Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.2 %

Procedure:
A solution of 0.299 g (0.001 mol) of N-benzyloxycarbonylphenylalanine (Z-Phe), 0.08 g (0.001 mol) of pyridine and 0.256 g (0.001 mol) of DSC in 10 ml of acetonitrile was stirred at ambient temperature. After silica gel TLC. showed that Z-Phe (the free acid form) disappeared in the solution, the reaction solution was admixed with 0.075 g (0.001 mol) of glycine (Gly-OH) and 0.101 g (0.001 mol) of triethylamine, followed by stirring at ambient temperature for 24 hours. The resultant reaction mixture was concentrated to a small volume, admixed with ethyl acetate, washed with aqueous 4% NaHCO3, with 1 N-HCl and with a saturated aqueous solution of sodium chloride, followed by drying over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was distilled to remove the solvent, affording a colorless crystalline substance. Recrystallization of this solid substance from ethyl acetate-petroleum ether gave 0.30 g of N-benzyloxycarbonylphenylalanylglycine (Z-Phe-Gly-OH) as a colorless crystalline substance. Yield 83.4%.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH:22]([OH:24])[CH3:23])[C:6](=[O:25])[N:5]([CH3:26])[C:4]=2[N:3]=1.[CH2:27]([SH:30])[CH2:28][CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH:22]([OH:24])[CH3:23])[C:6](=[O:25])[N:5]([CH3:26])[C:4]=3[N:3]=[C:2]2[S:30][CH2:27][CH2:28][CH3:29])=[CH:13][CH:14]=1
Reactant: CC(O)CCn1c(=O)c2c(nc(Br)n2Cc2ccc(Cl)cc2)n(C)c1=O
Reactant: CCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1nc2c(c(=O)n(CCC(C)O)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-1-(3-hydroxybutyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (100 mg, 0.23 mmol, example 97, step 1) in DMF (5 mL) was added propane-1-thiol (20.7 mg, 0.27 mmol) followed by potassium carbonate (93.9 mg, 0.68 mmol). The reaction was stirred at 60° C. for 3 h. The reaction was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give crude product (80 mg, 80.9% yield) as yellow oil. LCMS MH+ 437.
Reaction SMILES: CO[C:3](=[O:20])[C:4]([OH:19])=[CH:5][C:6](=[O:18])[N:7]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=1)[CH3:8].C=O.C(N[N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)CC.ClC1[CH:34]=[C:35](C=CC=1Cl)[CH2:36][N:37](C)[C:38](C1CN(C)C(=O)C=1O)=O>>[Cl:17][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[Cl:16])[CH2:9][N:7]([CH3:8])[C:6]([C:5]1[CH2:38][N:37]([CH2:36][CH2:35][CH2:34][N:27]2[CH:31]=[CH:30][N:29]=[CH:28]2)[C:3](=[O:20])[C:4]=1[OH:19])=[O:18]
Reactant: COC(=O)C(O)=CC(=O)N(C)Cc1ccc(Cl)c(Cl)c1
Reactant: CCCNn1ccnc1
Reactant: CN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Agent: C=O
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCCn2ccnc2)C1
Yield: 28 %

