Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH2:10])[S:9][C:5]=2[CH:4]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:36][O:37][C:38]1[CH:48]=[CH:47][C:46](/[CH:49]=[CH:50]/[C:51](=[O:64])[C:52]2[CH:57]=[C:56]([O:58][CH3:59])[C:55]([O:60][CH3:61])=[C:54]([O:62][CH3:63])[CH:53]=2)=[CH:45][C:39]=1[O:40][CH2:41][C:42](O)=[O:43]>ClCCl.O>[F:14][C:2]([F:1])([F:13])[C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([NH:10][C:42](=[O:43])[CH2:41][O:40][C:39]3[CH:45]=[C:46](/[CH:49]=[CH:50]/[C:51](=[O:64])[C:52]4[CH:53]=[C:54]([O:62][CH3:63])[C:55]([O:60][CH3:61])=[C:56]([O:58][CH3:59])[CH:57]=4)[CH:47]=[CH:48][C:38]=3[O:37][CH3:36])[S:9][C:5]=2[CH:4]=1
Reactant: Nc1nc2ccc(C(F)(F)F)cc2s1
Reactant: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(/C=C/C(=O)c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccc(C(F)(F)F)cc2s1
Yield: 796.6 %

Procedure:
To a solution of 6-(trifluoromethyl)-2-aminobenzothiazole (218 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(E)-3-oxo-3-(3,4,5-trimethoxy phenyl)-1-propenyl]phenoxy}acetic acid (2) (402 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (9i) (480 mg, 80% yield)
Reaction SMILES: C([O:8][N:9]1[C@@H:12]([CH3:13])[C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:10]1=[O:22])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:18]([O:17][C:15]([NH:14][C@H:11]1[C@H:12]([CH3:13])[N:9]([OH:8])[C:10]1=[O:22])=[O:16])([CH3:20])([CH3:19])[CH3:21]
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Yield: 79 %

Procedure:
A solution of 9.18 g of (3S-trans)-N-benzyloxy-3-t-butoxycarbonylamino-4-methylazetidinone in 300 ml of 95% ethanol is stirred in an atmosphere of hydrogen with 1.85 g of 10% palladium on charcoal. After 141 minutes the slurry is filtered and evaporated in vacuo. The residue is recrystallized from ether-hexane to yield 5.12 g of the title compound.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.C([Sn](CCCC)(CCCC)[C:43]1[N:48]=[CH:47][CH:46]=[CH:45][N:44]=1)CCC>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:43]4[N:48]=[CH:47][CH:46]=[CH:45][N:44]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Product: Cc1ccc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)cc1Cc1ccc(-c2ncccn2)s1

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-methylbenzene obtained in Example 159-(1) and tri-n-butyl(2-pyrimidinyl)tin 54 were treated in a manner similar to Example 128-(5) and (6) to give the target compound. APCI-Mass m/Z 429 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:28])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[O:12][C:11](=[O:27])[CH:10]=1.C([Sn](CCCC)(CCCC)[C:34]([O:36][CH2:37][CH3:38])=[CH2:35])CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:28][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:34]([O:36][CH2:37][CH3:38])=[CH2:35])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([O:21][CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[O:12][C:11](=[O:27])[CH:10]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Br)cc(=O)oc2c1OC1CCCC1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1cncc(Cl)c1Nc1cc(=O)oc2c(OC3CCCC3)c(OC)ccc12
Temperature: 80 °C

Procedure:
A mixture of 4-(3-bromo-5-chloropyridin-4-ylamino)-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one (0.206 g, 0.441 mmol, Example 11), PdCl2(PPh3)2 (31 mg, 0.044 mmol), tributyl(1-ethoxyvinyl)tin (0.20 mL, 0.57 mmol), and toluene (5 mL) was heated at 80° C. under N2 for 4 h. After allowing to cool to rt, the mixture was filtered through Celite and washed with EtOAc. The filtrate was washed with aqueous KF, dried, filtered, concentrated, and purified by silica gel chromatography (0→50% EtOAc/hexanes) to give 4-(3-chloro-5-(1-ethoxyvinyl)pyridin-4-ylamino)-8-(cyclopentyloxy)-7-methoxy-2H-chromen-2-one: 1H NMR (400 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.80 (s, 1H), 8.65 (s, 1H), 7.94 (d, 1H), 7.16 (d, 1H), 4.83 (m, 1H), 4.53 (m, 2H), 4.41 (d, 1H), 3.90 (s, 3H), 3.61 (m, 2H), 1.85-1.52 (m, 8H), 0.89 (t, 3H); MS (ESI): 457.1.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]([NH2:10])=[O:9])=[CH:5][CH:4]=1)=O.FC(F)(F)C([NH:15]OC(=O)C(F)(F)F)=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[S:7][C:6]([C:8]([NH2:10])=[O:9])=[CH:5][CH:4]=1)#[N:15]
Reactant: NC(=O)c1ccc(C=O)s1
Reactant: O=C(NOC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C(N)=O)s1
Yield: 39.5 %

