Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:19](=[O:20])[CH2:18][CH2:17][Cl:16])=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCCl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CCCl)cc1

Procedure:
The title compound, m.p. 126° C. and MS: m/e=313 (M+), was prepared from 4-(tert-Butyl-dimethyl-silanyloxy)-phenylamine and 3-chloropropionyl chloride.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][CH2:26][OH:27])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1O)([CH3:4])([CH3:3])[CH3:2].[C:28](OC(=O)C)(=[O:30])[CH3:29]>C1(C)C=CC=CC=1>[C:28]([O:27][CH2:26][CH2:25][N:18]1[C:19]2=[N:20][CH:21]=[CH:22][CH:23]=[C:24]2[C:16]([C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([C:12]([CH3:14])([CH3:13])[CH3:15])[CH:8]=2)=[N:17]1)(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1cc(-c2nn(CCO)c3ncccc23)cc(C(C)(C)C)c1O
Solvent: Cc1ccccc1
Product: CC(=O)OCCn1nc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)c2cccnc21
Temperature: 20 °C
Yield: 86.4 %

Procedure:
To a solution of 40 g of the compound of Example 43 in 320 ml of toluene is added 22 g of acetic anhydride under stirring, and refluxed for 8 hours. After completion of the reaction, the reaction mixture is cooled to 20° C., washed with 300 ml of water twice and dried over anhydrous sodium sulfate. The toluene is concentrated and the residue is recrystallized from ethanol and dried to give 37 g of 1-(2-acetoxyethyl)-3-(3,5-di-tertiary butylphenyl)-1H-pyrazolo[3,4-b]pyridine, melting at 115°-116° C.
Reaction SMILES: NC1C([Cl:12])=CC=CC=1C(OC)=O.[CH:13]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][CH:22]([N:26]([C:42](=[O:44])[CH3:43])[CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:21]2[CH:45]=[CH:46][CH:47]=[CH:48][C:20]1=2)=[O:18])([CH3:15])[CH3:14]>>[C:42]([N:26]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:29]=1)[CH:22]1[CH2:23][CH2:24][CH2:25][N:19]([C:17]([O:16][CH:13]([CH3:15])[CH3:14])=[O:18])[C:20]2[C:48]([Cl:12])=[CH:47][CH:46]=[CH:45][C:21]1=2)(=[O:44])[CH3:43]
Reactant: COC(=O)c1cccc(Cl)c1N
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccccc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(Cl)cccc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 1 wherein replacement of 2-amino-benzoic acid methyl ester with methyl 2-amino-3-chlorobenzoate following the procedure of Example 1, Steps 1-8 for the synthesis of 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester. CI MS 551 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl.Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1>CN1CCCC1=O>[N:21]1[CH:22]=[CH:23][C:18]([NH:1][C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]=2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:19][CH:20]=1
Reactant: Clc1ccncc1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1N
Agent: Cl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1[nH]c2ccccc2c1Nc1ccncc1
Yield: 60.7 %

Procedure:
A solution ethyl 3-aminoindole-2-carboxylate (4.94 g, 24.2 mmole) and 4-chloropyridine hydrochloride (3.63 g, 24.2 mmole) in 70 mL of 1-methyl-2-pyrrolidinone was heated at 165° C. for 6 hours. The reaction mixture was then quenched into water and the aqueous phase was washed with ethyl acetate. After basification with a potassium carbonate solution, a solid was filtered, rinsed with water and ether and dried to give 4.13 g of a brown solid. A 2.2 g portion was recrystallized from methanol (charcoal treatment) to give 1.40 g of an off-white solid, mp: 248-250° C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.[NH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[C:11]2[CH:19]=[CH:18][C:14]([C:15]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)=[O:17])=[CH:13][CH:12]=2)=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Reactant: Nc1cccnc1
Product: O=C(Nc1cccnc1)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
320 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 400 mg of 4-(methoxycarbonyl)benzoic acid via Procedure G to give methyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate. 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate was then hydrolyzed via Procedure M to give 550 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid. 50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3-aminopyridine via Procedure G. The organic layer was evaporated to dryness and purified on reverse phase HPLC to yield N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-3-yl)terephthalamide. MS (Q1) 429 (M)+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:20]2[S:24][C:23]([C:25]([OH:28])([CH3:27])[CH3:26])=[N:22][CH:21]=2)[CH:6]=[C:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)[CH:8]=1)#[CH:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]1[CH:4]=[C:5]([C:20]2[S:24][C:23]([C:25]([OH:28])([CH3:27])[CH3:26])=[N:22][CH:21]=2)[CH:6]=[C:7]([NH:9][C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)[CH:8]=1)[CH3:2]
Reactant: C#Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)O)s2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C(C)(C)O)s2)c1
Reaction time: 8 h
Yield: 61.7 %

