Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[O:16]1[CH2:20][CH2:19][C:18](=O)[CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[N:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]3[C:13](=[O:14])[NH:15][C:18]4([CH2:19][CH2:20][O:16][CH2:17]4)[NH:1][C:2]=3[CH:6]=2)=[CH:12][CH:11]=1
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: O=C1CCOC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC2(CCOC2)Nc2cc(-c3ccncc3)sc21
Temperature: 80 °C
Reaction time: 5 h
Yield: 11.5 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), dihydro-3(2H)-furanone (0.215 g, 2.50 mmol), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (3.0 mL) was stirred for 5 h at 80° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 100 mL, 50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to 90:10 dichloromethane/methanol) to afford the title compound (0.0165 g, 11%) as a yellow solid:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].CCN(CC)CC.[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([CH2:24][C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:26])[CH2:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C1CCN(CC(=O)OC(C)(C)C)CC1
Reaction time: 18 h
Yield: 4.7 %

Procedure:
To a solution of piperidine-4-carboxylic acid methyl ester (10 g, 70 mmol, 1 eq.) and Et3N (19.5 mL, 140 mmol, 2 eq.) in 150 mL of THF was added bromo-acetic acid tert-butyl ester (13.6 g, 70 mmol, 1 eq.) in 150 mL of THF. The resulting mixture was heated at reflux overnight. After 18 h, the resulting mixture was concentrated and purified by silica gel column chromatography (98/1/1 CH2Cl2/MeOH/NH4OH) to give the title compound as a yellow oil (0.84 g). Exact mass calculated for C13H24N1O4 258.2. MS (ESI) m/z 258.6 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][CH2:13][CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:5]([O:7][CH3:8])=[O:6].CC1(C)[SiH2][SiH]=NC(C)(C)C1(C)C.[Na].[S:36]1[C:40]2[C:41]3[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=3[O:43][CH2:44][CH2:45][C:39]=2[CH:38]=[C:37]1[C:50](Cl)=[O:51]>C1COCC1>[Si:16]([O:15][CH2:14][CH2:13][N:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[Cl:1])[C:50]([C:37]1[S:36][C:40]2[C:41]3[CH:49]=[CH:48][CH:47]=[CH:46][C:42]=3[O:43][CH2:44][CH2:45][C:39]=2[CH:38]=1)=[O:51])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc(NCCO[Si](C)(C)C(C)(C)C)c(Cl)c1
Reactant: O=C(Cl)c1cc2c(s1)-c1ccccc1OCC2
Agent: CC1(C)N=[SiH][SiH2]C(C)(C)C1(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N(CCO[Si](C)(C)C(C)(C)C)C(=O)c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.3 %

Procedure:
To a soln. of methyl 3-chloro-4-(2-(tert-butyldimethylsilyloxy)ethylamino)benzoate (1.3 g 3.78 mmol) pretreated with 1M of sodium hexamethyldisilazine in THF (3.46 ml) in tetrahydrofuran (12.2 ml) was added at room temperature 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbonyl chloride (1.00 g, 3.79 mmol) portion-wise. The reaction mixture was stirred at room temperature under nitrogen for 1 hour. The reaction mixture was concentrated in vacuo and the residue taken into ethyl acetate and washed with water, then saline and dried (Na2SO4) to give 1.37 grams of crude methyl 4-(N-(2-(tert-butyldimethylsilyloxy)ethyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoate. MS: (ESI+)=572.1
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[N:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=1.Cl.O.[OH-].[Na+]>O1CCOCC1>[CH:2]([C:6]1[CH:7]=[C:8]([NH:12][C:13](=[O:21])[C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[N:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=1)=[O:1]
Reactant: Cc1cncc(C(=O)Nc2cccc(C3OCCO3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cncc(C(=O)Nc2cccc(C=O)c2)c1
Temperature: 60 °C

Procedure:
A solution of N-(3-[1,3]dioxolan-2-yl-phenyl)-5-methyl-nicotinamide (3.0 g, 10.55 mmol) in dioxane (50 mL) is treated with a 4M HCl in 1,4-dioxane (30 mL). The mixture is heated at 60° C. for 3 h. Water (100 mL) is added to the mixture followed by NaOH 2M (70 mL) solution to get pH 10. The mixture is extracted twice with EtOAc (100 mL). The combined organic phases are dried over MgSO4, filtered and evaporated. The crude title compound is obtained as a brownish solid (1.744 g. 69%) LC-MS A: tR=0.58 min; [M+H]+=241.24.
Reaction SMILES: [O:1]1[C:5]2([CH2:15][CH2:14][C:8]3([CH2:12][CH2:11][NH:10][C:9]3=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:19][CH:18]=1.CNCCNC.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[CH3:27][O:26][CH2:25][CH2:24][CH2:23][C:20]1[CH:21]=[CH:22][C:17]([N:10]2[CH2:11][CH2:12][C:8]3([CH2:14][CH2:15][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[C:9]2=[O:13])=[CH:18][CH:19]=1
Reactant: COCCCc1ccc(Br)cc1
Reactant: O=C1NCCC12CCC1(CC2)OCCO1
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCCc1ccc(N2CCC3(CCC4(CC3)OCCO4)C2=O)cc1
Temperature: 80 °C

