Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].Cl.[CH3:15][NH:16][CH3:17].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([N:16]([CH3:17])[CH3:15])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C(Br)c1cccnc1
Reactant: CNC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(c1cccnc1)N(C)C
Yield: 53 %

Procedure:
Bromopyridin-3-yl-acetic acid ethyl ester (2.54 g; 10.2 mmol) was reacted in a sealed tube, at rt., in CH2Cl2, overnight with N,N-dimethylamine hydrochloride (3.34 g; 41.0 mmol; 4 equiv) and Et3N (5.8 mL; 41.0 mmol; 4 equiv). The reaction solution was evaporated to dryness, dissolved in CH2Cl2, washed five times with saturated NaHCO3 (aq), washed once with saturated NaCl (aq), dried with Na2SO4, filtered, and concentrated in vacuo. The resulting brown oil was purified with silica gel chromatography in a 3×25 cm glass column using a 0.5% methanol/chloroform (v/v) mobile phase. The desired product was isolated as a yellow oil (1.12 g; 53% yield). MS(ES) calc'd: [M+H]+=208.1 m/z. Found: 208.1 m/z.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[H-].[Na+].Cl[C:14]1[CH:15]=[C:16]2[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:21][N:17]2[C:18](=[O:20])[N:19]=1>>[C:6]([C:5]1[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=1)[CH2:2][O:1][C:14]1[CH:15]=[C:16]2[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:21][N:17]2[C:18](=[O:20])[N:19]=1)#[N:7]
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Reactant: N#Cc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1cccc(C#N)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 3-(hydroxymethyl)benzonitrile, sodium hydride and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH2:14][C:15]#[N:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C[C:21]([S:24]([CH2:27]C#N)(=[O:26])=[O:25])=CC=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([C:14](=[C:27]([S:11]([CH3:8])(=[O:13])=[O:12])[S:24]([CH3:21])(=[O:26])=[O:25])[C:15]#[N:16])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)CC#N)cc1
Reactant: N#CCS(=O)(=O)c1ccc(Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)C(C#N)=C(S(C)(=O)=O)S(C)(=O)=O)cc1

Procedure:
The titled compound was prepared in an analogous fashion to Intermediate 2 except that 2-(4-tert-butylbenzenesulfonyl) acetonitrile is utilized in place of 2-(4-chlorobenzenesulfonyl) acetonitrile.
Reaction SMILES: [CH:1]1([C:4]([NH2:6])=[NH:5])[CH2:3][CH2:2]1.[CH:7](=[C:14]([C:17]#[N:18])[C:15]#[N:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[NH2:18][CH2:17][C:14]1[C:15]([NH2:16])=[N:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N=C(N)C1CC1
Reactant: N#CC(C#N)=Cc1ccccc1
Product: NCc1c(N)nc(C2CC2)nc1-c1ccccc1

Procedure:
The title compound, MS: m/e=240.1 (M+), was prepared from cyclopropanecarboxamidine and 2-benzylidene-malononitrile in analogy to the process described in Example 11 as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH3:15])=[CH:9][CH:8]=1)=[CH2:6])[CH3:2].[F:17][C:18]([F:22])=[C:19]([F:21])[F:20]>CC1C2C(C)(C)C(C2)CC=1.C1C=CC=CC=1>[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2([C:4]([O:3][CH2:1][CH3:2])=[O:16])[CH2:6][C:18]([F:22])([F:17])[C:19]2([F:21])[F:20])=[CH:8][CH:9]=1)[CH3:15]
Reactant: C=C(C(=O)OCC)c1ccc(OCC)cc1
Reactant: FC(F)=C(F)F
Agent: CC1=CCC2CC1C2(C)C
Solvent: c1ccccc1
Product: CCOC(=O)C1(c2ccc(OCC)cc2)CC(F)(F)C1(F)F
Reaction time: 17 h
Yield: 75 %

Procedure:
2-(4-ethoxyphenyl)propenoic acid ethyl ester (13.2 g) was mixed with benzene (7.5 ml), α-pinene (2 drops) N-ethyldiisopropyl amine (2 drops) and tetrafluoroethylene (15.5 ml) and heated to 150°-155° for 24 hours then 155°-60° C. for 17 hours. After evaporation of volatile materials the residue (16.6 g) was dissolved in dichloromethane and chromatographed on a column of silica gel to give the ester as a colourless oil 14.5 g (75%).
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14]I)[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][N:25]=[N+:26]=[N-:27])[O:12][C@@H:11]([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CI)O2)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Temperature: 0 °C
Yield: 90 %