Procedure:
To a solution of 2-[5-(3-ethynyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propan-2-ol (19 mg, 0.047 mmol) in ethyl acetate (1 mL) was added Pd/C (10 wt %, 10.0 mg, 9.4 μmol, and the reaction vessel was then purged with H2 and stirred under an atmosphere of H2 (balloon) overnight. The catalyst was deactivated by addition of dichloromethane, then the mixture was filtered through Celite (ethyl acetate rinse) and concentrated in vacuo. The residue was then purified by preparative HPLC (50-90% CH3CN in 15 mM NH4HCO3(aq)) which provided 12 mg (0.029 mmol, 63%) of 2-[5-(3-ethyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propan-2-ol as a white solid. MS ESI: [M+H]+ m/z 409.1. 1H NMR (400 MHz, (CD3)2CO): δ 9.20 (s, 1H); 8.82 (d, J=4.9 Hz, 1H); 8.12 (s, 1H); 7.94 (s, 1H); 7.67 (s, 1H); 7.25-7.20 (m, 2H); 5.02 (s, 1H); 2.70 (q, J=7.6 Hz, 2H); 1.63 (s, 6H); 1.28 (t, J=7.6 Hz, 3H). rhSYK activity=+++
Reaction SMILES: Cl.[C:2]1([C:8](C2C=CC=CC=2)=[CH:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:26])[CH2:13][CH2:12]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([OH:35])C>>[O:35]=[C:8]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])[CH2:13][CH2:12]1
Reactant: O=C1c2ccccc2CN1C1CCN(CC=C(c2ccccc2)c2ccccc2)CC1
Reactant: CCO
Agent: Cl
Product: O=C(CCN1CCC(N2Cc3ccccc3C2=O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37 %

Procedure:
To a solution of Example 2 Part A compound (1.93 g, 8.92 mmol) in dry ethanol (15 mL) at RT was added a solution of Part B compound (1.1 g, 7.43 mmol) in dry ethanol (2 mL). The reaction was stirred at RT for 4 h. The reaction was evaporated to dryness. Ethyl ether (150 mL) was added, and the solution was washed water (2×30 mL), brine (2×30 mL) and dried over MgSO4. Purification was performed by flash chromatography on silica gel (150 g), loaded and eluted with 4% methanol in dichloromethane. Pure fractions were combined and evaporated to give title compound (1.0 g, 37%) as a yellowish solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH:16](OCC)O)=[CH:11][C:10]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24])C1C=CC=CC=1.Cl.[CH3:28][O:29][C:30]1[CH:42]=[CH:41][C:33]([CH2:34][C:35]2([NH2:40])[CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:32][CH:31]=1.Cl>>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][NH:40][C:35]2([CH2:34][C:33]3[CH:41]=[CH:42][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[CH2:36][CH2:37][CH2:38][CH2:39]2)=[CH:11][C:10]=1[NH:22][S:23]([CH3:26])(=[O:24])=[O:25]
Reactant: COc1ccc(CC2(N)CCCC2)cc1
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: Cl
Product: COc1ccc(CC2(NCC(O)c3ccc(O)c(NS(C)(=O)=O)c3)CCCC2)cc1

Procedure:
Prepared from 645 mg (1.70 mmol) N-[2-benzyloxy-5-(2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 411 mg (1.70 mmol) 1-(4-methoxy-benzyl)-cyclopentylamine hydrochloride according to general method 6. Yield: 369 mg (46%, hydrochloride). Mass spectroscopy: [M+H]+=435.
Reaction SMILES: O=C[C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[O:13]=O>CO>[O:13]=[C:3]([OH:4])[C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6]
Reactant: O=O
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CO
Product: O=C(O)[C@@H](O)[C@H](O)[C@H](O)CO
Yield: 78 %

