Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].C(N(CC)CC)C>ClCCl>[C:12]([C:10]1[C:9]([N:15]2[CH2:16][CH2:17][N:18]([C:23]([N:22]([CH3:26])[CH3:21])=[O:24])[CH2:19][CH2:20]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)(=[O:14])[CH3:13]
Reactant: CN(C)C(=O)Cl
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)N(C)C)CC1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with N,N-dimethylcarbamoyl chloride (0.014 mL, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL, 16 mmol) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (27 mg, 72%). LCMS calculated for C18H22ClN4O2 (M+H)+: m/z=361.1; Found: 361.0.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([NH2:10])=[N:7][CH:6]=1)=[O:4].[C:11]12([C:21](O)=[O:22])[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2>>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8](=[N:10][C:21]([C:11]23[CH2:20][CH:15]4[CH2:14][CH:13]([CH2:19][CH:17]([CH2:16]4)[CH2:18]2)[CH2:12]3)=[O:22])[NH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cnc(N)s1
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Product: COC(=O)c1c[nH]c(=NC(=O)C23CC4CC(CC(C4)C2)C3)s1
Yield: 357.5 %

Procedure:
2-Amino-thiazole-5-carboxylic acid methyl ester (1.58 g, 10.0 mmole) and 1-adamantanecarboxylic acid (1.98 g, 1.1 mmol) were processed as described in Example 3B to afford 1.26 g (49%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.62-1.79 (m, 6H) 1.86 (d, J=3 Hz, 6H) 1.99 (s, 3H) 3.26 (s, 3H) 3.64-3.81 (s, 3H) 8.30 (s, 1H); MS (DCI/NH3) m/z 321 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][O:16][CH2:17][CH2:18][OH:19])[C:13]([CH3:20])=[N:12][C:11]=2[CH:21]([CH3:23])[CH3:22])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO[C:26]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1>>[C:26]1([O:19][CH2:18][CH2:17][O:16][CH2:15][N:14]2[C:10]([S:9][C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)=[C:11]([CH:21]([CH3:23])[CH3:22])[N:12]=[C:13]2[CH3:20])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=1
Reactant: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCO
Reactant: COC1=CCCCCCC1
Product: Cc1nc(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)n1COCCOC1=CCCCCCC1
Yield: 69.8 %

