Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20]C)=[O:19])[CH:13]=2)[C:10]([C:22]#[N:23])=[C:9]([CH3:24])[NH:8][C:7]1=[O:25])=[O:5])[CH3:2].CO.[OH-].[Li+].Cl>O>[CH2:1]([NH:3][C:4]([N:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:20])=[O:19])[CH:13]=2)[C:10]([C:22]#[N:23])=[C:9]([CH3:24])[NH:8][C:7]1=[O:25])=[O:5])[CH3:2]
Reactant: CCNC(=O)N1C(=O)NC(C)=C(C#N)C1c1cccc(C(=O)OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCNC(=O)N1C(=O)NC(C)=C(C#N)C1c1cccc(C(=O)O)c1
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a mixture of 6-(3-carbomethoxyphenyl)-5-cyano-3,6-dihydro-4-methyl-2-oxo-1-(2H)-pyrimidinecarboxylic acid, 1-ethyl amide (0.34 g, 1.0 mmol), MeOH (9 mL) and water (3 mL) at 0° C. was added lithium hydroxide (0.84 g, 20.0 mmol). The reaction mixture was stirred for 1 h, acidified to pH 2 with 1 N HCl and extracted with EtOAc. The extract was dried (MgSO4) and concentrated in vacuo to give 6-(3-carboxyphenyl)-5-cyano-3,6-dihydro-4-methyl-2-oxo-1-(2H)-pyrimidinecarboxylic acid, 1-ethyl amide as a colorless solid (0.30 g, 92%): 1H NMR (MeOH-d4, 400 MHz) δ 8.98 (s, 1H), 7.89 (m, 2H), 7.46 (d, 1H, J=7.5 Hz), 7.42 (t, 1H, J=7.5 Hz), 6.12 (s, 1H), 3.16 (m, 2H), 2.06 (s, 3H), 1.03 (t, 3H, J=7.0 Hz).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.O>CS(C)=O>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:31][CH:30]=1
Reactant: COc1ccc(CN)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CNCC2COc3ccc4c(c3O2)CC(=O)N4)cc1
Temperature: 85 °C
Yield: 56.3 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.00 g, 2.66 mmole) and 4-methoxybenzylamine (1,40 ml, 10.7 mmole) were combined in 10 ml of dry DMSO and heated to 85° C. for 3.5 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 35% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 2% methanol/CH2Cl2 as eluant. The free base of the title compound (0.51 g, 64%) was obtained as an oil upon concentration in vacuum. The product was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.44 g of the (S) enantiomer of the title compound as an off-white solid fumarate, one-quarter hydrate, m.p. 205°-205.5° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:4]([O:6][CH3:7])=[O:5].CCN(C(C)C)C(C)C.[N+:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35])([O-:27])=[O:26]>C(Cl)Cl>[C:12]([O:11][C:9]([NH:8][C@@H:3]([CH2:2][NH:1][S:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[N+:25]([O-:27])=[O:26])(=[O:35])=[O:36])[C:4]([O:6][CH3:7])=[O:5])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
To a mixture of methyl 3-amino-2(S)-(tert-butoxycarbonylamino)propanoate ii (1.6 g, 7.3 mmoL) in DCM (50 mL) was added DIPEA (1.64 mL, 9.4 mmoL) and 2-nitrobenzene sulfonyl chloride (1.62 g, 7.3 mmoL). The mixture was stirred at rt for 2 h. It was then concentrated, dissolved in ethyl acetate, which was then washed with sat. sodium bicarbonate, brine and dried over magnesium sulfate. It was then filtered, concentrated to yield 2.9 g (98%) of methyl 2(S)-(tert-butoxycarbonylamino)-3-(2-nitrophenylsulfonamido)propanoate iii as a yellow foam. 1H NMR (CD3OD, 300 MHz) δ 1.41 (s, 9 H), 3.36-3.51 (m, 2 H), 3.71 (s, 3 H), 4.22 (m, 1 H), 7.80-7.90 (m, 3 H), 8.07-8.10 (m, 1 H).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9].[OH-].[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:12]([O:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][O:4][C:3]=1[CH3:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1occc(=O)c1O
Reactant: ClCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1occc(=O)c1OCc1ccccc1
Yield: 73.6 %

