Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:4][C:5]([O:30][CH2:31][CH3:32])=[C:6]([C:8]2[N:9]([C:27](Cl)=[O:28])[C@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[C@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:12]=2)[CH:7]=1.Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:43])=[O:42]>>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C@H:11]2[C@@H:10]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[N:9]([C:27]([N:49]3[CH2:48][CH2:47][N:46]([CH2:45][CH2:44][S:41]([CH3:40])(=[O:42])=[O:43])[CH2:51][CH2:50]3)=[O:28])[C:8]([C:6]3[C:5]([O:30][CH2:31][CH3:32])=[CH:4][C:3]([C:33]([CH3:34])([CH3:35])[C:36]#[N:37])=[C:2]([Cl:1])[CH:7]=3)=[N:12]2)=[CH:18][CH:17]=1
Reactant: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C#N)c(Cl)cc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CCS(C)(=O)=O)CC1

Procedure:
2-(4-{(4S,5R)-4,5-Bis-(4-chloro-phenyl)-1-[4-(2-methanesulfonyl-ethyl)-piperazine-1-carbonyl]-4,5-dihydro-1H-imidazol-2-yl}-2-chloro-5-ethoxy-phenyl)-2-methyl-propionitrile was prepared from (4S,5R)-2-[5-Chloro-4-(cyano-dimethyl-methyl)-2-ethoxy-phenyl]-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12k) and 1-(2-methanesulfonylethyl)piperazine dihydrochloride (example 17) in an analogous manner as described in example 25. LR-MS: 730.3 [(M+H)+]
Reaction SMILES: [PH2:1](=[O:3])[OH:2].C(N(CC)CC)C.C[Si](Cl)(C)C.[CH2:16]=[C:17]([CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(Cl)(Cl)Cl>[CH2:21]([O:20][C:18]([CH:17]([CH2:28][CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])[CH2:16][PH:1](=[O:2])[OH:3])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=[PH2]O
Reactant: C=C(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(CCC(C[PH](=O)O)C(=O)OCc1ccccc1)OCc1ccccc1
Temperature: 0 °C

Procedure:
Dry phosphinic acid (100 g, 1.52 mol) was dissolved in 100 mL of chloroform and treated with triethylamine (155 g, 1.52 mol). The mixture was evaporated and transferred to a three liter flask containing 750 mL of chloroform. The solution was stirred by means of a mechanical stirrer and the flask cooled to 0° C. The clear solution was treated with triethylamine (277 g, 2.72 mol) followed by trimethylsilyl chloride (281 g, 2.58 mol). Once addition of trimethylsilyl chloride was complete dibenzyl 2-methylenepentanedioate (2) in 150 mL of chloroform was added dropwise over 20 minutes. The low temperature bath was removed and the mixture warmed to room temperature. After 6 hours the thick slurry was filtered and the filtrate cooled to 0° C. The filtrate was then quenched with 5% hydrochloric acid and the organic layer removed. The aqueous layer was extracted with chloroform, the organics combined, dried (MgSO4) and evaporated under reduced pressure to give 55 g or 2,4-di(benzyloxycarbonyl)butylphosphinic acid (6) as a light yellow liquid. The liquid was purified by flash chromatography and eluted using 3:1 hexanes/ethyl acetate containing 5% trifluoroacetic acid to give 40 g (7%) of the desired product. Rf 0.28 (3:1 Hexane/EtOAc 5% TFA).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:29]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl>[CH:29]1([C:34]([N:13]2[CH2:14][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:1])[F:21])=[CH:4][CH:5]=3)[CH2:10][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12]2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)C1CNCC(c2ccc(C(F)(F)F)cc2)C1
Reactant: O=C(Cl)C1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.2 g (13.5 mmol) of ethyl 5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylate were dissolved in 33 ml of dichloromethane, and 2.04 g (20.2 mmol) of triethylamine were added at 0° C. 2.37 g (17.5 mmol) of cyclopentanecarbonyl chloride were then added dropwise. The reaction mixture was stirred at RT for 2 h. For work-up, the mixture was twice washed with water. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. Yield: 5.9 g (100% of theory)
Reaction SMILES: [C:1]([NH:4][CH:5]([C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:6]([O:8][CH3:9])=[O:7])(=O)[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.FC(F)(F)C(O)=O>C(#N)CCC>[CH3:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1[N:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:1]([CH3:2])=[N:4][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: COCCCCC(=O)C(NC(C)=O)C(=O)OC
Reactant: Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCC#N
Product: COCCCCc1c(C(=O)OC)nc(C)n1-c1ccccc1
Temperature: 25 °C

