Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH:10]1[CH2:14][CH2:13][CH:12](O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:30]=[N+:31]=[N-:32])(C2C=CC=CC=2)=O)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:1]([O:9][CH:10]1[CH2:14][CH2:13][CH:12]([N:30]=[N+:31]=[N-:32])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC1CCC(O)C1)c1ccccc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: [N-]=[N+]=NC1CCC(OC(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
To a solution of 3-hydroxycyclopentyl benzoate (630 mg) in anhydrous tetrahydrofuran (15 mL) were added diphenylphosphoryl azide (925 mg), diethyl azodicarboxylate (585 mg) and triphenylphosphine (881 mg). After stirring for 2 hours at ambient temperature, the mixture was partitioned between ethyl acetate and water. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of hexane and ethyl acetate (10:1) to give 3-azidocyclopentyl benzoate as pale yellow oil (531 mg).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[N:21]([CH3:23])[C:20](=[O:24])[C:19]2([CH3:26])[CH3:25].[CH3:27][Si:28](Cl)([CH3:30])[CH3:29]>O1CCCC1>[F:13][C:14]1[C:15]([Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:16][CH:17]=[C:18]2[C:22]=1[N:21]([CH3:23])[C:20](=[O:24])[C:19]2([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)Cl
Reactant: CN1C(=O)C(C)(C)c2cccc(F)c21
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CN1C(=O)C(C)(C)c2ccc([Si](C)(C)C)c(F)c21
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (5.4 g, 7.6 ml, 52.8 mmol) in dry tetrahydrofuran (23 ml) under an argon atmosphere was cooled to −40° C. and a solution of n-BuLi (1.6 M in hexane, 31.6 ml, 50.5 mmol) was added dropwise. The mixture was stirred at −40° C. for 30 minutes and then added to a solution of 7-fluoro-1,3,3-trimethylindolin-2-one (8.875 g, 45.9 mmol) and trimethylsilyl chloride (5.49 g, 6.46 ml, 50.5 mmol) in dry tetrahydrofuran (69 ml) at −75° C. The reaction mixture was warmed to room temperature within 16 hours. The reaction mixture was carefully quenched with water (2 ml) and diluted with ethyl acetate and water. The aqueous phase was extracted ethyl acetate, the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was evaporated and the residue purified by silica gel chromatography using ethyl acetate/heptane as eluent. The title compound was obtained as light yellow oil (8.55 g).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:11]([CH3:12])[N:10]=[CH:9][C:8]=2[N+:13]([O-])=O)[CH2:3][CH2:2]1>CO.[Pd]>[CH3:12][N:11]1[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[C:8]([NH2:13])[CH:9]=[N:10]1
Reactant: Cn1ncc([N+](=O)[O-])c1C1=CCOCC1
Agent: [Pd]
Solvent: CO
Product: Cn1ncc(N)c1C1CCOCC1
Yield: 92.1 %

Procedure:
A solution of 5-(3,6-dihydro-2H-pyran-4-yl)-1-methyl-4-nitro-1H-pyrazole (80 mg, 0.38 mmol) in MeOH (20 mL) was passed through the H-Cube® (30 bar, 25° C., flow rate: 1 mL/min, 30 mm 10% Pd/C cartridge). The solvent was removed under reduced pressure to afford crude 1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-amine as a light yellow oil (64 mg, 0.35 mmol). To a solution of this amine (60 mg, 0.33 mmol) in DCM (20 mL) was added DIPEA (0.5 mL, 2.87 mmol), PyBOP (0.34 g, 0.66 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid (124 mg, 0.35 mmol) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM and washed with water. The organic layer was separated, dried over MgSO4 and the solvent removed under reduced pressure. Purification via silica gel column chromatography (0-80% EtOAc/isohexane) gave tert-butyl 2-(2,6-difluorophenyl)-4-(1-methyl-5-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as an off-white solid (102 mg, 59%). This solid (100 mg, 0.19 mmol) was stirred in HCl in 1,4-dioxane (4.0 M, 1.9 mL) at room temperature for 18 hr. The solvents were removed under reduced pressure and the crude residue was re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and 7 N ammonia in MeOH to yield 301 as a peach solid (59 mg, 73%). 