Procedure:
1,4-Dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (276 mg, obtained in example 121, step 3) was dissolved in DMF (18 mL) at r.t. Then, 1-bromo-4-(3-methoxy-propyl)-benzene (599 mg, obtained in example 130, step 2), N,N′-dimethylethylenediamine (sym) (230 mg), Cuprous iodide (373 mg) and K3PO4 (832 mg) were added to the reaction mixture and the mixture was heated to 80° C. for 3 hours. The reaction mixture was cooled, poured into ice/water and was extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The title compound was obtained as a yellow liquid (460 mg, 93%) and was used without further purification. MS (m/e): 360.2. [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)[CH:21]=[CH:22][C:23](O)=O>>[Cl:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][CH:28]=1)/[CH:21]=[CH:22]/[C:23]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: O=C(O)C=Cc1cccc(Cl)c1
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Product: CCCn1c(=O)c2[nH]c(/C=C/c3cccc(Cl)c3)nc2n(CCC)c1=O
Yield: 68 %

Procedure:
Substantially the same procedure as in Reference Example 1 was repeated using 3.95 g (17.5 mmol) of 5,6-diamino-1,3-dipropyluracil and 3.51 g (19.2 mmol) of 3-chlorocinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/water to give 4.44 g (yield 67%) of Compound 38 as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]#[N:27])[CH:21]=2)=[C:16]([F:28])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-:31].[K+].[K+].OO>CS(C)=O.O>[C:1]([O:5][C:6](=[O:29])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26](=[O:31])[NH2:27])[CH:21]=2)=[C:16]([F:28])[CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(C)CCN(Cc1ccc(-c2cccc(C#N)c2)c(F)c1)C(=O)OC(C)(C)C
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)CCN(Cc1ccc(-c2cccc(C(N)=O)c2)c(F)c1)C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
(3′-Cyano-2-fluoro-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-5d: 1.20 g, 3.02 mmol) was dissolved in dimethyl sulfoxide (5.5 ml) and treated with potassium carbonate (0.502 g, 3.6 mmol) and 0.250 ml of a 30% hydrogen peroxide solution. After 18 hours, the reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound (1.25 g, 99%), which was pure enough to be taken on and used directly in the next reaction.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1)([F:12])[F:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH:19]O.O>C(Cl)(Cl)Cl.C[Re](=O)(=O)=O.[O-2].[Mn+4].[O-2]>[Si:1]([O:8][CH2:9][C:10]([C:13]1[CH:18]=[CH:17][N+:16]([O-:19])=[CH:15][CH:14]=1)([F:12])[F:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: OO
Reactant: CC(C)(C)[Si](C)(C)OCC(F)(F)c1ccncc1
Agent: C[Re](=O)(=O)=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(F)(F)c1cc[n+]([O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[2-(tert-butyldimethylsilanyloxy)-1,1-difluoroethyl]pyridine (0.14 g) prepared in (3) in chloroform (3 mL) were added methyltrioxorhenium (VII) (0.0010 g) and aqueous 30% hydrogen peroxide (0.11 mL). The reaction mixture was stirred at RT for 4 hr. To the mixture was added manganese (IV) oxide. The reaction mixture was stirred at RT for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over MgSO4. The solvent was removed under reduced pressure to give the crude title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]=[C:12]=[S:13])=[O:10])=[CH:4][CH:3]=1.[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:34][C:33]3[C:28](=[N:29][CH:30]=[CH:31][C:32]=3[O:35][C:36]3[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][C:37]=3[F:43])[CH:27]=2)=[N:24][CH:25]=1>C1(C)C=CC=CC=1.C(O)C>[O:14]1[CH2:19][CH2:18][CH2:17][O:16][CH:15]1[C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:34][C:33]3[C:28](=[N:29][CH:30]=[CH:31][C:32]=3[O:35][C:36]3[CH:42]=[CH:41][C:39]([NH:40][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[S:13])=[CH:38][C:37]=3[F:43])[CH:27]=2)=[N:24][CH:25]=1
Reactant: O=C(Cc1ccc(F)cc1)N=C=S
