Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27]([CH:39]=O)[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]>O1CCCC1>[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27](/[CH:39]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 40.4 %

Procedure:
A solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.110 g, 4.299 mmol) in tetrahydrofuran (17 ml) was added with lithium hydroxide monohydrate (0.171 g, 4.08 mmol), and the mixture was stirred for approximately 1.2 hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.962 g, 2.41 mmol) in tetrahydrofuran (3 ml) was added thereto, and the mixed solution was heat refluxed for approximately 48 hours. After cooling to room temperature, the solution was concentrated under reduced pressure. Ethyl acetate and water were added to the residue and stirred, then, the mixture was let to stand and separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 38 g; ethyl acetate:hexane=1:4), to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (0.517 g; 0.973 mmol; yield: 40.4%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]2.CC1(C)COB([C:23]2[CH:24]=[CH:25][C:26]([F:36])=[C:27]([CH:35]=2)[CH2:28][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)OC1>>[F:36][C:26]1[CH:25]=[CH:24][C:23]([C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([C:12]([F:15])([F:14])[F:13])=[N:7]3)=[CH:35][C:27]=1[CH2:28][N:29]1[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2n1
Reactant: CC1(C)COB(c2ccc(F)c(CN3CCOCC3)c2)OC1
Product: Fc1ccc(-c2ccnc3nc(C(F)(F)F)ccc23)cc1CN1CCOCC1
Yield: 11.6 %

Procedure:
5-Chloro-2-trifluoromethyl[1,8]naphthyridine (50 mg, 0.22 mmol) was coupled to 4-[5-(5,5-dimethyl[1,3,2]dioxaborinan-2-yl)-2-fluorobenzyl]morpholine (86 mg, 0.28 mmol) as described in Example 7 part g), affording 5-(4-fluoro-3-morpholin-4-ylmethylphenyl)-2-trifluoromethyl[1,8]naphthyridine (10 mg, 12%). δH (360 MHz, CDCl3) 2.54 (4H, t, J 4.2), 3.68 (2H, s), 3.71 (4H, t, J 4.4), 7.26 (1H, t, 8.8), 7.37 (1H, m), 7.55-7.58 (2H, m), 7.82 (1H, d, J 8.4), 8.49 (1H, d, J 8.4), 9.27 (1H, d, J 4.2). m/z (ES+) 392 [MH]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[CH:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5](O)=[O:6].C(OC(=O)C)(=O)C>C(Cl)(Cl)Cl>[F:1][C:2]([F:13])([F:12])[CH:3]1[CH2:8][C:9](=[O:11])[O:10][C:5](=[O:6])[CH2:4]1
Reactant: O=C(O)CC(CC(=O)O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(C(F)(F)F)CC(=O)O1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
Into a 2 liter 3-necked flask equipped with a mechanical stirrer and reflux condenser were added 320 g (1.6 mol) 3-(trifluoromethyl)glutaric acid and 775 ml acetic anhydride. The solution was refluxed for 2.5 hours and allowed to cool to room temperature. The majority of the acetic anhydride was removed in vacuo (80° C.) to afford a brown solid which was dissolved in 800 ml of CHCl3 on a steam bath. Following the addition of 200 ml hexanes, a white precipitate began to form. Further crystallization was induced by storage in a refrigerator. The white flocculent solid was filtered and oven dried (50° C., 30 mm Hg) to afford 261 g (89% yield) of the desired product, m.p. 88°-91° C.
Reaction SMILES: C([C:3]1[C:21]([C:22]([OH:24])=[O:23])=[C:6]2[N:7]=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:9]=[C:10]([CH:11]3[CH2:13][CH2:12]3)[N:5]2[N:4]=1)C.[OH-].[Na+]>CO.O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:8]2[CH:9]=[C:10]([CH:11]3[CH2:13][CH2:12]3)[N:5]3[N:4]=[CH:3][C:21]([C:22]([OH:24])=[O:23])=[C:6]3[N:7]=2)=[CH:15][CH:16]=1
Reactant: CCc1nn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc2c1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cnn2c(C3CC3)cc(-c3ccc(Cl)cc3)nc12
Temperature: 80 °C
Yield: 85.4 %