1H NMR (400 MHz, CDCl3) δ 8.42 (s, 1H), 7.69 (s, 1H), 7.34-7.29 (m, 1H), 7.02 (t, J=8.7 Hz, 2H), 6.11 (s, 2H), 4.09 (dd, J=11.6, 4.2 Hz, 2H), 3.88 (s, 3H), 3.50 (t, J=11.6 Hz, 2H), 3.02-2.95 (m, 1H), 2.17-2.08 (m, 2H), 1.78 (d, J=13.4 Hz, 2H). LCMS (ES+) m/z 420 (M+1)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[O:43])[N:13]([CH2:20][C:21]2[CH:22]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[C:29]([CH2:34][NH:35]C(=O)OC(C)(C)C)[CH:28]=4)[CH:24]=[CH:25][CH:26]=2)[C:14]3=[O:19])=[O:8])=[CH:4][CH:3]=1.Cl>>[ClH:1].[NH2:35][CH2:34][C:29]1[CH:28]=[C:27]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([CH2:20][N:13]3[C:12](=[O:43])[C:11]4[C:15](=[CH:16][CH:17]=[CH:18][C:10]=4[NH:9][C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)=[O:8])[C:14]3=[O:19])[CH:22]=2)[CH:32]=[CH:31][C:30]=1[F:33]
Reactant: CC(C)(C)OC(=O)NCc1cc(-c2cccc(CN3C(=O)c4cccc(NC(=O)c5ccc(Cl)s5)c4C3=O)c2)ccc1F
Agent: Cl
Product: NCc1cc(-c2cccc(CN3C(=O)c4cccc(NC(=O)c5ccc(Cl)s5)c4C3=O)c2)ccc1F

Procedure:
Starting with tert-butyl {3′-[(4-{[(5-chloro-2-thienyl)carbonyl]amino}-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4-fluoro[1,1′-biphenyl]-3-yl}methylcarbamate, by treating the crude product with etheral hydrochloric acid solution, it is possible to obtain N-(2-{[3′-(aminomethyl)-4′-fluoro[1,1′-biphenyl]-3-yl]methyl}-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl)-5-chloro-2-thiophenecarboxamide hydrochloride.
Reaction SMILES: C([Li])CCC.C(O[C:14]([NH:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2)=O)C1C=CC=CC=1.[C:27]([O:32][CH2:33][C@@H:34]1[O:36]C1)(=[O:31])CCC.[NH4+].[Cl-]>CCCCCC.C1COCC1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[N:23]1[C:24]2[C:19](=[CH:18][C:17]([N:16]3[CH2:14][C@H:33]([CH2:34][OH:36])[O:32][C:27]3=[O:31])=[CH:26][CH:25]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(Nc1ccc2ncccc2c1)OCc1ccccc1
Reactant: CCCC(=O)OC[C@H]1CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1O[C@@H](CO)CN1c1ccc2ncccc2c1
Temperature: 25 °C
Yield: 45.2 %

Procedure:
4.70 ml (11.78 mmol) of a 2.5M solution of n-butyllithium in n-hexane are slowly added to a stirred solution, cooled to -78° C., of 3.28 g (11.78 mmol) of 6-benzyloxycarbonylamino-quinoline and 1 mg of 1,10-phenanthroline hydrate in 30 ml of anhydrous THF until the colour changes. Thereafter, 1.67 ml (11.78 mmol) of (R)-glycidyl butyrate are added dropwise and the reaction mixture is allowed to warm to room temperature in the course of 16 hours. 30 ml of saturated aqueous NH4Cl solution are then added dropwise in the course of 15 minutes. The aqueous phase is extracted with 3×60 ml of ethyl acetate and the organic phases are combined, washed with 2×50 ml of NaCl solution and dried over MgSO4. Evaporation of the solvent in vacuo, tritration of the residue with ether and recrystallization from 25 ml of ethanol gives 1.30 g (45%) of the title compound as colourless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH:18]=O)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:36]=[C:35]([CH2:37]P(OCC)(OCC)=O)[CH:34]=[CH:33][C:31]=3[N:32]=2)=[CH:24][CH:23]=1.CO>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([CH:18]=[CH:37][C:35]4[CH:34]=[CH:33][C:31]5[N:32]=[C:28]([C:25]6[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=6)[O:29][C:30]=5[CH:36]=4)[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nc3ccc(C=O)cc3o2)cc1
