Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([N+:21]([O-])=O)[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.O1CCCC1.[Pd]>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([NH2:21])[C:15]3[N:16]([C:17]([CH3:20])=[N:18][N:19]=3)[C:11]=2[CH:10]=[C:9]1[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(cc([N+](=O)[O-])c3nnc(C)n32)n1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc2c(cc(N)c3nnc(C)n32)n1Cc1ccccc1

Procedure:
A degassed suspension of 6-benzyl-1,7-dimethyl-4-nitro-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyridine (0.20 g, 0.62 mmol, from Step 2) in methanol (20 mL) and tetrahydrofuran (20 mL) was hydrogenated over Palladium (10% on carbon (Degussa type, Aldrich), 0.066 g, 0.062 mmol) under 1 atm H2 overnight. The reaction mixture was filtered, and the solvent was removed in vacuo. The product was purified by flash chromatography, eluting with 7% MeOH/DCM (0.7% NH4OH). The product thus obtained (190 mg) was triturated in 2.5 mL MTBE and 0.25 mL DCM. The solid title product of step 3 was isolated by filtration and dried at 40° C. under vacuum overnight. Yield: (0.13 g, 69%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([O:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:16]N1C(=O)CCC1=O>FC1C=CC=CC=1>[Cl:16][C:5]1[CH:6]=[C:7]([O:9][C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13])[CH:8]=[C:2]([F:1])[C:3]=1[NH2:4]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)C(=O)Oc1ccc(N)c(F)c1
Solvent: Fc1ccccc1
Product: CC(C)(C)C(=O)Oc1cc(F)c(N)c(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 7.3 g (0.035 mol) of 2-fluoro-4-pivaloyloxyaniline and 5.1 g (0.038 mol) of N-chlorosuccinimide in 50 ml of fluorobenzene is heated to reflux under a nitrogen atmosphere for two hours. After cooling to room temperature, the solvent is removed, water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed with 1 N sodium hydroxide, and saturated brine, and dried over magnesium sulfate. Filtration and removal of the solvents gives a residue which is purified by silica gel chromatography (20% ethyl acetate/hexane) to give 2-chloro-4-pivaloyloxy-6-fluoroaniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]2[C:12](=O)[NH:13][CH:14]=[CH:15][C:16]=2[N:17]=1.P(Br)(Br)([Br:21])=O>CC#N>[Br:21][C:12]1[C:11]2[S:10][C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:17][C:16]=2[CH:15]=[CH:14][N:13]=1
Reactant: O=c1[nH]ccc2nc(-c3c(F)cccc3Cl)sc12
Reactant: O=P(Br)(Br)Br
Solvent: CC#N
Product: Fc1cccc(Cl)c1-c1nc2ccnc(Br)c2s1
Temperature: 100 °C
Yield: 58.2 %

Procedure:
To a stirred solution of 2-(2-chloro-6-fluorophenyl)thiazolo[5,4-c]pyridin-4(5H)-one (0.30 g, 1.1 mmol) in MeCN (50 mL), was added POBr3 (0.92 g, 3.2 mmol). The mixture was heated at 100° C. for 2 hours and then cooled to room temperature. The reaction was quenched with ice and extracted with EtOAc (3×20 mL). The combined organic extract was washed with saturated NaHCO3 solution (100 mL) and brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with a 0-10% gradient of EtOAc in petroleum ether to give the desired product as a white solid (0.22 g, 60% yield). 1H NMR (500 MHz, DMSO-d6): δ 8.59 (d, J=5.5 Hz, 1H), 8.27 (d, J=5.5 Hz, 1H), 7.76-7.68 (m, 3H). LCMS (ESI) m/z: 342.9 [M+H+].
Reaction SMILES: [C:1]1([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=2[O:17][CH2:18][CH:19]2[CH2:21][O:20]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:26][NH:27][CH3:28]>O1CCCC1>[CH3:26][N:27]([CH3:28])[CH2:21][CH:19]([OH:20])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(OCC2CO2)c(CCCCc2cccc3ccccc23)c1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCCc1cccc2ccccc12
Yield: 77 %

