Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[CH2:9]([O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19](=[O:29])[C:20]2[CH:28]=[CH:27][C:23]([C:24]([O:1][C:2]3[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:7])=[CH:17][CH:18]=3)=[O:25])=[CH:22][CH:21]=2)=[CH:18][CH:17]=1)=[O:7])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCOC(=O)c1ccc(O)cc1
Product: CCCCCCCCOC(=O)c1ccc(OC(=O)c2ccc(C(=O)Oc3ccc(C(=O)OCCCCCCCC)cc3)cc2)cc1

Procedure:
Octyl p-hydroxybenzoate and terephthalic dichloride are allowed to react and treated in a similar procedure to Example 4. The residue obtained is recrystallized from ethyl acetate-chloroform (1:1) to give di(p-octyloxycarbonylphenyl)terephthalate, m.p. 108°-110° C., as white crystals.
Reaction SMILES: C([O:4][C:5]([CH3:17])([CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)(=O)C.[Li+].[OH-]>CO>[CH3:17][C:5]([OH:4])([CH3:16])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1
Reactant: CC(=O)OC(C)(C)Cc1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 32.5 %

Procedure:
To a solution of 1,1-dimethyl-2-(4-nitrophenyl)ethyl acetate (52 mmol) in MeOH (50 ml) was added 4N—LiOH (40 ml) and the mixture was stirred at 50° C. for 2 h. After the solvent was removed, this mixture was diluted with water and extracted with EtOAc (4×50 ml). The organic layer was washed with brine, dried (MgSO4) and concentrated. This crude was purified by SiO2 column chromatography developing with hexane/ethyl acetate (5/1) to give the title compound as yellow oil (3.3 g, 33%).
Reaction SMILES: [C:1]1(CCCC(NN)=O)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.OC1O[C@H](CO)[C@@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O>CS(C)=O>[CH:8]1[C:7]2[C:16]3=[C:15]4[C:4](=[CH:5][CH:6]=2)[CH:3]=[CH:2][CH:1]=[C:14]4[CH:13]=[CH:12][C:11]3=[CH:10][CH:9]=1
Reactant: NNC(=O)CCCc1ccc2ccc3cccc4ccc1c2c34
Agent: OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O
Solvent: CS(C)=O
Product: c1cc2ccc3cccc4ccc(c1)c2c34
Temperature: 90 °C

Procedure:
10 μl of a solution containing 400 nmol of 1-pyrenebutanoic acid, hydrazide (Molecular Probes) in DMSO was added to 50 nmol of lactose which had been dried adequately, and lactose was fully dissolved by sonication. 1 μl of acetic acid was added thereto and the mixture was stirred adequately. The reaction mixture was then heated at 90° C. for 1 hour. After the reaction mixture was dried using a centrifugation concentrator, 10 μl of a solution containing 2.5 M borane-dimethylamine complex and 30% acetic acid in DMSO was added to the residue, and the residue was fully dissolved by sonication. The mixture was then heated at 80° C. for 1 hour. The reaction mixture was dried using a centrifugation concentrator. The residue was re-dissolved in 50% acetonitrile and purified using normal phase high performance liquid chromatography. The molecular weight of the purified pyrene-labeled lactose was determined using a triple-quadrupole ion-spray mass-spectrometer API-300. As a result, a positive molecular ion (629.3) was observed.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[NH2:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.C(Cl)Cl>[F:23][C:2]([F:24])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:26][NH:25][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNc1ccccn1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNc1ccccn1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
A 500-mL, 3-necked, round-bottomed flask was charged with a suspension of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (10 g, 1.0 eq.) in 1:1 CH2Cl2:AcOEt (200 mL). 2-Hydrazinopyridine (3.11 g) was added at −40° C. T3P (50% in ethylacetate) (21.75 g) was added dropwise followed by DIPEA (7.36 g) and the reaction mixture was stirred for 30 min at −40° C. before being concentrated under reduced pressure (35° C., 20 mm Hg) to afford a crude brown oil that was purified by column chromatography (the compound eluted with 1.3% MeOH in CH2Cl2). Fractions containing desired compound were combined to afford 6.0 g (yield: 48%) (Z)-3-(3-(3,5-bis-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyridin-2-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ, 10.41 (s, 1H), 9.66 (s, 1H), 8.59 (s, 1H), 8.53 (s, 2H), 8.28 (s, 1H), 8.06-8.08 (d, J=5.2 Hz, 1H), 7.48-7.53 (m, 1H), 7.49-7.52 (d, J=10.4, 1H), 6.71-6.75 (m, 1H), 6.66-6.68 (d, J=8.4 Hz, 1H), 6.07-6.09 (d, J=10.4, 1H). LCMS for C18H12F6N6O [M+H]+ predicted: 443.33, found: 443.44 (RT 2.45 min, purity: 100%).
Reaction SMILES: C[O:2][C:3]([CH2:5][S:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=O.CC(C[AlH]CC(C)C)C.O>C(OCC)C>[CH:3]([CH2:5][S:6][S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:2]
Reactant: CCCCCCCCSSCC(=O)OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCOCC
Solvent: O
Product: CCCCCCCCSSCC=O
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 97 %

Procedure:
MeOC(O)CH2SSC8H17 (1.85 g, 7.39 mmol) was dissolved in dry diethyl ether (40 mL) in a N2 purged flask. The solution was cooled to −78° C., and DIBAL-H (8.87 mL, 1.0 M in cyclohexane, 8.87 mmol) was added to the cold solution dropwise via syringe. The reaction was stirred at −78° C. for 1 h 45 min, after which H2O (5 mL) was added, the cold bath removed and the solution was allowed to slowly warm to room temperature. Additional diethyl ether (60 mL) was added, and the organic phase was washed with 1N HCl (3×100 mL), dried over MgSO4, and concentrated to yield HC(O)CH2SSC8H17 (1.58 g, 97.02%) as a milky oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.S(Cl)(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:2]2[CH:10]=[CH:9][CH:5]=[CH:4][CH:3]=2)=[O:8])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(c1ccccc1)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 4-Bromo-2-nitro-benzoic acid (1.33 g, 0.0054 mol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The thionyl chloride was then distilled off and benzene (20 mL) and aluminum trichloride (0.676 g, 0.0051 mol) was added to the reaction mixture and the reaction was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([Cl:49])[CH:45]=[CH:46][CH:47]=2)[NH:42][CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Si]([O:69][CH2:70][CH2:71][C:72]1[CH:79]=[CH:78][C:75]([CH2:76]Br)=[CH:74][CH:73]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.O>CN(C)C=O.O1CCCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:11][C@H:10]1[C:40]1[C:48]2[C:43](=[C:44]([Cl:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:76][C:75]2[CH:78]=[CH:79][C:72]([CH2:71][CH2:70][OH:69])=[CH:73][CH:74]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c[nH]c12
Reactant: CC(C)(C)[Si](OCCc1ccc(CBr)cc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OCCc1ccc(Cn2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3cccc(Cl)c32)cc1
Reaction time: 0.25 h
Yield: 86.9 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-7-chloro-1H-indole (0.48 g) in N,N-dimethylformamide (5 mL) was added 55% sodium hydride (37 mg) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added a solution of 4-[2-(tert-butyldiphenylsilyloxy)ethyl]benzyl bromide (0.42 g) in tetra hydrofuran (2 mL) at the same temperature, and the mixture was stirred at the same temperature for 15 minutes, and stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in tetra hydrofuran (5 mL). To the solution was added tetra(n-butyl)ammonium fluoride (1.0 mol/L tetra hydrofuran solution, 1.07 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was washed with a mixed solvent of n-hexane and ethyl acetate (5/1), and dried under reduced pressure to give the title compound (0.50 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:24]2[S:28][C:27]([C:29]3([O:33]COC)[CH2:32][CH2:31][CH2:30]3)=[N:26][CH:25]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.ClC1C(C2SC(C3(OCOC)CCC3)=NC=2)=C2C=C(C3N=C(C4CCCN(C(OC(C)(C)C)=O)C4)ON=3)NC2=NC=1>>[Cl:1][C:2]1[C:3]([C:24]2[S:28][C:27]([C:29]3([OH:33])[CH2:30][CH2:31][CH2:32]3)=[N:26][CH:25]=2)=[C:4]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(NC(=O)CN(C)C)cc5)cc34)s2)CCC1
Agent: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5noc(C6CCCN(C(=O)OC(C)(C)C)C6)n5)cc34)s2)CCC1
Product: CN(C)CC(=O)Nc1ccc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc3[nH]2)cc1

Procedure:
The title compound was prepared as described in Example 22E, substituting N-(4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-2-(dimethylamino)acetamide (Example 23C) for 1 tert-butyl 3-(3-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (Example 22D). 1H NMR (500 MHz, DMSO-d6) ppm 12.49 (s, 1H) 9.88 (s, 1H) 8.31 (s, 1H) 8.25 (s, 1H) 7.95 (d, 2H) 7.78 (d, 2H) 6.99 (s, 1H) 6.68 (s, 1H) 3.09 (s, 2H) 2.63 (m, 2H) 2.40 (m, 2H) 2.29 (s, 6H) 1.99 (m, 2H); MS ESI(+) m/z 482.0 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9]([NH2:11])=[NH:10])=[CH:5][CH:4]=1.[F:14][C:15]([F:24])([F:23])[C:16]#[C:17][C:18](OCC)=[O:19].[OH-].[K+]>C(O)C>[OH:19][C:18]1[CH:17]=[C:16]([C:15]([F:24])([F:23])[F:14])[N:11]=[C:9]([C:6]2[CH:7]=[N:8][C:3]([C:2]([F:12])([F:1])[F:13])=[CH:4][CH:5]=2)[N:10]=1
Reactant: N=C(N)c1ccc(C(F)(F)F)nc1
Reactant: CCOC(=O)C#CC(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Oc1cc(C(F)(F)F)nc(-c2ccc(C(F)(F)F)nc2)n1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
A mixture of 6-(trifluoromethyl)pyridine-3-amidine (1 g, 5.26 mmol) and ethyl 4,4,4-trifluoro-2-butynoate (1.1 ml, 7.89 mmol) in ethanol (100 ml) was stirred at 0° C. for 20 min. The temperature of the mixture was raised to 60° C. and was let to stir at this temperature for 30 min. Then aqueous KOH (0.86 g in 20 ml water) was added dropwise. The mixture was refluxed for 4 h. The mixture was cooled to room temperature, rotary evaporated and isolated as a white solid (1.5 g, 94%). 1H NMR (CDCl3): 9.72 (d, J=2.4 Hz, 1H), 8.87 (dd, J=2.1, 8.7 Hz, 1H), 7.93 (d, J=8.1 Hz, 1H), 7.00 (s, 1H).
Reaction SMILES: BrC1C=C(F)C=C2C=1O[C@@H]([CH2:12][O:13][S:14]([C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=1)(=[O:16])=[O:15])C=C2.COC1C=CC=CC=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([O:13][CH3:12])(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COS(=O)(=O)c1ccc(C)cc1

Procedure:
To a solution of (R)-(8-bromo-6-fluoro-2H-chromen-2-yl)methyl-4-methylbenzenesulfonate (0.40 g, 0.97 mmol) and 2-methoxyphenylboronic acid (0.44 g, 2.9 mmol) in dioxane (10 mL) was added potassium carbonate (0.33 g, 2.4 mmol), dichlorobis(tri-o-tolylphosphine)palladium (II) (23 mg, 0.029 mmol) and water (2 mL). The reaction mixture was heated to reflux for 2 hours. The cooled reaction mixture was then partitioned between ethyl acetate (100 mL) and 2.0 M aqueous sodium hydroxide (100 mL). The organic layer was separated, washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash chromatography using a solvent gradient of 0 to 20% ethyl acetate in hexane gave 0.46 g (100%) of(R)-6-fluoro-8-(2-methoxyphenyl)-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. MS (ES) m/z 441.0 ([M+H]+).
Reaction SMILES: [P:1]([OH:32])([OH:31])([O:3][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[N:19][C:20]([NH:23][C:24]4[N:28]([CH3:29])[N:27]=[N:26][N:25]=4)=[CH:21][CH:22]=3)=[C:13]([F:30])[CH:12]=2)[CH2:6]1)=[O:2].C[O-].[Na+:35]>CO>[Na+:35].[Na+:35].[P:1]([O-:31])([O-:32])([O:3][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[N:19][C:20]([NH:23][C:24]4[N:28]([CH3:29])[N:27]=[N:26][N:25]=4)=[CH:21][CH:22]=3)=[C:13]([F:30])[CH:12]=2)[CH2:6]1)=[O:2]
Reactant: Cn1nnnc1Nc1ccc(-c2ccc(N3C[C@H](COP(=O)(O)O)OC3=O)cc2F)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cn1nnnc1Nc1ccc(-c2ccc(N3C[C@H](COP(=O)([O-])[O-])OC3=O)cc2F)cn1
Yield: 71.6 %

Procedure:
(R)-(3-(3-fluoro-4-(6-((1-methyl-1H-tetrazol-5-yl)amino)pyridin-3-yl)phenyl)-2-oxooxazolidin-5-yl)methyl dihydrogen phosphate (140 mg, 0.3 mmol) was dissolved in 15 mL methanol. Sodium methoxide (48 mg, 0.9 mmol) was added, and reacted at room temperature for 12 h. After filtration 110 mg of product was obtained, at a yield of 71.6%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([C:37]([O:39]CC)=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.[OH-].[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([C:37]([OH:39])=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Br)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Br)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 70 °C
Yield: 64.1 %

Procedure:
To a mixture of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (120 mg, 0.19 mmol) in methanol (4 mL) was added a solution of NaOH (24 mg, 0.6 mmol) in water (2 mL). The mixture was heated at 70° C. for 3 h, evaporated to remove most of methanol, cooled to room temperature, and acidified to “pH” 1 with aqueous HCl solution. The precipitate was collected and dried to give product as a white solid (75 mg). m/z (M+H)+: 615
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([NH:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][CH2:24][CH3:25])[C:20]([C:26]([F:29])([F:28])[F:27])=[CH:19][N:18]=1>CC(O)(C)C>[CH2:24]([NH:23][C:21]1[C:20]([C:26]([F:28])([F:29])[F:27])=[CH:19][N:18]=[C:17]([NH:1][C:2]2[C:7]3[O:8][CH2:9][CH2:10][O:11][C:6]=3[C:5]([C:12]([NH:14][CH3:15])=[O:13])=[CH:4][CH:3]=2)[N:22]=1)[CH3:25]
Reactant: CNC(=O)c1ccc(N)c2c1OCCO2
Reactant: CCNc1nc(Cl)ncc1C(F)(F)F
Solvent: CC(C)(C)O
Product: CCNc1nc(Nc2ccc(C(=O)NC)c3c2OCCO3)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 21.5 %

Procedure:
A microwave vial equipped with a magnetic stirrer was charged with 8-amino-N-methyl-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxamide (50 mg, 0.18 mmol), 2-chloro-N-ethyl-5-(trifluoromethyl)pyrimidin-4-amine (40 mg, 0.18 mmol), and t-BuOH (1.0 mL). The mixture was heated at 100° C. for 2 h under microwave irradiation. It was then concentrated and the residue was purified by reverse-phase prep-HPLC to afford the title compound as white solid (15.4 mg, 32%). LCMS: ESI (10 minute run), m/z=398.1 Retention time: 5.471 minute. 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=9.0 Hz, 1H), 8.17 (s, 1H), 7.82 (d, J=4.5 Hz, 1H), 7.67˜7.62 (m, 1H), 7.50˜7.47 (m, 1H), 5.20 (s, 1H), 4.46˜4.44 (m, 2H), 4.41˜4.40 (m, 2H), 3.63˜3.56 (m, 2H), 3.01 (d, J=5.0 Hz, 3H), 1.31 (t, J=7.5 Hz, 3H).
Reaction SMILES: [CH2:1]([N:8]1CCCC[CH2:9]1)[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CN.C1CCCCC=1.CN(CC1CCCCC1)CC1CCCCC1>>[CH:2]1([CH2:1][NH:8][CH3:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCC(CN2CCCCC2)CC1
Agent: CN
Agent: CN(CC1CCCCC1)CC1CCCCC1
Solvent: C1=CCCCC1
Product: CNCC1CCCCC1

Procedure:
In place of piperidine of Example 4, there was used methylamine as the amine reactant. Ca. 70% of cyclohexene was converted to methyl-di-(cyclohexylmethyl)-amine. N-formyl derivative of N-(cyclohexylmethyl)-methylamine was also isolated as a further product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][N:17]=[C:18]([O:19][C@@H:20]4[O:46][C@H:45]([CH2:47][O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@@H:37]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C@H:21]4[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:11]=23)=[CH:4][CH:3]=1.[C:55]([OH:60])(=[O:59])[CH2:56][CH:57]=[CH2:58].C(N(CC)CC)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:55]([CH2:56]/[CH:57]=[CH:58]/[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[NH:16][N:17]=[C:18]([O:19][C@@H:20]4[O:46][C@H:45]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:42])([CH3:43])[CH3:41])[C@@H:47]([O:48][C:49](=[O:54])[C:50]([CH3:53])([CH3:52])[CH3:51])[C@H:29]([O:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:33])[CH3:35])[C@H:21]4[O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:25])[CH3:26])[C:11]=23)=[CH:4][CH:3]=1)([OH:60])=[O:59]
Reactant: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(Br)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Reactant: C=CCC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](Oc2n[nH]c3nccc(CCc4ccc(/C=C/CC(=O)O)cc4)c23)[C@H](OC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@@H]1OC(=O)C(C)(C)C
Yield: 69.9 %

Procedure:
A mixture of 4-[2-(4-bromophenyl)ethyl]-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazolo[3,4-b]-pyridine (0.27 g), 3-butenoic acid (56 mg), triethylamine (0.23 mL), palladium (II) acetate (7 mg) and tris(2-methyl-phenyl)phosphine (20 mg) in acetonitrile (5 mL) was heated for reflux under an argon atmosphere overnight. The reaction mixture was diluted with dichloromethane, and the insoluble material was removed by filtration. The filtrate was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=20/1) to give the title compound (0.19 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[CH:7]=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:21][C:22](=[CH2:24])[CH3:23]>ClCCl>[C:22]([O:10][C:9]([C:8]1[CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]([C:13]([O:15][C:6]([CH3:13])([CH3:7])[CH3:5])=[O:14])[CH:7]=1)=[O:11])([CH3:23])([CH3:21])[CH3:24]
Reactant: C=C(C)C
Reactant: O=C(O)c1cc(C(=O)O)cc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(C(=O)OC(C)(C)C)cc([N+](=O)[O-])c1

Procedure:
5-Nitroisophthalic acid (4.22 g, 20 mmol) was suspended in dichloromethane (80 ml) and concentrated sulphuric acid (1 ml) was added. The solution was stirred and then saturated with isobutylene gas. The reaction vessel was stoppered and stirred at room temperature overnight. The solution was filtered and anhydrous potassium carbonate was added to the filtrate the solution was filtered and evsaporated and the residue recrystallised from ethanol to leave the title compound as a white solid (2.2 g).
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:24](=O)[CH2:25][CH3:26]>>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][CH3:26])[CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC=O
Reactant: c1ccc(Cn2nc(-c3ccccc3)c3c2CCNCC3)cc1
Product: CCCN1CCc2c(-c3ccccc3)nn(Cc3ccccc3)c2CC1

Procedure:
The title compound (0.05 g) was prepared from 1-benzyl-3-phenyl-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 44, 0.09 g) and 23 μL of propionaldehyde as in Example 35. MS (ESI): exact mass calculated for C23H27N3, 345.22. found, m/z 346.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.56-7.54 (m, 2H), 7.47-7.28 (m, 6H), 7.21-7.19 (m, 2H), 5.44 (s, 2H), 3.70-3.66 (m, 2H), 3.41-3.07 (m, 8H), 1.86-1.76 (m, 2H), 1.03 (t, J=7.3 Hz, 3H).