Reactant: CCOP(=O)(Cc1ccc2nc(-c3ccc(OC)cc3)oc2c1)OCC
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(-c2nc3ccc(C=Cc4ccc5nc(-c6ccc(OC)cc6)oc5c4)cc3o2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A solution of 5.06 g (0.02 Mole) of 2-p-methoxyphenyl-6-formylbenzoxazole of the formula ##STR33## (melting point: 161.5°-162.5° C.) and 7.50 g (0.02 mole) of 2-(p-methoxyphenyl)-6-(diethylphosphonomethyl)-benzoxazole of the formula ##STR34## (melting point: 85°-88° C.) in 150 ml of dimethyl formamide is heated to 50° C. and 2.1 g of sodium tert.butylate are added in small amounts to the solution over the course of 15 minutes. The reaction mixture is stirred at room temperature overnight, then poured into 400 ml of methanol with stirring. The product is collected by filtration, washed with water and then with 140 ml of methanol, and subsequently recrystallised from chlorobenzene with the addition of fuller's earth, affording 7.1 g (75% of theory) of 1,2-bis-(2-p-methoxyphenyl-benzoxazol-6-yl)-ethylene of the formula ##STR35## in the form of pale yellow crystals with a melting point of over 300° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][CH2:8][C:7](=O)[N:6]1C(OC(C)(C)C)=O)=[O:4].Br[C:20]1[CH:25]=[C:24]([F:26])[C:23]([F:27])=[C:22]([F:28])[CH:21]=1.[Mg]>C1COCC1.FC1C=C([Mg]Br)C=C(F)C=1F>[F:26][C:24]1[CH:25]=[C:20]([C@H:7]2[NH:6][C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9][CH2:8]2)[CH:21]=[C:22]([F:28])[C:23]=1[F:27]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: COC(=O)[C@H]1CCCC(=O)N1C(=O)OC(C)(C)C
Agent: Fc1cc([Mg]Br)cc(F)c1F
Agent: [Mg]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CCC[C@@H](c2cc(F)c(F)c(F)c2)N1
Reaction time: 2 h
Yield: 39.6 %

Procedure:
To a solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (13.0 g) in THF (140 mL), 3,4,5-trifluorophenylmagnesium bromide (prepared from 1-bromo-3,4,5-trifluorobenzene (11.7 g) and magnesium (1.48 g) by the method described in Org. Synth., 2001, 79, 176) was added in a nitrogen atmosphere at −78° C. over 30 minutes. The reaction solution was stirred at −78° C. to −10° C. for two hours, and then quenched with a saturated ammonium chloride solution at −10° C. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. A solution of 4 N hydrochloric acid in ethyl acetate (150 mL) was added to a solution of the residue in ethyl acetate (150 mL) at room temperature, and the reaction solution was stirred at room temperature for nine hours. The reaction solution was concentrated under reduced pressure, and the residue was made basic with a saturated sodium bicarbonate solution. Then, chloroform was added to the residue, and the mixture was stirred at room temperature for two hours. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. 10% palladium-carbon (700 mg) was added to a solution of the residue in methanol (200 mL), and the reaction solution was stirred in a hydrogen atmosphere at room temperature for nine hours. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 5.47 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: [CH3:1][N:2]1[C:8]([CH3:10])([CH3:9])[C:6](=[O:7])[NH:5][C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][CH2:19][O:20][C:21](=[CH2:24])[CH2:22]Cl>CN(C=O)C>[CH3:1][N:2]1[C:8]([CH3:10])([CH3:9])[C:6](=[O:7])[N:5]([CH2:24][C:21]([O:20][CH2:19][O:18][CH3:17])=[CH2:22])[C:3]1=[O:4]