Procedure:
Following a procedure similar to that described in Example 1(b), 300 mg of 2-{2-[4-(1-naphthyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] dissolved in 6 ml of tetrahydrofuran were treated with 1.2 ml of 50% by volume aqueous dimethylamine. The crude product was purified as described in Example 1(b), to give 265 mg (yield 77%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].Cl.[NH2:28][OH:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:28][OH:29])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: NO
Agent: Cl
Product: O=C(NO)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to hydroxylamine hydrochloride via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-hydroxyterephthalamide. MS (Q1) 403 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[C:5]([CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6].C([NH:24][C@H:25]([CH:29]=O)[CH:26]([CH3:28])[CH3:27])(OC(C)(C)C)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[NH2:24][CH:25]([CH:26]([CH3:28])[CH3:27])[CH2:29][N:10]1[CH2:9][CH2:8][CH:7]([C:5]([C:4]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:2]([Cl:1])[CH:3]=2)=[O:6])[CH2:12][CH2:11]1
Reactant: O=C(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Reactant: CC(C)[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)C(N)CN1CCC(C(=O)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 24 h
Yield: 86.3 %

Procedure:
A mixture of 4-(3,4-dichlorobenzoyl)piperidine (1.28 g, 4.96 mmol) (see., Boswell et. al., J. Med. Chem., 21, 136, (1977)) and DL-N-BOC-Valinal (1.33 g, 6.6 mmol) (see., Stanfield et. al., J. Org. Chem., 46(23), 4797, (1981)) in dichloromethane (150 mL) was treated with sodium triacetoxyborohydride (1.36 g, 6.4 mmol). The reaction mixture was stirred under nitrogen for 1 day, then directly purified by filtration through a pad of silica gel by elution with hexanes and ethyl acetate. The organics were removed and the resultant oil (2.1 g) was dissolved in dichloromethane (22 mL) and treated with trifluoroacetic acid (8 mL). After stirring under nitrogen for 1 h, the solvent was removed in vacuo. The residue was treated with aqueous sodium bicarbonate until basic and the product was extracted into chloroform. The organic layer was dried with magnesium sulfate, filtered and concentrated to give [1-(2-amino-3-methylbutyl)piperidin-4-yl]-(3,4-dichlorophenyl)methanone (1.47 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.N1C(C)=CC(C)=CC=1C.[CH2:24]([S:31](Cl)(=[O:33])=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1.C(OCC)(=O)C>[CH2:24]([S:31]([NH:1][C:2]1[C:3](=[O:14])[N:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:33])=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)Cn1cccc(N)c1=O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)Cn1cccc(NS(=O)(=O)Cc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54561.1 %

Procedure:
A stirred solution of ethyl (3-amino-2-oxo-1,2-dihydropyridyl)acetate (40.0 g, 0.204 mole) and 2,4,6-collidine (54 mL, 0.408 mole) in tetrahydrofuran (200 mL) was cooled in an ice bath. A solution of benzylsulfonyl chloride (38.9 g, 0.204 mmole) in tetrahydrofuran (200 mL) was added over a 50-minute period. After addition was complete, the solution was stirred for 30 minutes at 0° C. The reaction mixture was diluted with ethyl acetate (1.2 L), washed with 1.0N HCl (until aqueous layer is pH 1), water (50 mL), saturated sodium bicarbonate (100 mL), and brine (2×50 mL). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed. The residue was recrystallized from chloroform. 39 g of the title compound was isolated. To the mother liquor was added silica gel. The solution was swirled, then filtered through a sintered glass funnel, washing with 50% ethyl acetate in dichloromethane. The solvent was removed from the filtrate, and the residue was recrystallized from chloroform. An additional 13 g of the title compound was isolated to afford a total of 52.00 g (75% yield) of the title compound as a tan solid. Rf =0.32 (silica gel, 20% ethyl acetate in dichloromethane). m.p. 48°-49° C.
Reaction SMILES: [O:1]([CH2:8][C:9]([OH:11])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39].C(=O)(O)[O-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[O:1]([CH2:8][C:9]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCCN
Reactant: O=C(O)COc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCCCCNC(=O)COc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.4 %

