (3 mL, 5 eq., 45.5 mmol)) at 0° C. During the reaction small aliquots of the reaction mixture were taken out as samples, treated with ice, extracted with ethyl acetate, and the ethyl acetate layers were analyzed by thin layer chromatography (TLC). TLC analysis showed that the reaction was complete after 30 min. Then the resulting thick reaction mixture was poured onto the crushed ice with vigorous stirring to give a yellow gummy material mostly in the bottom of the flask. This mixture was extracted with CH2Cl2, the organic layers were dried over anhydrous MgSO4, and concentrated under reduced pressure to give Intermediate 17 (2.2 g, 40%) as a white foam.
Reaction SMILES: [C:1]([C:4]1[C:13]([CH3:14])=[N+:12]([O-:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:16])(=[O:3])[CH3:2].[Br:17]Br>CO>[C:1]([C:4]1[C:13]([CH2:14][Br:17])=[N+:12]([O-:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:16])(=[O:3])[CH3:2]
Reactant: BrBr
Reactant: CC(=O)c1c(C)[n+]([O-])c2ccccc2[n+]1[O-]
Solvent: CO
Product: CC(=O)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a stirred suspension of 2-acetyl-3-methylquinoxaline-1,4-dioxide (1.57 moles) in 3 liters of methanol was added bromine (1.74 moles) over a period of 2 hours. The reaction mixture was then stirred for 5 days at room temperature. The resulting yellow solid was collected by filtration, washed with methanol and ether. Yield, 331 grams (71%); m.p. 164-6° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13](Br)=[C:12]([CH3:17])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].C(N(C(C)C)CC)(C)C>>[CH2:1]([O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH:21]=[CH:20][C:19]([O:23][CH3:24])=[O:22])=[C:12]([CH3:17])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Cc1cc(C(=O)OCc2ccccc2)ccc1Br
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C=Cc1ccc(C(=O)OCc2ccccc2)cc1C
Temperature: 110 °C
Yield: 84.7 %

Procedure:
To a solution of 4-bromo-3-methyl-benzoic acid benzyl ester (36 g, 118 mmol) in propronitrile (1000 mL) is added methyl acrylate (43.3 mL) and diisopropylethyl amine (42 mL), the solution is degassed and filled with nitrogen for three times. To this mixture are added tri-o-tolyl-phosphane (14.5 g) and palladium acetate (5.34 g) under nitrogen, then heated at 110° C. overnight, cooled to room temperature, filtered through celite. The solvent is evaporated, the residue is taken into ethyl acetate and washed with water and brine, dried over sodium sulfate. Concentration and column chromatography on silica gel eluted with hexanes and ethyl acetate gave the title compound (31 g, 84.7%).
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].C([O:8][C:9]([C:11]1([C:38](OCC)=[O:39])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:17]=[N:18][C:19]([O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[N:27]=[CH:26]3)=[CH:20][CH:21]=1)=O)C>C(O)C>[N:34]1[CH:35]=[CH:36][CH:37]=[C:32]([N:28]2[C:29]3[C:25](=[CH:24][C:23]([O:22][C:19]4[N:18]=[CH:17][C:16]([N:12]5[C:11]6([C:38](=[O:39])[NH:5][C:3](=[O:4])[NH:2][C:9]6=[O:8])[CH2:15][CH2:14][CH2:13]5)=[CH:21][CH:20]=4)=[CH:31][CH:30]=3)[CH:26]=[N:27]2)[CH:33]=1
Reactant: NC(N)=O
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc3c(cnn3-c3cccnc3)c2)nc1
Agent: [Na]
Solvent: CCO
Product: O=C1NC(=O)C2(CCCN2c2ccc(Oc3ccc4c(cnn4-c4cccnc4)c3)nc2)C(=O)N1
Temperature: 80 °C

Procedure:
To a flame dried flask is added ethanol (6 mL) and freshly cut sodium metal (62.4 mg, 2.71 mmol). The solution is stirred until homogenous. Recrystallized urea (98 mg, 1.63 mmol) is added and the solution is stirred at room temperature for 5 minutes. 1-[6-(1-Pyridin-3-yl-1H-indazol-5-yloxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.54 mmol) is added, and the solution is heated to 80° C. for 30 minutes, then cooled to 50° C. and stirred for 16 hours. The reaction is then quenched by the addition of 10 mL water, and 1N hydrochloric acid is added to adjust the pH to 5. The aqueous layer is extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers are washed with saturated sodium chloride, dried with magnesium sulfate, filtered, and concentrated under vacuum to produce crude product. This material is chromatographed on silica gel (ISCO MPLC purification, 30 minutes, 50-100% ethyl acetate gradient, Biotage flash 40s column) to provide 1-[6-(1-Pyridin-3-yl-1H-indazol-5-yloxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane-6,8,10-trione.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:18][S:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=O)(C)(C)C.Cl.O1CCOCC1>ClCCl>[NH2:8][C@@H:9]([CH2:18][S:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:10][O:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc(CSC[C@@H](COC(=O)C(C)(C)C)NC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(CSC[C@H](N)COC(=O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.4 %