Reactant: CN1C(=O)NC(=O)C1(C)C
Reactant: C=C(CCl)OCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(CN1C(=O)N(C)C(C)(C)C1=O)OCOC
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 88.8 %

Procedure:
A mixture of 1,5,5 trimethylhydantoin (7.0 g, 49.2 mmol), powdered potassium carbonate (8.16 g, 59 mmol) and 2-methoxymethyloxy-allyl chloride (7.65 g, 56 mmol) in dry DMF (100 mL) was heated to 100° C. with stirring for 1.5 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated, then partitioned between ethyl acetate and water. The organic extract was washed twice with water, brine, dried and concentrated, then purified via silica gel chromatography eluting with 50% ethyl acetate: hexane to give 10.58 g (89%) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[S:23][CH2:24][C:25]([CH3:28])([CH3:27])[N:26]=4)=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:31]N(C)C=O.IC>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]=[C:22]4[N:26]([CH3:31])[C:25]([CH3:28])([CH3:27])[CH2:24][S:23]4)=[CH:17][CH:16]=3)[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(c3ccc(NC4=NC(C)(C)CS4)cc3)CC2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1ccc(N2CCN(c3ccc(N=C4SCC(C)(C)N4C)cc3)CC2)cc1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A mixture of 37 parts of 4,5-dihydro-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-4,4-dimethyl-2-thiazolamine, 5 parts of a sodium hydride dispersion 50% and 376 parts of N,N-dimethylformamide was stirred for 2 hours at 70° C. After cooling to room temperature, 14.1 parts of iodomethane were added slowly to the reaction mixture. The whole was stirred for 1 hour at room temperature. The reaction mixture was diluted with water. The precipitated product was filtered off, washed with water and 2-propanol and purified by column chromatography (HPLC) over silica gel using a mixture of dichloromethane and methanol (96:4 by volume) as eluent. The first fraction was collected and the eluent was evaporated. The residue was further purified by column chromatography over silica gel using a mixture of dichloromethane and methanol (98:2 by volume). The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 4-[4-(4-methoxyphenyl)-1-piperazinyl]-N-(3,4,4 -trimethyl-2-thiazolidinylidene)-benzenamine (int. 9). The second fraction was collected and boiled in 2-propanol. After cooling, the product was filtered off and dried, yielding 19.5 parts (51.0%) of 4,5-dihydro-N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]-N,4,4-trimethyl-2-thiazolamine; mp. 166.6° C. (int. 10)
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][O:7][Si](C(C)C)(C(C)C)C(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][OH:7]
Reactant: CC(C)[Si](OCCOc1cc(F)ccc1F)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCOc1cc(F)ccc1F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The solution of 1.80 g of [2-(2,5-difluorophenoxy)ethoxy]triisopropylsilane and 23 ml of tetrahydrofuran admixed with 4.37 ml of tetrabutylammonium fluoride solution (1M in tetrahydrofuran) and stirred at 60° C. over 1 hour. The reaction mixture is cooled, poured onto water (70 ml) and extracted with tert-butyl methyl ether (2×70 ml). The organic phases are washed with brine (1×50 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.19 (2:1 EtOAc-heptane); Rt=3.17.