Procedure:
To phenoxyacetic acid (50.0 g, 0.33 mol) dissolved in tetrahydrofuran (210 mL) was slowly added 1,1′-carbonyldiimidazole (56.0 g, 0.35 mol) with additional tetrahydrofuran (30 mL). After stirring for 1.5 hr at room temperature, triethylamine (92 mL, 0.66 mol) was added all at once and methyl 6-aminohexanoate hydrochloride (66.0 g, 0.36 mol) was added in portions over 20 min. The reaction mixture was stirred at room temperature overnight, heated at 50° C. for 20 min, and then stirred at room temperature for 20 hr. The reaction mixture was concentrated under reduced pressure, added to 1 N hydrochloric acid (750 mL) and extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with 1 N hydrochloric acid (1×100 mL), water (1×100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a yellow oil. NMR analysis indicated presence of phenoxyacetic acid. The concentrate was dissolved in toluene (450 mL) and stirred 15 min with 25% sodium bicarbonate (200 mL). The organic layer was filtered through 1 PS paper, concentrated under reduced pressure, diluted with hexanes, and concentrated again, to give 76.89 g (84%) of the title compound, amide, as a yellow oil.
Reaction SMILES: [CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[CH:13])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1.I[C:15]1[CH:16]=[C:17]([CH:39]=[CH:40][C:41]=1[CH3:42])[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:22]=1)=[O:19]>>[CH:1]1([NH:5][C:6]2[N:7]=[N:8][C:9]([C:12]#[C:13][C:40]3[CH:39]=[C:17]([CH:16]=[CH:15][C:41]=3[CH3:42])[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:22]=3)=[O:19])=[CH:10][CH:11]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C#Cc1ccc(NC2CCC2)nn1
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Product: Cc1ccc(C(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cc1ccc(NC2CCC2)nn1

Procedure:
The title compound was synthesized from N-cyclobutyl-6-ethynylpyridazin-3-amine and 3-iodo-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide in a manner similar to that described for in Example 1. The product was obtained as a pale yellow solid. Mp: 120-121° C.; 1H NMR (300 MHz, CDCl3) δ: 9.10 (1H, s), 8.05 (1H, s), 7.97-7.80 (1H, d, J=9.0 Hz), 7.94 (1H, s), 7.81-7.83 (1H, d, J=6.0 Hz), 7.64-7.66 (1H, d, J=6.0 Hz), 7.28-7.31 (1H, d, J=9.0 Hz), 7.26-7.28 (1H, d, J=6.0 Hz), 6.57-5.59 (1H, d, J=2.0 Hz), 5.53 (1H, s), 4.22-4.27 (1H, m), 3.64 (2H, s), 2.65 (8H, brs), 2.49 (3H, s), 2.45 (3H, s), 2.44 (2H, m), 1.93-1.99 (2H, m), 1.83-1.89 (2H, m). HRMS (ESI-TOF+): m/z [M+H]+ calcd for C31H34F3N6O: 563.2741. found: 563.2768.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([CH:12]([OH:15])[CH2:13][CH3:14])[C:5]([OH:11])=[C:6]([C:9]=1[CH3:10])[CH:7]=[O:8].Cl[C:18]1[C:19](O)=[C:20]([CH:28](O)[CH2:29][CH2:30][CH2:31]C)C(O)=[C:22]([C:25]=1C)C=O.ClC1C(O)=C(C(O)CCCCCC)C(O)=C(C=1C)C=O.ClC1C(O)=C(C(O)CCCCCCCC)C(O)=C(C=1C)C=O.ClC1C(O)=C(C(O)CCCCCCCCC)C(O)=C(C=1C)C=O>>[Cl:1][C:2]1[C:3]([OH:16])=[C:4]([CH:12]([OH:15])[CH2:13][CH2:14][CH2:22][CH2:25][CH2:18][CH2:19][CH2:20][CH2:28][CH2:29][CH2:30][CH3:31])[C:5]([OH:11])=[C:6]([C:9]=1[CH3:10])[CH:7]=[O:8]
Reactant: CCC(O)c1c(O)c(Cl)c(C)c(C=O)c1O
Reactant: CCCCC(O)c1c(O)c(Cl)c(C)c(C=O)c1O
Agent: CCCCCCC(O)c1c(O)c(Cl)c(C)c(C=O)c1O
Agent: CCCCCCCCC(O)c1c(O)c(Cl)c(C)c(C=O)c1O
Agent: CCCCCCCCCC(O)c1c(O)c(Cl)c(C)c(C=O)c1O
Product: CCCCCCCCCCCC(O)c1c(O)c(Cl)c(C)c(C=O)c1O