Procedure:
5-Formyl-2-thiophenecarboxylic acid (2.64 g) (synthesized in accordance with the method described in Tetrahedron, 41, 3803 (1985)) was dissolved in tetrahydrofuran (30 ml), and N,N-dimethylformamide (3 drops) was added. Oxalyl chloride (2.2 ml) was added dropwise at room temperature, and the mixture was stirred for 2 hours. The reaction mixture was concentrated under reduced pressure and the concentrate was dissolved in ethyl acetate (50 ml). The resulting solution was added dropwise to a mixture of 25% aqueous ammonia (50 ml) and ethyl acetate (200 ml) with stirring under ice-cooling. The resulting mixture was stirred at room temperature, and then the organic layer was collected. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure to give 5-formyl-2-thiophenecarboxamide (1.77 g). A mixture of 5-formyl-2- thiophenecarboxamide (1.55 g), N,O- bis(trifluoroacetyl)hydroxyamine (3.5 g), pyridine (2 ml) and toluene (110 ml) was stirred under reflux for 1 hour, and then cooled, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-cyano-2-thiophenecarboxamide (0.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[F:11][C:12]([F:39])([F:38])[C:13]([N:15]([CH2:26][C:27]1[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[CH:29][N:28]=1)[CH2:16][C:17](=[O:25])[NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:14]>>[F:38][C:12]([F:11])([F:39])[C:13]([N:15]([CH2:26][C:27]1[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[CH:29][N:28]=1)[CH2:16][C:17](=[O:25])[NH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[CH2:21][CH2:20]1)=[O:14]
Reactant: COc1ccccc1C=O
Reactant: CCOC(=O)c1ccnc(CN(CC(=O)NC2CCNCC2)C(=O)C(F)(F)F)c1
Product: CCOC(=O)c1ccnc(CN(CC(=O)NC2CCN(Cc3ccccc3OC)CC2)C(=O)C(F)(F)F)c1

Procedure:
Prepared by General Procedure A from 2-methoxybenzaldehyde and ethyl 2-[(2,2,2-trifluoro-N-{[(piperidin-4-yl)carbamoyl]methyl}acetamido)methyl]pyridine-4-carboxylate. 1H-NMR (300 MHz, CDCl3): δ 8.75 & 8.71 (2d, 1H; rotamer), 7.91-7.78 (m, 2H), 7.36 (m, 1H), 7.25 (m, 1H), 7.99-7.86 (m, 2H), 4.95 & 4.72 (2s, 2H, rotamer), 4.45 (q, 2H), 4.30 & 4.08 (2s, 2H; rotamer), 3.83 (m, 4H), 3.60 (m, 2H) 2.95 (m, 2H), 2.22 (m, 2H), 1.90 (m, 2H), 1.60 (m, 2H), 1.40 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][CH2:11][OH:12]>>[CH2:11]([O:12][C:6](=[NH:7])[C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:10]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CCO
Product: CCOC(=N)c1ccc(Br)cc1
Temperature: 2.5 °C
Reaction time: 5 h

Procedure:
4-Bromo-benzonitrile (5 g) was suspended in absolute EtOH (100 ml) and cooled to 0-5° C. HCl gas was bubbled through, initially vigorously for several minutes and later slowly for 5 hours. The resulting solution was allowed to stir overnight. Most of solvent was removed and the precipitate was filtered, washed with EtOH twice and dried to afford compound 2BO (4.1 g) as white solid.
Reaction SMILES: B#B.[CH3:3][C:4]1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][C:5]=1[C:16](O)=[O:17].CO>O1CCCC1>[OH:17][CH2:16][C:5]1[O:6][C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=2[C:4]=1[CH3:3]
Reactant: Cc1c(C(=O)O)oc2ccc([N+](=O)[O-])cc12
Agent: B#B
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(CO)oc2ccc([N+](=O)[O-])cc12
Reaction time: 0.5 h