Reaction SMILES: O[C:2]1([CH3:12])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:12][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]=1
Reactant: CC1(O)CCCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1=CCCc2ccccc21
Yield: 139.6 %

Procedure:
A solution of 101.9 g (0.628 mol) of 1-hydroxy-1-methyl-1,2,3,4-tetrahydronaphthalene and 1.3 g of p-toluenesulphonic acid monohydrate in 1.3 liters of toluene was heated to reflux for 3 h with water being collected by means of a Dean Stark trap. The reaction mixture was cooled, washed with water (3×400 ml), then with saturated sodium chloride solution (400 ml), dried (K2CO3) and evaporated in vacuo to leave 126.4 g of brown liquid. This was vacuum distilled to yield 78.6 g (87%) of the title product as a pale yellow oil, b.p. 59°-62° C./1 mm of Hg. NMR δ(CDCl3) 2.06 (3H, m), 2.26 (2H, m), 2.76 (2H, t), 5.86 (1H, m), 7.11-7.27 (4H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:15][C:16](=[O:26])[C:17]3[N:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[C:18]=3[N:19]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:6]=1.[CH3:27][O:28][C:29]([N:31]([CH3:33])[NH2:32])=[O:30]>CN(C=O)C>[CH3:27][O:28][C:29]([N:31]([CH3:33])[NH:32][C:16]([C:17]1[C:18]([NH:19][C:14]([C:4]2[N:5]([C:7]3[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=3)[N:6]=[C:2]([Br:1])[CH:3]=2)=[O:15])=[C:20]([CH3:25])[CH:21]=[C:22]([Cl:24])[N:23]=1)=[O:26])=[O:30]
Reactant: Cc1cc(Cl)nc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Reactant: COC(=O)N(C)N
Solvent: CN(C)C=O
Product: COC(=O)N(C)NC(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
2-[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-6-chloro-8-methyl-pyrido[3,2-d][1,3]oxazin-4-one (140 mg) (example 7, step 4) was dissolved in DMF (10 mL) and N-methyl-hydrazinecarboxylic acid methyl ester (161 mg) was added. The solution was stirred for 3 hours at 80° C., then 12 hours at room temperature and again for 3.5 hours at 80° C. The reaction mixture was quenched was diluted with MTB-ether and washed 4× with water, washed with brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (hexane/ethyl acetate=2:1, then 1.5:1, Rf=0.15 in hexane/ethyl acetate=2:1) to afford 112 mg of compound 8 of the present invention of the formula
Reaction SMILES: Br[C:2]1[C:3]([C:8]2([C:31]#[N:32])[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:18](=[O:25])[N:19]4[C:24]=3[CH:23]=[CH:22][CH:21]=[CH:20]4)[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:33]([B-](F)(F)F)=[CH2:34].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:31]([C:8]1([C:3]2[C:2]([CH:33]=[CH2:34])=[CH:7][CH:6]=[CH:5][N:4]=2)[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:18](=[O:25])[N:19]3[C:24]=2[CH:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)#[N:32]
Reactant: CCOC(=O)c1cc(CN2CCC(C#N)(c3ncccc3Br)CC2)c2ccccn2c1=O
Reactant: C=C[B-](F)(F)F
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=Cc1cccnc1C1(C#N)CCN(Cc2cc(C(=O)OCC)c(=O)n3ccccc23)CC1
Temperature: 160 °C

Procedure:
In a 2-5 mL Emrys™ process vial, the ethyl 1-{[4-(3-bromopyridin-2-yl)-4-cyanopiperidin-1-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylate (50 mg, 0.10 mmol) was dissolved in 0.40 mL of anhydrous THF and treated with potassium vinyltrifluoroborate (40.6 mg, 0.30 mmol) and 1M cesium carbonate solution (0.20 mL, 0.20 mmol). The reaction was purged with a stream of nitrogen, charged with bis(tri-tert-butylphosphine)palladium(0) (5.2 mg, 0.010 mmol), and heated via Emrys Optimizer™ microwave to 160° C. for 10 minutes. Filtration and solvent removal provided material, which was subjected to preparative reverse phase HPLC. Collection of product containing fractions and removal of solvent afforded the ethyl 1-{[4-cyano-4-(3-vinylpyridin-2-yl)piperidin-1-yl]methyl}-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:22]N1C(=O)CCC1=O.CN(C)C=O>O>[Br:22][C:13]1[CH:14]=[CH:15][C:9]2[C:8]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[O:11][C:10]=2[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2oc3ccccc3c2-c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc2c(-c3ccccc3)c(-c3ccccc3)oc2c1
Temperature: 70 °C
Yield: 72 %

Procedure:
43.2 g of 2,3-diphenylbenzo[b]furan, 31.3 g of N-bromosuccinimide, and 400 mL of N,N-dimethylformamide were loaded into a flask, and the mixture was stirred under heat at 70° C. for 8 hours. After having been cooled to room temperature, the reaction solution was poured into 2 L of water. The precipitated crystal was separated by filtration, washed with methanol, water, and methanol in the stated order, and purified by silica gel column chromatography, whereby 40.2 g of a pale yellow crystal were obtained (72% yield).