Procedure:
In addition to this compound, 5-chloro-2,4-dihydroxy-3-(1-hydroxypropyl)-6-methylbenzaldehyde (196-3), 5-chloro-2,4-dihydroxy-3-(1-hydroxypentyl)-6-methylbenzaldehyde (196-5), 5-chloro-2,4-dihydroxy-3-(1-hydroxyheptyl)-6-methylbenzaldehyde (196-7), 5-chloro-2,4-dihydroxy-3-(1-hydroxynonyl)-6-methylbenzaldehyde (196-9) and 5-chloro-2,4-dihydroxy-3-(1-hydroxydecyl)-6-methylbenzaldehyde (196-10) were synthesized by the same reaction with the use of respective corresponding starting raw materials.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=2[N:26]([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[S:27]([CH3:30])(=[O:29])=[O:28])[C:9]([O:11][CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])=[O:10])[CH2:3][CH2:2]1>CO.[Pd]>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=2[N:26]([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]2)[S:27]([CH3:30])(=[O:28])=[O:29])[C:9]([O:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[CH2:3][CH2:2]1
Reactant: CN1CCN(CCN(c2ccc(C(=O)OCC(=O)OCc3ccccc3)cc2OCC2CC2)S(C)(=O)=O)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(CCN(c2ccc(C(=O)OCC(=O)O)cc2OCC2CC2)S(C)(=O)=O)CC1
Yield: 87 %

Procedure:
The mixture of 2-(benzyloxy)-2-oxoethyl 3-(cyclopropylmethoxy)-4-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)benzoate (370 mg, 0.661 mmol) and a catalytic amount of 10% Pd/C in MeOH (20 ml) was hydrogenated at 20 psi for 2 hours. The catalyst was filtered off and the solvent was evaporated to give 2-(3-(cyclopropylmethoxy)-4-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)-benzoyloxy)acetic acid (270 mg, 0.575 mmol, 87% yield, MS/ESI+ 470.0 [MH]+) that was used in the following step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:13][CH:14]=[C:15]([CH2:17][C:18](O)=[O:19])[N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:13][CH:14]=[C:15]([CH2:17][CH2:18][OH:19])[N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(-c2nc(CC(=O)O)c[nH]2)ccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(-c2nc(CCO)c[nH]2)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 16 h

Procedure:
1.45 g (5.23 mmol) [2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-acetic acid are dissolved in 36 ml THF and cooled to 0° C. and combined with 10 ml (18 mmol) borane-THF complex (1.8 mol/V). After 1 h the mixture is heated to 20° C. and stirred for 16 h. Water is added until the development of gas has ended. Then the mixture is extracted twice with saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic phases are combined, dried and freed from the solvent in vacuo.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]=1[C:14]#[N:15].O=[CH:17][C:18]1[CH:26]=[CH:25][C:23]([OH:24])=[C:20]([O:21][CH3:22])[CH:19]=1>CCO.N1CCCCC1>[OH:24][C:23]1[CH:25]=[CH:26][C:18]([CH:17]=[N:1][C:2]2[NH:6][N:5]=[C:4]([NH:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:3]=2[C:14]#[N:15])=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1cc(C=O)ccc1O
Reactant: N#Cc1c(Nc2ccccc2)n[nH]c1N
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(C=Nc2[nH]nc(Nc3ccccc3)c2C#N)ccc1O
Yield: 38.8 %