Procedure:
2,2-Dimethyl-propionic acid (R)-2-t-butoxycarbonylamino-3-(4-methoxy-benzylsulfanyl)-propyl ester (81 g, 196 mmol) prepared in Step D was dissolved in dichloromethane (300 mL). 4N hydrochloric acid/1,4-dioxane solution (100 mL) was added thereto, and the mixture was stirred for 8 h at room temperature. After completion of the reaction, the solvent was thoroughly removed under reduced pressure. The residue was recrystallized from diethylether, and dried to give the title compound (68 g, Yield 95%).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C)C=O.[NH2:21][C:22]1[CH:23]=[C:24]([OH:29])[CH:25]=[CH:26][C:27]=1[F:28].C(=O)([O-])O.[Na+]>C(Cl)(=O)C(Cl)=O.O1CCCC1.O>[Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][C:22]1[CH:23]=[C:24]([OH:29])[CH:25]=[CH:26][C:27]=1[F:28])=[O:6]
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Reactant: Nc1cc(O)ccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cc(O)ccc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (4.42 g, 20 mmol) produced in Example C62(ii) in oxalyl chloride (10 mL) was added N,N-dimethylformamide (100 μL), and the mixture was stirred at room temperature for 1 hr, and concentrated to dryness under reduced pressure. This was dissolved in tetrahydrofuran (10 mL), and the solution was added dropwise with vigorous stirring to a two-layer mixture of a solution of 3-amino-4-fluorophenol (2.54 g, 20 mmol) in tetrahydrofuran (10 mL) and a solution (10 mL) of sodium hydrogen carbonate (2.70 g, 30 mmol) in water under ice-cooling. The reaction mixture was stirred at room temperature for 1 hr, and poured into water (200 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→50/50) to give the title compound (6.50 g, 98%) as white crystals.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([CH3:17])[C:7]([CH3:16])=[C:8]([O:11][CH2:12][C:13]([OH:15])=[O:14])[CH:9]=2)[C:4](=[O:18])[CH:3]1[CH2:19][CH3:20].[BH4-].[K+].Cl>O>[OH:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:17])[C:7]([CH3:16])=[C:8]([O:11][CH2:12][C:13]([OH:15])=[O:14])[CH:9]=2)[CH:4]([OH:18])[CH:3]1[CH2:19][CH3:20]
Reactant: CCC1C(=O)c2cc(OCC(=O)O)c(C)c(C)c2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Solvent: O
Product: CCC1C(O)c2cc(OCC(=O)O)c(C)c(C)c2C1O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A stirred suspension of (1,3-dioxo-2-ethyl-4,5-dimethyl-6-indanyloxy)acetic acid (5.52 g., 0.02 mole) in water (200 ml.) is cooled to 5° C. and treated with a solution of potassium borohydride (4.0 g., 0.075 mole) in water (200 ml.) during a 1 hour period. The reaction is stirred for one hour then acidified with hydrochloric acid affording (1,3-dihydroxy-2-ethyl-4,5-dimethyl-6-indanyloxy)acetic acid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:17]=[C:18]([NH2:29])[CH:19]=[CH:20][C:21]=1[S:22][C:23]1[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:19]=[CH:20][C:21]=1[S:22][C:23]1[N:24]([CH3:28])[CH:25]=[CH:26][N:27]=1
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Reactant: N#Cc1cnc2cc(F)ccc2c1Cl
Agent: Cl
Solvent: CCOCCO
Solvent: c1ccncc1
Product: Cn1ccnc1Sc1ccc(Nc2c(C#N)cnc3cc(F)ccc23)cc1Cl