Procedure:
The compound 8 (450 mg, 1.2 mmol) was converted to the enol ether with 1-methoxycyclooctene (1.51 g, 12 mmol) in the same manner as the example 10 to give the compound 11 (405 mg, 70%) as oil. Rf 0.50 (Al2O3 60, Type E, 10:1 toluene -EtOAc).
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[C:18]([F:20])[C:17]([N:21]3[CH:26]=[CH:25][C:24](=[O:27])[CH2:23][CH2:22]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)=O)CCC.CO.[NH3:31]>>[O:27]=[C:24]1[CH:25]=[CH:26][N:21]([C:17]2[C:16]([F:28])=[CH:15][C:14]([N:10]3[CH2:9][C@H:8]([C:6]([NH2:31])=[O:5])[O:12][C:11]3=[O:13])=[CH:19][C:18]=2[F:20])[CH2:22][CH2:23]1
Reactant: N
Reactant: CCCCOC(=O)[C@H]1CN(c2cc(F)c(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Solvent: CO
Product: NC(=O)[C@H]1CN(c2cc(F)c(N3C=CC(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(5R)-3-[3,5-Difluoro-4-(4-oxo-3,4-dihydro-2H-pyridin-1-yl)phenyl]-2-oxo-5-oxazolidinecarboxylic acid butyl ester (Step 5, 200 mg, 0.50 mmol) is dissolved in a 2M solution of NH3 in MeOH (4 mL, 8 mmol). The resulting solution is stirred at room temperature for 3 h at which time the reaction mixture is concentrated under reduced pressure. The residue is washed with ether to give the title compound as an off white solid (139 mg, 82%), 1H NMR (300 MHz, DMSO) δ 7.89 (br s, 1H), 7.64 (br s, 1H), 7.54-7.38 (m, 3H), 5.07-4.98 (m, 2H), 4.26 (t, 1H), 4.01 (dd, 1H), 3.78 (t, 2H); MS for C15H13F2N3O4 m/z 338.4 (M+H)+.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[F:20][C:21]1[CH:22]=[C:23]([CH2:28][C:29](O)=[O:30])[CH:24]=[C:25]([F:27])[CH:26]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:19])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:23]3[CH:22]=[C:21]([F:20])[CH:26]=[C:25]([F:27])[CH:24]=3)[N:11]=2)=[CH:13][CH:14]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Product: O=C(Cc1cc(F)cc(F)c1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(3,5-difluorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.77-11.78 (bs, 1H), 8.39-8.42 (m, 1H), 7.89-8.03 (m, 2H), 7.69-7.74 (m, 1H), 7.60-7.65 (m, 4H), 7.06-7.20 (m, 3H), 3.76 (s, 2H); MS (ESI+) m/z 426 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C:17]2[C:12](=[CH:13][C:14](B(O)O)=[CH:15][CH:16]=2)[C:11]([CH3:21])=[CH:10][C:9]1([CH3:23])[CH3:22])=O)(C)(C)C.Br[C:25]1[C:26]([CH3:33])=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29]>>[C:28]([C:27]1[C:26]([CH3:33])=[C:25]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[NH:8][C:9]([CH3:22])([CH3:23])[CH:10]=[C:11]3[CH3:21])[CH:32]=[CH:31][CH:30]=1)#[N:29]
Reactant: Cc1c(Br)cccc1C#N
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(B(O)O)cc21
Product: CC1=CC(C)(C)Nc2ccc(-c3cccc(C#N)c3C)cc21
Yield: 20.2 %

Procedure:
This compound was prepared according to General Method 2 (EXAMPLE 9) from Compound 9 (56.5 mg, 0.18 mmol) and 3-bromo-2-methylbenzonitrile (34.8 mg, 0.18 mmol). The crude material was purified by flash column chromatography (50 ml silica, hexane to 20% acetone/hexane) followed by a second flash column chromatography (75 mL silica, hexane to 20% acetone/hexane to afford 10.5 mg (20%) of Compound 278. Data for Compound 278: 1H NMR (400 MHz, acetone-d6) 7.59 (dd, J=7.7, 0.9, 1 H), 7.48 (dd, J=7.8, 0.8, 1 H), 7.36 (t, J=15.3, 7.7, 1 H), 6.99 (d, J=1.8, 1 H), 6.91 (dd, J=8.1, 1.9, 1 H), 6.58 (d, J=8.1, 1 H), 5.37 (s, 1 H), 5.30 (s, 1 H), 2.48 (s, 3 H), 1.97 (s, 3 H), 1.30 (s, 6 H).
Reaction SMILES: [S:1]([NH:11][NH2:12])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[Cl:13][CH:14]([Cl:17])[CH:15]=O>C(O)(=O)CC>[S:1]([NH:11][N:12]=[CH:15][CH:14]([Cl:17])[Cl:13])([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=1)(=[O:2])=[O:3]
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=CC(Cl)Cl
Solvent: CCC(=O)O
Product: Cc1ccc(S(=O)(=O)NN=CC(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
Tosylhydrazine (234 g, 1.26 mol) was suspended in propionic acid (2 L) and dichloroacetaldehyde (142 g, 1.26 mol) was added at 15-20° C. The mixture was stirred at room temperature for 2 hours and under ice-cooling for 3 hours. The precipitated crystals were collected by filtration and washed with toluene. The crystals were dried under reduced pressure to give 2,2-dichloroacetaldehyde tosylhydrazone (247 g, yield 70%).
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.O.[NH3:17]>O1CCCC1>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH2:17])(=[O:14])=[O:13])=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: N
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NS(=O)(=O)c1ccc(-c2cnco2)cc1
Yield: 87 %

