Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]=2Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][CH2:17][C:16]=2[C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC1(C)CCC(Br)=C(CN2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC1(C)CCC(c2ccc(Cl)cc2)=C(CN2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 100 °C
Yield: 71 %

Procedure:
To a degassed solution of 4-(2-bromo-5,5-dimethyl-cyclohex-1-enylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (1.3 g, 3.36 mmol) and 4-chlorophenyl boronic acid (0.78 g, 5.04 mmol) in 2:1 MeOH/1,4-dioxane (20 ml) at rt was added a solution of 2M Na2CO3 (3.3 ml, 6.72 mmol). Nitrogen was bubbled through the mixture for 2 min and then PdCl2[dppf] (200 mg, 0.28 mmol) was added. The reaction flask was sealed and heated to 100° C. where it was maintained for 1 h. After this time the suspension was cooled to rt and filtered through Celite®. The collected solids were washed with additional dichloromethane and the combined filtrate and washings were concentrated under reduced pressure. Purification by column chromatography on silica eluting with 6% EtOAc/heptanes gave 4-[2-(4-chloro-phenyl)-5,5-dimethyl-cyclohex-1-enylmethyl]-piperazine-1-carboxylic acid tert-butyl ester (1.0 g, 71%). HPLC-MS 419, 421 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][N:14](CC(NC3SC=CN=3)=O)[CH2:13][CH2:12]2)[C:5]([Br:26])=[CH:4][N:3]=1.BrC1C(Cl)=C([N+]([O-])=O)C(N)=NC=1.[CH3:39][S:40](N1CCNCC1)(=[O:42])=[O:41]>C(O)(C)C>[Br:26][C:5]1[C:6]([N:11]2[CH2:12][CH2:13][N:14]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:15][CH2:16]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Reactant: CS(=O)(=O)N1CCNCC1
Agent: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: CC(C)O
Product: CS(=O)(=O)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Yield: 34 %

Procedure:
This was prepared using the same procedure as for 2-(4-(2-amino-5-bromo-3-nitropyridin-4-yl)piperazin-1-yl)-N-(thiazol-2-yl)acetamide, but here using 5-bromo-4-chloro-3-nitropyridin-2-amine (200 mg, 0.79 mmol), isopropanol (12 mL) and 1-methanesulfonylpiperazine (1.1 eq, 0.87 mmol, 143 mg). After 18 h the precipitate was filtered and washed with cold water (2×3 mL) to give the product (101 mg, 34%) as an orange solid; δH (500 MHz, DMSO-d6) 2.94 (s, 3H, CH3), 3.12 (s, br, 4H, piperazine N(CH2)2), 3.25 (s, br, 4H, piperazine N(CH2)2), 7.06 (s, br, 2H, NH2), 8.22 (s, 1H, pyridine H-6);
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](#[N:10])[CH:8]=[CH2:9]>CO>[CH:1]1([NH:6][CH2:9][CH2:8][C:7]#[N:10])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC#N
Reactant: NC1CCCC1
Solvent: CO
Product: N#CCCNC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At room temperature, cyclopentylamine (5.794 mL, 58.7 mmol) was added dropwise to a solution of acrylonitrile (5.79 mL, 88.1 mmol) in methanol (7 mL). The solution was stirred at room temperature for 30 mins and at reflux for 1 hr, cooled to room temperature, and concentrated under reduced pressure. The desired product as obtained by distillation under vacuum to provide a clear liquid (7.4 g, 91%). 1H NMR (CDCl3, 300 MHz) δ 3.14-3.04 (quint, 1H, J=6.3 Hz), 2.91-2.87 (t, 2H, J=6.9 Hz), 2.53-2.48 (td, 2H, J=0.9, 6.9 Hz), 1.88-1.78 (m, 2H), 1.73-1.49 (m, 4H), 1.36-1.24 (m, 2H), 1.19 (br s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6](=[O:16])[N:7]2[C:12]=1[C:11]1[S:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8]2.[H-].[Na+].Cl[C:26]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[O:27]>CN(C)C=O>[O:16]=[C:6]1[N:7]2[NH:8][CH2:9][C:10]3[CH:15]=[CH:14][S:13][C:11]=3[C:12]2=[C:3]([CH2:2][O:1][C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH:4]=[C:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=c1c(-c2ccccc2)cc(CO)c2n1NCc1ccsc1-2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1cc(-c2ccccc2)c(=O)n2c1-c1sccc1CN2)N1CCOCC1
Temperature: 0 °C