Procedure:
A mixture of ethyl 5-(4-chloro-phenyl)-7-cyclopropyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.95 g, 2.8 mmol) and 2 N NaOH solution (5.6 mL) in MeOH (35 mL) was heated to 80° C. for 0.5 h. The mixture was cooled, diluted with water (150 mL) and washed with diethyl ether. The aqueous layer was acidified by the addition of 3N HCl to pH 2. The precipitate formed was isolated by filtration, washed with water, and dried to give the title compound (0.75 g, 86%). Off-white solid. MS (ISN) 312.3 [(M−H)−]; mp 256° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:17]=[C:16](Cl)[N:15]=2)[CH:8]=1)=[O:5].C(N(C(C)C)CC)(C)C.[CH3:38][S:39]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)(=[O:41])=[O:40]>C(O)C>[Cl:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([Cl:1])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:17]=[C:16]([N:45]3[CH2:46][CH2:47][N:42]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:43][CH2:44]3)[N:15]=2)[CH:8]=1)=[O:5]
Reactant: CC(C)c1cc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)ccn2)nc(Cl)n1
Reactant: CS(=O)(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)c1cc(Nc2cc(NC(=O)c3c(Cl)cccc3Cl)ccn2)nc(N2CCN(S(C)(=O)=O)CC2)n1
Temperature: 140 °C
Yield: 48.3 %

Procedure:
To a microwave tube with a solution of 2,6-dichloro-N-(2-(2-chloro-6-isopropylpyrimidin-4-ylamino)pyridin-4-yl)benzamide (0.050 g, 0.11 mmol) in ethanol (2 mL) was added diisopropylethylamine (1.5 mL) and 1-(methylsulfonyl)piperazine (0.18 g, 1.1 mmol). The resulting mixture was heated to 140° C. under microwave irradiation for 2 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to give the desired product (30 mg, 46% yield). 1H NMR ((500 MHz, DMSO-d6): δ 11.05 (s, 1H), 9.77 (s, 1H), 8.77 (s, 1H), 8.16 (d, J=5.5 Hz, 1H), 7.63 (s, 1H), 7.61 (s, 1H), 7.54 (m, 1H), 6.87 (m, 1H), 6.48 (s, 1H), 3.95-3.91 (m, 4H), 3.17-3.14 (m, 4H), 2.85 (s, 3H), 2.67 (m, 1H), 1.17 (d, J=7.0 Hz, 6H). LCMS (ESI) m/z: 564.0 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:19])[CH2:9][C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.Cl>ClCCl.C(N(CC)CC)C>[CH2:20]([N:22]([CH2:23][CH3:24])[C:14](=[O:16])[C:13]1[CH:12]=[CH:11][C:10]([CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:19])=[CH:18][CH:17]=1)[CH3:21]
Reactant: O=C(O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: CCNCC
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(CC(=O)c2ccc(F)cc2)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-[2-(4-fluorophenyl)-2-oxoethyl]benzoic acid (0.560 g, 2.17 mmol, Example 3, Step 1), triethylamine (0.620 ml), and diethylamine (0.230 ml) in dichloromethane (5 ml) at room temperature was added bis(2-oxo-3-oxazolidinyl)-phosphinic chloride (0.560 g). After 3 hours, HCl 1M (10 ml) was added and the product was extracted with dichloromethane (10 ml). The organic phase was washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. The residue was purified by flash chromatography using hexane/ethyl acetate 50% giving 0.44 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH2:30])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][CH2:29][NH:30][C:35]([NH:34][CH2:32][CH3:33])=[O:36])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: CCN=C=O
Reactant: Cc1cc(F)ccc1-c1nc(NCCN)nc2c1ccc(=O)n2-c1c(F)cccc1F
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)NCCNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
The product of Example 157 (42.5 mg., 0.0001 mol) stirring at 23° in dry THF (5 mL), under Ar, was treated with ethyl isocyanate (9.6 mg, 0.0001 mol) in one portion. After 30 min., the resulting red solution was stripped to dryness; taken up in methylene chloride (5 mL) and applied to a Chromatotron™ Rotor Plate (1000 u thickness); plate eluted with methylene chloride-methanol gradient (0% to 2% MeOH), to afford 30 mg (60.4%) of pure title compound. (m.p. 130′-133′). LC MS (m/e)=497 (MH+). Rt=2.04 min.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]=O)=[N:21][CH:22]=1>C1(C)C=CC=CC=1>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([CH:23]2[O:4][CH2:1][CH2:2][O:3]2)=[N:21][CH:22]=1
Reactant: OCCO
Reactant: O=Cc1ccc(Br)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(C2OCCO2)nc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 83.9 %