Procedure:
To a stirred solution of 4-(1,3-oxazol-5-yl)benzenesulfonyl chloride (1.00 g, 4.10 mmol) in tetrahydrofuran (15.0 mL) was added 25% ammonia water solution (5.00 mL) at room temperature. After 1 h the reaction mixture was partitioned between ethyl acetate (100.0 mL) and 1.0 N hydrochloric acid (10.0 mL) and separated. The organic layer was washed with water (2×40 mL), saturated sodium chloride (80 mL), dried (MgSO4), filtered. The filtrate was concentrated under reduced pressure to provide 4-(1,3-oxazol-5-yl)benzenesulfonamide (800 mg, 87%) as a solid.
Reaction SMILES: CS[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1.[ClH:12]>>[Cl:12][C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=1
Reactant: CSc1nc2cccnc2[nH]1
Reactant: Cl
Product: Clc1nc2cccnc2[nH]1
Temperature: 0 °C

Procedure:
2-(Methylthio)-3H-imidazo[4,5-b]pyridine (3.5 g) was dissolved in conc. HCl (10 mL), and then the mixture was cooled to 0° C. Chlorine gas was bubbled through the mixture for 2 h in iced bath. The mixture was poured onto ice, and neutralized to pH 7 with aqueous ammonium solution. The precipitate was collected by filtration to give the title compound as white crystals (1.0 g).
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH3:23])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24]([C@:26]1([OH:34])[CH:31]2[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]2)[CH2:27]1)#[CH:25].C(N(CC)CC)C.N>[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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:25]#[C:24][C@:26]2([OH:34])[CH:31]3[CH2:32][CH2:33][N:28]([CH2:29][CH2:30]3)[CH2:27]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]([O:20][CH3:21])[C@H:17]([O:22][CH3:23])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1OC
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: [Pd]
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CO[C@H]1CN(c2ccc(C#C[C@@]3(O)CN4CCC3CC4)c(Cc3ccccc3)n2)C[C@H]1OC
Temperature: 75 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
A mixture of 510 mg of 2-benzyl-6-(cis-3,4-dimethoxypyrrolidine-1-yl)-3-iodopyridine, 200 mg of (3R)-3-ethynyl-3-quinuclidinol, 139 mg of tetrakis (triphenylphosphine) palladium (0), 11 mg of cuprous iodide, 0.50 ml of triethylamine and 5.0 ml of N,N-dimethylformamide was heated under stirring at 75° C. for 2 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia and extracted with ethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1), to give 281 mg of the target compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21](O)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[N:46]1([C:52]2[CH:59]=[CH:58][CH:57]=[CH:56][C:53]=2[C:54]#[N:55])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>C(Cl)Cl.C(N(CC)CC)C>[C:17]([O:16][C:14](=[O:15])[NH:13][CH:11]1[CH2:10][CH:9]([C:21]([N:49]2[CH2:48][CH2:47][N:46]([C:52]3[CH:59]=[CH:58][CH:57]=[CH:56][C:53]=3[C:54]#[N:55])[CH2:51][CH2:50]2)=[O:22])[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:12]1)([CH3:18])([CH3:20])[CH3:19]
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)NC1CC(C(=O)O)N(Cc2ccccc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CC(C(=O)N2CCN(c3ccccc3C#N)CC2)N(Cc2ccccc2)C1
Reaction time: 8 h

Procedure:
The mixture of 1-benzyl-4-tert-butoxycarbonylamino-pyrrolidine-2-carboxylic acid, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimidehydrochloride, N-hydroxybenzotriazole, 2-piperazin-1-yl-benzonitrile and triethylamine in DCM is stirred overnight. The crude product is purified to afford {1-benzyl-5-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-pyrrolidine-3-yl}carbamic acid tert-butyl ester (41).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]3[NH:14][CH:15]=[CH:16][C:9]=23)[C:5]([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)=[N:4]1)[CH3:2].[CH:24]1([N:30]=[C:31]=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:30][C:31]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([C:5]3[C:6]([C:8]4[CH:13]=[CH:12][N:11]=[C:10]5[NH:14][CH:15]=[CH:16][C:9]=45)=[CH:7][N:3]([CH2:1][CH3:2])[N:4]=3)=[CH:18][CH:19]=2)=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C=NC1CCCCC1
Reactant: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Product: CCn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)NC3CCCCC3)cc2)n1