Procedure:
2.62 g of 4,5-dihydro-10-(hydroxymethyl)-8-phenyl-7H-pyrido[1,2-b]thieno[2,3-d]pyridazin-7-one are dissolved in 80 ml of N,N-dimethylformamide and cooled to 3° in an ice-bath. 440 mg of 55 percent sodium hydride (NaH) dispersion are added portionwise thereto and the mixture is stirred for an additional hour after the last portion has been added. A solution of 1.5 g of N-chlorocarbonylmorpholine in 3 ml of N,N-dimethylformamide is now added dropwise thereto. The reaction mixture is left to stir at about 5° for an additional 45 minutes and poured into 800 ml of ice-water, whereby the crude product crystallizes out. After washing with water and drying, the crude product is purifed by chromatography on silica gel and recrystallization. There is obtained (4,5-dihydro-7-oxo-8-phenyl-7H-pyrido[1,2-b]-thieno[2,3-d]pyridazin-10-yl)methyl-4-morpholinecarboxylate of m.p. 207°-210° (acetonitrile).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:17]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[S:20]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][C:17]2[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[S:20])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: COC(=S)c1ccc(C)cc1O
Product: COC(=S)c1ccc(C)cc1O[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Using a procedure analogous to Example 1-D, trans-4-(t-butoxycarbonylamino)cyclohexanol and methyl 2-hydroxy-4-methylthiobenzoate gave the title compound as a white solid (16.0 g, 16%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]Cl.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: CCOP(OCC)OCC
Reactant: FC(F)(F)c1ccccc1CCl
Product: CCOP(=O)(Cc1ccccc1C(F)(F)F)OCC
Temperature: 160 °C

Procedure:
A mixture of 2-trifluoromethylbenzyl chloride (2.0 g, 10.0 mmol) and triethyl phosphite (2.13 g, 13 mmol) was heated at 160° C. under nitrogen for 3 hours. The excess triethyl phosphite was removed by distillation and the crude product obtained was distilled at 87°-90° C. (0.05 mm Hg) and isolated as a colorless oil; yield, 1.68 g, 56.8%; D.C.I.M.S.[MH+,297].
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[CH3:13]O.S(=O)(=O)(O)O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH3:13])=[O:9])=[CH:11][CH:12]=1
Reactant: CO
Reactant: O=C(O)C=Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C=Cc1ccc(O)cc1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
To a 250 mL round bottom flask fitted with a reflux condenser and a nitrogen inlet tube was added 20.0 g (121.8 mmol) 4-hydroxycinnamic acid, 100 mL (246.9 mmol) methanol, and 5.0 g (50.0 mmol) concentrated sulfuric acid. The reaction vessel was heated at 75°-80° C. overnight. After cooling to room temperature, the resulting solution was diluted with 150 mL distilled water, and cooled to 0° C. The resulting precipitate was filtered, washed with sat. NaHCO3 solution, and recrystallized from EtOH/water to afford 16.8 g (77%) methyl 4-hydroxycinnamate which was used without further purification: mp.=139°-140° C.; 1H NMR (CD3SOCD3, 300 MHz) δ 3.42 (broad s, 1H), 3.70 (s, 3H), 6.40 (d, J=16.0 Hz, 1H), 6.81 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H), 7.58 (d, J=16.0 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:11])[NH:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2].F[B-](F)(F)F.[CH2:17]([O+](CC)CC)[CH3:18]>ClCCl>[C:1]([C:3]1[C:4]([O:11][CH2:17][CH3:18])=[N:5][C:6]([CH3:10])=[CH:7][C:8]=1[CH3:9])#[N:2]
Reactant: Cc1cc(C)c(C#N)c(=O)[nH]1
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOc1nc(C)cc(C)c1C#N

