Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.OO.CC([OH:29])C>C(O)=O.[Pd]>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:15][CH2:16][C@:17]2([OH:29])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: CC(C)O
Agent: [Pd]
Agent: OO
Solvent: O=CO
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reaction time: 16 h

Procedure:
Thebaine (67 g, 0.215 mol) was dissolved in formic acid (98-100%, 120 g) and hydrogen peroxide (30% in water, 24.5 g, 0.216 mol) added at 0° C. The mixture was pumped continuously at 2 ml/min through a 30 ml continuous flow reactor at 80° C. (15 min residence time). An analytical control after the continuous reactor showed less than 1% Thebaine remaining. The continuous stream was added directly to the hydrogenation autoclave that was precharged with 2-propanol (204 g), formic acid (98-100%, 64 g) and 5% Pd/C (7.6 g) and held at 100° C. under H2 (40 bar). The hydrogenation was stirred for 16 h. After the hydrogenation, the catalyst was filtered off and the crude mixture was either basified with NaOH to obtain the low impurity Oxycodone base, or treated with HCl in 2-Propanol to give the Oxycodone HCl. The yields were 82% for the base and 78% for the HCl salt. The 14-Hydroxycodeinone content of the base was 49 ppm and of the HCl salt 29 ppm.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Br[CH2:18][C:19]1[N:29]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:22]2[N:23]=[C:24]([C:27]#[N:28])[N:25]=[CH:26][C:21]=2[CH:20]=1>CN(C=O)C.C1OCCOCCOCCOCCOCCOC1>[CH3:32][C:31]([CH3:34])([CH3:33])[CH2:30][N:29]1[C:22]2[N:23]=[C:24]([C:27]#[N:28])[N:25]=[CH:26][C:21]=2[CH:20]=[C:19]1[CH2:18][N:14]1[CH2:15][CH2:16][N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH3:3])[CH2:12][CH2:13]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(Cc2cc3cnc(C#N)nc3n2CC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
To a suspension of NaH (0.91 mmol) in DMF (10 ml), 1-(2-methoxyphenyl)piperazine (1.04 mmol) and 18-crown-6 (0.003 mmol) are successively added at 0° C. To the mixture, 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.65 mmol) is added at 0° C. and the mixture is stirred for 2 h at ambient temperature. The reaction mixture is quenched with ice-water and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over magnesium sulfate. Chromatography on silica gel (eluent; n-hexane:AcOEt=1:1) give 227 mg of desired 7-(2,2-Dimethyl-propyl)-6-[4-(2-methoxy-phenyl)-piperazin-1-ylmethyl]-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 83% yield.
Reaction SMILES: C(O[CH:4](OCC)[N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])C.[NH2:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].CN(C=O)C>CCOCC>[C:20]([C:19]1[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=1[N:17]=[CH:4][N:5]1[CH2:9][CH2:8][NH:7][C:6]1=[N:10][N+:11]([O-:13])=[O:12])#[N:21]
Reactant: N#Cc1ccccc1N
Reactant: CCOC(OCC)N1CCNC1=N[N+](=O)[O-]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: N#Cc1ccccc1N=CN1CCNC1=N[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 85.4 %

Procedure:
0.05 g of boron trifluoride ether complex was added to a mixture of 2.0 g of 1-diethoxymethyl-2-nitroiminoimidazolidine, 1.02 g of o-aminobenzonitrile and 5 ml of DMF, followed by agitation at room temperature for 15 minutes. Ether was added to the reaction mixture, and the resultant crystals were collected by filtration and dried to give 1.9 g of 1-(2-cyanophenyliminomethyl)-2-nitroiminoimidazolidine.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.C(C1([SiH2][C:35]([O:52]C(C2C=NC(C3CC3)=CC=2)([SiH2]C2C=CC=CC=2)[SiH2]C2(C(C)(C)C)C=CC=CC2)([C:43]2[CH:44]=[N:45][C:46]([CH:49]3[CH2:51][CH2:50]3)=[CH:47][CH:48]=2)[SiH2]C2C=CC=CC=2)C=CC=CC1)(C)(C)C>O1CCCC1>[CH:49]1([C:46]2[N:45]=[CH:44][C:43]([CH2:35][OH:52])=[CH:48][CH:47]=2)[CH2:51][CH2:50]1