Procedure:
Following the procedure of Example 1, a mixture of 1.2 g (5.81 mmol) 4-chloro-7-fluoro-3-quinolinecarbonitrile, 1.53 g (6.39 mmol) of 3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamine and 0.671 g (5.81 mmol) of pyridine hydrochloride are refluxed in 2-ethoxyethanol (12 mL) at 120° C. for 45 minutes to yield 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-7-fluoroquinoline-3-carbonitrile as an off-white solid, mp 268-272° C.
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([OH:14])=O)[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH3:48][O:49][C:50](=[O:54])[C@@H:51]([CH3:53])[NH2:52].CCN(CC)CC>CCOC(C)=O>[NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:12]([NH:52][C@@H:51]([C:50]([O:49][CH3:48])=[O:54])[CH3:53])=[O:14])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)[C@@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of Boc-Ser(OBn) (4.12 g, 13.95 mmol) in EtOAc (100 mL) at 0° C. was added HOBT (2.35 g, 15.35 mmol) and DCC (3.17 g, 15.35 mmol). D-Alanine methyl ester hydrochloride (1.95 g, 13.95 mmol) was added followed by Et3N (2.14 mL, 15.35 mmol). The mixture was allowed to warm to room temperature and stirred overnight. The mixture was filtered, and the filtrate was washed with saturated aqueous NaHCO3, brine, dried (MgSO4), and concentrated. Flash chromatography (40% EtOAc/hexane) gave 2.60 g of the title compound as a colorless oil; CI-MS 381 (m+1).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:10][C:11](=[O:34])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]3[N:24]([CH:25]=2)[N:23]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32]C)=[CH:28][CH:27]=2)[S:21]3)=[CH:14][CH:13]=1)C.O>ClCCl>[OH:32][C:29]1[CH:30]=[CH:31][C:26]([C:22]2[S:21][C:20]3=[N:19][C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:11]([OH:34])=[O:10])=[CH:13][CH:14]=4)=[CH:25][N:24]3[N:23]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)c1ccc(-c2cn3nc(-c4ccc(OC)cc4)sc3n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)c1ccc(-c2cn3nc(-c4ccc(O)cc4)sc3n2)cc1
Temperature: 25 °C
Yield: 130.6 %

Procedure:
To a suspension of 4-[2-(4-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid ethyl ester trifluoroacetic acid salt (1.0 g) in dichloromethane (10 ml) was added borone tribromide (1.0M solution in dichloromethane) (8.0 ml) at 0° C. and the mixture was stirred at ambient temperature for 1 week. The reaction mixture was pulverized with cold water. The precipitate was collected by filtration and dried to give 4-[2-(4-hydroxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-6-yl]benzoic acid (893 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([O:16]C)=[O:15])[C:9]1=[O:18].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=[O:15])[C:9]1=[O:18]
Reactant: COC(=O)c1cccn(-c2ccccc2C)c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1-n1cccc(C(=O)O)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
To a solution (9 mL) of methyl 1-(2-methylphenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (880 mg, 3.62 mmol) in methanol was added 1N aqueous sodium hydroxide solution (5 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was adjusted to pH<7 with 1N hydrochloric acid and concentrated under reduced pressure. The precipitate was collected by filtration and washed with water to give the title compound (704 mg, 85%) as yellow crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH3:11][N:12]([CH3:22])[C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](Cl)=[O:17]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[C:6]([NH:7][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([N:12]([CH3:11])[CH3:22])[CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1cccc(C(=O)Nc2cccc([N+](=O)[O-])c2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.9 %

Procedure:
3-Nitroaniline (3.84 g) in methylene chloride (50 ml) was added dropwise to an ice-cooled solution of 3-dimethylaminobenzoyl chloride (9.74 g crude weight) and 4-dimethylaminopyridine (308 mg) in methylene chloride (30 ml) and triethylamine (8.8 ml). The reaction was stirred at ambient temperature for 72 hours and then partitioned between methylene chloride and saturated sodium bicarbonate. The organic phase was then washed with brine, dried over magnesium sulphate, filtered and evaporated to dryness affording N-(3-nitrophenyl)-3-dimethylaminobenzamide as a solid (8.64 g, 99.9%); NMR (CDCl3) 3.02 (s, 6H), 6.9 (m, 1H), 7.09 (s, 1H), 7.25 (m, 1H), 7.35 (t, 1H), 7.53 (t, 1H), 7.99 (m, 1H), 8.05 (broad s, 1H), 8.1 (m, 1H), 8.5 (m, 1H); m/s: M+H+ 286.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[C:5]([CH2:7][NH:8][CH3:9])[N:6]=1.[CH2:20]([C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:13]([NH:12][C:10]([C:4]1[S:3][C:2]([NH:1][C:31](=[O:32])[C:30]2[CH:29]=[CH:28][C:27]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:35][CH:34]=2)=[N:6][C:5]=1[CH2:7][NH:8][CH3:9])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNCc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Product: CNCc1nc(NC(=O)c2ccc(Cc3ccccc3)cc2)sc1C(=O)NCc1ccccc1