Procedure:
3-Cyano-2-ethoxy-4,6-dimethylpyridine was prepared by reacting 3-cyano-4,6-dimethylpyrid-2-one with triethyloxonium tetrafluoroborate in dichloromethane.
Reaction SMILES: [H-].[Na+].[S:3]1[C:7]([CH2:8][C:9]2[C:10]([O:38][CH3:39])=[N:11][C:12]3[C:17]([C:18]=2[Cl:19])=[CH:16][C:15]([C:20]([C:32]2[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=2)([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)[OH:21])=[CH:14][CH:13]=3)=[CH:6][C:5]2[CH:40]=[CH:41][CH:42]=[CH:43][C:4]1=2.[C:44](OC(=O)C)(=[O:46])[CH3:45].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:44]([O:21][C:20]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([O:38][CH3:39])[C:9]([CH2:8][C:7]1[S:3][C:4]3[CH:43]=[CH:42][CH:41]=[CH:40][C:5]=3[CH:6]=1)=[C:18]2[Cl:19])([C:32]1[N:36]([CH3:37])[CH:35]=[N:34][CH:33]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=1)(=[O:46])[CH3:45]
Reactant: COc1nc2ccc(C(O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1cc2ccccc2s1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc2ccc(C(OC(C)=O)(c3ccc(C(F)(F)F)nc3)c3cncn3C)cc2c(Cl)c1Cc1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (0.12 g, 2.98 mmol) was added to a yellow solution of (3-(benzo[b]thiophen-2-ylmethyl)-4-chloro-2-methoxyquinolin-6-yl)(1-methyl-1H-imidazol-5-yl)(6-(trifluoromethyl)pyridin-3-yl)methanol (0.88 g, 1.49 mmol, Intermediate 51: step c) in dry DMF (25 mL) at room temperature. The mixture was stirred at room temperature for 45 minutes and then acetic anhydride (0.28 mL, 2.98 mmol) was added. The resulting dark mixture was stirred at room temperature overnight. Ice was added followed by NaHCO3 (saturated aqueous solution). The aqueous mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to provide the title compound which was carried on to the next step without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[C:16]#[CH:17]>CC(C)=O>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:17][C:16]#[CH:15])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCNCC1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCN1CCN(CC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the 1-ethylpiperazine (2.33 g, 20.2 mmol) and K2CO3 (2.79 g, 20.2 mmol) in acetone (27 ml) was added propargyl bromide (2.00 g, 13.5 mmol) dropwise at 0° C. under N2. The reaction was stirred at room temperature overnight. The reaction was filtered and the salts washed with a small amount of acetone. The filtrates were combined and evaporated gently to concentration. The residue was taken up in EtOAc and washed with water. The aqueous phase was re-extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The product was filtered and evaporated to dryness to leave a pale orange oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[C:17]3[N:24]([CH2:25][CH3:26])[C:23]([C:27]4[C:31]([NH2:32])=[N:30][O:29][N:28]=4)=[N:22][C:18]=3[CH:19]=[N:20][CH:21]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.CO>[NH2:32][C:31]1[C:27]([C:23]2[N:24]([CH2:25][CH3:26])[C:17]3[C:16]([CH2:15][NH:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:21][N:20]=[CH:19][C:18]=3[N:22]=2)=[N:28][O:29][N:30]=1
Reactant: CCn1c(-c2nonc2N)nc2cncc(CNC3CCN(C(=O)OC(C)(C)C)CC3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CCn1c(-c2nonc2N)nc2cncc(CNC3CCNCC3)c21
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A solution of the product from Step 2 (0.075 g, 0.17 mmol) in dichoromethane (1 ml) was treated with trifluoroacetic acid (1 ml). After 2 hours the reaction was reduced in vacuo, dissolved in methanol and applied to a SCX ion exchange column and eluted with methanol and then a mixture of methanol/0.880 ammonia (9:1). The basic fractions were then reduced to afford the title compound, (0.053 g, 91%); MS (ES+) m/e 343 [M+H]+.
Reaction SMILES: C([N:3](C([O-])=O)[N:4]=[C:5]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)C.O=[S:29](Cl)Cl>>[CH3:24][O:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[C:5]1[N:4]=[N:3][S:29][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: CCN(N=C(Cc1ccc(OC)cc1)c1ccc(OC)cc1OC)C(=O)[O-]
Reactant: O=S(Cl)Cl
Product: COc1ccc(-c2snnc2-c2ccc(OC)cc2OC)cc1
Temperature: 25 °C
Yield: 44.7 %