Procedure:
Methyl 2-(acetylamino)-7-methoxy-3-oxoheptanoate (5.45 g), 5 aniline (3.01 ml) and trifluoroacetic acid (2.48 ml) were dissolved in butyronitrile (30 ml), and the reaction mixture was heated under reflux for 2 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. 3.6M Aqueous potassium carbonate solution was added to the obtained residue and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (3.88 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([S:10][CH2:11][CH:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([OH:15])=O)(=[O:9])[CH3:8].Cl.[NH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(N(C(C)C)CC)(C)C>C(OCC)C.CN(C)C=O.C(Cl)Cl>[C:7]([S:10][CH2:11][CH:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([NH:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:15])(=[O:9])[CH3:8]
Reactant: COC(=O)CCCN
Reactant: CC(=O)SCC(Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COC(=O)CCCNC(=O)C(CSC(C)=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Oxalyl chloride (0.37 ml., 4.2 mmole) is added, under nitrogen, to a solution of (±)-2-[(acetylthio)methyl]-3-phenylpropanoic acid (0.95 g., 4.0 mmole) in ethyl ether (8 ml.). This mixture is cautiously treated with a catalytic amont of dimethylformamide (3 drops), and then stirred for one hour at room temperature. After concentrating in vacuo, the residue is treated with tetrahydrofuran (10 ml.) and again concentrated to remove excess oxalyl chloride. The resulting residue is treated with methylene chloride (5 ml.), and the soluble portion is transferred to a dropping funnel. This soluton is added, dropwise over 10 minutes, to a cold (-5°), stirred solution of 4-aminobutanoic acid, methyl ester, hydrochloride (0.68 g., 4.4 mmole) and diisopropylethylamine (1.6 ml., 9.0 mmole) in methylene chloride (10 ml.) under nitrogen. After stirring for 3 hours in the cold, the yellow solution is concentrated in vacuo. The residue is treated with ethyl acetate (60 ml.), filtered to remove diisopropylethylamine hydrochloride, and washed sequentially with 10% potassium bisulfate, water, 50% saturated sodium bicarbonate, and 50% brine (30 ml. each). The organic layer is dried (Na2SO4) and concentrated to a light brown solid (1.34 g.). This solid is adsorbed onto a small amount of silica gel (230- 400 mesh), dried, and applied to column of 80 g. of the same silica. Elution with 5:2 hexane/acetone yields 1.09 g. of (±)-4-[[2-[(acetylthio)methyl-1-oxo-3-phenylpropyl]amino]butanoic acid, methyl ester as a white solid; m.p. 81°-82°.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:9]=2[O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])[C:5]2[CH:26]=[CH:27][NH:28][C:4]=2[C:3]1=[O:29].CN1C=C(C2C=C([N+]([O-])=O)C=CC=2OC2C=CC=CC=2)C2C=CNC=2C1=O>>[NH2:23][C:21]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])=[C:8]([C:6]2[C:5]3[CH:26]=[CH:27][NH:28][C:4]=3[C:3](=[O:29])[N:2]([CH3:1])[CH:7]=2)[CH:22]=1
Reactant: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2C#N)c2cc[nH]c2c1=O
Agent: Cn1cc(-c2cc([N+](=O)[O-])ccc2Oc2ccccc2)c2cc[nH]c2c1=O
Product: Cn1cc(-c2cc(N)ccc2Oc2ccccc2C#N)c2cc[nH]c2c1=O

