Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:4](=[O:25])[C:3]1=[N:26]NC1C=CC=CC=1>C(O)(=O)C.O.[Zn]>[NH2:26][CH:3]1[C:2](=[O:1])[N:8]([CH2:9][CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:4]1=[O:25]
Reactant: CC(C)CCn1c(=O)c(=NNc2ccccc2)c(=O)n(-c2ccccc2F)c2ccccc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CCN1C(=O)C(N)C(=O)N(c2ccccc2F)c2ccccc21
Reaction time: 3 h
Yield: 60.4 %

Procedure:
A solution of the intermediate 2 (5.8 g) in glacial acetic acid (50 ml) was added, dropwise, to a suspension of zinc dust (6.37 g) in glacial acetic acid (20 ml) cooled to 0°. The mixture was stirred at 23° for 3 h, then diluted with water (200 ml) and decanted from zinc. Solid sodium carbonate was added until pH=9 and the mixture extracted with ethyl acetate (2×300 ml). The combined organic extracts were washed with brine (300 ml), dried and concentrated in vacuo to an oil which was purified by flash chromatography (eluting in gradient from CH-EA 2:1 to EA) to give the title compound as a white foam (2.8 g). M.P. 125°-6°. T.l.c. DCM-methanol (30:1), Rf0.38.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2].C(N(CC)C(C)C)(C)C.Br[CH2:21][CH2:22][OH:23]>O>[CH2:1]([N:3]([CH2:21][CH2:22][OH:23])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)[CH3:2]
Reactant: OCCBr
Reactant: CCNc1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCN(CCO)c1ccc(Br)cc1
Temperature: 125 °C
Yield: 69.5 %

Procedure:
17.3 g (86.7 mmols) of N-ethyl-4-bromoaniline, 22.7 ml (1.5-fold equivalent weight) of N,N-diisopropylethylamine and 9.64 ml (1.5-fold equivalent weight) of 2-bromoethanol were mixed, and the mixture obtained was heated at 125° C. for 2 hours in an atmosphere of argon. Next, to the reaction solution obtained, 1.5 ml (0.1-fold equivalent weight) of diisopropylethylamine and 0.64 ml (0.1-fold equivalent weight) of 2-bromoethanol were added, and the mixture obtained was heated at 125° C. for 3 hours in an atmosphere of argon. Water was added to the reaction solution obtained, which was then extracted with ethyl acetate. The organic layer obtained was dried with anhydrous magnesium sulfate and then concentrated. The residue thus obtained was purified by silica gel column chromatography developing system (chloroform) to obtain 14.7 g of N-ethyl-N-(2-hydroxyethyl)-4-bromoaniline (yield: 69.5%; a colorless oily liquid).
Reaction SMILES: F[C:2]1C=CC(COC2C=C(C)N(C3C=C(C=CC=3C)C(O)=O)C(=O)C=2)=C(CNC(OC)=O)C=1.Br[C:35]1[C:36](=[O:69])[N:37]([C:59]2[CH:60]=[C:61]([CH:65]=[CH:66][C:67]=2[CH3:68])[C:62]([OH:64])=[O:63])[C:38]([CH3:58])=[CH:39][C:40]=1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=1[CH2:50][NH:51][C:52]([NH:54][CH:55]1[CH2:57][CH2:56]1)=[O:53]>>[CH:55]1([NH:54][C:52]([NH:51][CH2:50][C:44]2[CH:45]=[C:46]([F:49])[CH:47]=[CH:48][C:43]=2[CH2:42][O:41][C:40]2[CH:39]=[C:38]([CH3:58])[N:37]([C:59]3[CH:60]=[C:61]([CH:65]=[CH:66][C:67]=3[CH3:68])[C:62]([O:64][CH3:2])=[O:63])[C:36](=[O:69])[CH:35]=2)=[O:53])[CH2:57][CH2:56]1
Reactant: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1
Reactant: Cc1ccc(C(=O)O)cc1-n1c(C)cc(OCc2ccc(F)cc2CNC(=O)NC2CC2)c(Br)c1=O
Product: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3CNC(=O)NC3CC3)cc2=O)c1