Procedure:
Ethyleneglycol (14.88 g, 0.24 mol) and p-toluenesulfonic acid (3 g, 0.16 mol) are added to a solution of 5-bromopyridine-2-carbaldehyde (30 g, 0.16 mol) in toluene (150 ml) at room temperature and the mixture is stirred for 10 hrs at refluxing temperature. After cooling to room temperature, the mixture is quenched with saturated aqueous NH4Cl, extracted with CH2Cl2 and washed with H2O. The aqueous layer is extracted with CH2Cl2 and the combined organic extract is washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (hexane-AcOEt (9:1 VAT)) to afford 5-bromo-2-(1,3-dioxolan-2-yl)pyridine (30.9 g, 84%) as a colorless oil). 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 7.87 (m, 1H), 7.45 (m, 1H), 5.83 (s, 1H), 4.13 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5][NH:4][C:3]1=[O:11].[H][H]>C(O)(=O)C.[Pd]>[Cl:1][CH:2]1[CH2:8][C:7]([CH3:9])([CH3:10])[CH2:6][CH2:5][NH:4][C:3]1=[O:11]
Reactant: [H][H]
Reactant: CC1(C)CCNC(=O)C(Cl)(Cl)C1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CCNC(=O)C(Cl)C1
Yield: 90 %

Procedure:
15.2 g (0.086 moles) of 3,3-dichloro-5,5-dimethyl-2-oxoperhydroazepine were dissolved in 900 ml of glacial acetic acid and shaked at 40 psi of hydrogen with 7 g of 10% Pd/C as in Description 14, to yield 13.6 g of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]#[C:10][C:11]1[C:19]2[C:18]([Cl:20])=[N:17][C:16]([NH2:21])=[N:15][C:14]=2[N:13]([CH2:22][C:23]2[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=2)[CH:12]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][C:9]#[C:10][C:11]1[C:19]2[C:18]([Cl:20])=[N:17][C:16]([NH2:21])=[N:15][C:14]=2[N:13]([CH2:22][C:23]2[C:28]([CH3:29])=[C:27]([O:30][CH3:31])[C:26]([CH3:32])=[CH:25][N:24]=2)[CH:12]=1
Reactant: COc1c(C)cnc(Cn2cc(C#CCNC(=O)OC(C)(C)C)c3c(Cl)nc(N)nc32)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C)cnc(Cn2cc(C#CCN)c3c(Cl)nc(N)nc32)c1C

Procedure:
A solution of {3-[2-Amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo [2,3-d]pyrimidin-5-yl]-prop-2-ynyl}-carbamic acid tert-butyl ester (see previous example, 22 mg) in DCM (3 mL) was treated with TFA (0.6 mL) at rt for 15 min. Evaporation, work-up (DCM/sat. aq. NaHCO3), drying (Na2SO4), and evaporation gave the title compound as an oil. tR=3.85 min. 1H NMR (CDCl3) δ 8.24 (s, 1H), 7.06 (s, 1H), 5.32 (s, 2H), 5.02 (s, 2H), 3.75 (s, 3H), 2.27 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33].CO>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[O:24][CH3:23])=[O:33])=[CH:18][CH:17]=1
Reactant: COc1ccccc1N=C=O
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccccc1NC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OC)cc23)cc1
Yield: 45 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml), and 2-methoxyphenyl isocyanate (27 μl) was then added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 34 mg (yield 45%) of the title compound.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].[C:6](OC(C)(C)C)(=[O:11])[CH2:7][C:8]([CH3:10])=[O:9]>C1(C)C=CC=CC=1>[C:6]([O:5][CH2:4][CH:2]1[O:3][CH2:1]1)(=[O:11])[CH2:7][C:8]([CH3:10])=[O:9]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: OCC1CO1
Solvent: Cc1ccccc1
Product: CC(=O)CC(=O)OCC1CO1
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
Glycidyl acetoacetate was prepared according to the method of Witzeman and Nottingham (J. Org. Chem, 1991, 56, 1713). Glycidol (Dixie Chemical Company, Pasadena, Tex.), 296 g, t-butyl acetoacetate, 632.8 g, and toluene, 500 ml, were mixed in a 1-liter reactor equipped with mechanical stirrer, thermocouple, condenser and nitrogen inlet. The reactor contents were heated to 110° C. and held at that temperature for 30 minutes. The reactor was then fitted with a distillation head and the toluene/t-butanol azeotrope was distilled from the reactor over 2 hours under moderate nitrogen flow. Peak temperature reached in the reactor was 120° C. After 4 hours total time, the reaction mixture was cooled and stripped on a rotary evaporator at 70° C. for 2 hours. The yellow liquid product was analyzed by proton NMR. Essentially quantitative conversion of glycidol to glycidyl acetoacetate was confirmed.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2/[C:7](=[C:10]3\[C:11](=[O:24])[NH:12][C:13]4[C:18]\3=[CH:17][C:16]([S:19](=[O:23])(=[O:22])[NH:20][CH3:21])=[CH:15][CH:14]=4)/[CH2:8][CH2:9][C:4]=2[C:3]=1[C:25]([OH:27])=O.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:42][CH2:43][CH:44]([OH:51])[CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1>CN(C=O)C>[OH:51][CH:44]([CH2:45][N:46]1[CH2:50][CH2:49][CH2:48][CH2:47]1)[CH2:43][NH:42][C:25]([C:3]1[C:4]2[CH2:9][CH2:8]/[C:7](=[C:10]3/[C:11](=[O:24])[NH:12][C:13]4[C:18]/3=[CH:17][C:16]([S:19](=[O:22])(=[O:23])[NH:20][CH3:21])=[CH:15][CH:14]=4)/[C:5]=2[NH:6][C:2]=1[CH3:1])=[O:27]
Reactant: CNS(=O)(=O)c1ccc2c(c1)/C(=C1\CCc3c1[nH]c(C)c3C(=O)O)C(=O)N2
Reactant: NCC(O)CN1CCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CNS(=O)(=O)c1ccc2c(c1)/C(=C1\CCc3c1[nH]c(C)c3C(=O)NCC(O)CN1CCCC1)C(=O)N2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.6 %