Procedure:
To a stirred solution of the 3'-O-t-butyldimethylsilyl-5'-iodo-5'-deoxythymidine (10.8 g, 20 mmol) prepared according to the method of Example 25 in dry DMF (50 ml) was added sodium azide (3.9 g, 60 mmol) and the mixture heated at 0° C. for 12 hours. Then the reaction mixture was diluted with ethyl acetate (200 ml) washed with water (2×50 ml) and brine (50 ml) and then dried with sodium sulfate. The title compound was purified by flash chromatography using 50% ethyl acetate in hexance in 90% yield.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[I:6][C:7]1[CH:8]=[N:9][N:10]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][OH:21])[CH2:14][CH2:13]2)[CH:11]=1.CCN(C(C)C)C(C)C.Cl>C1COCC1>[Cl:1][CH2:2][C:3]([N:18]([CH2:19][CH2:20][OH:21])[CH:15]1[CH2:14][CH2:13][CH:12]([N:10]2[CH:11]=[C:7]([I:6])[CH:8]=[N:9]2)[CH2:17][CH2:16]1)=[O:4]
Reactant: OCCNC1CCC(n2cc(I)cn2)CC1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)N(CCO)C1CCC(n2cc(I)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Chloro-acetyl chloride (0.25 mL; 3.14 mmol; 1.1 eq.) was added dropwise over 2 min to a solution of 2-[4-(4-Iodo-pyrazol-1-yl)-cyclohexylamino]-ethanol (intermediate 25; 1.0 g; 2.89 mmol; 1.0 eq.) and DIEA (2.00 ml; 11.45 mmol; 3.96 eq.) in THF (80.00 mL) at −30° C. The reaction solution was allowed to warm slowly to RT and stirred for 16 h. It was then poured into a 1 N HCl solution and extracted with DCM. Combined organic phases were washed with saturated NaHCO3 solution, dried over magnesium sulfate, filtrated and concentrated to give 2-Chloro-N-(2-hydroxy-ethyl)-N-[4-(4-iodo-pyrazol-1-yl)-cyclohexyl]-acetamide as a brown oil. This oil was redissolved in THF (30 mL; 370 mmol; 128 eq.) and sodium tert-butoxide (2M solution in THF; 30 mL; 60.0 mmol; 21 eq.) was added in one portion. The reaction solution was heated at 40° C. for 1 h then cooled to RT and poured into 1 N HCl solution. It was extracted with DCM (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was triturated sequentially with EtOAc and Et2O, filtered and dried to give the title compound as a yellow solid (275 mg; 21%). 1H NMR (300 MHz, DMSO) δ 7.98 (s, 1H), 7.50 (s, 1H), 4.40-4.25 (m, 1H), 4.25-4.10 (m, 1H), 4.03 (s, 2H), 3.87-3.75 (m, 2H), 3.32-3.23 (m, 2H), 2.14-1.99 (m, 2H), 1.93-1.60 (m, 6H). MS (ESI+): 376.2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].C1(C)C=CC(S(O[CH2:18][CH:19]2[CH2:23][S:22][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:20]2)(=O)=O)=CC=1>CN(C)C=O.C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:18][CH:19]1[CH2:23][S:22][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:20]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CSC(NC(=O)OC(C)(C)C)=N2)cc1
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1=NC(Cc2ncc[nH]2)CS1
Temperature: 70 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
0.21 g of imidazole predissolved in 10 cm3 of dimethylformamide is added to a solution of 0.085 g of sodium hydride in 20 cm3 of dimethylformamide. After the sodium hydride has disappeared, a solution of 1 g of tert-butyl N-[(4RS)-4-(p-toluenesulfonyloxymethyl)-4,5-dihydro-2-thiazolyl]carbamate in 10 cm3 of dimethylformamide is added and the mixture is then stirred at a temperature in the region of 70° C. for 3 hours. The reaction medium is diluted with ethyl acetate, washed with water, dried over magnesium sulfate and then concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue obtained is chromatographed on a column of alumina, eluting with ethyl acetate and a mixture of ethyl acetate/methanol (80/20 by volume). The fractions containing the expected product are combined and then concentrated under the above conditions to give 0.25 g of tert-butyl N-[(4RS)-4-(1-imidazolylmethyl)-4,5-dihydro-2-thiazolyl]carbamate in the form of a sticky yellow mass [mass spectrum: DCI m/z=283 MH+ m/z=183 (M-C5H7O2)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[CH:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(F)c(Cl)c1
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(F)c(Cl)c4)nc23)cc(C)n1
Yield: 46.1 %