Procedure:
Prepared using a procedure similar to that used in the preparation of 3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid. 1H NMR (CD3OD/400 MHz) δ 8.02 (m, 1H), 7.74 (s, 1H), 7.48 (m, 2H), 7.12 (m, 1H), 7.01 (m, 1H), 6.22 (s, 1H), 6.08 (s, 1H), 5.19 (s, 2H), 4.44 (s, 2H), 2.48 (m, 1H), 2.11 (s, 3H), 1.90 (s, 3H), 0.69 (m, 2H), 0.47 (m, 2H). ES HRMS m/z 480.1921 (M+H calculated for C26H27FN3O5 requires 480.1929). Step 3: Preparation of 3-[3-bromo-4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:15][CH3:16])[CH:6]([CH3:14])[CH2:7][CH2:8][CH:9]([OH:13])[CH:10]([CH3:12])[CH3:11].[H][H].[CH3:19]I>O1CCCC1.O.CN(C)P(=O)(N(C)C)N(C)C>[CH3:16][O:15][CH:5]([O:4][CH3:3])[CH:6]([CH3:14])[CH2:7][CH2:8][CH:9]([O:13][CH3:19])[CH:10]([CH3:12])[CH3:11]
Reactant: [H][H]
Reactant: CI
Reactant: COC(OC)C(C)CCC(O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC(CCC(C)C(OC)OC)C(C)C

Procedure:
To a mixture of 2.4 g. of clean sodium hydride in 200 ml. of dry tetrahydrofuran containing 20 ml. of dry HMPT (hexamethylphosphorictriamide) is added dropwise a solution of 20.4 g. of 1,1-dimethoxy-5-hydroxy-2,6-dimethylheptane in dry tetrahydrofuran. The mixture is stirred at room temperature until evolution of hydrogen ceases and then 16 g. of methyl iodide is added. The reaction mixture is refluxed for 3 hours and then cooled, diluted with water and extracted with ether. The etheral extracts are evaporated under reduced pressure to yield crude 1,1,5-trimethoxy-2,6-dimethylheptane which can be purified by distillation or chromatography on Florisil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:19])[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[NH:14][C:15](=[O:18])[CH2:16][CH3:17])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:31][CH2:32][CH:33]=[C:34]1[C:40]2[CH:41]=[CH:42][CH:43]=[N:44][C:39]=2[CH2:38][O:37][C:36]2[CH:45]=[CH:46][C:47]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:48][C:35]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:19])[CH2:13][CH2:12][N:11]([CH2:31][CH2:32][CH:33]=[C:34]3[C:40]4[CH:41]=[CH:42][CH:43]=[N:44][C:39]=4[CH2:38][O:37][C:36]4[CH:45]=[CH:46][C:47]([C:49]([OH:52])([CH3:51])[CH3:50])=[CH:48][C:35]3=4)[CH2:10][CH:9]2[NH:14][C:15](=[O:18])[CH2:16][CH3:17])=[CH:6][CH:7]=1.[CH:8]([O-:19])=[O:37]
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: CCC(=O)NC1CNCCC1(O)c1ccc(Cl)cc1
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CCC(=O)NC1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Product: O=C[O-]
Temperature: 80 °C
Reaction time: 14 h
Yield: 1078.9 %