Procedure:
A mixture of 2-methyl-6-[5-methylsulfamoyl-2-oxo-1,2-dihydro-indol-(3Z)-ylidene]-1,4,5,6-tetrahydro-cyclopenta[b]pyrrole-3-carboxylic acid (Example 5, 78 mg, 0.2 mmol), HOBt (27 mg, 0.2 mmol) and EDC (77 mg, 0.4 mmol) in dry DMF (2 mL) was stirred at room temperature for 30 min. Then 1-amino-3-pyrrolidine-1-yl-propan-2-ol (0.4 mmol) was added and stirring was continued for 48 hours. The solvent was removed under reduced pressure and the residue was crystallized and purified on a silica gel column to give 54 mg of the titled compound as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:26])[CH:11]=2)[N:6]=1)=O.[CH3:27][CH2:28][O:29][C:30]([CH:32](P(OCC)(OCC)=O)[CH3:33])=[O:31].Cl.C(O)C>O1CCCC1>[CH2:28]([O:29][C:30](/[C:32](/[CH3:33])=[CH:3]/[C:5]1[N:14]=[C:13]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]3[O:23][CH2:24][O:25][C:19]=3[CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:26])[CH:11]=2)[N:6]=1)=[O:31])[CH3:27]
Reactant: O=Cc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)/C(C)=C/c1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Temperature: 25 °C
Yield: 40.1 %

Procedure:
0.52 g (0.013 mol) of sodium hydride was added to a solution of 4.00 g (0.0117 mol) of 2-formyl-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline in 250 ml of tetrahydrofuran. 2.8 ml (0.013 mol) of triethyl 2-phosphonopropionate was dropped into the mixture prepared above under stirring and cooling with ice. The mixture thus prepared was stirred under cooling with ice for a while, heated to room temperature and stirred for additional one hour, followed by the addition of 1.5 ml of 8M hydrochloric acid/ethanol. The obtained mixture was passed through a small amount of silica gel and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) and recrystallized from chloroform/n-hexane to give 2.00 g of the title compound.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][C:5](=[CH:8][CH2:9][CH:10]1[CH2:14][CH:13]=[C:12]([CH3:15])[C:11]1([CH3:17])[CH3:16])[CH:6]=[O:7].Cl>C(OCC)C>[CH3:4][CH:5]([CH:8]([CH3:1])[CH2:9][CH:10]1[CH2:14][CH:13]=[C:12]([CH3:15])[C:11]1([CH3:17])[CH3:16])[CH:6]=[O:7]
Reactant: CC(C=O)=CCC1CC=C(C)C1(C)C
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Product: CC1=CCC(CC(C)C(C)C=O)C1(C)C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
100 ml (0.30 mol) of methylmagnesium bromide solution in diethyl ether was added to 60.0 g (0.32 mol) of cuprous iodide suspended in 350 ml of the same solvent at −10° C., followed by addition of 52.0 g (0.27 mol) of 2-methyl-4-(2,2,3-trimethylcyclopent-3-enyl)but-2-enal dissolved in 300 ml of anhydrous diethyl ether at 0° C. and stirring at the same temperature was continued for 0.5 hours. The reaction mixture was treated with 200 ml of 1.0 N hydrochloric acid, decanted and the organic layer was washed with 2×300 ml of brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: hexane/MTBE 15:1) to give 28.2 g (50% yield) of 2,3-dimethyl-4-(2,2,3-trimethylcyclopent-3-enyl)butanal.
Reaction SMILES: C1N2CCN(CC2)C1.[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:25])[NH:16][C:17]2[C:22]([C:23]=1Cl)=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:13])[CH3:10].[N:26]1([C:32]([C:34]2[S:35][CH:36]=[CH:37][CH:38]=2)=[O:33])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>CC(N(C)C)=O>[CH2:9]([O:11][C:12]([C:14]1[C:15](=[O:25])[NH:16][C:17]2[C:22]([C:23]=1[N:29]1[CH2:30][CH2:31][N:26]([C:32]([C:34]3[S:35][CH:36]=[CH:37][CH:38]=3)=[O:33])[CH2:27][CH2:28]1)=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:13])[CH3:10]
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2cccnc2[nH]c1=O
Agent: C1CN2CCN1CC2
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cccnc2[nH]c1=O
Temperature: 110 °C
Yield: 39.6 %