Procedure:
Acylhydrazone 15 (4.32 g, 11.6 mmol) was added to SOCl2 (50 ml) at 0° C. The reaction was allowed to warm to room temperature. The reaction was complete (by TLC) after 3 hours. SOCl2 was removed under reduced pressure and the crude brown oil was chromatographed on 350 g SIO2, eluting with 4:1, CH2Cl2 :Hexane to afford 13 (1.7 g, 44.7%), m.p. 90-91.5.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[C:23]2[C:18](=[CH:19][C:20]([S:24]([N:27](CC3C=CC(OC)=CC=3OC)[C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:21][CH:22]=2)[N:17]([CH3:44])[CH:16]=1>>[CH3:44][N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[C:20]([S:24]([NH:27][C:28]3[S:32][N:31]=[CH:30][N:29]=3)(=[O:25])=[O:26])[CH:19]=2)[C:15]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:16]1
Reactant: OB(O)c1cccc2ccccc12
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cn(C)c3c2)c(OC)c1
Product: Cn1cc(-c2cccc3ccccc23)c2ccc(S(=O)(=O)Nc3ncns3)cc21

Procedure:
The title compound was prepared in an analogous manner to that described in Example 28 using naphthalen-1-ylboronic acid and 3-bromo-N-(2,4-dimethoxybenzyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, and the desired product, 1-methyl-3-(naphthalen-1-yl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide, was isolated as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 3.98 (s, 3 H) 7.37 (d, J=8.36 Hz, 1 H) 7.44-7.48 (m, 2 H) 7.51-7.62 (m, 3 H) 7.80 (s, 1 H) 7.93 (dd, J=8.19, 4.64 Hz, 2 H) 7.97-8.03 (m, 2 H) 8.08 (s, 1 H). m/z (ESI) 420.1 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[CH:14]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[C:15]([CH3:19])([CH3:18])[S:16](=O)[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[ClH:36].N1C=CC=CC=1>ClC(Cl)CCl>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:28](=[O:29])[N:13]3[CH:14]([C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])[C:15]([CH3:19])([CH2:18][Cl:36])[S:16][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cl
Reactant: CC1(C)C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)[C@H]2S1=O
Solvent: c1ccncc1
Solvent: ClCC(Cl)Cl
Product: CC1(CCl)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Temperature: 100 °C
Yield: 17.3 %