Procedure:
3-Hydroxy-2-methyl-4-pyrone (22.2 g) in methanol (225 ml) is added to aqueous sodium hydroxide (25 ml H2O containing 7.5 g NaOH). Benzyl chloride (25.5 g) is added and the mixture is refluxed for 6 hours and is then allowed to cool overnight. The bulk of the methanol is removed under vacuum and the residue is treated with water (50 ml). The mixture is extracted into dichloromethane (3×25 ml). The extracts are combined, washed with 5% w/v NaOH (2×25 ml), then water (2×25 ml) and dried over magnesium sulphate. Evaporation of the solvent gives crude 3-benzyloxy-2-methyl-4-pyrone (35 g, 92%) which is purified by distillation in nitrogen under reduced pressure to yield a colourless oil (28 g) of b.p. 148° C./0.2 mm.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH:12]([CH3:15])[CH2:13][OH:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]([CH3:15])[CH:13]=[O:14])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(CO)Cc1ccc(C(C)(C)C)cc1
Solvent: O
Product: CC(C=O)Cc1ccc(C(C)(C)C)cc1
Reaction time: 0 h
Yield: 71 %

Procedure:
Using a similar method to Example 1, a mixture of 300 parts of 3-(p-tert.-butylphenyl)-2-methyl-1-propanol and 200 parts of water with 250 parts of air and 250 parts of nitrogen is passed per hour over the catalyst at 560° C. and 1.1 bar. The residence time is 0.025 second and the throughput is 0.42 tonne/m2.h. 211 parts of 3-(p-tert.-butylphenyl)-2-methylpropanal (in the form of a 77 percent strength by weight organic phase) are obtained per hour, corresponding to a yield of 71% of theory. The conversion is 95 percent and the space-time yield is 10 grams of 3-(p-tert.-butylphenyl)-2-methylpropanal per cm3 of catalyst volume per hour.
Reaction SMILES: [CH3:1][O:2][C:3]([C@:5]1([NH:15][S:16]([C:19]2[S:23][C:22]([NH2:24])=[N:21][CH:20]=2)(=[O:18])=[O:17])[CH2:7][C@:6]1([CH3:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[Br:25][CH2:26][C:27]([CH2:29]Br)=O>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@:5]1([NH:15][S:16]([C:19]2[S:23][C:22]3=[N:24][C:27]([CH2:26][Br:25])=[CH:29][N:21]3[CH:20]=2)(=[O:18])=[O:17])[CH2:7][C@:6]1([CH3:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)[C@]1(NS(=O)(=O)c2cnc(N)s2)C[C@]1(C)c1ccccc1
Reactant: O=C(CBr)CBr
Solvent: CCOC(C)=O
Product: COC(=O)[C@]1(NS(=O)(=O)c2cn3cc(CBr)nc3s2)C[C@]1(C)c1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 24.2 %