Procedure:
Following the procedure as described in Example 22, making variation only as required to use 2-amino-N-benzyl-4-((methylamino)methyl)thiazole-5-carboxamide in place of 2-amino-N-benzyl-4-((diethylamino)methyl)thiazole-5-carboxamide to react with 4-benzylbenzoic acid, the title compound was obtained; 1H NMR (CD3OD, 400 MHz) δ 7.93 (d, J=8.6 Hz, 2H), 7.35-7.15 (m, 12H), 4.49 (s, 2H), 4.06 (s, 2H), 4.02 (s, 2H), 3.09 (s, 2H), 2.37 (s, 3H); MS (ES+) m/z 471 (M+1).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH:16]1[C:20](=[O:21])[CH2:19][CH2:18][C@H:17]1[C:22]([OH:24])=O.OC1C2N=NNC=2C=CC=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>ClCCl>[N:35]1([C:22]([C@H:17]2[NH:16][C:20](=[O:21])[CH2:19][CH2:18]2)=[O:24])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1
Reactant: C1COCCN1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: O=C1CC[C@@H](C(=O)N2CCOCC2)N1
Temperature: 25 °C

Procedure:
To a mixture of 48 g dicyclohexylcarbodiimide, 30 g commercially available L-pyroglutamic acid and 3.1 g hydroxybenzotriazole 20.2 g of morpholine were added in 170 ml dichloromethane at about −15° C. The mixture was allowed to warm to room temperature. The suspension was filtered and diluted with 290 ml THF. The mixture was concentrated to obtain a suspension, which was filtered yielding 41 g of (S)-5-(morpholine-4-carbonyl)pyrrolidin-2-one.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K].[I-].[Na+]>CN(C=O)C>[OH:5][C:3]([CH3:6])([CH3:4])[CH2:2][C:9]12[CH:13]=[CH:14][CH:15]=[CH:16][CH:8]1[C:7]([NH:11][C:10]2=[O:12])=[O:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(O)CCl
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(O)CC12C=CC=CC1C(=O)NC2=O
Yield: 37 %

Procedure:
A solution of 1-chloro-2-methyl-2-propanol (2.23 g, 97%, 0.02 mol), potassium phthalimide (3.780 g, 98%, 0.02 mol) and sodium iodide (60 mg, 4 mmol) in anhydrous DMF (40 mL) was heated to reflux overnight. The solvent was evaporated under reduced pressure. The resulting product was triturated with a mixture of 3:2 ethyl acetate/hexanes and the ensuing white precipitate was removed by filtration. The yellow filtrate was concentrated under reduced pressure and purified by flash chromatography in a mixture of 2:3 ethyl acetate/hexanes. The impure product thus isolated was triturated with hot hexanes (125 mL) and filtered to remove an insoluble white impurity. After evaporation of the solvent under reduced pressure, the obtained white solid was recrystallized in hexanes. The product was yielded as colorless crystals that were collected by filtration and dried under high vacuum (1.63 g, 37% yield). m.p.: 104-105° C.; TLC Rf 0.20 (2:3 ethyl acetate/hexanes); FTIR (KBr): 3524, 3456, 3097, 3031, 2973, 2930, 1773, 1698, 1611, 1466, 1427, 1389, 1319, 1190, 1076, 990, 965, 912, 890, 838, 766, 724, 712, 638 cm−1; 1H-NMR(500 MHz, CDCl3): δ 1.26 (s, 6H, 2 CH3), 2.74 (s, 1H, OH), 3.75 (s, 2H, CH2), 7.72 (dd, 2H, Jo=5.44 Hz, Jm=3.04 Hz, 2 Hc), 7.85 (dd, 2H, Jo=5.42 Hz, Jm=3.06 Hz, 2 Hb); 13C-NMR(126 MHz, CDCl3): δ 27.6 (2 CH3), 49.3 (CH2), 71.6 (CMe2), 123.6 (2 Cb), 132.0 (2 Ca), 134.3 (2 Cc), 169.3 (2 CO).
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].Br[CH2:9][CH2:10][CH2:11][CH2:12]Br.O>CN(C)C=O>[C:5]([C:4]1([C:3]#[N:7])[CH2:12][CH2:11][CH2:10][CH2:9]1)#[N:6]
Reactant: N#CCC#N
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC1(C#N)CCCC1
Reaction time: 8 h

Procedure:
Sodium hydride (37.8 g; 0.94 moles) was suspended in dimethylformamide (250 mL) under an atmosphere of N2. A solution of malononitrile (30 g; 0.45 moles) and 1,4-dibromobutane 99.7 g; 0.45 moles) in dimethylformamide (150 mL) was added dropwise at such a rate so as not to exceed 30° C. The mixture was stirred for overnight, poured into H2O (500 mL), and then washed with two portions of ethyl ether. The organics were combined, washed with brine, and dried over magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated in vacuo, leaving a bilayered liquid. The lower portion was separated (28.8 g) and identified as the desired product.