Procedure:
As a comparative example, it will be noted that Vuorinen et al. (Starke, 43 No. 5, pp. :94-198), in carrying out the oxidation of glucose without methanol, had to use a pressure of pure oxygen of 26 bar in order to obtain an arabinonic acid yield of 78% only with 3.5% and 6.5% impurities consisting of glyceric acid and glycolic acid respectively.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][CH2:19][N:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][C:21]3=[O:34])=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:27]([O:26][C:23]1[CH:24]=[CH:25][N:20]([CH2:19][CH2:18][C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9]3)=[CH:14][CH:13]=2)[C:21](=[O:34])[CH:22]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ccc(OCc4ccccc4)cc3=O)cc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cc(OCc2ccccc2)ccn1CCc1ccc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 400 mg (0.87 mmol) 7-[2-(4-benzyloxy-2-oxo-2H-pyridin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example 24.1) in 5.0 mL DCM is added at RT 0.5 mL trifluoroacetic acid. The reaction mixture is stirred overnight at RT and is neutralized with aqueous 5% NaHCO3-solution. The layers are separated, the organic phase is washed with water, dried over MgSO4, filtered and the solvent is evaporated. The residue is elutriated in tertbutylmethyether, the precipitate is collected and dried.
Reaction SMILES: [C:1]1([N:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:23]1([CH2:28][C:29]2[CH:30]=[CH:31][C:32](Br)=[N:33][CH:34]=2)[CH:27]=[CH:26][N:25]=[CH:24]1>>[N:23]1([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:11]3[CH:12]=[CH:13][C:8]([N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:9][CH:10]=3)=[N:33][CH:34]=2)[CH:27]=[CH:26][N:25]=[CH:24]1
Reactant: Brc1ccc(Cn2ccnc2)cn1
Reactant: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Product: c1ccc(N(c2ccccc2)c2ccc(-c3ccc(Cn4ccnc4)cn3)cc2)cc1

Procedure:
Synthesized using 4-(diphenylamino)phenylboronic acid (364 mg, 1.26 mmol) and 1a (150 mg, 0.63 mmol) according to Method C. Yellow solid. Yield: 140 mg, 0.34 mmol, 55%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.16, (s, 2H), 6.93 (t, J=1.3 Hz, 1H), 7.06 (tt, J=7.3, 1.3 Hz, 2H), 7.12-7.15 (m, 7H), 7.25-7.29 (m, 4H), 7.45 (dd, J=8.2, 2.2 Hz, 1H), 7.58 (br, s, 1H), 7.65 (dd, J=8.2, 0.6 Hz, 1H), 7.83-7.86 (m, 2H), 8.54 (dd, J=2.5, 0.6 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=48.2, 119.0, 119.8, 122.8, 123.4, 124.9, 127.7, 129.2, 129.3, 130.2, 132.0, 135.7, 137.3, 147.3, 148.5, 149.1, 157.3; MS (ESI): m/z=402.94 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11].C(Br)(Br)(Br)[Br:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:16][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:14])[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CN(c1ccccc1CO)S(C)(=O)=O
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(c1ccccc1CBr)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
196 d) To a stirred mixture of N-(2-hydroxymethyl-phenyl)-N-methyl-methanesulfonamide (0.90 g, 4.2 mmol) and carbon tetrabromide (2.40 g, 7.24 mmol) in dry tetrahydrofuran (50 mL) was added triphenylphosphine (1.90 g, 7.23 mmol). The mixture was stirred at room temperature for 18 hours. The volatiles were evaporated under reduced pressure. The residue was triturated with ethyl acetate (30 mL) then filtered and evaporated under reduced pressure. The residue was purified via chromatography (silica gel column 40 g 5%→100% ethyl acetate:hexane). N-(2-Bromomethyl-phenyl)-N-methyl-methanesulfonamide was isolated as pale yellow solid (0.86 g, 74%), 1H NMR (400 MHz, CDCl3, δ, ppm): 7.57-7.52 (m, 1H), 7.41-7.34 (m, 2H), 7.30-7.25 (m, 1H), 5.29-4.30 (br m, 2H), 3.34 (s, 3H), 2.98 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH:5]([O:9][CH3:10])[CH:6]([OH:8])[CH3:7].[CH2:11](Br)[CH:12]=[CH2:13]>CN(C)C=O>[CH3:3][O:4][CH:5]([O:9][CH3:10])[CH:6]([CH3:7])[O:8][CH2:13][CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: COC(OC)C(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(C)C(OC)OC
Reaction time: 0.25 h

Procedure:
60% sodium hydride (992 mg) was added to a solution of 1,1-dimethoxy-propan-2-ol (2.49 g) in dimethylformamide (50 mL) at 0° C., followed by stirring for 15 minutes. Allyl bromide (1.96 mL) was added at the same temperature, followed by stirring for 15 minutes. Ice was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (3.46 g).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O[CH:24]=[C:25]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]([O:28][CH2:29][CH3:30])=[O:27])C>N1C=CC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]([CH:24]=[C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:12][CH:13]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: c1cc(NC2CCOCC2)ccc1CN1CCOCC1
Solvent: c1ccncc1
Product: CCOC(=O)C(=CN(c1ccc(CN2CCOCC2)cc1)C1CCOCC1)C(=O)OCC
Temperature: 140 °C