Procedure:
To a solution of the N-[4-(4-chloro-phenyl)-4-hydroxy -piperidin-3-yl]-propionamide (0.133 g, 0.47 mmol) in isopropanol (5.0 mL) was added 2,6-lutidine (0.055 mL, 0.47 mmol) and catalytic potassium iodide. This mixture was heated to 80° C., and treated with 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.176 g, 0.35mmol), added in portions over 2 h. The solution was then stirred at 80° C. for an additional 14 h. The reaction was concentrated in vacuo, then purified by HPLC (acetonitrile/H2O/Formic acid) to yield the title compound as a white formate salt (0.085 g, 27%). 1H-NMR (CDCl3): δ 0.780 (t, 3H), 1.55 (s, 6H), 1.90 (m, 3H), 2.60 (m, 2H), 2.92-3.28 (m, 6H), 4.50 (d, 1H), 5.26 (bs, 2H), 6.00 (t, 1H), 6.82 (d, 1H), 7.22-7.37 (m, 6H), 7.44 (s, 1H), 7.56 (d, 1H), 8.20 (d, 1H), 8.34 (s, 1H), 8.47 (d, 1H). ESI-MS m/z: 576 (M+1), retention time 1.43.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23](Br)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:33][O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1>O1CCOCC1.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23]([C:39]4[CH:38]=[CH:37][CH:36]=[C:35]([O:34][CH3:33])[CH:40]=4)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3cc(Br)cnc3N)o2)CC1
Reactant: COc1cccc(B(O)O)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: C1COCCO1
Solvent: O
Product: COc1cccc(-c2cnc(N)c(-c3nnc(C4CCN(C(=O)OC(C)(C)C)CC4)o3)c2)c1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[5-(2-amino-5-bromo-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.35 mmol) in dioxane (20 mL) and water (20 mL) were added K2CO3 (0.95 g, 7.05 mmol), 3-methoxyphenyl boronic acid (0.39 g, 2.59 mmol) in a sealed tube. The reaction mixture was degassed with argon for 20 min, then Pd(PPh3)4 (0.13 g, 0.11 mmol) was added to the reaction mixture. The reaction mixture was stirred for 18 h at 100° C. The reaction mixture was diluted with water (100 mL) extracted with ethyl acetate (2×150 mL) and organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude product. The crude compound was purified by column chromatography using 100-200 mesh silica gel and compound was eluted with 40% ethyl acetate in petroleum ether to afford 500 mg, which was further purified by washing with diethyl ether and hexane to afford the title compound as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[NH2:20][CH2:21][CH2:22][OH:23].O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:20][CH2:21][CH2:22][OH:23])[N:14]=1)=[O:8]
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CI)cs1
Reactant: NCCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1cccc(F)c1)Nc1nc(CNCCO)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Fluorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea (Intermediate 7) was taken up in tetrahydrofuran and an excess of the 2-amino-ethanol (20 equiv.) was added. The reaction was allowed to stir overnight at room temperature. The reaction was poured into water and extracted with EtOAc, partitioned with brine, dried over Na2SO4, filtered, and volatiles were removed in vacuo. The resulting solid was triturated with EtOAc, followed by diethyl ether to give the title compound.
Reaction SMILES: [CH3:1][C:2]1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)[C:8](=[O:9])[N:4]2[C@H:3]1C([O-])=O.[K+].C[C@@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H]([NH:40]C(N)=N)[C@@H](O)[C@@H]2NC(N)=N)[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O.N[C@H:66]([C:72]([OH:74])=O)[CH2:67][CH2:68][C:69](=[O:71])[NH2:70]>>[C@@H:69]1([N:70]2[CH:1]=[CH:2][C:3]([NH2:40])=[N:4][C:8]2=[O:9])[O:71][C@H:66]([CH2:72][OH:74])[CH:67]=[CH:68]1
Reactant: NC(=O)CC[C@H](N)C(=O)O
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: [K+]
Product: Nc1ccn([C@H]2C=C[C@@H](CO)O2)c(=O)n1