Procedure:
Example 25b was prepared according to the procedure used for the preparation of Example 3, substituting the product of Example 25a for the product of Example 2b, to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][N:66]1[C:74](=[O:75])[C:73]2[C:68](=[CH:69][CH:70]=[CH:71][CH:72]=2)[C:67]1=[O:76])[C:20]([C:22]1[N:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][OH:35])[CH:29]=2)[C:25]([C:36]#[C:37][C:38]([OH:51])([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[C:24](/[CH:52]=[CH:53]/[C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH:23]=1)=[O:21]>CCOC(C)=O.[Pd]>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][N:66]1[C:67](=[O:76])[C:68]2[C:73](=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:74]1=[O:75])[C:20]([C:22]1[N:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][OH:35])[CH:29]=2)[C:25]([CH2:36][CH2:37][C:38]([OH:51])([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[C:24]([CH2:52][CH2:53][C:54]([O:56][CH2:57][CH3:58])=[O:55])[CH:23]=1)=[O:21]
Reactant: CCOC(=O)/C=C/c1cc(C(=O)N(CCCCCCCN2C(=O)c3ccccc3C2=O)CCCCCCCN2C(=O)c3ccccc3C2=O)n(Cc2cccc(CO)c2)c1C#CC(O)(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(C(=O)N(CCCCCCCN2C(=O)c3ccccc3C2=O)CCCCCCCN2C(=O)c3ccccc3C2=O)n(Cc2cccc(CO)c2)c1CCC(O)(c1ccccc1)c1ccccc1
Yield: 99.4 %

Procedure:
The compound 6 (4 mg) obtained above was subsequently reduced by passing H2 through a stirred suspension in EtOAc (2 mL) and 10% Pd—C (4 mg) for 6 hours (or until the reaction completed by NMR). The catalyst was filtered off (Celite), the filtrate was evaporated in vacuo to give 4 mg of the title compound as a crude mixture; 1H NMR (400 MHz, CDCl3) δ 7.82 (m, 4H), 7.70 (m, 4H), 7.20-7.32 (m, 14H), 6.10 (s, 1H), 5.10 (s, 2H), 4.56 (s, 2H), 4.04 (m, 2H), 3.64 (m 4H), 3.25 (m, 4H), 2.09-2.62 (m, 8H), and 1.17-1.62 (m, 23H).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:9][C:10](O)=[O:11])=[O:6])[CH3:3].Cl.[F:31][C:32]([F:44])([F:43])[C:33]1[N:34]=[CH:35][C:36]2[CH2:42][CH2:41][NH:40][CH2:39][C:37]=2[N:38]=1.C(N(C(C)C)CC)(C)C.ON1C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C>[CH3:1][C:2]([CH3:29])([O:4][C:5]([NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:9][C:10]([N:40]1[CH2:41][CH2:42][C:36]2[CH:35]=[N:34][C:33]([C:32]([F:44])([F:31])[F:43])=[N:38][C:37]=2[CH2:39]1)=[O:11])=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)Cc1cc(F)ccc1OCc1ccccc1
Reactant: FC(F)(F)c1ncc2c(n1)CNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2cnc(C(F)(F)F)nc2C1)Cc1cc(F)ccc1OCc1ccccc1
Reaction time: 8 h
Yield: 86.1 %

Procedure:
A mixture of 363 mg (0.9 mmol) of (3R)-3-[(1,1-dimethylethoxycarbonyl)amino]4-(2-benzyloxy-5-fluorophenyl)butanoic acid, 72 mg (0.3 mmol) of 2-(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloride, 0.174 mL (1.0 mmol) of diisopropylethylamine, 136 mg (1.0 mmol) of 1-hydroxy-7-azabenzotriazole (HOAT) and 380 mg (1.0 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) in 5 mL of dichloromethane was stirred under an atmosphere of nitrogen overnight. The reaction mixture was diluted with 100 mL of ethyl acetate, washed sequentially with 5% hydrochloric acid, saturated aqueous sodium bicarbonate solution, and brine, dried over magnesium sulfate, and concentrated. Purification by preparative TLC (silica gel, 70% ethyl acetate/hexane) gave 152 mg (86%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([C@@H:23]1[CH2:27][O:26][C:25](=[O:28])[NH:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[CH2:16]([C@@H:23]1[CH2:27][O:26][C:25](=[O:28])[N:24]1[C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(O)CCCCOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: O=C(CCCCOCc1ccccc1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.4 %