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a solution of 2 (2.69 g, 13.80 mmol) in toluene (16.5 mL) and ethanol (16.5 mL) was added a suspension of 31 (4.87 g, 11.50 mmol) in toluene (41 mL) and ethanol (41 mL). The mixture was stirred for 1 h at room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography (eluent EtOAc/MeOH, 98/2) to afford intermediate 32 (5.31 g, 8.58 mmol, 74% yield) as a beige solid. MS (m/z): 619.2 (M+H). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.47 (s, 1H), 11.83 (s, 1H), 8.63 (d, J=2.0 Hz, 1H), 8.54 (d, J=5.2 Hz, 1H), 8.38 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.02 (dd, J=12.4, 1.6 Hz, 1H), 7.92 (dd, J=8.2, 1.8 Hz, 1H), 7.54-7.52 (m, 2H), 7.37 (dd, J=8.6, 5.8 Hz, 2H), 7.17 (t, J=9.0 Hz, 2H), 6.68 (d, J=5.2 Hz, 1H), 5.66 (s, 1H), 4.18 (dd, J=10.6, 5.0 Hz, 2H), 3.97-3.94 (m, 2H), 3.82 (s, 2H), 2.10-1.98 (m, 1H), 1.47 (dd, J=14.0, 1.6 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C:19]#[N:20])=[C:14]([CH3:28])[CH:13]=1.[O:29](C(OC(C)(C)C)=O)[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=O.[BH4-].[Na+]>CCO.C1COCC1>[C:33]([O:32][C:30](=[O:29])[NH:20][CH2:19][CH:18]([C:15]1[CH:16]=[CH:17][C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:13][C:14]=1[CH3:28])[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: COCCCc1ccccc1-c1ccc(C(C#N)Cc2cccnc2)c(C)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2cccnc2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[2′-(3-methoxypropyl)-3-methylbiphenyl-4-yl]-3-pyridin-3-ylpropanenitrile from step 2 (1 eq.) in EtOH/THF (3:1; 0.1M) at room temperature was added cobaltous chloride hexahydrate (CoCl2.6H2O; 2 eq.), followed by (BOC)2O (2 eq.) and finally sodium borohydride (10 eq.) portionwise. The final black mixture was stirred for 3 h at room temperature, quenched with HCl (1N). The pH was adjusted to 8 using saturated aqueous Na2CO3 and the resulting mixture was extracted several times with EtOAc. The combined organic extracts were dried over Na2SO4, filtered and concentrated. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (10 to 75% in 30 min) afforded the desired compound as a colorless oil.
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: COc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3cc(Br)cnc3N)o2)CC1
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: O
Solvent: C1COCCO1
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: C(OC(N[C:8]1[CH:12]=[CH:11][S:10][C:9]=1/[C:13](=[CH:15]/[CH:16]([CH3:18])[CH3:17])/[CH3:14])=O)(C)C.[CH:19]([O:22][C:23](NC1C=CSC=1/C(=C\C(C)C)/C)=[O:24])([CH3:21])[CH3:20].C(OC(NC1C=CSC=1C(CC(C)C)=C)=O)(C)C>[C].[Pd].CO>[CH:19]([O:22][C:23]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:13]([CH3:14])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:24])([CH3:21])[CH3:20]
Reactant: C/C(=C/C(C)C)c1sccc1NC(=O)OC(C)C
Reactant: C/C(=C\C(C)C)c1sccc1NC(=O)OC(C)C
Agent: [Pd]
Agent: C=C(CC(C)C)c1sccc1NC(=O)OC(C)C
Solvent: CO
Product: CC(C)CC(C)c1sccc1C(=O)OC(C)C
Reaction time: 9 h
Yield: 70 %

Procedure:
2.06 g (7.72 mmol) of the mixture of 3-isopropoxycarbonylamino-{2-(E)-(4-methyl-2-penten-2-yl)}thiophene, 3-isopropoxycarbonylamino-{2-(Z)-(4-methyl-2-penten-2-yl)}thiophene, and 3-isopropoxycarbonylamino-{2-(4-methyl-1-penten-2-yl) }thiophene obtained in Example 13 and 0.41 g of 5% palladium carbon (Degussa chemical catalyst E106R/W) were charged into 20 ml of methanol, and after nitrogen purge, a hydrogenation reaction was conducted at normal pressure under hydrogen atmosphere for 9 hours. After nitrogen purge, the catalyst was filtrated off, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 1.61 g of the intended compound as a colorless crystal (yield: 70%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14]O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.S(Cl)([Cl:24])=O>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][Cl:24])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Nc1ccc(SCCCO)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(SCCCCl)cc1
Temperature: 0 °C
Yield: 57.4 %