Procedure:
Reaction of 1-(3-chloro-4-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (134 mg, 0.5 mmol), prepared from commercially available 3-chloro-4-fluoro-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (97 mg, 46%). MS (ISP) 421.1 [(M+H)+]; mp 271° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]1[N:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]2=[N:12][C:11]=1[CH2:19][NH:20][CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24].C(N(CC)CC)C.[Cl:33][C:34]1[C:42]([O:43][CH2:44][CH2:45][Br:46])=[C:41]([O:47][CH3:48])[CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37].[OH-].[Na+]>ClCCl>[Cl:33][C:34]1[C:42]([O:43][CH2:44][CH2:45][Br:46])=[C:41]([O:47][CH3:48])[CH:40]=[CH:39][C:35]=1[C:36]([N:20]([CH2:19][C:11]1[N:12]=[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]2[C:10]=1[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:37]
Reactant: COc1ccc(C(=O)Cl)c(Cl)c1OCCBr
Reactant: COc1ccccc1Cc1c(CNCCC(C)C)nc2ccccn12
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1Cc1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OCCBr)c2Cl)nc2ccccn12
Temperature: 25 °C
Reaction time: 65 h
Yield: 64.4 %

Procedure:
To a solution of ({3-[(2-methoxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl) (3-methylbutyl) amine (1.4 g, 4.2 mmol) in dichloromethane (15 ml) is added triethylamine (0.7 ml, 5 mmol) followed by 2-chloro-3-bromoethoxy-4-methoxybenzoic acid chloride (1.5 g, 4.5 mmol). The reaction mixture is stirred at ambient temperature for 65 h. Aqueous 1 N sodium hydroxide (20 ml) is added and the resulting mixture is extracted with dichloromethane (3×20 ml). The combined organic layers are dried over magnesium sulfate, filtered, and evaporated at reduced pressure. Chromatography on silica gel with ethyl acetate provides 1.7 g (65%)of (2-chloro-3-bromoethoxy-4-methoxyphenyl)-N-({3-[(2-methoxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)} methyl)-N-(3- methylbutyl)carboxamide.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:27][CH:26]=1.N1CCCCC1>CN(C=O)C>[CH2:35]([O:34][C:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([NH:24]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:30][CH:29]=1)=[O:33])[CH3:36]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CCOC(=O)Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and ethyl 4-aminophenylacetate in DMF and subsequent treatment with piperidine.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[Br:19]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:19][CH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccccc1Oc1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccccc1Oc1ccc(CBr)cc1
Temperature: 25 °C
Yield: 9.7 %

Procedure:
A solution of 35.08 g of methyl 2-(4-methylphenoxy)benzoate, 25.7 g of N-bromosuccinimide, 0.57 g of azobisisobutyronitrile, and 1200 mL of carbon tetrachloride was refluxed for 3 hours. After cooling to room temperature the resulting suspension was filtered and then concentrated in vacuo to provide 4.51 g of crude methyl 2-(4-bromomethylphenoxy)benzoate which was used in a subsequent reaction without further purification; NMR (200 MHz, CDCl3): δ 7.92 (d of d, 1H); 7.45 (t of d, 1H); 7.16 (m, 3H); 6.90 (m, 3H); 4.49 (s, 2H); 3.83 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[NH:11][CH2:10][C@H:9]1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>CC#N.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])[N:11]([CH2:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:10][C@H:9]1[CH3:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: C[C@@H]1CN[C@@H](CN2CCCC2=O)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: C[C@@H]1CN(CC(=O)OCc2ccccc2)[C@@H](CN2CCCC2=O)CN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 97.7 %

Procedure:
To (2R,5S)-2-methyl-5-(2-oxo-pyrrolidin-1-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (2.73 g, 9.19 mmol) and potassium carbonate (1.4 g, 10.1 mmol) in MeCN (9.8 mL) was added benzyl bromoacetate (2.11 g, 9.2 mmol) at room temperature. The reaction was stirred at this temperature for 18 h then diluted with chloroform, filtered and the filtrate concentrated. Chromatography (silica gel, gradient elution, 0-60%, EtOAc in petrol 40-60) gave the title compound (4 g). MS: [M+H]+=446.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:14]1[CH2:17][C:16](=O)[CH2:15]1.ClC1C=CC(C2C(C=O)=CC=CC=2)=CC=1>>[O:14]1[CH2:17][CH:16]([N:4]2[CH2:3][CH2:2][C@H:6]([NH:1][C:7](=[O:8])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH2:5]2)[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C1COC1
Agent: O=Cc1ccccc1-c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C2COC2)C1