Procedure:
To a solution of (1S,2R)-1-(2-amino-thiazol-5-sulfonylamino)-2-methyl-2-phenyl-cyclopropanecarboxylic acid methyl ester (0.21 g, 0.58 mmol) in ethyl acetate (6.4 mL) was added 1,3-dibromoacetone (0.18 mL, 0.87 mmol), and the mixture was stirred at 60° C. for 18 hours. After cooling to room temperature, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over sodium sulfate. After filtration and evaporation, the obtained residue was separated and purified by silica gel chromatography (hexane:ethyl acetate=1:1) to give the title compound (68 mg, yield 24%) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].Br[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]#[N:10]>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH2:1]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]#[N:10])[CH3:2]
Reactant: CC[Mg]Br
Reactant: N#Cc1ccc(OCc2ccccc2)c(Br)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: CCc1cc(C#N)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 1M solution of ethyl magnesium bromide (2 mL, 1.5 equiv), THF (10 mL) was added and the reaction mixture was cooled down to 0° C. A solution of 0.5 M in THF of zinc dichloride (4 mL, 1.5 equiv) was added slowly and the reaction mixture was stirred for 30 min at the same temperature. Pd(tBu3P)2 (102 mg, 0.1 equiv) was added followed by the addition of a solution of 3-bromo-4-[(phenylmethyl)oxy]benzonitrile (Intermediate 110, 576 mg) in THF and the reaction was allowed to reach room temperature. After stirring 30 minutes, some additional Pd(tBu3P)2 was added (51 mg, 0.05 equiv), then 30 min stirring, then third addition of Pd(tBu3P)2 (51 mg, 0.05 equiv) and stirring 30 min. The reaction mixture was quenched with an aqueous saturated solution of NH4Cl (100 mL) and extracted 3 times with ethyl acetate (3×150 mL). The gathered organic phases were filtrated on celite, dried over sodium sulphate. The residue obtained was purified by chromatography on silica gel (Companion system, 40 g Si cartridge) using as eluent a gradient cyclohexane/ethyl acetate 100:0, then 100:0 to 90:10. Evaporation afforded the title compound (336 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH:11]([N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>O1CCCC1>[N:18]1([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[CH:10]=[C:2]3[C:3]([C:4](=[O:5])[NH:6][C:23](=[O:24])[NH:1]3)=[CH:7][CH:8]=2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)c1ccc(C(c2ccccc2)n2ccnc2)cc1N
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)c2ccc(C(c3ccccc3)n3ccnc3)cc2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a stirred solution of 4.6 parts of 2-amino-4-[(1H-imidazol-1-yl)phenylmethyl]benzamide in 90 parts of tetrahydrofuran were added 3.52 parts of 1,1'-carbonylbis[1H-imidazole]. The mixture was stirred first overnight at room temperature and then for 48 hours at reflux temperature. The solution was concentrated under reduced pressure and the concentrate was treated with water. The product was extracted with dichloromethane. A white product was precipitated in the dichloromethane layer. This product was filtered off and crystallized from hot acetonitrile. The product was filtered off, washed with acetonitrile and 2,2'-oxybispropane and dried in vacuo at 60°-70° C., yielding 1.77 parts (35.4%) of 7-[(1H-imidazol-1-yl)phenylmethyl]-2,4(1H,3H)-quinazolinedione; mp. 287.2° C. (comp. 29).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][C:3]=1[NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:29][C:30]1[N:35]=[C:34]([CH3:36])[CH:33]=[CH:32][N:31]=1>C1COCC1>[Cl:29][C:30]1[N:35]=[C:34]([CH2:36][C:6]([C:5]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]([NH:12][C:13](=[O:14])[O:15][CH2:16][CH:17]=[CH2:18])[CH:4]=2)=[O:8])[CH:33]=[CH:32][N:31]=1
Reactant: C=CCOC(=O)Nc1cc(C(=O)OC)ccc1F
Reactant: Cc1ccnc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOC(=O)Nc1cc(C(=O)Cc2ccnc(Cl)n2)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.2 %

Procedure:
To a solution of methyl 4-fluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (60 g, 237 mmol) in dry THF (500 mL) at −10° C., LiHMDS (1M in THF, 735 mmol, 735 mL) was added dropwise and the solution was allowed to stir for 1 h at 0° C. A solution of 2-chloro-4-methylpyrimidine (30.5 g, 237 mmol) in THF (50 mL) was then added dropwise to the solution of ester and base at 0° C. over 20 min. The solution was allowed to stir 1 h at rt. TLC showed the reaction was complete. The reaction was quenched by addition of the saturated aqueous NH4Cl (200 mL) at 0° C. The reaction mixture was extracted with EtOAc (500 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column on silica gel, eluting with DCM. This solution was evaporated to obtain a solid. The orange solid was triturated with a small amount of EtOAc and filtered, rinsing with diethyl ether to give the title compound (69.8 g, 81.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.66 (br, 0.55H), 8.79-8.83 (m, 0.36H), 8.53-8.61 (m, 0.91H), 8.33-8.37 (m, 0.59H), 7.65-7.72 (m, 0.40H), 7.50-7.57 (m, 0.59H), 7.26-7.30 (m, 0.35H), 7.08-7.19 (m, 1H), 6.92-7.12 (br, 1H), 6.87-6.92 (m, 0.64H), 5.90-6.21 (m, 1.5H), 5.39 (d, J=18.1 Hz, 1H), 5.29 (d, J=10.4 Hz, 1H), 4.70 (d, J=5.5 Hz, 2H), 4.44 (s, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1B(O)O.Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:15]1[CH:16]=[C:17]([NH2:18])[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(Br)c1
Reactant: OB(O)c1ccc2ccccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1cccc(-c2ccc3ccccc3c2)c1
Temperature: 25 °C
Yield: 63 %