Procedure:
Nucleoside Analogs: One millimolar solutions were prepared in glass distilled water and filter sterilized through 0.2μ filters. Subsequent dilutions were prepared in RPMI 1640 medium containing 15% fetal calf serum, penicillin, streptomycin and glutamine.
Reaction SMILES: N([O-])=O.[Na+].O.N[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].NC(N)=[O:18].[N+]([O-])(O)=O>S(=O)(=O)(O)O>[NH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH:7]([OH:18])[C:13]([OH:15])=[O:14]
Reactant: NC(N)=O
Reactant: NCCCC[C@H](N)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: NCCCCC(O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An aqueous solution (100 ml) of sodium nitrite (25.9 g, 0.36 mole) was gradually added to a stirred solution of L-lysine hydrate (19.0 g, 0.097 mole) in 10% sulfuric acid (250 mL) at 45-50° C. over a 2 hr period. After addition was complete, the solution was stirred at 25° C. for 3 hr. Urea was added to the solution in order to decompose nitric acid formed in the reaction process and the aqueous solution was poured on to an ion exchange column (Amberlite IR-120, H+ form, 200 ml). After the column was thoroughly washed with water, it was eluted with aqueous ammonium hydroxide until the eluant became negative to ninhydrin test. Combined fractions were evaporated in vacuo, which gave a yellow oil, 7.5 grams.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[O:11])[CH2:5]1.[O:22]=[C:23]1[NH:27][CH:26]=[C:25]([C:28](O)=[O:29])[O:24]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CN(C=O)C>[O:22]=[C:23]1[NH:27][CH:26]=[C:25]([C:28]([NH:1][CH2:2][CH2:3][CH:4]2[O:9][CH2:8][CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=3)=[O:11])[CH2:5]2)=[O:29])[O:24]1
Reactant: NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1
Reactant: O=C(O)c1c[nH]c(=O)o1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCC1CN(C(=O)OCc2cc(Cl)cc(Cl)c2)CCO1)c1c[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 2-(2-aminoethyl)morpholine-4-carboxylate (Example 11, step 2) (178 mg, 0.534 mmol), 2-oxo-2,3-dihydrooxazole-5-carboxylic acid (Example 21, step 1) (68.9 mg, 0.534 mmol), T3P® (50% in DMF) (510 mg, 0.801 mmol), Huenig's base (466 μl, 2.67 mmol) in DMF (1781 μl) was stirred at room temperature. Another 1 equivalent of 2-oxo-2,3-dihydrooxazole-5-carboxylic acid was added and the reaction mixture was left stirring at room temperature overnight. The resulting reaction mixture was concentrated under reduced pressure and the crude product was diluted with EtOAc. The organic portion was dried with MgSO4, filtered and concentrated under reduced pressure. The crude material was dried loaded using silica onto an ISCO 4 g column eluting with 0-100% EtOAc (1% acetic acid) in iso-hexane. The product fractions were concentrated under reduced pressure to afford the title compound;
Reaction SMILES: Cl.Cl.Cl.Cl.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH2:19][CH2:18]3)=[O:14])=[CH:8][C:7]=1[NH:30][C:31]1[N:36]=[C:35]([C:37]2[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=2)[CH:34]=[CH:33][N:32]=1.C(N(CC)CC)C.[C:50](Cl)(=[O:52])[CH3:51]>CN(C=O)C>[C:50]([N:27]1[CH2:26][CH2:25][N:24]([CH:20]2[C:21]3[C:17](=[CH:16][C:15]([C:13]([NH:12][C:9]4[CH:10]=[CH:11][C:6]([CH3:5])=[C:7]([NH:30][C:31]5[N:36]=[C:35]([C:37]6[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=6)[CH:34]=[CH:33][N:32]=5)[CH:8]=4)=[O:14])=[CH:23][CH:22]=3)[CH2:18][CH2:19]2)[CH2:29][CH2:28]1)(=[O:52])[CH3:51]
Reactant: Cc1ccc(NC(=O)c2ccc3c(c2)CCC3N2CCNCC2)cc1Nc1nccc(-c2cccnc2)n1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(C2CCc3cc(C(=O)Nc4ccc(C)c(Nc5nccc(-c6cccnc6)n5)c4)ccc32)CC1
Reaction time: 0.33 h
Yield: 54.8 %

Procedure:
N-(4-Methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-1-piperazin-1-yl-2,3-dihydro-1H-indene-5-carboxamide tetrahydrochloride (100 mg, 0.15 mmol) was dissolved in DMF (2 mL), and triethylamine (101 mg, 1 mmol) was added followed by acetyl chloride (16 mg, 0.2 mmol) while being cooled in an ice bath. After being stirred for 20 minutes, the solution obtained was purified by high performance liquid chromatography at pH=10 to obtain 45 mg (55% yield) of the title compound. MS (+1)=548.27. 1HNMR (DMSO-d6, ppm): δ 10.15 (s, 1H); 9.26 (s, 1H); 8.99 (s, 1H); 8.66 (d, J=4.8 Hz, 1H); 8.49 (d, J=5.2 Hz, 1H); 8.45 (d, J=8.4 Hz); 8.05 (s, 1H); 7.79 (s, 1H); 7.76 (d, J=8.0 Hz, 1H); 7.50 (dd, J=8.0 & 4.8 Hz, 1H); 4.37 (t, J=7.0 Hz, 1H); 3.42 (m, 1H); 3.40 (m, 3H); 2.91 (m, 1H); 2.83 (m, 1H); 2.2-2.5 (m, 4H); 2.20 (s, 3H); 2.06 (m, 2H); 1.95 (s, 3H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].C([O:9][C:10](=O)[CH3:11])(=O)C.[C:13](O)(=O)C>>[C:1]([O:5][C:10](=[O:9])[CH:11]=[CH2:13])(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(=O)OC(C)=O
Reactant: C=CC(=O)O
Reactant: CC(=O)O
Product: C=CC(=O)OC(=O)C=C
Reaction time: 5 h
Yield: 75 %