Procedure:
5-amino-3-(phenylamino)-1H-pyrazole-4-carbonitrile (100 mg) was suspended in EtOH (4 mL) and Vanillin (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain A21 as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr (65 mg, 38.8% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH:15]([OH:18])CO)=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2].C1COCC1>O>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH:15]=[O:18])=[CH:14][C:9]=2[S:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc2cc(C(O)CO)ccc12
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)Cc1csc2cc(C=O)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a mixture of ethyl(6-(1,2-dihydroxyethyl)-1-benzothiophen-3-yl)acetate (200 mg), THF (2 mL) and water (2.0 mL) was added NaIO4 (458 mg) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was quenched with saturated aqueous Na2S2O3 at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with brine twice, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (160 mg).
Reaction SMILES: CCN(CC)CC.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[CH2:8]([NH:15][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)CNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of Et3N (13.55 g, 133.9 mmol) and benzylamine (11.96 g, 111.6 mmol) in THF (25 ml) was added 2-bromo-1-(4-methoxy-phenyl)-ethanone (25.56 g, 111.6 mmol). The reaction was stirred at RT for 60 minutes, then filtered and the filtrate concentrated in vacuo. The residue was purified via flash chromatography (SiO2, gradient column 35% to 80% EtOAc/hexanes) to give the title product (17.12 g, 67.0 mmol, 60% yield).
Reaction SMILES: [C:1]1([CH:7]([OH:35])[CH2:8][CH2:9][C:10]2[NH:11][C:12]([CH3:34])=[C:13]([C:30]([O:32][CH3:33])=[O:31])[CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=3)[C:15]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:36](O)=[O:37]>O>[CH:36]([O:35][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][C:10]1[NH:11][C:12]([CH3:34])=[C:13]([C:30]([O:32][CH3:33])=[O:31])[CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([N+:27]([O-:29])=[O:28])[CH:22]=2)[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[O:37]
Reactant: O=CO
Reactant: CCOC(=O)C1=C(CCC(O)c2ccccc2)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Solvent: O
Product: CCOC(=O)C1=C(CCC(OC=O)c2ccccc2)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A solution of diastereoisomers of 2-(3-phenyl-3-hydroxypropyl)-3-carboethoxy-5-carbomethoxy -4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (100 mg) in formic acid (2 ml) is stirred for 24 hours at room temperature, then it is diluted with water (10 ml) and extracted with ethyl ether (15 ml); the organic phase is washed with a NaHCO solution (5%, 3×5 ml , water (3×5 ml), dried (Na2SO4) and concentrated under vacuum to give 2-(3-formyloxy-3-phenylpropyl)-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine, diastereoisomer mixture identical to the compound obtained in example 1.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:21])([F:20])[CH:17]1[O:19][CH2:18]1>>[O:1]([C:8]1[CH:9]=[C:10]([NH:11][CH2:18][CH:17]([OH:19])[C:16]([F:21])([F:20])[F:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Oc2ccccc2)c1
Reactant: FC(F)(F)C1CO1
Product: OC(CNc1cccc(Oc2ccccc2)c1)C(F)(F)F
Temperature: 100 °C
Yield: 70.6 %