Procedure:
Naphthalene-2-boronic acid (0.119 g, 0.693 mmol) and 3-bromoaniline (0.05 mL, 0.462 mmol) in DME (2 mL) were combined in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.485 mL, 0.970 mmol) and Pd(PPh3)4 (0.017 g, 0.014 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in H2O and extracted with CH2Cl2. The organic phase was dried over MgSO4 and concentrated under vacuum. The crude product was purified by silica column chromatography (5-20% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.063 g in 63% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[N:7]([C@H:9]([C:11](=[O:39])[NH:12][C@@H:13]1[C:19](=[O:20])[N:18]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=3)[CH:25]=[CH:24][C:23]=2[O:33][CH3:34])[C:17]2[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=2[NH:15][CH2:14]1)[CH3:10])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:41][O:42][C:43](=[O:53])[C:44]1[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=1.O=P(Cl)(Cl)Cl>N1C=CC=CC=1>[CH3:41][O:42][C:43](=[O:53])[C:44]1[CH:52]=[CH:51][C:47]([C:48]([N:15]2[CH2:14][C@H:13]([NH:12][C:11](=[O:39])[C@@H:9]([N:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:40])[CH3:8])[CH3:10])[C:19](=[O:20])[N:18]([CH2:21][C:22]3[C:31]4[C:26](=[CH:27][C:28]([Br:32])=[CH:29][CH:30]=4)[CH:25]=[CH:24][C:23]=3[O:33][CH3:34])[C:17]3[CH:35]=[CH:36][CH:37]=[CH:38][C:16]2=3)=[O:49])=[CH:46][CH:45]=1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc2cc(Br)ccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)CNc2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)N2C[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N(Cc3c(OC)ccc4cc(Br)ccc34)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of {(S)-1-[(S)-1-(6-bromo-2-methoxy-naphthalen-1-ylmethyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (Intermediate 11) (1.5 g, 2.455 mmol) in pyridine (20 mL) at 0° C. was added terephthalic acid monomethyl ester (884 mg, 4.91 mmol). The mixture was stirred for 10 min at 0° C. and POCl3 (0.472 mL, 5.155 mmol) was slowly added, the cooling bath removed and the mixture stirred at RT. After 16 h the mixture was evaporated and the residue diluted with ice water and extracted with ethyl acetate. The combined extracts were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to give the title compound. The sequence was repeated to provide a total of 4.2 g of the title compound from as an off white solid. LC-MS: 773 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH:6]=C.[O:23]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[C:4]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:5][CH:6]=[O:23]
Reactant: O=[O+][O-]
Reactant: C=CCC(NC(=O)OC(C)(C)C)(C(=O)OC)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(CC=O)(NC(=O)OC(C)(C)C)c1ccccc1
Yield: 35.8 %

Procedure:
The solution of compound 12 (30.5 g, 0.1 mol) in CH2Cl2 (300 mL) at −78° C. was bubbled with O3 until the solution turned gray-blue. Then PPh3 (40 g, 0.15 mol) was added slowly to quench the reaction. After concentration, the residue was purified by column chromatography on silica gel (PE: EA=10:1) to give compound 13 (11 g, 35.8%). 1H NMR (400 MHz, CDCl3) δ 1.37 (s, 9 H), 3.57-3.61 (d, 1 H, J=18 Hz), 3.71 (s, 3H), 3.98-4.12 (m, 1 H), 6.16 (bs, 1 H), 7.31-7.43 (m, 5 H), 9.74 (s, 1H).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:19])[CH:13]=[C:14]([NH2:18])[O:15][CH2:16][CH3:17])[CH3:10]>C(O)(C)C>[CH2:9]([O:11][C:12]([C:13]1[CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:13]([C:12]([O:11][CH2:9][CH3:10])=[O:19])[C:14]([O:15][CH2:16][CH3:17])=[N:18][C:14]=1[NH2:18])=[O:19])[CH3:10]
Reactant: CCOC(=O)C=C(N)OCC
Reactant: O=Cc1ccccc1
Solvent: CC(C)O
Product: CCOC(=O)C1=C(N)N=C(OCC)C(C(=O)OCC)C1c1ccccc1

Procedure:
Upon boiling a solution of 5.3 g of benzaldehyde and 15.9 g of 3-amino-3-ethoxyacrylic acid ethyl ester in 30 ml of alcohol for 12 hours, 2-amino-4-phenyl-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 119°C (isopropanol) is obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[CH:15][C:14]([N+:18]([O-])=O)=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:21])=[N:12]3)[CH2:3][CH2:2]1.[OH-].[Na+]>C(O)(=O)C.Cl.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]([F:17])=[CH:15][C:14]([NH2:18])=[C:13]3[C:8]=2[CH:9]=[CH:10][C:11]([CH3:21])=[N:12]3)[CH2:3][CH2:2]1
Reactant: Cc1ccc2c(N3CCOCC3)c(F)cc([N+](=O)[O-])c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc2c(N3CCOCC3)c(F)cc(N)c2n1
Yield: 80.5 %