Procedure:
In this example, the mole ratio between acrylic acid and acetic anhydride is equal to 1.5. The reaction mixture is subjected to stirring and, throughout the reaction which lasts for 5 hours, the acetic acid is drawn off under a pressure of 100 mmHg, the temperature being 85° C. at the beginning of the reaction and 95° C. at the end of the reaction. In addition, during the reaction and during the distillation, 500 ppm of copper sulphate and 500 ppm of phenothiazine are gradually introduced into the top of the distillation column. After the reaction, distillation is performed. There are distilled, as a first fraction, unreacted acetic anhydride and acrylic acid, acrylic acetic mixed anhydride as well as a little acrylic anhydride, under 200 mmHg at a temperature of 57° to 76° C. under 20 mmHg. This fraction represents 140 parts by weight. The acrylic anhydride is then distilled at 76° C. under 20 mmHg. 250 parts by weight of acrylic anhydride are collected. The yield is 75%.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4]C.[CH:6]([NH:9][CH:10](C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29]#[N:30])=[CH:26][CH:27]=3)[CH2:22][O:21]2)=[CH:16][CH:15]=1>COCCOC>[CH3:6][N:9]([CH3:10])[CH2:2][CH2:3][CH2:4][C:20]1([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[C:28]2[C:23](=[CH:24][C:25]([C:29]#[N:30])=[CH:26][CH:27]=2)[CH2:22][O:21]1
Reactant: [Li]CCCC
Reactant: CC(C)NC(C)C
Reactant: N#Cc1ccc2c(c1)COC2c1ccc(F)cc1
Solvent: COCCOC
Product: CN(C)CCCC1(c2ccc(F)cc2)OCc2cc(C#N)ccc21
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 76 %

Procedure:
n-BuLi (1.6 N in hexane, 320 mL) is added to diisopropylamine (55 g, 0.5 mole) dissolved in DME (150 mL) at −50° C. over a nitrogen atmosphere. 1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile (62 g, 0.26 mole) is dissolved in DME (500 mL) and added dropwise while the temperature is kept below −40° C. After addition (45 min), the dark red solution is stirred for an additional period of 20 min. 3-Dimethylpropylchloride (100 g, 0.82 mole) is added in one portion at −50° C. and the cooling is removed. After 60 min, the solution is warmed to 50° C. for 120 min. The reaction mixture is poured onto ice water (1 L) and extracted with toluene (2×500 mL). The organic phase is extracted with HCl (4 N, 500 mL). The acid solution is made alkaline (pH=10) with NaOH (10 N) and extracted with toluene (500 mL) which is washed with water (3×200 ml). The toluene phase is dried anhydrous Na2SO4 (50 g), treated with active carbon and the solvents are removed in vacuo. The title compound (64-71 g, 76-84%) is obtained as an oil.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH2:25](I)[CH3:26].CN(C=O)C.[H-].[Na+]>O>[C:21]([O:20][C:18]([N:17]([CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)[CH2:25][CH3:26])=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)C1CCNCC1
Reaction time: 16 h
Yield: 126.1 %