Procedure:
5-Benzyloxyvaleric acid (87.97 g), (R)-4-benzyl-2-oxazolidinone (74.8 g) and chloroform (880 mL) were mixed. To the mixture were added 4-dimethylaminopyridine (51.5 g) and WSC.HCl (85 g). The mixture was stirred at RT for 2.5 hr. The reaction mixture was concentrated in vacuo. To the resultant residue was added ethyl acetate (360 mL). To the mixture were added 2 N hydrochloric acid (211 mL) and water (100 mL), and the mixture was extracted with ethyl acetate (180 mL). The organic layer was washed with 2 N hydrochloric acid (105 mL), water (90 mL), saturated aqueous sodium bicarbonate (90 mL×2) and brine (90 mL), then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (148 g) as a crude product.
Reaction SMILES: N[C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9].[ClH:18].N([O-])=O.[Na+].C(OCC)(=O)C>C(O)(=O)C>[Cl:18][C:2]1[CH:3]=[C:4](/[CH:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:10])[CH3:9]
Reactant: Cl
Reactant: CCOC(=O)/C=C/c1ccc(C(C)C)c(N)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)/C=C/c1ccc(C(C)C)c(Cl)c1
Reaction time: 0.5 h

Procedure:
4.67 g of ethyl (E)-3-(3-amino-4-isopropylphenyl)acrylate was dissolved in 46.7 ml of acetic acid. To the solution was added 46.7 ml of 2N hydrochloric acid with ice-cooling. To the mixture was dropwise added 10 ml of an aqueous solution containing 1.52 g of sodium nitrite. The mixture was stirred for 30 minutes at the same temperature. The reaction mixture was added to 30 ml of 6N hydrochloric acid solution containing 2.18 g of cuprous chloride, with ice-cooling. The mixture was stirred for 1 hour at the same temperature and then for 2 hours at room temperature. To the reaction mixture was added 100 ml of ethyl acetate. The organic layer was separated and washed with water. Thereto was added 50 ml of water. The mixture was adjusted to about pH 7 with sodium hydrogencarbonate. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/ethyl acetate=20/1) to obtain 3.57 g of colorless oily ethyl (E)-3-(3-chloro-4-isopropylphenyl)acrylate.
Reaction SMILES: [NH:1]([C:8](=[O:27])[CH:9]([C:14]1[CH:26]=[CH:25][C:17]([C:18]([O:20]C(C)(C)C)=[O:19])=[CH:16][CH:15]=1)[CH2:10][N:11]([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:28].O1CCOCC1>>[ClH:28].[NH:1]([C:8](=[O:27])[CH:9]([C:14]1[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:25][CH:26]=1)[CH2:10][N:11]([CH3:12])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CC(C(=O)Nc1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CN(C)CC(C(=O)Nc1ccccc1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl 4-{2-anilino-1-[(dimethylamino)methyl]-2-oxoethyl}benzoate (350 mg, 0.95 mmol) was taken up in 4 M HCl/dioxane (10 mL) and stirred at room temperature for 16 h. The solution was concentrated to dryness to give 4-{2-anilino-1-[(dimethylamino)methyl]-2-oxoethyl}benzoic acid hydrochloride as a white, flaky solid. MS (ESI) calcd [M+H]+ 313.1, found 313.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][CH2:8][C:9]([NH2:11])=O)[CH:2]=1.[F:12][C:13]1[CH:14]=[C:15]([NH:25][C:26](=[O:31])[CH2:27][C:28](=O)[CH3:29])[CH:16]=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.CCOC(C)=O.O>C1(C)C(C)=CC=CC=1.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.C([O-])(C)C.[Ti+4]>[F:12][C:13]1[CH:14]=[C:15]([N:25]2[C:26](=[O:31])[CH:27]=[C:28]([CH3:29])[N:11]=[C:9]2[CH2:8][O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:16]=[CH:17][C:18]=1[N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: NC(=O)COc1cccnc1
Reactant: CC(=O)CC(=O)Nc1ccc(N2CCOCC2)c(F)c1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1cc(=O)n(-c2ccc(N3CCOCC3)c(F)c2)c(COc2cccnc2)n1
Temperature: 165 °C
Reaction time: 50 h
Yield: 287.4 %