Procedure:
3-[(3,4-Dichloro-benzyl-methyl-carbamoyl]-2-hydroxy-acrylic acid methyl ester (Compound 12-B) was treated with paraformaldehyde and N-propylamino imidazole as described in the preparation of Compound 12. The resulting residue was purified by chromatography (YMC Combiprep ODS-A, 30 mm×50 mm, MeOH/H2O/0.1% TFA) to yield the title compound as an amber foam (59.1 mg, 28% yield). 1H NMR (300 MHz, DMSO) δ: 14.47 (bs, 1H), 11.05 (bs, 1H), 9.10 (s, 1H), 7.82 (s, 1H), 7.70 (s, 1H), 7.62 (d, 1H, J=8.05), 7.52 (s, 1H), 7.25 (d, 1H, J=7.32), 4.59 (s, 2H), 4.19 (t, 1H, J=6.95), 4.09 (s, 2H), 3.41 (t, 2H, J=6.59), 2.98 (s, 3H), 2.13 (t, 2H, J=6.59). HRMS (M+H) calcd for C19H21N4Cl2O3: 423.0990. found: 423.0982.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N+:18]([O-:20])=[O:19])[S:9][C:6]2=[N:7][CH:8]=1.[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(N(CC)CC)C>C(#N)C>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:10]1[S:9][C:6]2[C:5]([N:11]=1)=[CH:4][C:3]([CH2:2][N:31]1[CH2:30][CH2:29][N:28]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:33][CH2:32]1)=[CH:8][N:7]=2)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1-c1nc2cc(CBr)cnc2s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(Cc2cnc3sc(-c4ccccc4[N+](=O)[O-])nc3c2)CC1
Yield: 74 %

Procedure:
A solution of crude 6-(bromomethyl)-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine (4.0 g), Boc-piperazine (1.99 g, 10.7 mmol), triethylamine (Et3N) (1.5 mL, 10.7 mmol) and acetonitrile (100 mL) was stirred at 50° C. (4 h) and then at room temperature (60 h). TLC demonstrated that the reaction was complete. The mixture was concentrated in vacuo and purified by silica gel chromatography (petroleum ether:ethyl acetate:Et3N=100:10:1) to afford tert-butyl 4-((2-(2-nitrophenyl)thiazolo[5,4-b]pyridin-6-yl)methyl)piperazine-1-carboxylate as a yellow solid (3.6 g, yield: 74% over 2 steps).
Reaction SMILES: [NH2:1][C:2]1([O:11][CH:10]=[CH:9][CH2:8]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[C:14]([O:18][C:19](ON=C(C1C=CC=CC=1)C#N)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCOCC1.O>[C:14]([O:18][C:19]([NH:1][C:2]1([O:11][CH:10]=[CH:9][CH2:8]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Reactant: NC1(CCC(=O)O)CC=CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NC1(CCC(=O)O)CC=CO1

Procedure:
5.0 pts. by wt. of 2-amino-furfurylacetic acid (Rohm and Haas, Netherlands Application 66,07754) in 100 pts. by vol. of 80 percent strength aqueous dioxane are brought to pH with 4 N sodium hydroxide solution. 8.0 pts. by wt. of 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile are added and the mixture is warmed to 70° for 2 hrs. During this time, the above pH is maintained by adding 4 N sodium hydroxide solution. Thereafter, 80 pts. by vol. of water are added, the dioxane is stripped off and the reaction mixture is extracted several times with ethyl acetate. The aqueous phase is brought to pH 4 with 10 percent strength citric acid, and is saturated with sodium chloride and extracted by shaking with ethyl acetate. The ethyl acetate phases are dried over sodium sulphate and concentrated. The residue is recrystallized from a little abs. carbon tetrachloride. 4.3 pts. by wt. of 2-t-butoxycarbonylamino-furfurylacetic acid of melting point 99°-101° are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9].C(O)=O>>[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]=[N:18][N:19]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([N:5]([CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[CH3:6])=[O:28])=[CH:24][N:23]=3)[C:20]=2[OH:21])=[C:12]([CH3:31])[CH:11]=1)#[N:9]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CNCCN(C)C
Solvent: O=CO
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N(C)CCN(C)C)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 284 using N1,N1,N2-trimethylethane-1,2-diamine and 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid to give a formic acid salt (61 mg, 0.135 mmol, 72.3%) as an off-white solid. MS: 405 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 3 H) 2.53-2.70 (m, 4 H) 3.02 (s, 3 H) 3.11-3.80 (m, 6 H) 7.53 (d, J=8.3 Hz, 1 H) 7.58 (s, 1 H) 7.89-7.99 (m, 2 H) 8.10 (br. s., 1 H) 8.50 (m, 2 H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[CH:10]=[C:9]([C:21]([F:24])([F:23])[F:22])[N:8]=2)[CH:6]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([C:21]([F:24])([F:23])[F:22])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:29]4[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-n2cnc(Br)c2)n1
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example E.39) (0.22 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a yellow solid (0.022 g, 10%). MS (ISP) 451.1 [(M+H)+]; mp 282.5° C.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:11](Cl)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.C([SH:16])C.C(N([CH2:22][CH3:23])CC)C>CCOCC>[Cl:1][C:2]1[S:3][C:4]([C:11](=[S:16])[O:12][CH2:22][CH3:23])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: O=C(Cl)c1sc(Cl)nc1C(F)(F)F
Reactant: CCN(CC)CC
Reactant: CCS
Solvent: CCOCC
Product: CCOC(=S)c1sc(Cl)nc1C(F)(F)F
Yield: 68 %