Procedure:
To a solution of 476 mg (1.42 mmol) of 1-benzyloxycarbonyl-4-(t-butoxycarbonylamino)piperidine from Step B and 0.24 mL (2.8 mmol) of ethyl iodide in 10 mnL of DMF was added 85 mg (2.1 mmol) of 60% sodium hydride in mineral oil. The reaction was stirred for 16 h and was then poured into water and extracted three times with ether. The organic layers were each washed with a portion of water and brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 15% ethyl acetate in hexanes to afford 409 mg of title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:18][Si:19](Cl)([CH3:21])[CH3:20]>>[CH2:16]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[Si:19]([CH3:21])([CH3:20])[CH3:18])=[O:5])[CH3:17]
Reactant: CCN(CC)C(=O)c1cccc2ccccc12
Reactant: C[Si](C)(C)Cl
Product: CCN(CC)C(=O)c1c([Si](C)(C)C)ccc2ccccc12
Yield: 71 %

Procedure:
N,N-Diethyl-1-naphthalenecarboxamide was reacted with 2 eq TMSCl according to General Method A. The resulting reaction mixture was worked up in the usual manner, then purified by chromatography with 20% ethyl acetate/80% hexanes to afford 2.1 g of the desired compound as a clear oil, a 71% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH2:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][OH:32])[CH2:26][CH2:25]1.CN1C(=O)CCC1>C(Cl)Cl.CN(C=O)C>[OH:32][CH2:31][CH2:30][N:27]1[CH2:28][CH2:29][N:24]([NH:23][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:16])[CH2:25][CH2:26]1
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Reactant: NN1CCN(CCO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: O=C(NN1CCN(CCO)CC1)c1cnc(-c2cccc(F)c2)nc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (0.28 g, 1.4 mmol) in anhydrous DCM (10 mL) at 0° C. is added the oxalyl chloride (0.18 mL, 1.4 mmol) followed by the addition of DMF (0.11 mL). The mixture is stirred at 0° C. for 30 min, and then allowed to warm up to rt and stirred for 30 min. The mixture is concentrated in vacuo. The residue is dissolved in anhydrous DCM (10 mL). 2-(4-Amino-piperazin-1-yl)-ethanol (0.145 g, 1 mmol) is added at rt followed by the addition of NMP (0.19 mL, 2 mmol). The mixture is stirred at rt for 2 h and the mixture is then concentrated in vacuo. The residue is triturated in Et2O and the resulting solid is collected by filtration to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-amide (0.16 g). MS: 346 (M+H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([CH:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[NH:21][C:22]([NH:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:23])[C:12]2=O)=O)=[CH:7][CH:6]=1.O.[NH2:35][NH2:36].CC(O)=O>CCO>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]2[NH:36][N:35]=[C:12]3[C:13]4[C:18]([C:19](=[O:20])[C:11]=23)=[C:17]([NH:21][C:22]([NH:24][N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:23])[CH:16]=[CH:15][CH:14]=4)=[CH:7][CH:6]=1
Reactant: O=C(Nc1cccc2c1C(=O)C(C(=O)c1ccc(OCCCl)cc1)C2=O)NN1CCOCC1
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1cccc2c1C(=O)c1c-2n[nH]c1-c1ccc(OCCCl)cc1)NN1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.8 %

Procedure:
To a suspension of 1-{2-[4-(2-chloroethoxy)benzoyl]-1,3-dioxo-indan-4-yl}-3-morpholin-4-yl-urea (39 g, 82.6 mmol) in EtOH (425 mL) was added hydrazine monohydrate (20.7 g, 413 mmol) followed by AcOH (9.9 g, 165.3 mmol). The reaction mixture was heated at reflux for 48 h. The reaction mixture was cooled to room temp. The yellow solid was collected by filtration, rinsed with EtOH and dried under vacuum. The solid was suspended in THF (1000 mL) and 1N HCl (500 mL) was added. The resulting suspension was stirred for 90 min. Brine (500 mL) was added and the pH was adjusted to 13 with 50% NaOH. The layers were separated and the aqueous layer was washed with THF (2×300 mL). The combined organic layers were washed with 1N HCl/brine (1×250 mL, 1:1), then brine (1×250 mL), dried (MgSO4), and concentrated under reduced pressure. The yellow solid was triturated with Et2O then dried under vacuum to give the desired pyrazole (23.5 g, 61% yield).