Procedure:
DABCO (0.57 g, 5.14 mmol) was added to a solution of 4-chloro-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (15) (0.65 g, 2.57 mmol) and piperazine-1-yl-thiophene-2-yl-methanone (0.60 g, 3.08 mmol) in dimethylacetamide at room temperature. The solution was heated overnight at 110° C. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried to yield 420 mg (39%) of 2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (16) as white solids. MP: 239° C.; 1H-NMR (DMSO-d6): δ 1.30 (t, J=7.0 Hz, 3H), 3.13 (m, 4H), 3.87 (m, 4H), 4.30 (q, J=7.0 Hz, 2H), 7.15 (dd, J=3.5, 4.8 Hz, 1H), 7.40 (dd, J=4.8, 8.0 Hz, 1H), 7.45 (d, J=3.6 Hz, 1H), 7.80 (d, J=4.8 Hz, 1H), 8.24 (dd, J=1.5, 7.5 Hz, 1H), 8.56 (dd, J=1.5, 7.5 Hz, 1H) 12.25 (s, 1H); EIMS: 413 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[NH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(CC)CC)C>C(#N)C>[Cl:8][C:4]1[N:3]=[C:2]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:6][CH:5]=1
Reactant: CCOC(=O)CN
Reactant: Clc1cncc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CNc1cncc(Cl)n1
Temperature: 80 °C
Yield: 48.8 %

Procedure:
To 2,6-dichloropyrazine (50 g, 336 mmol) and ethyl 2-aminoacetate (34.6 g, 336 mmol) was added triethylamine (140 mL, 1007 mmol) and acetonitrile (350 mL). The reaction was heated at 80° C. for 3 d. Precipitated triethylamine salts were removed by filtration and washed with ethyl acetate and hexane (1:1) multiple times. The filtrate and wash solvent were combined and concentrated. The resulting white-yellow precipitate was filtered and washed with 20% ethyl acetate in hexane to afford an off-white solid. The filtrate was subjected to the same process to give an additional batch of off-yellow solid. The batches were combined to afford the title compound (35.5 g, 164 mmol, 49% yield). MS (ESI) m/z 216.1 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25](O)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:61][NH:62][CH2:63][C:64]1[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=1>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:62]([CH3:61])[CH2:63][C:64]4[CH:65]=[N:66][CH:67]=[CH:68][CH:69]=4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]([F:37])([F:36])[F:35]
Reactant: CNCc1cccnc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)O)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)N(C)Cc4cccnc4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
To a stirred solution of the 10-{[2-methoxy-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl}-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxylic acid of Step E (0.17 g, 0.37 mmol) in N,N-dimethylformamide (15 mL), was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.092 g, 0.48 mmol) and 1-hydroxybenzotriazole monohydrate (0.065 g, 0.48 mmol). After the solution became homogeneous 3-(methylaminomethyl) pyridine (0.045 g, 0.37 mmol) was added, and the solution was stirred at room temperature overnight. The solution was then poured into water and extracted with ethyl acetate. The combined ethyl acetate layers were washed with water, dried and concentrated to dryness. The residue was subjected to silica chromatography eluting with 10% methanol in chloroform. The pure fractions were concentrated and the residue azeotroped and triturated several times with hexane to provide the title product (0.150 g) as an amorphous white solid, 150–153° C. (dec.)