Procedure:
To a stirred suspension of 5.62 g (0.025 mole) of 3-(4'-acetamidophenylthio)propanol in 25 ml of methylene chloride and 2.03 ml of pyridine (0.025 mole) is added 3.7 g of thionyl chloride (0.031 mole) in 10 ml of methylene chloride. After the exothermic reaction subsides, the mixture is heated at reflux for 0.5 hr. The reaction mixture is poured into 100 ml of ice-water with stirring. The organic layer is separated, dried and concentrated to a dark red solid. Extraction of the latter with ether in a Soxlet apparatus yields 3.5 g of 3-(p-acetamidophenylthio)propyl chloride having the correct IR and NMR spectra.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22]>CC(C)=O>[Br:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:3])=[O:22]
Reactant: OCCCCCCCBr
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: O=C(O)CCCCCCBr
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
2 N Jones' reagent (20 ml) was gradually and dropwise added to an acetone (20 ml) solution of 7-bromoheptanol (1.95 g, 10 mmols) with cooling with ice, and then stirred at room temperature for 10 minutes. The reaction mixture was extracted three times with ether (80 ml). The organic layer was washed with water, and then extracted three times with an aqueous saturated solution of sodium hydrogencarbonate (120 ml). The aqueous layers were combined, then made acidic (pH=1) with 5% sulfuric acid added thereto, and extracted with ethyl acetate. The resulting organic layer was washed with water and saturated saline in that order, and dried with anhydrous sodium sulfate, and the solvent was evaporated. 1.45 g (70%) of 7-bromoheptanoic acid was obtained as colorless needle-like crystals. WSC (891 g, 4.7 mmols) and HOBt (628 g, 4.7 mmols) were added to a DMF (20 ml) solution of the resulting carboxylic acid (1.06 g, 5 mmols) and 2,6-diisoproylaniline (738 g, 4.2 mmols), and stirred at room temperature for 12 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl, an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer: hexane/acetone=5/1), and the resulting crystals were recrystallized from ether-hexane to obtain 466 g (yield: 30%) of 7-bromo-N-(2,6-diisopropylphenyl)heptanamide as colorless needle-like crystals.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])(C)(C)C.[CH2:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1)[CH3:26].[Cl-].[NH4+]>C1COCC1.CCCCC>[CH2:25]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]([C:2]2[C:7]([O:8][CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:6][CH:5]=[CH:4][N:3]=2)[OH:32])=[CH:29][CH:28]=1)[CH3:26]
Reactant: CC[Si](CC)(CC)CCOCOc1cccnc1Br
Reactant: CCc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCc1ccc(C(O)c2ncccc2OCOCC[Si](CC)(CC)CC)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 33.7 %

Procedure:
Next, to a solution of 2-bromo-3-[2-(triethylsilyl)ethoxymethoxy]pyridine (2.0 g, 6.57 mmol) in THF (22 mL), a 1.47 M n-pentane solution of tert-butyllithium (9.6 mL, 14.1 mmol) was slowly added dropwise at −78° C. After 20 minutes, a solution of 4-ethylbenzaldehyde (1.0 g, 7.45 mmol) in THF (5 mL) was added dropwise to the reaction mixture. After stirring at −78° C. for 10 minutes, the reaction mixture was warmed to room temperature and saturated aqueous ammonium chloride was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 4-ethylphenyl-[3-[2-(triethylsilyl)ethoxymethoxy]]pyridin-2-yl-methanol (0.89 g, 38%).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:29][C:4]([C:6]2[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=2[OH:12])=[O:5])=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2OC)n(C)c(=O)c1O
Reactant: NCc1ccc(F)cc1
Product: COc1ccccc1-c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C

Procedure:
Prepared according to the procedure described for example 2 from 5-hydroxy-2-(2-methoxy-phenyl)-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (45.6 mg, 0.15 mmol) and 4-fluorobenzylamine (95 mg, 0.75 mmol). The title product was obtained as a pink solid (37 mg, 64% yield). 1HNMR (500 MHz, CDCl3) δ: 12.13 (1H, s), 7.90 (1H, t, J=5.50 Hz), 7.48 (1H, td, J=7.02, 1.83 Hz), 7.29–7.26 (3H, m), 7.06 (1H, t, J=7.33 Hz), 7.02–6.97 (3H, m),4.53 (2H, d, J=6.41 Hz), 3.81 (3H, s), 3.34 (3H, s). HRMS (ESI) calcd for C20H19FN3O4 (M+H): 384.1360; found: 384.1370.