Procedure:
A flask containing N-[4-(4-morpholinylmethyl)phenyl]tetrahydro-2H-pyran-4-amine (0.34 g) is treated with diethyl ethoxymethylenemalonate (0.30 mL) and pyridine (0.20 mL). The flask is tightly capped and heated to 140° C. for 2 hours. The reaction is cooled to room temperature and azeotroped under reduced pressure with toluene (3×). The residue is dissolved in dichloromethane and washed with water, brine, dried and concentrated under reduced pressure. The residue is chromatographed on silica eluting with 2% to 6% methanol in dichloromethane. The product-containing fractions are evaporated to give 0.41 g of diethyl 2-{[4-(4-morpholinylmethyl)(tetrahydro-2H-pyran-4-yl)anilino]methylene}malonate as a tan oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:21]=[C:22]([S:27]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)(=[O:29])=[O:28])[CH:23]=[CH:24][C:25]=1[CH3:26])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1Br
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: Cc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-(3-bromo-4-methyl-benzenesulfonyl)-4-methyl-piperazine (Intermediate 144), the title compound was obtained after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [OH:1][CH:2]([CH2:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=1)[CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([C:18](OCC)=O)[CH2:16][CH2:17][C:5]1=2.[H-].[H-].[H-].[H-].[Li+].[Al+3].CO>C1COCC1>[CH3:18][N:15]1[CH2:16][CH2:17][C:5]2[N:4]([CH2:3][CH:2]([OH:1])[CH2:23][NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH3:32])[CH:26]=3)[C:12]3[CH:11]=[CH:10][C:9]([CH3:13])=[CH:8][C:7]=3[C:6]=2[CH2:14]1
Reactant: CCOC(=O)N1CCc2c(c3cc(C)ccc3n2CC(O)CNc2cccc(OC)c2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(NCC(O)Cn2c3c(c4cc(C)ccc42)CN(C)CC3)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 4.7 %

Procedure:
Following a literature procedure (Zoidis, G; Kolocouris, N; Naesens, L; De Clercq, E. Bioorg. Med. Chem. 2009, 17, 1534-1541), the title compound of Example 18 (0.015 g, 0.034 mmol) was dissolved in anhydrous THF (0.34 mL) and cooled to 0° C. A solution of LAH (0.10 mL, 1.0 M in THF) was added dropwise, and the reaction was stirred for 2 h at 0° C. MeOH was added to quench the remaining LAH and after 45 min, the mixture was partitioned between EtOAc/H2O. The organic layer was separated and the aqueous layer was extracted with EtOAc (3×), and the combined organic layers were washed with satd. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (SiO2, 0-20% MeOH/Acetone+1% Et3N), followed by PTLC (10% MeOH/Acetone+1% Et3N) to afford the desired product (0.6 mg, 5%).
Reaction SMILES: [NH2:1][C:2]([N:4]1[CH2:9][CH2:8][CH:7](NC([C@H]2CC[C@H](O[N+]([O-])=O)CC2)=O)[CH2:6][CH2:5]1)=[O:3].N1CCC(NC([C@H]2CC[C@H]([O:38][N+:39]([O-:41])=[O:40])CC2)=O)CC1>C(O)C>[NH2:1][C:2]([N:4]1[CH2:5][CH2:6][CH:7]([O:40][N+:39]([O-:41])=[O:38])[CH2:8][CH2:9]1)=[O:3]
Reactant: NC(=O)N1CCC(NC(=O)[C@H]2CC[C@H](O[N+](=O)[O-])CC2)CC1
Reactant: O=C(NC1CCNCC1)[C@H]1CC[C@H](O[N+](=O)[O-])CC1
Solvent: CCO
Product: NC(=O)N1CCC(O[N+](=O)[O-])CC1
Yield: 25 %

Procedure:
trans-N-(1-aminocarbonylpiperidin-4-yl)-4-nitroxycyclohexanecarboxylic acid amide from trans-4-nitroxycyclohexanecarboxylic acid piperidin-4-ylamide; yield 25% of theory; solvent: ethanol; m.p. 187°-188° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]1[C:8]([O:10][CH3:11])=[O:9].P(Cl)(Cl)(Cl)=O.C[CH2:18][O:19]CC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[CH3:1][N:2]1[C:6]([CH:18]=[O:19])=[C:5]([CH3:7])[CH:4]=[C:3]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(C)cn1C
Reactant: CCOCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(C)c(C=O)n1C
Temperature: 90 °C
Yield: 84 %