Procedure:
Following the procedure described in Example 1 with 4-[1-ethyl-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-3-yl]aniline and cyclohexyl isocyanate provided the title compound. ESMS [M+H]+: 429.2
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=1)=[C:2]=[S:3].[H-].[Na+].[NH2:18][C:19]1[C:24]([C:25](OC)=[O:26])=[CH:23][CH:22]=[C:21]([Cl:29])[N:20]=1.Cl>CN(C)C=O.C(OCC)C>[Cl:29][C:21]1[CH:22]=[CH:23][C:24]2[C:25](=[O:26])[N:1]([C:4]3[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]([F:13])([F:15])[F:14])=[CH:8][CH:9]=3)[C:2](=[S:3])[NH:18][C:19]=2[N:20]=1
Reactant: COC(=O)c1ccc(Cl)nc1N
Reactant: FC(F)(F)COc1ccc(N=C=S)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=c1c2ccc(Cl)nc2[nH]c(=S)n1-c1ccc(OCC(F)(F)F)cc1
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
1-Isothiocyanato-4-(2,2,2-trifluoroethoxy)benzene (4.06 g) was dissolved in N,N-dimethylformamide (50 ml), and sodium hydride (60% in oil, 1.39 g) was added thereto under ice-cooling. Methyl 2-amino-6-chloropyridine-3-carboxylate (2.95 g) was dissolved in N,N-dimethylformamide (25 ml), the solution was added dropwise to the reaction mixture under ice-cooling, and the mixture was stirred for 20 min, and then at room temperature for 1 hr and 30 min. The reaction mixture was poured into 0.5M hydrochloric acid (80 ml), and the white precipitate was collected by filtration. The precipitate was dissolved in tetrahydrofuran (100 ml), and the solution was diluted with ethyl acetate (200 ml), washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a white residue. The residue was suspended in diethyl ether (100 ml), and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane), and washed with diethyl ether to give the white title compound (1.1 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([NH2:13])=[N:9][NH:10][C:11]=1[NH2:12].[Br:14][CH:15]([CH:18]=O)[CH:16]=O>C(O)C.C(O)(=O)C>[Br:14][C:15]1[CH:16]=[N:12][C:11]2[N:10]([N:9]=[C:8]([NH2:13])[C:7]=2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:18]=1
Reactant: O=CC(Br)C=O
Reactant: Nc1n[nH]c(N)c1-c1ccccn1
Solvent: CC(=O)O
Solvent: CCO
Product: Nc1nn2cc(Br)cnc2c1-c1ccccn1
Temperature: 25 °C
Yield: 19.5 %

Procedure:
4-(Pyridin-2-yl)-1H-pyrazole-3,5-diamine (2.54 g, 14.51 mmol) and 2-bromo-malonaldehyde (2.41 g, 15.97 mmol) were suspended in dry ethanol (35 mL). A small amount of glacial acetic acid (30 drops) was added and the mixture was heated at reflux for 3 hours. After allowing the reaction to cool to room temperature the mixture was concentrated under reduced pressure. The resulting solid was purified by silica gel chromatography eluting with EtOAc containing 2% NH3(aq) solution to afford the title compound as a yellow solid (0.82 g, 19% yield). MS (ES+) 290/292. δH (DMSO-d6) 7.2 (3H, m), 7.9 (1H, t), 8.5 (1H, d), 8.6 (2H, m), 9.3 (1H, s).
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH3:10])[CH:5]=[N:4][C:3]=1[C:11]1[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][N:12]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][C:21]=1[F:29]>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[N:6]([CH2:7][CH2:8][O:9][CH3:10])[CH:5]=[N:4][C:3]=2[C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][N:12]=2)=[CH:22][C:21]=1[F:29]
Reactant: COCCn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: COCCn1cnc(-c2cc(C#N)ccn2)c1-c1ccc(Cl)c(F)c1