Reactant: CC(C)(C)C1([SiH2]C(OC([SiH2]c2ccccc2)([SiH2]C2(C(C)(C)C)C=CC=CC2)c2ccc(C3CC3)nc2)([SiH2]c2ccccc2)c2ccc(C3CC3)nc2)C=CC=CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1ccc(C2CC2)nc1
Reaction time: 1 h
Yield: 119.9 %

Procedure:
After adding 1.0 M tetra n-butylammonium fluoride-tetrahydrofuran (3.7 ml, 3.7 mmol) to a solution of 1-(tert-butyl)-1,1-diphenylsilyl [(6-cyclopropyl-3-pyridyl)methyl]ether (1.3 g) in tetrahydrofuran (7 ml) dropwise while cooling on ice, the mixture was stirred for 1 hour. After confirming completion of the reaction by thin layer chromatography, the solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (283 mg, two steps, 14%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:6](=[CH:7][N:8](COCC[Si](C)(C)C)[N:9]=2)[CH:5]=[C:4]([CH2:19][CH:20]([C:41]2[CH:42]=[C:43]([CH:47]=[CH:48][N:49]=2)[C:44]([OH:46])=O)[O:21][C:22]([N:24]2[CH2:29][CH2:28][CH:27]([N:30]3[CH2:39][C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[NH:32][C:31]3=[O:40])[CH2:26][CH2:25]2)=[O:23])[CH:3]=1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH:61]1[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]1>C(Cl)Cl>[O:40]=[C:31]1[N:30]([CH:27]2[CH2:26][CH2:25][N:24]([C:22]([O:21][CH:20]([C:41]3[CH:42]=[C:43]([C:44]([N:61]4[CH2:66][CH2:65][CH2:64][CH2:63][CH2:62]4)=[O:46])[CH:47]=[CH:48][N:49]=3)[CH2:19][C:4]3[CH:5]=[C:6]4[C:10](=[C:2]([CH3:1])[CH:3]=3)[NH:9][N:8]=[CH:7]4)=[O:23])[CH2:29][CH2:28]2)[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32]1
Reactant: C1CCNCC1
Reactant: Cc1cc(CC(OC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cc(C(=O)O)ccn2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(CC(OC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2cc(C(=O)N3CCCCC3)ccn2)cc2cn[nH]c12
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a solution of (±)-2-(2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidine-1-carbonyloxy)ethyl)isonicotinic acid (39.2 mg, 0.057 mmol, 1.0 equiv.) in methylene chloride (0.7 mL) was added a drop of dimethylformamide (catalytic) followed by dropwise addition of oxalyl chloride (2 M in methylene chloride, 0.15 mL, 0.3 mmol, 5 equiv) at room temperature under nitrogen. After 2 h, excess piperidine was added dropwise and the mixture was further stirred for 1 h. The mixture was concentrated to a gel and was suspended in methylene chloride (2 mL). Trifluoroacetic acid (1 mL) was added and the resulting clear tan solution was stirred at room temperature for 6 h. The solvents were removed in vacuo and the residue was partitioned between 1 N sodium hydroxide and ethyl acetate. The layers were separated. The organic layer was washed with brine, dried and concentrated. Purification by flash column chromatography (6% methanol/methylene chloride) afforded the desired product (30.4 mg, 85.4%) as an off-white powder. MS (ESI) [M+H]+=622. 1H-NMR (400 MHz, CDCl3) δ 8.69 (d, J=4.4 Hz, 1H), 7.95 (br., 1H), 7.70 (br., 1H), 7.50-6.80 (m, 6H), 6.68 (br., 1H), 6.05-5.94 (m, 1H), 4.65-3.80 (m, 4H), 3.64 (br., 2H), 3.50-3.18 (m, 2H), 3.18-2.60 (m, 4H), 2.48 (s, 3H), 1.85-1.44 (m, 9H), 1.44-1.10 (m, 4H). HPLC tR=1.79 min.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH2:19][CH3:20].[C:40](O)(=[O:46])[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CN(C)C1C=CN=CC=1.ClCCl>[C:40]([O:39][C:36]1[CH:35]=[CH:34][C:33]([C:30]2[CH:31]=[N:32][C:27]([C:24]3[CH:23]=[CH:22][C:21]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=3)=[N:28][CH:29]=2)=[CH:38][CH:37]=1)(=[O:46])[CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCC(=O)O