Procedure:
5.95 g (25.7 mmol) of 2-chloro-4-trifluoromethyl-5-thiazolecarbonyl chloride in 50 ml of anhydrous ether was added dropwise at 0° C. to a mechanically stirred mixture of ethyl mercaptan (2.1 ml, 28.3 mmol) and triethylamine (3 g, 30 mmol) in 100 ml of anhydrous ether. The workup for this reaction was the same as Example 1 except that the crude pale yellow oil was distilled in a Kugelrohr at 80° C./0.55 mm to yield a colorless oil, 5.59 g. This oil was crystallized from petroleum ether at -72° C. to yield ethyl 2-chloro-4-trifluoromethyl-5-thiazolecarbothioate as a white solid; 4.8 g (68% yield), mp 28°-32° C.
Reaction SMILES: [F:1][C:2](=[C:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=1.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)=[CH:29][CH:28]=1>CS(C)=O.C(N(CC)CC)C.O>[F:1][C:2]([C:3]1[CH:19]=[CH:18][CH:17]=[C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:15])([F:16])[F:14])=[CH:9][N:8]=2)[CH:4]=1)=[C:20]1[CH2:25][CH2:24][N:23]([C:34]([NH:33][C:30]2[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=2)=[O:35])[CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Oc2ccccc2)cn1
Reactant: FC(=C1CCNCC1)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)N2CCC(=C(F)c3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)cn1
Reaction time: 12 h
Yield: 59.3 %