Procedure:
A mixture of 2-(pyridin-3-yloxy)acetamide (120 mg, 0.79 mmol), N-(3-fluoro-4-morpholinophenyl)-3-oxobutanamide (221.1 mg, 0.79 mmol) and titanium tetraisopropanolate (1.79 g, 6.30 mmol) in xylene (16 mL) was stirred at 165° C. for 50 h. The mixture was then cooled to rt and 30 mL of EtOAc and 5 mL of water were added. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc) to give the title compound as a yellow solid (0.90 g, 29%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: Br[CH2:2][C:3]([C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]3)[CH2:6]1)[CH2:12]2)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([SH:23])[CH:19]=[CH:20][C:21]=1[Cl:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:15][C:16]1[CH:17]=[C:18]([S:23][CH2:2][C:3]([C:5]23[CH2:14][CH:9]4[CH2:10][CH:11]([CH2:13][CH:7]([CH2:8]4)[CH2:6]2)[CH2:12]3)=[O:4])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=C(CBr)C12CC3CC(CC(C3)C1)C2
Reactant: Sc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(CSc1ccc(Cl)c(Cl)c1)C12CC3CC(CC(C3)C1)C2

Procedure:
1-adamantyl bromomethyl ketone (1.3 g.), 1.1 g. of 3,4-dichlorothiophenol and 800 mg. of anhydrous potassium carbonate in 30 ml. of acetone are stirred at reflux overnight. The solvent is then removed and 60 ml. of water is added to the reaction mixture. The product is filtered off, washed with water and recrystallized from methanol to yield 1-adamantyl 3,4-dichlorophenylthiomethyl ketone, M.P. 105°-110.5° C.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([S:20][CH3:21])=[N:15][CH:16]=2)[NH:11]1)[CH:8]=[CH2:9].[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25].N>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O.C(Cl)(Cl)Cl>[CH2:7]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([S:20][CH3:21])=[N:15][CH:16]=2)[N:11]1[C:30]1[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=1)[C:24]([O:23][CH3:22])=[O:25])[CH:8]=[CH2:9]
Reactant: C=CCn1[nH]c2nc(SC)ncc2c1=O
Reactant: COC(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.7 %

Procedure:
20 mL of pyridine was added to a chloroform solution of 7.5 g of 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one, 6.1 g of copper(II) acetate and 10 g of [3-(methoxycarbonyl)]phenylboronic acid, and stirred at room temperature for 3 days. Aqueous 30% ammonia solution and saturated saline water were added to the reaction liquid in that order, and extracted with chloroform. The organic layer was washed with saturated saline water, then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The crude product was purified through silica gel column chromatography (hexane/ethyl acetate) to obtain 6.7 g of methyl 3-[2-allyl-6-(methylthio)-3-oxo-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-1-yl]benzoate as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][C:7]=1Br.[F:14][C:15]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[CH:24][C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][C:7]=1[C:26]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])=[C:15]([F:14])[CH:27]=1
Reactant: CCOC(=O)c1cnc(N)c(Br)n1
Reactant: CC(C)(C)OC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N)c(-c2ccc(C(=O)OC(C)(C)C)c(F)c2)n1
Yield: 74 %

Procedure:
A mixture of ethyl 5-amino-6-bromopyrazine-2-carboxylate (210 mg, 0.853 mmol), tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (357 mg, 1.109 mmol), PdCl2(dppf).CH2Cl2 adduct (69.7 mg, 0.085 mmol) and Na2CO3 (362 mg, 3.41 mmol) (2M solution was used) in DME (5 mL) was placed into a 20 ml vial and sealed. The mixture was microwaved for 15 min at 110° C. The mixture was diluted with EtOAc, washed with water twice and brine, dried, filtered, and concentrated to afford the crude as a light yellow solid. The crude product was purified by ISCO (12 g, 10-55% EtOAc in heptane, 30 min) to afford 228 mg (74% yield) of light yellow solid. LC-MS (m/z): 362.1 (MH+), 0.89 min.