Reactant: CCCCCc1ccc(-c2ncc(-c3ccc(O)cc3)cn2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCC(=O)Oc1ccc(-c2cnc(-c3ccc(CCCCC)cc3)nc2)cc1
Reaction time: 8 h
Yield: 76.4 %

Procedure:
0.8 g of N,N'-dicyclohexylcarbodiimide is added within 5 minutes while stirring to a solution of 1.0 g of 4-(2-[4-pentylphenyl]-5pyrimidinyl)phenol, 0.4 g of caproic acid and 0.05 g of 4-(dimethylamino)pyridine in 30 ml of dichloro-methane. The reaction mixture is stirred overnight, then filtered, the filtrate is washed with saturated sodium bicarbonate solution and with water and concentrated. Chromatography of the residue on silica gel with hexane/ethyl acetate (vol. 4:1) and two-fold recrystallization of the fractions which are pure according to thin-layer chromatography give 1.0g of 4-(2-[4-pentylphenyl]-5-pyrimidinyl)phenyl hexanoate; m.p. (C-SC) 124° C., phase transition (SC -SA) 185° C., cl.p. (SA -I) 224° C.
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:9][C@H:8]([O:10][CH3:11])[C@@H:7]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:6]1)=[O:4].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=[O:34])=[CH:24][C:23]=1[F:35]>>[F:35][C:23]1[CH:24]=[C:25]([N:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]2=[O:34])[CH:26]=[CH:27][C:22]=1[NH:21][C:3]([C@@H:5]1[CH2:6][C@H:7]([NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[C@@H:8]([O:10][CH3:11])[CH2:9]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OC)C1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Product: CO[C@H]1C[C@H](C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
In analogy to example 1C, (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-methoxy-cyclopentanecarboxylic acid methyl ester was reacted with 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-4-[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-2-methoxy-cyclopentyl}-amide. Light yellow amorphous solid. MS: 490.1 ([M+H]+).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[NH:14][C:15]([C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23](Cl)=[N:22][C:21]=12)=[O:16].[NH3:29]>CC(O)C>[F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[O:13][N:12]=[CH:11][C:10]=1[NH:14][C:15]([C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23]([NH2:29])=[N:22][C:21]=12)=[O:16]
Reactant: N
Reactant: O=C(Nc1cnoc1-c1ccccc1C(F)(F)F)c1cnn2ccc(Cl)nc12
Solvent: CC(C)O
Product: Nc1ccn2ncc(C(=O)Nc3cnoc3-c3ccccc3C(F)(F)F)c2n1
Temperature: 120 °C
Yield: 31 %

Procedure:
A mixture of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-amide (200 mg, 0.49 mmol, 1.0 equiv) and 2M ammonia in propan-2-ol (4 mL) was sealed and heated in a microwave reactor at 120° C. for 40 minutes. The solvent was removed under vacuum and the resultant residue was purified by flash column chromatography on silica gel (gradient: 0 to 5% methanol in dichloromethane) to afford 58.6 mg (31%) of 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-amide. LCMS (ESI) m+H=389.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.60 (s, 1H), 9.07 (s, 1H), 8.63 (d, 1H), 8.18 (s, 1H), 7.99 (d, 1H), 7.95-7.77 (m, 3H), 7.70-6.60 (br, 2H), 6.39 (d, 1H).