Procedure:
Ex-588B) A mixture of solid 3-phenoxyaniline (2.96 g, 16 mmol) and 1,1,1-trifluoro-2,3-epoxypropane (1.30 mL, 15.0 mmol) was placed in a sealed tube and heated to 100° C. giving a dark solution. The stirred solution was heated 18 h and cooled to give a dark oil. Purification by flash chromatography on silica gel eluting with dichloromethane gave 3.15 g (71%) of the desired 3-[(N-3-phenoxy-phenyl)amino]-1,1,1-trifluoro-2-propanol product as a colorless oil. Anal. calcd. for C15H14NO2F3.0.05 CH2Cl2: C, 59.92; H, 4.71; N, 4.64. Found: C, 59.92; H, 4.53; N, 4.73. HRMS calcd. 298.1055 [M+H]+, found: 298.1056.
Reaction SMILES: O[CH2:2][C@@H:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][O:5][C:6](=[O:8])[CH3:7].[Br:15][C:16]1[C:17](=[O:33])[NH:18][C:19](=[O:32])[N:20]([CH2:23][C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=2[F:31])[C:21]=1[CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>C1COCC1>[Br:15][C:16]1[C:17](=[O:33])[N:18]([CH2:2][C@@H:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][O:5][C:6](=[O:8])[CH3:7])[C:19](=[O:32])[N:20]([CH2:23][C:24]2[C:25]([F:31])=[CH:26][CH:27]=[CH:28][C:29]=2[F:30])[C:21]=1[CH3:22]
Reactant: CC(=O)OC[C@@H](CO)c1ccccc1
Reactant: Cc1c(Br)c(=O)[nH]c(=O)n1Cc1c(F)cccc1F
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)OC[C@@H](Cn1c(=O)c(Br)c(C)n(Cc2c(F)cccc2F)c1=O)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
A solution of acetic acid 3-hydroxy-2-(R)-phenyl-propyl ester (1.87 g, 9.64 mmol) in THF (50 mL) was treated with 5-bromo-1-(2,6-difluorobenzyl)-6-methyluracil 4d.1 (3.19 g, 9.64 mmol) and triphenylphosphine (3.16 g, 12.1 mmol) at ambient temperature, then di-tert-butylazodicarboxylate (2.77 g, 12.1 mmol) was introduced. The reaction mixture was stirred at ambient temperature for 16 h and volatiles were evaporated. The residue was partitioned between saturated NaHCO3/H2O and EtOAc. The organic layer was dried (sodium sulfate), evaporated, purified by flash chromatography (silica, 33% EtOAc/hexanes) to give compound 8a (4.54 g, 93%). MS (CI) m/z 508.1 and 509.0 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][CH2:23][C:22]=4[CH:35]=3)[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].[ClH:36]>CCOCC>[ClH:36].[CH3:12][CH:10]([O:9][C:8]1[CH:7]=[CH:6][C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:19]=[CH:20][C:21]4[CH2:27][NH:26][CH2:25][CH2:24][CH2:23][C:22]=4[CH:35]=3)[N:14]=2)=[CH:4][C:3]=1[C:1]#[N:2])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCN(C(=O)OC(C)(C)C)C4)no2)cc1C#N
Agent: Cl
Solvent: CCOCC
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCCNC4)no2)cc1C#N
Yield: 85.7 %

Procedure:
1,1-Dimethylethyl 7-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carboxylate (Preparation 9) (310 mg, 0.653 mmol) was treated with HCl (3266 μl, 13.06 mmol) (4N in dioxan) and stirred. After 30 minutes a white precipitate had formed. After 1 hour ether (2 ml) was added and the precipitate filtered off and washed with ether. The title compound (230 mg) was obtained on drying. δH (400 MHz, d6DMSO) 1.39 (6H, d), 1.91 (2H, m), 3.11-3.13 (2H, m), 3.37-3.40 (2H, m), 4.42 (2H, s), 4.94-5.02 (1H, m), 7.57 (1H, d), 7.64 (1H, d), 7.96-8.00 (2H, m), 8.41 (1H, dd), 8.52 (1H, d), 9.04 (2H, broad s); MS (ES) C22H22N4O2 requires 374; found 375.0 [M+H]+.