Procedure:
The title compound was prepared by substituting (S)-tert-butyl pyrrolidin-3-ylcarbamate for tert-butyl piperazine-1-carboxylate and 3-oxetanone for 4′-chlorobiphenyl-2-carboxaldehyde in EXAMPLE 1A.
Reaction SMILES: [Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][CH:6]=[N:5][C:4]=2[C:3]=1[Cl:12].C[O-].[Na+].[CH3:16][O:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][CH3:27])=[O:25])[C@H:19]1[CH2:28][C:29](=[O:32])[CH2:30]Br.N1C2C=CS(=O)C=2C=NC=1>CO>[Cl:1][C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH2:30][C:29](=[O:32])[CH2:28][C@H:19]3[C@H:18]([O:17][CH3:16])[CH2:23][CH2:22][CH2:21][N:20]3[C:24]([O:26][CH3:27])=[O:25])[CH:6]=[N:5][C:4]=2[C:3]=1[Cl:12]
Reactant: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: O=c1[nH]cnc2c(Cl)c(Cl)sc12
Agent: C[O-]
Agent: O=S1C=Cc2ncncc21
Agent: [Na+]
Solvent: CO
Product: COC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2c(Cl)c(Cl)sc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under nitrogen in a flame dried round bottom flask with magnetic stirring, a solution of 0.440 g (0.002 moles) of 6,7-dichlorothieno[3,2-d]pyrimidin-4(3H)-one [M. Robba, J- M. Lecomte, and M. Cugnon de Sevricourt, Bull. soc. chim. France, 1970, 3630-3636], 5 ml of methanol, and 2.0 ml of 1.0N sodium methoxide in methanol was treated with a solution of 0.002 moles of methyl trans-3-methoxy-2-(3-bromo-2-oxopropyl)-1-piperidinecarboxylate and 2 ml of methanol. A colorless precipitate formed almost immediately; the reaction mixture was stirred for two hours at room temperature. The solid matter was some starting thienopyrimidinone, and was filtered. The filtrate was evaporated under reduced pressure to afford a greenish oil which was chromatographed under moderate pressure ("flash" chromatography) on a column of silica gel (Woelm 32-63 micrometers, i.d. 5 cm×height 18 cm); the eluant was initially 1% ethanol in chloroform but was changed to 2% ethanol later on. There was obtained the title compound: m.p. 58°-62° C.; yield 0.270 g (30%); mass spectrum peaks at 447 (molecular ion), 415 (--32, --CH3OH), 195 (parent) among others; 13C-nmr delta (CDCl3) 19.05 ppm, 23.42, 39.33, 40.81, 50.53, 52.93, 53.62, 56.35, 76.01, 119.92, 121.68, 149.62, 152.19, 155.49, 157.01, 199.22; 1H-nmr (CDCl3) delta 3.36 ppm (OCH3), 3.66 (CO2CH3) among others.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[C:11]([C:16]3[CH2:17][CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:21]=3)=[N:12][CH:13]=[CH:14][N:15]=2)=[CH:7][CH:6]=1)=[O:4].C1COCC1>[Pd].CCO>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:11]([CH:16]3[CH2:17][CH2:18][CH2:19][N:20]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:21]3)=[N:12][CH:13]=[CH:14][N:15]=2)=[CH:29][CH:30]=1)=[O:4]
Reactant: COC(=O)c1ccc(Oc2nccnc2C2=CN(C(=O)OC(C)(C)C)CCC2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1ccc(Oc2nccnc2C2CCCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a rb flask containing tert-butyl 5-(3-(4-(methoxycarbonyl)phenoxy)pyrazin-2-yl)-3,4-dihydropyridine-1(2H)-carboxylate (900 mg, 2.187 mmol) and palladium on carbon (233 mg, 0.219 mmol) (10 wt %) under N2 is added THF (5.5 mL) and EtOH (5.5 mL). The flask is purged with H2 (3×), then stirred under H2 at rt 3 h. The reaction was filtered through celite and the filter cake washed with EtOAc (2×10 mL). The combined filtrates were concentrated and the residue purified by ISCO (12 g SiO2, 0-50% EtOAc/Hexane) to give tert-butyl 3-(3-(4-(methoxycarbonyl)phenoxy)pyrazin-2-yl)piperidine-1-carboxylate as a brown solid.
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1.[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl.P([O-])([O-])([O-])=O>CN(C=O)C.C(OCC)(=O)C>[OH:3][CH2:4][C:5]1[CH:6]=[C:7]([S:11]([N:14]([CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])(=[O:12])=[O:13])[CH:8]=[CH:9][CH:10]=1