Reaction SMILES: [NH2:1][NH2:2].O[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2>O.[Cl-].[Na+].O>[NH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)[NH2:2]
Reactant: NN
Reactant: Oc1cccc2cccnc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: NNc1cccc2cccnc12
Temperature: 40 °C

Procedure:
A solution of hydrazine in water (equivalent to 250 ml of 100% hydrazine hydrate) was added to the 8-hydroxyquinoline and the mixture was refluxed under nitrogen for 68 hours. After cooling to about 40° C., brine was added and the mixture was extracted with benzene. The benzene solution was washed once with brine, three times with Claisen's alkali (prepared by dissolving 35 g of potassium hydroxide in 25 ml of water, cooling, and adding 100 ml of methanol), twice again with brine, dried over magnesium sulfate, filtered and evaporated to give 60.0 g of an orange oil which crystallized on standing. IR and NMR analysis confirmed the product to be 8-hydrazinoquinoline.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1C(C(O)=O)=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](Cl)(=O)[C:35]([Cl:37])=[O:36]>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:34]([C:35]([Cl:37])=[O:36])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)Cl)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
2-[(Benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (300 mg) was dissolved in THF (6.0 ml), and oxalyl chloride (122 μl) and DMF (1 drop) were added at 0° C. with stirring, and the mixture was stirred at room temperature for 2 hrs. and concentrated under reduced pressure. Toluene was added to the residue and they were boiled together several times and dried to give 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carbonyl chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15]OS(C)(=O)=O)=[CH:10][CH:9]=2)[C:6](=[O:21])[CH:5]=[CH:4][C:3]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.[NH2:31][C@H:32]([C:37]([OH:39])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35]>>[NH2:1][C:2]1[N:7]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][NH:31][C@H:32]([C:37]([O:39][C:3]([CH3:22])([CH3:4])[CH3:2])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:12][CH:13]=2)[C:6](=[O:21])[CH:5]=[CH:4][C:3]=1[C:22]([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)=[O:30]
Reactant: CS(=O)(=O)OCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1
Reactant: CC(C)C[C@H](N)C(=O)O
Product: CC(C)C[C@H](NCCc1ccc(-n2c(N)c(C(=O)c3ccc(F)cc3)ccc2=O)cc1)C(=O)OC(C)(C)C

Procedure:
From Intermediate 4J and L-Leucine tbutyl ester. LC/MS: m/z 522 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ: 9.40-9.10 (2H, m), 7.59-7.44 (5H, m), 7.38-7.30 (4H, m), 5.71 (1H, d, J=9.6 Hz), 4.00 (1H, brs), 3.40-3.28 (1H, m), 3.25-3.15 (1H, m), 3.10-3.00 (2H, m), 1.80-1.70 (3H, m), 0.96 (6H, d, J=5.1 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:20][C:21]4[CH:22]=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:24]=[C:25]([CH3:27])[CH:26]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: Cc1cc(N)cc(C(F)(F)F)c1