Reaction SMILES: FC1C(CSC)=C2C(C=CN2)=CC=1.[F:14][C:15]([F:25])([F:24])C1C=CC(C=O)=CC=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([CH:33]([C:44]2[C:52]3[C:47](=[C:48]([CH2:54][S:55][CH3:56])[C:49]([F:53])=[CH:50][CH:51]=3)[NH:46][CH:45]=2)[CH:34]2[C:39](=[O:40])[O:38][C:37]([CH3:42])([CH3:41])[O:36][C:35]2=[O:43])=[CH:29][CH:28]=1>>[CH3:41][C:37]1([CH3:42])[O:38][C:39](=[O:40])[CH:34]([CH:33]([C:44]2[C:52]3[C:47](=[C:48]([CH2:54][S:55][CH3:56])[C:49]([F:53])=[CH:50][CH:51]=3)[NH:46][CH:45]=2)[C:30]2[CH:31]=[CH:32][C:27]([C:15]([F:25])([F:24])[F:14])=[CH:28][CH:29]=2)[C:35](=[O:43])[O:36]1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CSCc1c(F)ccc2c(C(c3ccc(Cl)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: CSCc1c(F)ccc2cc[nH]c12
Product: CSCc1c(F)ccc2c(C(c3ccc(C(F)(F)F)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12

Procedure:
The title compound is prepared starting from 2.00 g (10.24 mmol) of the compound from Example 9A and 1.78 g (10.24 mmol) of 4-(trifluoromethyl)benzaldehyde in analogy to the synthesis of the compound from Example 21A. 3.83 g (75% of theory) of the title compound were obtained.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[S:6][CH:7]=1)=[O:2].[ClH:21].C(OCC)C>ClCCl>[ClH:21].[NH:11]1[CH2:10][CH2:9][CH:8]([C:5]2[S:6][CH:7]=[C:3]([CH:1]=[O:2])[N:4]=2)[CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1csc(C2CCNCC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 4-(4-formyl-2-thiazolyl)-1-piperidinecarboxylate (1.0 g, 3.4 mmol) in dichloromethane (20 mL) was added a solution of hydrogen chloride in diethyl ether (2.0 mL, 15 ml, 30 mmol). The reaction mixture was stirred under nitrogen at room temperature for 2 h and then evaporated under reduced pressure to give 1.2 g of the title compound as a white solid.
Reaction SMILES: Cl.[C:2]([CH2:4][C:5]([OH:7])=O)#[N:3].[CH2:8]([C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[CH2:8]([C@H:15]1[CH2:19][N:18]([C:5](=[O:7])[CH2:4][C:2]#[N:3])[C@H:17]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)=[CH:25][CH:24]=2)=[O:21])[CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: N#CCC(=O)O
Agent: Cl
Product: N#CCC(=O)N1C[C@H](Cc2ccccc2)C[C@H]1C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 23.3 %

Procedure:
Proceeding as in Example 1, but substituting 2-cyanoacetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 129, (2S,4R)-4-benzyl-1-(2-cyanoacetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (6.4 mg, 23.3%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 9.99 (s, 1H), 7.55-7.60 (m, 2H), 7.29-7.32 (m, 2H), 7.17-7.23 (m, 5H), 6.95-7.02 (m, 4H), 4.49 (m, 1H), 4.00 (m, 2H), 3.64 (m, 1H), 3.22 (m, 2H), 3.67 (m, 3H), 1.93 (m, 2H). MS (EI) for C27H24FN3O3. found 458.5 (MH+).