Procedure:
To a solution of 2-(3-(fluoro(piperidin-4-ylidene)methyl)phenoxy)-5-(trifluoromethyl)pyridine (110 mg, 0.312 mmol) and phenyl 6-methylpyridin-3-ylcarbamate (71.2 mg, 0.312 mmol) in DMSO (5 mL) under a N2 atmosphere was added 5 drops of triethyl amine and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water several times to remove the excess DMSO. The title compound was crystallized from hexane and diethyl ether to give the pure title compound (90 mg). 1H NMR (500 MHz, CDCl3): δ 2.5 (brs, 2H), 2.6 (brs, 2H), 2.8 (s, 3H), 3.7 (brs, 2H), 3.8 (brs, 2H), 7.0 (d, 1H, J=7.5 Hz), 7.1-7.3 (m, 3H), 7.4 (m, 2H), 7.9 (d, 1H, J=7.5 Hz), 8.4 (s, 1H), 9.0 (d, 1H, J=8.5 Hz), 9.4 (s, 1H), 9.8 (s, 1H); 13C NMR (125 MHz, CDCl3): 22.6, 25.6, 27.8, 44.2, 44.4, 53.4, 111.6, 114.1, 114.3, 121.4, 122.0, 123.8, 125.3, 129.7, 130.0, 133.8, 134.7, 136.9, 138.7, 145.4, 151.8, 153.0, 154.6, 165.4; m/z (487.4 M+ H+); HPLC: 98.9%; MP: 158-160° C.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:19][CH2:18][N:17]([CH:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH2:7][CH2:6]1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl.C(#N)C>[CH3:1][N:2]([CH3:33])[C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([CH2:15][CH2:16][N:17]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:18][CH2:19]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CCC2(CCN(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CN(C)C(=O)N1CCC2(CCN(C3CCNCC3)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The tert-butyl 4-(1′-(dimethylcarbamoyl)-2′,3′-dihydro-1′H-spiro[piperidine-4,4′-quinoline]-1-yl)piperidine-1-carboxylate 2ad (1.34 g, 2.93 mmol) was dissolved in 40 mL anhydrous dichloromethane and cooled to 0° C. The rapidly stirring solution was treated with TFA (20 mL) and allowed to come to room temperature over 2 hours. The reaction was diluted with ˜20 mL acetonitrile and concentrated to an oil. The oil was brought up in 100 mL 1.0 N HCL and washed with diethyl ether (3×30 mL). The aqueous solution was then basified with 5 N NaOH and the product extracted into dichloromethane (3×50 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to yield N,N-dimethyl-1-(piperidin-4-yl)-2′,3′-dihydrospiro[piperidine-4,4′-quinoline]-1′-carboxamide 2ae as a colorless oil. LC/MS (10-99% CH3CN/0.05% TFA gradient over 5 min): m/z 357.2, retention time 0.78 minutes. 1H NMR (400 MHz, DMSO-d6) δ 7.35 (d, J=7.8 Hz, 1H), 7.06 (t, J=7.3 Hz, 1H), 6.90 (t, J=7.5 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 3.40 (t, J=5.8 Hz, 2H), 3.13 (d, J=12.4 Hz, 2H), 2.77 (s, 6H), 2.71-2.61 (m, 5H), 2.42 (t, J=10.8 Hz, 3H), 1.92 (t, J=10.7 Hz, 2H), 1.86-1.78 (m, 5H), 1.58-1.45 (m, 4H).
Reaction SMILES: C(OC(N1C[CH2:12][N:11]([C:14]2[C:15](=[O:33])[N:16]([CH2:29][CH:30]([CH3:32])[CH3:31])[N:17]=[C:18]([C:21]3[CH:26]=[CH:25][C:24](C)=[C:23](F)[CH:22]=3)[C:19]=2[CH3:20])[CH2:10]C1)=O)(C)(C)C.C1(CN2C(=O)C(C[O:46][S:47]([CH3:50])(=O)=[O:48])=CC(C3C=CC(S(C)(=O)=O)=CC=3)=N2)CC1.CNC>>[CH:30]1([CH2:29][N:16]2[C:15](=[O:33])[C:14]([N:11]([CH3:10])[CH3:12])=[C:19]([CH3:20])[C:18]([C:21]3[CH:22]=[CH:23][C:24]([S:47]([CH3:50])(=[O:48])=[O:46])=[CH:25][CH:26]=3)=[N:17]2)[CH2:31][CH2:32]1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: CS(=O)(=O)OCc1cc(-c2ccc(S(C)(=O)=O)cc2)nn(CC2CC2)c1=O
Agent: CNC
Product: Cc1c(-c2ccc(S(C)(=O)=O)cc2)nn(CC2CC2)c(=O)c1N(C)C
Yield: 65.6 %

Procedure:
Following the procedure of Example 1 (10), 2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methyl-sulfonyl)phenyl]-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 65.6%).
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].[CH3:5][OH:6]>>[CH:1]([O:4][C:5]([CH2:3][C:1]1[O:4][C:1]([CH3:3])([CH3:2])[O:4][C:5](=[O:6])[CH:2]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)O
Product: CC(C)OC(=O)CC1=CC(=O)OC(C)(C)O1