Procedure:
The title compound was prepared from 2-[5-bromo-1-(2-methoxyethyl)-1H-imidazol-4-yl]pyridine-4-carbonitrile and 4-chloro-3-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C18H14ClFN4O, 358. Found, 357, 359.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:16]([NH:18][C@@H:19]([C:36]([OH:38])=[O:37])[CH2:20][CH2:21][C:22]([N:24]1[C@@H:32]2[C@@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:26][C@H:25]1[C:33]([OH:35])=[O:34])=[O:23])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[OH-].[Na+:40].C(#N)C.O>O>[C:1]([NH:9][C@H:10]([C:16]([NH:18][C@@H:19]([C:36]([OH:38])=[O:37])[CH2:20][CH2:21][C:22]([N:24]1[C@@H:32]2[C@@H:27]([CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:26][C@H:25]1[C:33]([O-:35])=[O:34])=[O:23])=[O:17])[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[Na+:40]
Reactant: NCCCC[C@H](NC(=O)c1cccnc1)C(=O)N[C@H](CCC(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@@H]21)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: NCCCC[C@H](NC(=O)c1cccnc1)C(=O)N[C@H](CCC(=O)N1[C@H](C(=O)[O-])C[C@@H]2CCCC[C@@H]21)C(=O)O

Procedure:
In 5 ml of water was dissolved 0.57 g of (2S,3aS,7aS)-1-(N2 -nicotinoyl-L-lysyl-gamma-D-glutamyl)octahydro-1H-indole-2-carboxylic acid (see Example 15), and 1 ml of 1N-NaOH was added. The resulting aqueous solution was subjected to CHP20P column chromatography (0%→20% acetonitrile/water gradient). Fractions containing the desired product were concentrated to dryness under reduced pressure. The residue was lyophilized to give 0.25 g of the captioned compound. [α]D26 : -24.6° (H2O).
Reaction SMILES: CC[C:3](C)=[O:4].[C:6]([O:10][C:11]12[CH2:20]C3CC(CC(O)(C3)C1)[CH2:18]2)(=[O:9])[CH:7]=C.CC(N=NC(C#N)(C)C)(C#N)C>CO>[CH3:20][CH:11]([O:10][C:6]([CH3:7])=[O:9])[CH2:18][O:4][CH3:3]
Reactant: C=CC(=O)OC12CC3CC(CC(O)(C3)C1)C2
Reactant: CCC(C)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CO
Product: COCC(C)OC(C)=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A monomer solution was prepared by placing 8000 g of MEK in a tank kept at a nitrogen atmosphere and dissolving 2080 g of (B) NLA, 2480 g of (A) EAM and 2220 g of 3-hydroxy-1-adamantyl acrylate (hereinafter inscribed as “HAA”). Also, a polymerization initiator was prepared by placing and dissolving 1000 g of MEK and 110 g of AIBN in another container kept at the nitrogen atmosphere. Into a polymerization tank kept at the nitrogen atmosphere, 5000 g of MEK was put and the temperature was raised to 80° C. with stirring. Subsequently, the monomer solution and the polymerization initiator solution kept at the temperature of 25 to 30° C. were fed into the polymerization tank kept at 80° C. over 4 hours, respectively. After the completion of feed, the polymerized solution was matured for 2 hours with keeping the polymerization temperature at 80° C., then cooled to room temperature and taken out. Polymer was precipitated from the resulting polymerized solution by dropping in 100 kg of aqueous methanol and filtrated. The resultant wet cake was washed with 100 kg of methanol, filtrated subsequently dissolved in MEK again, and passed through a filter 40QSH supplied from Cuno Incorporated to remove a trace amount of metals. Then, the solvent was replaced by PGMEA with removing MEK by heating under reduced pressure to pre-pare PGMEA solution containing 15% polymer. The features of the resultant polymer, the content of high polymer and the evaluation results of storage stability of PGMEA solution are shown in Table 1.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4]([NH:6][C@H:7]1[CH2:21][C@H:20]2[C@@H:10]([CH2:11][C:12]3[C:22]4[C:15](=[CH:16][CH:17]=[CH:18][C:19]2=4)[NH:14][C:13]=3[C:23]#[C:24][C:25](O)(C)C)[N:9]([CH3:29])[CH2:8]1)=[O:5])[CH3:2].[N:32]1[CH:37]=CC=C[CH:33]=1>>[CH3:33][N:32]([CH3:37])[C:25]#[C:24][CH2:23][C:13]1[NH:14][C:15]2[C:22]3[C:12]=1[CH2:11][C@@H:10]1[C@@H:20]([C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:21][C@H:7]([NH:6][C:4](=[O:5])[N:3]([CH2:1][CH3:2])[CH2:30][CH3:31])[CH2:8][N:9]1[CH3:29]
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(C#CC(C)(C)O)c(c34)C[C@H]2N(C)C1
Reactant: c1ccncc1
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cccc4[nH]c(CC#CN(C)C)c(c34)C[C@H]2N(C)C1