Procedure:
2,2,2-trichloroethyl 6-(2-phenylacetamido)-2,2-dimethylpenam-3-carboxylate-1-oxide (0.96 g.) was dissolved in 1,1,2-trichloroethane (15 cc), and pyridine (0.32 g.) and pyridine hydrochloride (0.12 g.) were added thereto. The mixture was heated at 100° C., for 3 hours, cooled, washed with water, dried and then concentrated. The residue was subjected to a chromatography of silica gel in which chloroform was used as the eluant. The eluate was concentrated to yield, as the residue, crystals (0.09 g.) of 2,2,2-trichloroethyl 6-(2-phenylacetamido)-2-methyl-2-chloromethylpenam-3-carboxylate, m.p. 104°-105° C.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[S:11][C:12]3[N:13]=[CH:14][N:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[C:22]([O:26][C:27](=[O:35])[NH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[C:22]([O:26][C:27](=[O:35])[NH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:8](=[O:21])[NH:9][C:10]2[S:11][C:12]3[N:13]=[CH:14][N:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)[CH2:31][CH2:30]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1ncnc2sc(NC(=O)Oc3ccccc3)nc12
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CC#N
Product: COc1ncnc2sc(NC(=O)N3CCC(NC(=O)OC(C)(C)C)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A solution of (7-methoxy-thiazolo[5,4-d]pyrimidin-2-yl)-carbamic acid phenyl ester (6 g, 19.8 mmol) and piperidin-4-yl-carbamic acid tert-butyl ester (4.37 g, 21.8 mmol) in acetonitrile (400 mL) was heated to reflux for 1 h and was then stirred at 25° C. overnight. The resulting solid was collected by filtration, rinsed with acetonitrile and dried in vacuo to afford [1-(7-methoxy-thiazolo[5,4-d]pyrimidin-2-ylcarbamoyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (7.3 g, 90%) as a white solid; ES-HRMS m/e calcd for C17H24N6O4S (M+H)+ 409.1653, found 409.1653.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH3:11])[CH:6]=[CH:5][C:4]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.B(Br)(Br)Br>>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:4]2[CH:5]=[CH:6][C:7]([CH2:9][CH2:10][CH3:11])=[CH:8][C:3]=2[OH:2])=[CH:14][CH:15]=1
Reactant: CCCc1ccc(Oc2ccc(OC)cc2)c(OC)c1
Agent: BrB(Br)Br
Product: CCCc1ccc(Oc2ccc(OC)cc2)c(O)c1
Yield: 32 %

Procedure:
According to the procedure of example 5(b) except substituting 2-fluoro-6-(2-methoxy-4-propylphenoxy)pyridine for 2-methoxy-1-(4-methoxyphenoxy)-4-propylbenzene (0.18 mmol; 50 mg) and adding 4 equivalents (0.735 mmol; 735 μl) of boron tribromide, the title compound was prepared in 32% yield (0.06 mmol; 15 mg) after purification by preparative TLC on silica gel (ethyl acetate/cyclohexane—20/80).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.O1CCCC1.C1(C)C=CC=CC=1.C[O:22][C:23](=O)[CH:24](NC)[NH:25][C:26](=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34].[Cl-].[NH4+]>O1CCCC1.O>[Br:1][C:2]1[C:3]([C:23](=[O:22])[CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:34])([F:36])[F:35])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CNC(NC(=O)c1ccccc1C(F)(F)F)C(=O)OC
Reactant: Brc1cncc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCC(=O)c1ncc(Br)cc1Br)c1ccccc1C(F)(F)F
Temperature: -20 °C
Yield: 13.7 %