Procedure:
The reaction was carried out in the same manner as in Example 2 except that 10 mL of isopropyl alcohol was used as the alcohol in lieu of methanol. The reaction mixture was treated in the same manner as mentioned above and the organic layer obtained by phase separation was dried and concentrated to give 0.999 g of nearly pure 6-isopropoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one. The yield of 6-isopropoxycarbonylmethyl-2,2-dimethyl-4H-1,3-dioxin-4-one was 74 mol% based on the starting material 6-chloromethyl-2,2-dimethyl-4H-1,3-dioxin-4-one. The NMR spectrum data on this compound are shown below.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:5]=[C:4]([NH2:15])[CH:3]=1.NC1C(C#N)=C(OC(C)C)N=C(N[C:30](=[O:42])[CH2:31][C:32]2[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=2[O:40][CH3:41])C=1>N1C=CC=CC=1.C(Cl)Cl.O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH2:12][O:13][CH3:14])[N:5]=[C:4]([NH:15][C:30](=[O:42])[CH2:31][C:32]2[CH:37]=[C:36]([O:38][CH3:39])[CH:35]=[CH:34][C:33]=2[O:40][CH3:41])[CH:3]=1
Reactant: COc1ccc(OC)c(CC(=O)Nc2cc(N)c(C#N)c(OC(C)C)n2)c1
Reactant: COCCOc1nc(N)cc(N)c1C#N
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCOc1nc(NC(=O)Cc2cc(OC)ccc2OC)cc(N)c1C#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.8 %

Procedure:
To a solution of 42 mg (0.20 mmol) of 4,6-diamino-2-(2-methoxy-ethoxy)-nicotinonitrile in 0.2 mL of pyridine and 1 mL of CH2Cl2 was added 75 mg (0.35 mmol) of 2,5-dimethoxyphenylacetyl chloride (Example 60B). The mixture was stirred at ambient temperature for 10 minutes then diluted with 1 mL of water and concentrated under reduced pressure. The residue was dissolved in 1 mL of ethyl acetate, then extracted with water (1×10 mL), 1M HCl(aq.) (2×5 mL), saturated NaHCO3(aq.) (2×5 mL), and brine (1×5 mL), dried over MgSO4, filtered, and concentrated to a yellow solid. The residue was recrystallized from 3 mL of ethyl acetate to provide 30 mg (38%) of a white solid. 1H NMR (300 MHz, d6-DMSO) δ 10.11 (s, 1H), 7.14 (s, 1H), 6.90 (m, 3H), 6.79 (m, 2H), 4.42 (m, 2H), 3.70 (s, 3H), 3.69 (s, 3H), 3.64 (m, 4H), 3.31 (s, 3H); MS (ESI) m/e=329 (M-CH2CH2OCH3+H)+, 387 (M+H)+, 385 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[OH:16][CH:13]1[CH2:14][CH2:15][N:11]([C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)[CH2:12]1
Reactant: OC1CCNC1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(N2CCC(O)C2)nc1
Temperature: 125 °C
Reaction time: 24 h
Yield: 70 %

Procedure:
To a solution of 6-chloronicotinamide (0.16 g, 1 mmol) and pyrrolidin-3-ol (0.87 g, 1 mmol) in DMF (5 ml) was added K2CO3 (0.41 g, 3 mmol). The resulting solution was stirred under nitrogen at 125° C. for 24 h, and then allowed to cool to ambient temperature. The reaction mixture was then filtered and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated to afford the title compound (0.145 g, 70%) as a yellow solid. [LCMS RtA=1.23 min, [M+H]+=208.1].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].C(N(CC)CC)C.[CH2:27]([C:34]1[CH:38]=[CH:37][NH:36][C:35]=1[CH2:39]O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CCOCC>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH2:39][C:35]1[NH:36][CH:37]=[CH:38][C:34]=1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:15]
Reactant: OCc1[nH]ccc1Cc1ccccc1
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1F)C(=O)OCc1[nH]ccc1Cc1ccccc1
Reaction time: 18 h