Procedure:
1 Molar diborane in tetrahydrofuran (18.0 ml, 18.0 mmole) was added dropwise to a suspension of 3-methyl-5-nitrobenzofuran-2-carboxylic acid (1.1 g, 5 mmole) in tetrahydrofuran at 0°. Stirring was continued at 0° for 30 minutes then at room temperature for 18 hours when a second portion of diborane (5.0 ml) was added and the reaction mixture was subjected to ultrasound for 2.5 hours. Methanol was then added cautiously to the reaction mixture and the solvent was removed by evaporation. The residue was taken up in ethyl acetate, washed with aqueous sodium bicarbonate, dried (MgSO4), the solvent removed by evaporation in vacuo and purified by column chromatography on silica eluting with methylene chloride. The product-containing fractions were combined and evaporated to give the title compound, yield 0.96 g. A sample was recrystallised from ethyl acetate, m.p. 149°-150°.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH3:16][N:17]1[C:22]2=[C:23]3[C:28](=O)[CH2:27][CH2:26][NH:25][N:24]3[C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:21]2[C:20](=[O:37])[N:19]([CH3:38])[C:18]1=[O:39].N1C(C)=CC=CC=1C>C(Cl)Cl>[CH3:16][N:17]1[C:18](=[O:39])[N:19]([CH3:38])[C:20](=[O:37])[C:21]2[C:22]1=[C:23]1[N:24]([C:30]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[NH:25][CH2:26][CH:27]=[C:28]1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(=O)CCN3
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(OS(=O)(=O)C(F)(F)F)=CCN3
Reaction time: 1.75 h

Procedure:
Trifluoromethanesulfonic anhydride (0.254 ml, 1.506 mmol) was added slowly to a solution of 1,3-dimethyl-5-phenyl-8,9-dihydropyrimido[4′,5′:3,4]pyrrolo[1,2-b]pyridazine-2,4,10(1H,3H,7H)-trione (step 4) (222 mg, 0.684 mmol) and 2,6-lutidine (commercial) (0.159 ml, 1.369 mmol) in DCM (10 ml) at 0° C. and the mixture stirred for 1.75 hours. The reaction mixture was quenched with sat. NaHCO3(aq) and extracted with DCM. The organic phase was passed through a hydrophobic frit and evaporated under reduced pressure. Purification of the residue by chromatography on silica, eluting with 20% EtOAc/hexane then 40% EtOAc/hexane afforded the title compound as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=O)=[CH:10][CH:9]=1.[CH3:19][C:20]1[C:21]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1>>[CH3:19][C:20]1[C:21]([N:27]2[CH2:28][CH2:29][N:30]([C:12]([C:11]3[CH:10]=[CH:9][C:8]([N:3]4[CH2:4][CH2:5][CH2:6][NH:7][C:2]4=[O:1])=[CH:18][CH:17]=3)=[O:14])[CH2:31][CH2:32]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: Cc1cnc(N2CCNCC2)c(C)c1
Reactant: CCOC(=O)c1ccc(N2CCCNC2=O)cc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCNC4=O)cc3)CC2)c(C)c1
Yield: 77.4 %

Procedure:
Using ethyl 4-(2-oxotetrahydropyrimidin-1-yl)benzoate (84 mg) described in Preparation Example 60 and 1-(3,5-dimethylpyridin-2-yl)piperazine (65 mg) described in Preparation Example 79 and by the reaction and treatment in the same manner as in Example 109, the title compound (103 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[C:11]1([CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH3:10][C:4]1[N:3]=[C:2]([N:20]2[CH2:19][CH2:18][CH:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:22][CH2:21]2)[CH:7]=[C:6]([NH:8][CH3:9])[N:5]=1
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CNc1cc(Cl)nc(C)n1
Product: CNc1cc(N2CCC(c3ccccc3)CC2)nc(C)n1
Yield: 74.4 %