Procedure:
Stannous chloride dihydrate (5.7 g) was added to a solution of 1.8 g of 5-morpholino-6-fluoro-8-nitroquinaldine in 30 ml of acetic acid and 20 ml of concentrated hydrochloric acid was added dropwise to the mixture with stirring. After completion of addition the mixture was stirred at room temperature for 1 hour, diluted with water and rendered alkaline with an aqueous sodium hydroxide solution to form precipitations, which then were extracted with dichloromethane, after drying over magnesium sulfate the solvent was distilled off to give 1.30 g of 5-morpholino-6-fluoro-8-aminoquinaldine.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:3]=1[C:4](/[N:6]=[C:7]1/[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)[N:9]([CH3:16])[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:11]/1)=[O:5].[CH:31](B(OCCCC)OCCCC)=[CH2:32].[F-].[Cs+]>CO.COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([C:10]1[N:9]([CH3:16])[N:8]([CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)/[C:7](=[N:6]/[C:4](=[O:5])[C:3]2[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:2]=2[CH:31]=[CH2:32])/[CH:11]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2Br)n1C[C@H]1CCCO1
Reactant: C=CB(OCCCC)OCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: C=Cc1ccc(C(F)(F)F)cc1C(=O)/N=c1\cc(C(C)(C)C)n(C)n1C[C@H]1CCCO1
Temperature: 130 °C
Yield: 86 %

Procedure:
To the mixture of Example 88, tetrakis(triphenylphosphine)palladium (0.231 g, 0.200 mmol), dibutyl vinylboronate (0.863 ml, 4.00 mmol) and cesium fluoride (1.82 g, 12.0 mmol) in MeOH (1 mL) and DME (2 mL) was added tetrakis(triphenylphosphine)palladium (0.231 g, 0.200 mmol). The mixture was heated in a sealed tube at 130° C. for 20 min. After cooling to ambient temperature, the solvent was removed under reduced pressure and the residue was diluted with EtOAc and water. The organic layer was washed with saturated aqueous NaHCO3 and brine and then concentrated. Purification by column chromatography (silica gel, 5-30% gradient of 9:1 MeOH/Et3N in EtOAC) provided the title compound 1.5 g (86% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.39 (s, 9H) 1.62-1.95 (m, 4H) 3.59-3.68 (m, 1H) 3.70-3.81 (m, J=7.14, 7.14 Hz, 1H) 3.90 (s, 3H) 4.11-4.22 (m, J=6.15, 4.16 Hz, 1H) 4.26-4.46 (m, 2H) 5.31 (d, J=12.29 Hz, 1H) 5.76 (d, J=17.85 Hz, 1H) 6.85 (s, 1H) 7.54-7.68 (m, 2H) 7.76 (d, J=8.33 Hz, 1H) 8.04 (d, J=1.59 Hz, 1H); MS (ESI) m/z 436 (M+H)+, 434 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.O[C@@H:13]1[CH2:18][C@H:17]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:29])[C:16]([CH3:31])([CH3:30])[CH2:15][CH2:14]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[CH3:30][C:16]1([CH3:31])[CH2:15][CH2:14][C@@H:13]([O:11][C:10]2[C:2]([CH3:1])=[C:3]3[C:7](=[CH:8][CH:9]=2)[NH:6][N:5]=[CH:4]3)[CH2:18][C@@H:17]1[N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29]
Reactant: CC1(C)CC[C@H](O)C[C@@H]1N1C(=O)c2ccccc2C1=O
Reactant: Cc1c(O)ccc2[nH]ncc12
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1c(O[C@@H]2CCC(C)(C)[C@@H](N3C(=O)c4ccccc4C3=O)C2)ccc2[nH]ncc12
Temperature: 100 °C
Reaction time: 7 h
Yield: 59.5 %

Procedure:
To a solution of the 4-methyl-1H-indazol-5-ol (500 mg, 1.83 mmol) obtained in Example 402 in toluene (8 ml) were added cis-2-(5-hydroxy-2,2-dimethylcyclohexyl)-1H-isoindole-1,3(2H)-dione (400 mg, 1.5 mmol) and cyanomethylenetri-n-butylphosphorane (494 mg, 2.1 mmol) at room temperature, and the resulting mixture was heated to 100° C. After stirring for 7 hours, the reaction solution was concentrated under reduced pressure and the resulting residue was dissolved in chloroform and washed with a 1M-aqueous sodium hydroxide solution. Extraction with chloroform was carried out again and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain trans-2-{2,2-dimethyl-5-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl}-1H-isoindole-1,3(2H)-dione (360 mg, 61%, containing about 10% of cis isomer).