Procedure:
To the acid chloride of 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoic acid (2.5 mmol) in ether is added 1.3 ml of triethylamine followed by 3-benzylpyrrolylmethyl alcohol (2.0 mmol) in ether over about 2 minutes. The reaction mixture is stirred for about 18 hours and then quenched with saturated aqueous sodium bicarbonate. The organic phase is washed with aqueous sodium bicarbonate, water and brine, dried over calcium sulfate and solvent evaporated. The crude product is chromatographed on a circular chromatograph eluting with 20% ether/hexane to give 3-benzylpyrrolylmethyl 2-(2-fluoro-4-trifluoromethylphenylamino)-3-methylbutanoate.
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[CH3:10][NH2:11].[H][H]>CO.[Pd].[OH-]>[F:1][C:2]1([F:9])[CH2:7][CH2:6][CH:5]([NH:11][CH3:10])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: O=C1CCC(F)(F)CC1
Reactant: CN
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: CNC1CCC(F)(F)CC1
Yield: 50 %

Procedure:
The title compound was prepared from 4,4-difluoro-cyclohexanone (prepared from 8,8-Difluoro-1,4-dioxa-spiro[4.5]decane by deprotection with sulfuric acid under standard conditions) and methylamine by reductive amination under standard conditions (Pd hydroxide in methanol, 1 atm hydrogen) in ˜50% yield. Recrystallization of the hydrochloride from ethanol/diethylether afforded analytical pure material. Light-brown solid, mp 137–144° C. MS: m/e=186 (M+H+).
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13].[S:14]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C@H:15]1[O:23][C@@H:22]([CH3:24])[C@@H:20]([OH:21])[C@@H:18]([OH:19])[C@@H:16]1[OH:17]>CN(C=O)C>[CH3:13][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[C:10]([CH3:11])[C:5]=1[CH2:4][O:17][C@H:16]1[C@H:18]([O:19][CH2:4][C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH3:13])[C@H:20]([O:21][CH2:4][C:5]2[C:10]([CH3:11])=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[CH3:13])[C@H:22]([CH3:24])[O:23][C@@H:15]1[S:14][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cc(C)c(CBr)c(C)c1
Reactant: C[C@@H]1O[C@H](Sc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(CO[C@@H]2[C@H](OCc3c(C)cc(C)cc3C)[C@H](C)O[C@H](Sc3ccccc3)[C@H]2OCc2c(C)cc(C)cc2C)c(C)c1
Temperature: 0 °C
Reaction time: 21 h

Procedure:
A dry 250 ml flask is filled with 6.6 g (152 mmol) of sodium hydride in mineral oil emulsion (55%). Dry dimethylformamide (10 ml) is added and the mixture is cooled to 0° C. To this mixture bromomethylmesitylene (32.4 g, 152 mmol) in dry DMF (20 ml) is added. Compound of example 9 (10 g, 39 mmol) is dissolved in dry DMF (20 mL) and added very to the above mixture over 40 minutes. After an additional hour the ice-bath is removed and the reaction is stirred at room temperature for 21 hours. Methanol (15 ml) is added to quench and the reaction mixture is stirred for another hour, then it is diluted with ethyl acetate (200 ml) and extracted with sat. NaHCO3 (200 ml), 1N HCl (200 ml), water (200 ml) and brine (200 ml). The title compound is obtained after column chromatography purification and crystallization.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-])=O)[CH:3]=1.[CH3:12][O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][O:19][CH3:20].[H][H]>C(#N)C.[Ni]>[NH2:9][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[N:16]([CH2:17][CH2:18][O:19][CH3:20])[CH2:15][CH2:14][O:13][CH3:12]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: COCCNCCOC
Agent: [Ni]
Solvent: CC#N
Product: COCCN(CCOC)c1ccc(Br)cc1N
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-1-fluoro-2-nitrobenzene (0.44 g, 2mmol) and N,N-bis(2-methoxyethyl)amine (0.266 g, 2.4 mmol) in acetonitrile (10 mL) in a capped 20 mL vial was shaken at 80° C. overnight and concentrated. The concentrate was dissolved in methanol (10 mL), and treated with Raney nickel (50% water suspension, 0.40 g, 6.8 mmol). The vial was filled with excessive hydrogen, shaken at 50° C. for 1 hour, filtered, and concentrated. The concentrate was purified by preparative HPLC with acetonitrile/water containing 0.1% TFA to provide the desired product. MS (APCI(+)) m/z 304 (M+H)+.