Reactant: NS(=O)(=O)c1cccc(CO)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(CO)c1
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% oil dispersion, 0.315 g) was added to 3-hydroxymethylbenzenesulfonamide (0.67 g) with stirring in DMF (20 ml) under nitrogen at 20°. After 15 min, 2-(trimethylsilyl)ethoxymethyl chloride (1.27 ml) was added and stirring was continued for 1.5 h. pH 6.4 Phosphate buffer and ethyl acetate were added. The aqueous layer was extracted twice with ethyl acetate and the combined organic layers were washed twice with brine, dried (MgSO4) and evaporated to an oil. This oil in dichloromethane was loaded onto a column of silica gel (75 g) set up in 10% ethyl acetate in 40-60 petroleum ether. The column was run with this, then 20%, 30% and 50% ethyl acetate in 40-60 petroleum ether to give the title compound (0.74 g) LCMS RT=4.00 min.
Reaction SMILES: [C:1]([C:9]1[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:31](C(OCC)=O)[C:32]([O:34]CC)=[O:33]>CN(C=O)C>[CH3:18][C:16]1[CH:17]=[C:9]2[C:10](=[CH:14][C:15]=1[CH3:19])[C:11](=[O:12])[O:13][C:31]([C:32]([OH:34])=[O:33])=[C:1]2[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Reactant: Cc1cc(C(=O)O)c(C(=O)c2ccccc2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Cc1cc2c(-c3ccccc3)c(C(=O)O)oc(=O)c2cc1C
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 2-benzoyl-4,5-dimethylbenzoic acid (11.4 g), acetone (300 ml), DMF (10 ml), potassium carbonate (6.83 g) and diethyl bromomalonate (12.84 g) was stirred at room temperature for 60 hours. After the solvent was distilled off, ethyl acetate was added to the residue. This mixture was washed with water and then dried, after which the solvent was distilled off. To the residue were added acetic acid (180 ml) and hydrochloric acid (180 ml), followed by heating at 110° C. for 5 hours. The reaction mixture was concentrated, and water was added to the concentrate, followed by extraction with ethyl acetate. The extract was washed with water and then dried, after which the solvent was distilled off, to yield colorless crystals. The crystals were recrystallized from ethyl acetate-isopropyl ether to yield 6,7-dimethyl-4-phenylisocoumarin-3-carboxylic acid (≡6,7-dimethyl-1-oxo-4-phenyl-1H-2-benzopyran-3-carboxylic acid).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([OH:11])=O.[NH2:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C@@H:14]1[O:24][CH2:25][CH:26]=[CH2:27].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl.Cl>ClCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:12][C@@H:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][C@@H:14]1[O:24][CH2:25][CH:26]=[CH2:27])=[O:11]
Reactant: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1N
Reactant: Cc1[nH]c(C(=O)O)c(Cl)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C=CCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid (WO200687543, 2.27 g, 11.8 mmol) and Ethyl (3S,4R)-4-amino-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate (Intermediate 18, 2.7 g, 11.8 mmol) in dichloromethane (180 mL) was added HOBt (1.85 g, 11.8 mM) and N-methylmorpholine (3.8 mL, 35.43 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (4.07 g, 21.3 mmol) was added. The resulting reaction mixture was stirred for room temperature overnight, treated by the addition of 2 N HCl (120 mL) and the resulting layers were evaporated. The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL) and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by column chromatography (silica gel, 35% ethylacetate in pet ether) to afforded 3.5 g (73.6%) as brown solid. NMR (400 MHz, DMSO-d6): δ 1.24 (t, 3H), 1.62 (m, 2H), 2.16 (s, 3H), 2.97 (m, 2H), 3.53 (m, 2H), 3.97 (m, 4H), 4.15 (q, 2H), 4.21 (m, 1H), 5.13 (d, 1H), 5.23 (d, 1H), 5.87 (m, 1H), 7.10 (d, 1H), 12.10 (s, 1H).