Procedure:
A mixture of 4-chloro-2-methyl-6-methylaminopyrimidine (525 mg, 3.3 mM; described in J. Pharm. Soc. (Japan) 1966, 86, p. 952) and 4-phenylpiperidine (1.08 g, 6.6 mM) was heated as a melt at 135°-140° C. for 1 hour. The residue, obtained after cooling, was triturated with ether and the mixture separated by filtration. The solid was suspended in a mixture of 50% w/v potassium hydroxide solution (50 ml) and isopropanol (50 ml). The mixture was heated under reflux for 2 hours and cooled. The organic layer was separated and the solvent removed in vacuo. The residue was dissolved in methylene chloride (50 ml), washed with water (2×25 ml), dried (MgSO4) and the solvent evaporated. The residue was purified by flash chromatography on silica (Merck Art. 9385, 100 g), using a mixture of methanol and methylene chloride (1:9 v/v) as eluant, to give 2-methyl-6-methylamino-4-(4-phenylpiperidino)-pyrimidine (700 mg, 75% yield), m.p. 186°-188° C.; microanalysis, found: C, 71.6; H,7.5; N,19.3%; C17H22N4.1/4H2O requires C,71.2; H,7.8; N,19.5%.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[C:26]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=1>C(Cl)Cl>[CH3:18][N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH2:3][C@H:2]([NH:1][C:32]([C:29]2[CH:30]=[CH:31][C:26]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:27][CH:28]=2)=[O:33])[CH2:11][CH2:10]3)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(-c4ccccc4)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) and triethylamine (62 μL, 0.45 mmol) in methylene chloride (20 mL) was added dropwise 4-biphenylcarbonyl chloride (89 mg, 0.41 mmol) in methylene chloride (5 mL). After the addition the reaction was allowed to stir at ambient temperature for 15 min and then washed with water. The phases were separated and the combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:2.5) as the eluent. Yield: 100 mg (59%) of the title compound as white crystals: mp 232-233° C.; EIMS (70 eV) m/z (relative intensity) 425 (11, M+).
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH:20]1[N:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[C:23](=[O:37])[CH:22](O)[CH2:21]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:19][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[C:13]=1[CH:20]1[N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][C:33]([F:35])([F:36])[F:34])=[CH:30][CH:31]=2)[C:23](=[O:37])[CH:22]([F:7])[CH2:21]1
Reactant: COc1cccc(OC)c1C1CC(O)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cccc(OC)c1C1CC(F)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A cooled (−78° C.) mixture of DAST (117 mg; 0.72 mmol) in anh. DCM (0.5 ml) was treated dropwise with a solution of rac-(3R*,5S*)-5-(2,6-dimethoxyphenyl)-3-hydroxy-1-(4-(trifluoromethoxy)benzyl)-pyrrolidin-2-one (100 mg; 0.24 mmol) in anh. DCM (0.5 ml). The resulting mixture was further stirred at −78° C., under nitrogen, for 1 h, at 0° C. for 30 min., and finally at rt for 1 h. Aq. sat. NaHCO3 was added, and the resulting mixture was extracted with DCM. The mixed organic layers were dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by preparative HPLC afforded rac-(3S*,5S*)-5-(2,6-dimethoxyphenyl)-3-fluoro-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one as a colorless solid. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 414.12 g/mol.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:11][CH3:12])=[O:9])[C:4](=[O:21])O1.[CH2:23]([C:30]1([S:33]([NH2:36])(=[O:35])=[O:34])[CH2:32][CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]([O:11][CH3:12])[C:8](=[O:9])[CH:7]=[C:5]([OH:6])[C:4]([NH:36][S:33]([C:30]2([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)(=[O:34])=[O:35])=[O:21])=[CH:19][CH:18]=1
Reactant: CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: NS(=O)(=O)C1(Cc2ccccc2)CC1
Product: CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)NS(=O)(=O)C1(Cc2ccccc2)CC1

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-benzyl)-N-methoxy-acetamide was treated with 1-benzyl-cyclopropanesulfonic acid amide as described in the preparation of compound 1 to yield the title compound. MS (M−H) calcd for C22H22FN2O6S: 461.1. Found: 461.2. HRMS (M+H) calcd for C22H24FN2O6S: 463.1339. Found: 463.1331. 1H NMR (500 MHz, CDCl3) 0.95 (m, 2), 1.26 (m, 2), 3.25 (s, 2), 3.85 (s, 3), 4.79 (s, 2), 6.43 (s, 1), 7.06-7.32 (overlapping m, 9). Anal calcd for C22H23FN2O6S: C, 57.13; H, 5.01; N, 6.05. Found: C, 56.06; H, 5.42; N, 6.25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([CH3:25])([CH3:24])[CH2:13][NH:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[O:8][CH:7]([C:26]([F:29])([F:28])[F:27])[C:6]([C:30]([O:32]CC)=[O:31])=[CH:5]2.[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([CH3:25])([CH3:24])[CH2:13][NH:14][C:15](=[O:23])[C:16]1[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=1)[O:8][CH:7]([C:26]([F:28])([F:29])[F:27])[C:6]([C:30]([OH:32])=[O:31])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(C(C)(C)CNC(=O)c3ccc(Cl)cc3)cc2OC1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(CNC(=O)c1ccc(Cl)cc1)c1cc2c(cc1Cl)C=C(C(=O)O)C(C(F)(F)F)O2
Reaction time: 2 h