Procedure:
1,1-diethyl-3-[2-(3-hydroxy-3-methyl-1-butynyl)-6-methyl-8α-ergolinyl]urea, mp starting with 132°-140° C., [α]D =+67.8° (c=0.2% in pyridine);
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2].C([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)(OC(C)(C)C)=O.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][N:16]([CH:29]3[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]3)[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CCOc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOc1cc(N2CCN(C3CCNCC3)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a stirred solution of 1-[3-(ethyloxy)-4-nitrophenyl]piperazine (Example 143, step A) (0.53 g, 2.1 mmol) and 1-BOC-4-piperidone (2.1 g, 10.6 mmol) in DCE (21 mL) was added HOAc (0.25 g, 4.2 mmol) followed by addition of sodium triacetoxyborohydride (2.2 g, 10.6 mmol). The reaction was stirred under N2 at rt for 3 h. The reaction was quenched with aqueous (saturated) NaHCO3 and extracted with DCM (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography. The desired fractions were concentrated under vacuum. The residue was dissolved and stirred in a 20% solution of TFA/DCM (50 mL) for approximately 2 h at rt. The mixture was concentrated under vacuum. The residue was dissolved in DCM and neutralized with aqueous (saturated) NaHCO3. The aqueous layer was extracted with DCM (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography. The desired fractions were concentrated under vacuum to give the title compound of step A (560 mg, 1.68 mmol, 79%) as a yellow solid. MS (ESI): 335 [M+H]+.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH:4]([OH:6])[CH3:5].[CH:7](=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:8]([CH:7]1[S:1][CH2:2][CH2:3][CH:4]([CH3:5])[O:6]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCC=O
Reactant: CC(O)CCS
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCCCCCC1OC(C)CCS1

Procedure:
75 ml of dichloromethane is placed in a 100 ml round-bottom flask. To the dichloromethane is added 5.3 grams (0.05 moles) of 4-mercapto-2-butanol. 8.58 grams (0.055 moles) n-decanal is then added followed by 0.1 grams of p-toluene sulfonic acid. Boiling chips are added to the flask. A Dean-Starke distilling receiver is placed on the flask, and a reflux condenser is placed on the receiver. The flask is then heated slowly until reflux occurs, and then the temperature is increased for a more vigorous reflux. The reflux lasts for a period of 2 hours before water of reaction ceases to be formed. The reaction mass is then cooled and neutralized with 10% aqueous sodium bicarbonate to a pH of 8. The reaction mass is filtered through fluted filter paper, and the dichloromethane solvent is removed by means of rotary evaporation. 11.8 grams of crude product are recovered after the rotary evaporation operation. The crude product is then distilled by means of vacuum distillation yielding the following 4 fractions: