Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(O)=O.[Cl:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]([NH2:15])=[NH:14])[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].CN(C)[CH:20]=[CH:21][C:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=O>C(O)C(C)C>[Cl:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:15]=[C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][N:14]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: N=C(N)Nc1cccc(Cl)c1
Reactant: CN(C)C=CC(=O)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)CO
Product: Clc1cccc(Nc2nccc(-c3ccncc3)n2)c1

Procedure:
2.8 g (12 mmol) of 3-chloro-phenyl-guanidine nitrate and 0.5 g (12 mmol) of sodium hydroxide are added to a suspension of 2.0 g (11.7 mmol) of 3-dimethylamino-1-(4-pyridyl)-2-propen-1-one [described in EP-A-0 233 461] in 100 ml of isobutanol and the reaction mixture is boiled under reflux for 5 hours. After cooling, the reaction product is isolated by filtration, washed with water and chromatographed (tetrahydrofuran). After crystallisation (tetrahydrofuran/diethyl ether), N-(3-chloro-phenyl)-4-pyridyl-2-pyrimidineamine is obtained; m.p. 167°-168°, Rf =0.38 (methylene chloride:methanol=9:1).
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.C(OCC)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[CH2:1])=[CH:19][CH:18]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(OCCCCc2ccccc2)cc1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1ccc(OCCCCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of methyltriphenylphosphonium bromide (4.98 g, 13.9 mmol) in anhydrous tetrahydrofuran (130 ml) at 0° C. and under inert atmosphere was added with a 1.6M butyl lithium solution in hexane (8.69 ml) and the mixture was left under stirring at 0° C. for 2 h. After that, a solution of 4-(4-phenylbutoxy)benzaldehyde (2.5 g, 9.84 mmol) in tetrahydrofuran (10 ml) was added and the mixture was left under stirring at room temperature for 36 h, then carefully added with water (20 ml) and extracted with ethyl ether (4×50 ml). The organic extracts were dried and the solvents were evaporated off under reduced pressure. The resulting crude was purified by chromatography through a silica gel column, eluting with petroleum ether:ethyl ether, 95:5, thereby recovering 4.20 g of the title compound (62% yield).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[CH3:8].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1>>[CH3:8][C:3]1[C:4](=[O:7])[CH2:5][CH2:6][C:2]=1[C:11]1[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=1
Reactant: CC1=C(Br)CCC1=O
Reactant: OB(O)c1cccnc1
Product: CC1=C(c2cccnc2)CCC1=O
Yield: 31 %

Procedure:
Synthesized from 3-bromo-2-methylcyclopent-2-enone and 3-pyridine boronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (0 to 100% ethyl acetate/hexanes) and further recrystallization yielded the product (38 mg, 31%) as a brown oil. 1H NMR (CDCl3, 300 MHz): δ 8.78 (s, 1H), 8.63 (br d, J=3.6 Hz, 1H), 7.82 (dt, J=8.1, 2.1 Hz, 1H), 7.40 (dd, J=8.1, 4.8 Hz, 1H), 2.91-2.96 (m, 2H), 2.56-2.59 (m, 2H), 1.98 (t, J=2.1 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 208.8, 162.5, 150.1, 148.3, 137.9, 134.5, 129.1, 123.4, 33.9, 29.0, 9.9. LCMS (ESI): mass calcd for (C11H11NO) m/z 173.08; measured [M+H]+: m/z 174.07.
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[CH3:13].[Cl:14][C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1.CC(C)([O-])C.[Na+]>C1COCC1>[Br:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:21]([C:17]3[CH:18]=[CH:19][CH:20]=[C:15]([Cl:14])[CH:16]=3)(=[O:23])=[O:22])=[C:4]2[C:3]=1[CH3:13]
Reactant: Cc1cc(N)c2c(C)c(Br)sc2n1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(C)c(Br)sc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.8 %

Procedure:
To a solution of 2-bromo-3,6-dimethylthieno[2,3-b]pyridin-4-amine (Description 62) (1.351 g, 5.25 mmol) in THF (10 mL) was added 3-chlorobenzenesulfonyl chloride (1.11 mL, 7.88 mmol), sodium tert-butoxide (1.262 g, 13.13 mmol) and the mixture stirred at RT for 16 h. The mixture was then evaporated to dryness and the resulting material taken-up in water (10 mL) and extracted with ethyl acetate (20 mL×3). The organics were then combined, dried (phase separation cartridge) and concentrated. Purification on silica, eluting with a gradient of 0-20% ethyl acetate in cyclohexane, followed by MDAP (acidic conditions), afforded the title compound (380 mg). LCMS (A) m/z: 431/433 [M+1]+, Rt 1.22 min (acidic).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:30])[CH2:6][C:7]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:29])[CH:13]=2)[CH:8]=1.Cl>O1CCCC1>[CH2:27]([S:24]([C:21]1[CH:22]=[CH:23][C:18]([O:17][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([F:29])[CH:13]=3)[CH:8]=[C:7]([CH2:6][C:5]([OH:30])=[O:4])[CH:16]=2)=[CH:19][CH:20]=1)(=[O:25])=[O:26])[CH3:28]
Reactant: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)OC)cc3ccc(F)cc23)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(Oc2cc(CC(=O)O)cc3ccc(F)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
5 N lithium hydroxide (6 mL) was added to a solution of [4-(4-ethanesulfonyl-phenoxy)-6-fluoro-naphthalen-2-yl]-acetic acid methyl ester (64 mg, 0.16 mmol) in tetrahydrofuran (4 mL). After being stirred at room temperature overnight, the resulting mixture was acidified to pH 3 with 5 N hydrochloric acid, and then extracted with ethyl acetate (10 mL×2). The organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was precipitated from ethyl ester/petroleum ether (1:10) to give [4-(4-ethanesulfonyl-phenoxy)-6-fluoro-naphthalen-2-yl]-acetic acid (25 mg) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.84-7.90 (m, 3H), 7.65 (s, 1H), 7.57 (dd, J=9.85, 2.53 Hz, 1H), 7.33 (td, J=8.65, 2.65 Hz, 1H), 7.09-7.14 (m, 3H), 3.80 (s, 2H), 3.13 (q, J=7.33 Hz, 2H), 1.30 (t, J=7.45 Hz, 3H); MS cald. for C20H17FO5S 388, obsd. (ESI+) [(M+H)+] 389.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[Mg]Br.[I:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>CCOCC.C1COCC1>[OH:22][C:15]1([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([I:11])[CH:13]=2)[NH:17][C:16]1=[O:21]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: COc1ccccc1[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C1Nc2ccc(I)cc2C1(O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3M 2-methoxyphenylmagnesium bromide (0.92 mL, 2.747 mmol) in Et2O is added drop wise to a suspension of 5-iodoisatin (300 mg, 1.099 mmol) in THF whilst cooling in ice. The mixture is then stirred at room temperature for 1 hour. The reaction mixture is quenched by adding ammonium chloride solution and extracted several times with ethyl acetate. The combined organic phases are washed several times with water, dried over MgSO4 and concentrated under reduced pressure. The precipitate is filtered off with suction, washed with very small amounts of ethyl acetate and dried. This afforded the desired product as a light yellow solid.
Reaction SMILES: [I:1]Cl.[CH:3](=[O:11])[C:4]1[C:5](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:6].[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[I:1][C:8]1[CH:7]=[C:5]([OH:6])[C:4](=[CH:10][CH:9]=1)[CH:3]=[O:11]
Reactant: O=Cc1ccccc1O
Reactant: ClI
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=Cc1ccc(I)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1 M solution of Iodine monochloride in dichloromethane (410 mL, 0.41 mol) is added to a solution of salicylaldehyde (50 g, 0.41 mol) in dichloromethane (150 mL) at 0° C. The resulting solution is warmed to room temperature and stirred overnight. The deep colored solution is discharged with saturated aqueous Na2SO3 (100 mL). The organic layer is separated, washed with water, dried over MgSO4, filtered and concentrated. The crude product is recrystallized from cyclohexane to give 4-iodosalicylaldehyde as yellow crystals (61 g, 0.25 mol). A solution of 4-iodosalicylaldehyde (12.4 g, 50 mmol) and MEM chloride (6 mL, 53 mmol) in THF (50 mL) is added to a suspension of 60% NaH (2.2 g, 55 mmol) in THF (50 mL) at 0° C. The resulting mixture is stirred at room temperature for 2 hours. Aqueous workup and concentration gives product as a liquid (15 g, 45 mmol). 1H NMR (CDCl3, 300 MHz) δ10.36 (s, 1H), 8.11 (d, 1H), 7.73 (dd, 1H), 7.03 (d, 1H), 5.37 (s, 2H), 3.88 (t, 2H), 3.52 (t, 2H), 3.36 (s, 3H). EI MS [M]+=436.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5](=[O:7])[O:4][C:3]=1[CH2:8][OH:9].[C:10]([SiH:14]([CH3:16])[CH3:15])([CH3:13])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C>[CH3:1][C:2]1[O:6][C:5](=[O:7])[O:4][C:3]=1[CH2:8][O:9][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:16])[CH3:15]
Reactant: C[SiH](C)C(C)(C)C
Reactant: Cc1oc(=O)oc1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1oc(=O)oc1CO[Si](C)(C)C(C)(C)C

Procedure:
A solution of 5-methyl-4-hydroxymethyl-2-oxo-1,3-dioxolene (1 mmole) in DMF was treated with tert-butyldimethylsilane (1.2 mmole) and imidazole (2.2 mmole) at 25° C. for 24 h. Extraction and chromatography gave 5-methyl-4-tert-butyldimethylsilyloxymethyl-2-oxo-1,3-dioxolene.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].ClC1C=CC=C(C(OO)=[O:23])C=1>C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH+:7]([O-:23])[C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)Nc1ccccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[NH+]([O-])c1ccccn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.1 %

Procedure:
tert-Butyl 2-pyridylcarbamate (7.4 g, 38 mmol) and 3-chloroperbenzoic acid (77%, 11.2 g, 50 mmol) were dissolved in ethyl acetate (100 ml), and the mixture was stirred at room temperature for 20 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with methanol-ethyl acetate (1:20, v/v) were collected and concentrated to give the titled compound (7.6 g, 95%).
Reaction SMILES: C(O)(=O)C.[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][NH:12][C:13](=[O:40])[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21](=O)[CH3:22])=[C:16]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:28][CH:27]=2)[CH:15]=1>C(O)C>[CH2:33]([O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:24]2[C:16]3[CH:15]=[C:14]([C:13](=[O:40])[NH:12][CH2:11][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][N:5]=4)[CH:19]=[CH:18][C:17]=3[N:20]=[C:21]2[CH3:22])=[CH:27][CH:28]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(=O)Nc1ccc(C(=O)NCc2ccccn2)cc1NCc1ccc(OCc2ccccc2)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc2ccc(C(=O)NCc3ccccn3)cc2n1Cc1ccc(OCc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 7 h
Yield: 89.8 %

Procedure:
Four milliliters of acetic acid and 8 ml of ethanol were added to 0.434 g of N-(2-pyridylmethyl)-4-acetylamino-3-(4-benzyloxybenzylamino)benzamide, and the mixture was stirred at 90° C. for 7 hours. The reaction solution was concentrated under reduced pressure. Ethyl acetate and ether were added to the residue for crystallization. The crystals were separated through filtration, and were dried to give 0.375 g of 1-(4-benzyloxybenzyl)-2-methyl-6-[(2-pyridylmethyl)carbamoyl]benzimidazole (242).
Reaction SMILES: [C:1]([O:9]CC)(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[OH-].[K+:13]>C(O)C>[C:3]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][C:1]([O-:9])=[O:8].[K+:13]
Reactant: CCOC(=O)CC(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)CC(=O)[O-]
Reaction time: 72 h

Procedure:
To a solution of diethyl malonate (10 g, 62.4 mmol, 1 eq) in absolute ethanol (40 mL) was added a solution of potassium hydroxide (4.2 g, 65.52 mmol, 1.05 eq) in absolute ethanol (40 mL) at room temperature over 30 minutes. The mixture was allowed to stir for 3 days. The precipitate was collected, washed with ether and dried under reduced pressure.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[Cl-].[Mg+2].[Cl-].[CH2:14]=[O:15].Cl>ClC(Cl)C.C(N(CC)CC)C>[F:1][C:2]1[C:3]([OH:10])=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH:14]=[O:15]
Reactant: COc1cccc(O)c1F
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(C=O)c(O)c1F
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
To a solution of 2-fluoro-3-methoxyphenol (22.0 g) and triethylamine (93.9 g) in dichloroethane (250 mL) was added magnesium chloride (71.7 g), and the mixture was stirred at 40° C. for 1 hr. To this mixture was added paraformaldehyde (46.5 g), and the mixture was stirred for 16 hr. The reaction solution was allowed to be cooled to room temperature, 1N hydrochloric acid was added thereto, and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by combi flash (petroleum ether/ethyl acetate) to give the title compound (26.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12]CC=C)[CH:7]=[O:8])[CH3:2].[OH-].[Na+].[C:18]1(C)[CH:23]=C(C)C=C(C)[CH:19]=1>>[CH2:23]([C:10]1[CH:9]=[C:6]([CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:11]=1[OH:12])[CH:7]=[O:8])[CH:18]=[CH2:19]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1ccc(C=O)cc1OCC
Agent: [Na+]
Agent: [OH-]
Product: C=CCc1cc(C=O)cc(OCC)c1O

Procedure:
3-Ethoxy-4-(2-propenyloxy)benzaldehyde (20.0 g, 0.087 mol) was heated under reflux in 75 ml mesitylene (1,3,5-trimethylbenzene) for 20 hours. After cooling, 250 ml 2N sodium hydroxide were added to the reaction mixture. The aqueous phase was washed two times with diethyl ether. The aqueous phase was subsequently acidified with concentrated hydrochloric acid under ice cooling and then extracted with ethyl acetate. After drying and concentrating the organic phase, there remained a light orange-colored oil that crystallized on cooling.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:26][CH3:27])=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=2[CH2:20][NH:21][C:22](=[O:25])[O:23][CH3:24])[CH:9]=1)([CH3:3])[CH3:2].[F:28][C:29]([F:39])([F:38])[C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33]Br.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O>C1COCC1.C1(C)C=CC=CC=1>[CH3:24][O:23][C:22](=[O:25])[N:21]([CH2:20][C:11]1[CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=[CH:6][C:7]=1[O:26][CH3:27])[CH2:33][C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([C:29]([F:28])([F:38])[F:39])[CH:31]=1
Reactant: COC(=O)NCc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)N(Cc1cccc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Reaction time: 2 h

Procedure:
Methyl {[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (20 mg, 0.053 mmol) was dissolved in THF (1 mL). 3-(Trifluoromethyl) benzyl bromide (122 μL, 0.79 mmol) was added followed by potassium bis(trimethylsilyl)amide (320 μL of a 0.5 M solution in toluene, 0.160 mmol). The reaction was stirred for two hours and then poured into H2O (10 mL). The mixture was extracted with EtOAc (50 mL), and the organic extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 2% to 25% EtOAc/hexanes afforded methyl{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}[3-(trifluoromethyl)benzyl]carbamate. Rf=0.67 (15% EtOAc/hexanes). LCMS=540.3 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.72 (s, 1H), 7.36 (dd, J=8.0, 1.0 Hz, 1H), 7.19-7.23 (m, 2H), 7.03-7.07 (m, 3H), 6.86 (m, 2H), 6.57 (d, J=8.5 Hz, 1H), 4.41 (s, 2H), 4.05 (s, 2H) 3.36 (s, 3H), 3.22 (s, 3H), 3.73 (m, 1H), 1.25 (d, J=6.5 Hz, 6H).
Reaction SMILES: [Na].[CH2:2]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1)[CH2:3][CH2:4][CH3:5]>C(O)C.[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1>[CH2:2]([O:6][C:7](=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[CH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:9]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCOC(=O)c1cccc(C=O)c1
Agent: [Cl-]
Agent: [Na]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: CCCCOC(=O)c1cccc(C=Cc2ccccc2)c1
Reaction time: 2 h
Yield: 151.9 %

Procedure:
2.3 g (0.1 mol) of sodium were dissolved in 50 ml of ethanol and this solution was added dropwise to a solution of 38.9 g (0.1 mol) of benzyl-triphenyl-phosphonium chloride in 150 ml of ethanol at an internal temperature of -5° to 0° C. 20.6 g (0.1 mol) of 3-formyl-benzoic acid n-butyl ester were then added to this mixture and the mixture was kept at 0° to 5° C. for two hours, whilst stirring, and allowed to come slowly to room temperature. After concentrating the mixture, the residue was extracted with toluene, the toluene extract was filtered and the solvent was distilled off from the filtrate in vacuo. 21.3 g (75% theory) of 3-(2-phenyl-vinyl)-benzoic acid n-butyl ester were obtained as a slightly yellowish oil (cis/trans isomer mixture in the ratio 1:1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[C:12]3[CH2:20][NH:19][CH2:18][CH2:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27](F)=[C:28]([CH:31]=1)[C:29]#[N:30].C(#N)C.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([N:19]2[CH2:18][CH2:17][C:13]3[N:14]=[CH:15][N:16]=[C:11]([NH:10][CH2:9][C:6]4[CH:7]=[N:8][C:3]([C:2]([F:21])([F:1])[F:22])=[CH:4][CH:5]=4)[C:12]=3[CH2:20]2)=[C:28]([CH:31]=1)[C:29]#[N:30]
Reactant: FC(F)(F)c1ccc(CNc2ncnc3c2CNCC3)cn1
Reactant: N#Cc1cc(Cl)ccc1F
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cc(Cl)ccc1N1CCc2ncnc(NCc3ccc(C(F)(F)F)nc3)c2C1
Yield: 45 %

Procedure:
A 2 mL microwave vial was charged with N-((6-(trifluoromethyl)pyridin-3-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (50 mg, 0.16 mmol), 5-chloro-2-fluorobenzonitrile (150 mg, 0.97 mmol), acetonitrile (0.4 mL), and N,N-diisopropylethylamine (84 μL, 0.48 mmol). The mixture was subjected to a microwave irradiation at 200° C. for 2 h. The mixture was diluted with chloroform (7 mL), and washed with 0.1 M NaH2PO4 (10 mL), dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column to yield a light yellow solid (32 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[N:21]1([C:27]2[CH:32]=[C:31]([CH:33]=O)[CH:30]=[CH:29][N:28]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:33]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:32]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccnc(N2CCOCC2)c1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccnc(N5CCOCC5)c4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 45.8 %

Procedure:
In a similar fashion compound to CXXV, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 2-Morpholin-4-yl-pyridine-4-carbaldehyde (36.0 mg, 0.187 mmol) and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to yield 36.32 mg (46%) of the title compound. (300 MHz, DMSO-d6) 12.35 (s, 1H), 8.26 (s, 1H), 7.79 (s, 1H), 7.52 (s, 1H), 7.38 (s, 2H), 7.25 (s, 1H), 6.39 (s, 2H), 5.15 (s, 1H), 3.75 (s, 4H), 3.54 (s, 4H), 2.90 (s, 1H), 2.80 (s, 1H), 2.62 (s, 1H), 2.26 (s, 1H), 1.38 (s, 1H). MS=466 (M+H), HPLC: 1.76 min. (G Method)
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:5](=[CH:6][C:7]([I:15])=[CH:8][C:9]=2[C:11]([F:14])([F:13])[F:12])[NH:4][C:3]1=[O:16].[OH2:18].Br>CO>[F:12][C:11]([F:14])([F:13])[C:9]1[CH:8]=[C:7]([I:15])[CH:6]=[C:5]2[C:10]=1[C:2](=[O:18])[C:3](=[O:16])[NH:4]2
Reactant: O=C1Nc2cc(I)cc(C(F)(F)F)c2C1(Br)Br
Reactant: O
Agent: Br
Solvent: CO
Product: O=C1Nc2cc(I)cc(C(F)(F)F)c2C1=O

Procedure:
The crude 3,3-dibromo-4-trifluoromethyl-6-iodooxindole (35.11 g) prepared above was dissolved in MeOH (1200 mL) and H2O (300 mL) was added. The resulting mixture was heated at reflux for 3 hours and then aqueous 48% HBr (10 mL) was added. The solution was then heated at reflux for 27 hours. The MeOH solvent was removed in vacuo to give a brown/yellow solid. The solid was isolated by filtration, washing the collected solid with copious amounts of H2O. The solid was then dried overnight in a vacuum desiccator (NaOH as desiccant) to give the desired isatin as a light brown solid (20.8214 g, 95% (two steps)).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=O)=[N+:2]=[N-:3].[NH2:14][C:15]1[C:16]([O:27][CH3:28])=[C:17]([CH:20]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:22]=1)[C:18]#[N:19].N(C1C=C(C=CC=1C)C(NC1C=C(C(C)(C)C)C=C(NS(C)(=O)=O)C=1OC)=O)=[N+]=[N-]>>[N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([NH:14][C:15]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:24])[CH3:25])[CH:20]=[C:17]([C:18]#[N:19])[C:16]=1[O:27][CH3:28])=[O:9])=[N+:2]=[N-:3]
Reactant: COc1c(N)cc(C(C)(C)C)cc1C#N
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Agent: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(C#N)cc(C(C)(C)C)cc1NC(=O)c1ccc(C)c(N=[N+]=[N-])c1

Procedure:
3-Azido-N-(5-tert-butyl-3-cyano-2-methoxy-phenyl)-4-methyl-benzamide was prepared from 3-azido-4-methyl benzoic acid (U.S. Ser. No. 04/102,492) and 3-amino-5-tert-butyl-2-methoxy-benzonitrile in the same manner as 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide (Example 15).
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]>[C].[Rh].CO>[N:1]1([CH:7]2[CH2:8][CH2:9][CH:10]([C:11]([OH:13])=[O:12])[CH2:14][CH2:15]2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: O=C(O)c1ccc(N2CCCC2=O)cc1
Agent: [Rh]
Solvent: CO
Product: O=C(O)C1CCC(N2CCCC2=O)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-(2-Pyrrolidon-1-yl)benzoic acid (4.0 g, 0.0195 mol), 5% rhodium-carbon catalyst (2.8 g, 3.0% mol) and methanol (80 mL) are charged in an autoclave (300 mL) and stirred at room temperature for 5 hours under hydrogen pressure (50 atm, conversion rate >99%, cis:trans=50:50). The reaction solution is cooled, filtrated to collect the catalysts, and washed with methanol. The filtrate is concentrated under reduced pressure, and the resulting crystals are washed with methanol to give 4-(2-pyrrolidon-1-yl)cyclohexylcarboxylic acid as a mixture of cis and trans isomers (3.4 g, 82.5%, cis:trans=79:21). A portion (3.0 g) is dissolved in methanol (15 mL) under heating, and cooled. The resulting crystals are washed with cooled methanol to give cis-4-(2-pyrrolidon-1-yl)cyclohexylcarboxylic acid (700 mg, >99% de). The tertiary structure of cis-4-(2-pyrrolidon-1-yl)cyclohexylcarboxylic acid was confirmed by X-ray structure analysis. Mp: 188° C.