Procedure:
To 5.5 g of 3,5-dibromopyridine in 1 ml of tetrahydrofuran, 22.7 ml of a 1.0M tetrahydrofuran-toluene solution of 2,2,6,6-tetramethylpiperidinylmagnesium chloride-lithium chloride complex was added dropwise with stirring at −20° C., and after the addition, the mixture was stirred at the same temperature for 30 minutes. Then, to the reaction mixture, 3.0 g of the N-[2-methoxy(methyl)amino-2-oxoethyl]-2-(trifluoromethyl)benzamide prepared in Step 1 in Synthetic Example 17 in 17 ml of tetrahydrofuran was added dropwise, and after the addition, the mixture was stirred at the same temperature for another 1 hour. After completion of the reaction, the reaction mixture was mixed with 30 ml of saturated aqueous ammonium chloride and 20 ml of water and extracted with ethyl acetate (50 ml×2), the resulting organic layers were combined, washed with water (50 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 659 mg of the desired product as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[C:23]([C:27]5[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=5)=[N:24][NH:25][CH:26]=4)[CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:34][N:35]1[CH2:40][CH2:39][CH:38](O)[CH2:37][CH2:36]1>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:16]3[N:21]=[C:20]([C:22]4[CH:26]=[N:25][N:24]([CH:38]5[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]5)[C:23]=4[C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)[CH:19]=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(O)CC1
Reactant: Cc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccc(CN4CCN(C)CC4)cc3)n2)cc1
Product: Cc1ccc(-c2c(-c3ccnc(Nc4ccc(CN5CCN(C)CC5)cc4)n3)cnn2C2CCN(C)CC2)cc1

Procedure:
The title compound is prepared as described in Example 54 starting from [4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-[4-(3-p-tolyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (Example 60 and 1-methyl-piperidin-4-ol.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:5][N:4]([C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][CH:15]=2)[C:9]([O:11][CH3:12])=[O:10])[CH2:3]1
Reactant: COC(=O)c1cccc(N2CC(O)C2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1cccc(N2CC(=O)C2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a solution of compound 3a (1.60 g, 7.7 mmol) in dry DCM (30 mL) was added Dess-Martin periodinane (6.5 g, 15.4 mmol) at 0° C. and the mixture was stirred at rt for 2 h under N2 atmosphere. The mixture was quenched with saturated sodium bicarbonate solution and diluted with EA. The organic portion was washed with brine, dried over Na2SO4, filtered, concentrated under reduced pressure and purified by CC (PE/EA=4:1) to give compound 3 (1.2 g, 75%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:46])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([CH3:45])=[N:23][N:24](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].FC(F)(F)C(O)=O>>[CH3:1][N:2]([CH3:46])[C:3]([N:5]1[CH2:6][CH2:7][N:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([CH3:45])=[N:23][NH:24][CH:25]=4)[CH:19]=3)[N:14]=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(N3CCN(C(=O)N(C)C)CC3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]cc1-c1ccc2nccc(N3CCN(C(=O)N(C)C)CC3)c2c1
Yield: 70.1 %

Procedure:
38 mg N,N-dimethyl 4-[6-(3-methyl-1-trityl-1H-pyrazolyl)-4-quinolyl]-1-piperazine carboxamide obtained in Example 182 and 0.2 mL trifluoroacetic acid were reacted in the same manner as in Example 165, to give 16 mg of the title compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([C:5]1[CH:31]=[CH:30][C:8](/[CH:9]=[CH:10]/[C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][CH2:23][CH2:24][C:25]([O:27]CC)=[O:26])[CH:14]=2)=[O:12])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(C1C=CC(C(CCC)CCCCCCC(C2C3C(=CC=CC=3)N(CCCC(OCC)=O)C=2)=O)=CC=1)C(C)C>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8](/[CH:9]=[CH:10]/[C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:14]=2)=[O:12])=[CH:30][CH:31]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCCn1cc(C(=O)/C=C/c2ccc(CC(C)C)cc2)c2ccccc21
Agent: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Product: CC(C)Cc1ccc(/C=C/C(=O)c2cn(CCCC(=O)O)c3ccccc23)cc1

Procedure:
The procedure of Ex. 16 was repeated except that (E)-ethyl 4-[3-(4-isobutylcinnamoyl)-1-indolyl]butyrate obtained in Ex. 56 was used in place of ethyl 4-[3-[8-(4-isobutylphenyl)undecanoyl]-1-indolyl]butyrate to give (E)-4-[3-(4-isobutylcinnamoyl)-1-indolyl]butyric acid as a powder.