Procedure:
The title product of Example 130 Step 2 was dissolved in 5 mL of MeOH, and a solution of 244 mg of 50% aqueous NaOH in 1 mL of water was added. After stirring for 2 h, the mixture was acidified, extracted with DCM, the combined organic extracts dried over Na2SO4, filtered, and evaporated. Chromatography of the residue over silica gel using 25% EtOAc—heptane—1% HOAc gave the title compound, 65 mg, as a pure white crystalline solid. 1H NMR (DMSO-d6) 8.34 (t, 1H, J=4.6 Hz), 7.86 (s, 1H), 7.72 (d, 2H, J=8.8 Hz), 7.60 (s, 1H), 7.48 (d, 2H, J=8.8Hz), 7.03 (s, 1H), 5.93 (q, 1H, J=7.2 Hz), 3.78 (m, 2H), 1.44 (s, 6H). LCMS m/z=488.0.
Reaction SMILES: C(O)C.C([O:6][C:7](=O)[CH2:8][CH2:9][N:10]([C:18]1[C:23]([NH2:24])=[CH:22][N:21]=[C:20]([Cl:25])[N:19]=1)[CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1([CH3:17])[CH3:16])C>C(O)(=O)C>[Cl:25][C:20]1[N:21]=[CH:22][C:23]2[NH:24][C:7](=[O:6])[CH2:8][CH2:9][N:10]([CH:11]3[CH2:15][CH2:14][CH2:13][C:12]3([CH3:17])[CH3:16])[C:18]=2[N:19]=1
Reactant: CCOC(=O)CCN(c1nc(Cl)ncc1N)C1CCCC1(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CC1(C)CCCC1N1CCC(=O)Nc2cnc(Cl)nc21
Yield: 74 %

Procedure:
A mixture of 50 mL of ethanol, 1 mL of acetic acid and 2.5 g of the (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-cyclopentyl)-amino]-propanoic acid ethyl ester (V-59) prepared in the previous step was heated at reflux overnight, and then concentrated under reduced pressure. The residue was taken up in dichloromethane and washed successively with 10% sodium bicarbonate solution, and then water and dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure. Trituration of the residue with ether, provided 1.6 g of (rac)-2-chloro-9-(2,2-dimethyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-59).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[CH2:30][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])(=O)=O>CN(C)C=O>[F:36][C:31]([F:37])([C:32]([F:35])([F:34])[F:33])[CH2:30][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:17])[F:1])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)F)C(F)(F)F
Reactant: N#CC(C#N)Cc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(Cc1ccc(OC(F)(F)F)cc1)CC(F)(F)C(F)(F)F
Yield: 26 %

Procedure:
Using 0.3 g of (4-(trifluoromethoxy)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 0.073 g of cesium carbonate, and 0.35 g of 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate, and according to the process described in the Production Example 1, there was obtained 0.12 g of 2-(2,2,3,3,3-pentafluoropropyl)-2-(4-(trifluoromethoxy)benzyl)malononitrile (the present compound (5)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9]Cl)[CH:5]=[CH:6][CH:7]=1.[C:11]1([CH:17]([NH:20][C:21]([C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][CH:27]=[CH:26]3)=[O:22])[CH2:18][CH3:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][CH2:9][N:28]1[C:29]2[C:25](=[CH:24][C:23]([C:21]([NH:20][CH:17]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:18][CH3:19])=[O:22])=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: ClCCc1cccc(Cl)c1
Reactant: CCC(NC(=O)c1ccc2[nH]ccc2c1)c1ccccc1
Product: CCC(NC(=O)c1ccc2c(ccn2CCc2cccc(Cl)c2)c1)c1ccccc1

Procedure:
The title compound was prepared following the same general protocol as described in Step 1 of Example 21, using 2-(3-chlorophenyl)ethyl chloride and N-(1-phenylpropyl)-1H-indole-5-carboxamide. LC-MS 417 (M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15]O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:37].O>C(Cl)Cl>[Br:37][CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][C:8]1[CH:7]=[CH:6][C:5]2[S:1][CH:2]=[CH:3][C:4]=2[CH:9]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCOCCc1ccc2sccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: BrCCCOCCc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
In 40 mL of methylene chloride was dissolved 2.00 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]-1-propanol, and 5.55 g of triphenylphosphine was added to the solution, after which a solution of 8.42 g of carbon tetrabromide in 10 mL of methylene chloride was added dropwise thereto under ice-cooling and the resulting mixture was stirred at room temperature for 20 minutes. To the reaction mixture was added 20 mL of water, and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. Diethyl ether was added to the residue and the insoluble materials were filtered off, after which the solvent was distilled off under reduced pressure. The residue was purified by a column chromatography (eluent; hexane:ethyl acetate=20:1 to 10:1) to obtain 1.93 g of 5-[2-(3-bromopropoxy)ethyl]-1-benzothiophene as a colorless oil.