Procedure:
A solution of methyl 1,4-dimethylpyrrole-2-carboxylate (2.5 g, 0.016 m) in 20 ml of dried 1,2-dichloroethane was added over two minutes to a stirred mixture of phosphorous oxychloride (2.3 ml) and dried, N,N-dimethylformamide (1.94 ml) in 50 ml of dichloroethane, and the resultant mixture heated at 90° C. (bath temperature) for 45 minutes. The cooled reaction mixture was treated with excess ice-water and ether, 10% aqueous sodium carbonate (50 ml) added, the ether layer removed and the aqueous phase re-extracted two times with fresh ether, and the combined ether layers washed well with water and dried over anhydrous sodium sulfate. Concentration of the ether solution yielded 2.48 g (84%) of methyl 1,4-dimethyl-5-formylpyrrole-2-carboxylate as a yellow solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[C:10]([Cl:18])[C:11]([CH2:14][N+:15]([O-:17])=[O:16])=[N:12][CH:13]=1.Cl[CH2:20][NH:21][C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]([F:32])([F:31])[F:30].Cl>CN(C)C=O>[Br:7][C:8]1[CH:9]=[C:10]([Cl:18])[C:11]([CH:14]([N+:15]([O-:17])=[O:16])[CH2:20][NH:21][C:22](=[O:33])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:29]([F:30])([F:32])[F:31])=[N:12][CH:13]=1
Reactant: O=[N+]([O-])Cc1ncc(Br)cc1Cl
Reactant: O=C(NCCl)c1ccccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCC(c1ncc(Br)cc1Cl)[N+](=O)[O-])c1ccccc1C(F)(F)F
Temperature: 0 °C
Yield: 67 %

Procedure:
To 4.2 g of potassium tert-butoxide in 72 ml of N,N-dimethylformamide, 7.8 g of 5-bromo-3-chloro-2-(nitromethyl)pyridine was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at the same temperature for another 1 hour. Then, to the reaction mixture, 4.7 g of the N-chloromethyl-2-(trifluoromethyl)benzamide prepared in Step 2 in Synthetic Example 19 in 30 ml of N,N-dimethylformamide was added dropwise with stirring under cooling with ice, and after the addition, the mixture was stirred at room temperature for another 2 hours. After completion of the reaction, the reaction mixture was carefully poured into 100 ml of ice-water, acidified with 10% aqueous hydrochloric acid and extracted with ethyl acetate (100 ml×2). The resulting organic layers were combined, washed with water (100 ml×2) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 6.0 g of the desired product as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=O)=[C:16]2[CH3:26])=[CH:11][C:10]=1[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:29][OH:30].CO>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]=[N:29][OH:30])=[C:16]2[CH3:26])=[CH:11][C:10]=1[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C=O)c2ccccc2n1-c1ccc(OCc2ccccc2)c(F)c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1c(C=NO)c2ccccc2n1-c1ccc(OCc2ccccc2)c(F)c1
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
To a stirred solution of 1-(4-benzyloxy-3-fluorophenyl)-2-methyl-1H-indole-3-carbaldehyde (0.81 g, 2.3 mmol), hydroxylamine hydrochloride (0.25 g, 3.6 mmol) and methanol (25 mL) was added pyridine (1 mL). The reaction mixture was heated to reflux and held for 30 min. The mixture was cooled, the methanol removed by evaporation and the residue taken up in ethyl acetate/water. The product was extracted into ethyl acetate (2×50 mL), the ethyl acetate washed with water and brine and dried over MgSO4. The solvent was evaporated, and the crude product was purified by silica gel chromatography (25% ethyl acetate-hexanes) to provide a white solid (0.7 gr, 83%): mp 167-168° C.; 1H NMR (DMSO-d6): δ 2.32 (3H, s), 5.29 (2H, s), 6.99-7.01 (1H, m), 7.10-7.17 (2H, m), 7.25-7.28 (1H, m), 7.37-7.42 (1H, m), 7.43-7.49 (3H, m), 7.49-7.54 (2H, m), 8.01-8.04 (1H, m), 8.41 (1H, s), 10.67 (1H, s); MS m/z (M+H)+ 375: Anal. for C23H19FN2O2: Calc'd: C, 73.78; H, 5.11; N, 7.48. Found: C, 73.53; H, 5.06; N, 7.32