Product: Cc1cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc(C(F)(F)F)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3-amino-5-methylbenzotrifluoride were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-methyl-5-trifluoromethylphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.57 (bs, 1H), 9.39 (bs, 1H), 8.12 (d, 1H, J=3.6 Hz), 7.77 (s, 2H), 7.25-7.13 (m, 2H), 7.02 (s, 1H), 6.79 (d, 1H, J=9.0 Hz), 4.20 (s, 4H), 2.27 (s, 3H); LCMS: purity: 100%; MS (m/e): 421 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32](=[O:34])[NH2:33])=[CH:28][N:27]=3)=[CH:20][CH:21]=2)[CH2:16]1)=O)(C)(C)C>ClCCl>[CH2:16]1[C:17]2[C:22](=[CH:21][CH:20]=[C:19]([O:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([NH2:33])=[O:34])=[CH:28][N:27]=3)[CH:18]=2)[CH2:23][CH2:24][NH:15]1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc(C(N)=O)cn3)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CNCC3)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
Add drop wise via an addition funnel a solution of trifluoroacetic acid (3.3 mL) in dichloromethane (10 mL) to a stirred solution of 7-(5-carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.2 g, 3.3 mmol)) in dichloromethane (50 mL) at 0° C. Warm to room temperature and stir for 18 hours. Evaporate on a rotary evaporator, dissolve the residue in methanol, and then apply in equal parts to 2-10 g SCX cartridges. Wash each cartridge with methanol until neutral pH then elute product with 2.0 M ammonia in methanol. Collect the basic eluent and concentrate on a rotary evaporator to yield 6-(1,2,3,4-tetrahydro-isoquinolin-7-yloxy)-nicotinamide (0.9 g, 3.3 mmol): 1H NMR (CDCl3, 300.00 MHz): 8.57 (s, 1H); 8.15 (d, 1H); 7.15-7.13 (m, 1H); 6.96-6.89 (m, 2H); 6.80 (s, 1H); 5.87 (br, 2H); 4.01 (s, 2H); 3.17-3.13 (m, 2H); 2.82-2.78 (m, 2H); 1.73 (br, 1H).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH:19]3[S:25][C:23](=[O:24])[NH:22][C:20]3=[O:21])=[CH:16][CH:17]=2)=[N:7][CH:8]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:29]>C(Cl)Cl>[CH2:2]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:29])[CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]3[S:25][C:23](=[O:24])[NH:22][C:20]3=[O:21])=[CH:14][CH:13]=2)=[N:7][CH:8]=1)[CH3:1]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCc1ccc(CCOc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Solvent: ClCCl
Product: CCc1ccc(C(O)COc2ccc(CC3SC(=O)NC3=O)cc2)nc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
The N-oxide of racemic pioglitazone (935 mg, 2.54 mmol) was suspended in 12 mL CH2Cl2, then trifluoroacetic anhydride (TFAA, 1.49 mL, 12.69 mmol., 5 equiv.) was added and the reaction mixture was shaken at 50° C. After 24 h, an additional equivalent of TFAA was added and the vial was shaken for another 24 h. After the solvent and excess TFAA were evaporated, the resuting light yellow residue (1.922 g) was dissolved in 5 mL tetrahydrofuran (THF), and next a saturated NaHCO3 aqueous solution was added until gas evolution stopped (4 mL). The resulting solution was diluted with water (10 mL) and the mixture extracted with ethyl acetate (EtOAc, 3×20 mL). The combined organic layers were dried over Na2SO4, filtered and evaporated to provide the alcohol in crude form. The crude alcohol was purified by preparative HPLC (0.1% TFA water/acetonitrile gradient). Fractions containing the pure product were neutralized by addition of triethylamine, combined, and evaporated to provide a residue. The residue was redissolved in EtOAc and the organic layer was washed with brine then dried over Na2SO4. Evaporation of the solvent gave pure 5-({p-[2-(5-ethylpyridin-2-yl)-2-hydroxyethoxy]phenyl}methyl)-1,3-thiazolidine-2,4-dione as a white foam (434.8 mg, 1.17 mmol, 46% yield). LC-MS: 373 (M+1).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@@:3]21[CH2:34][C:21]1=[N:22][C:23]3[CH:24]=[CH:25][C:26]([C:30](OC)=[O:31])=[CH:27][C:28]=3[CH:29]=[C:20]1[CH2:19]2.[NH2:35][NH2:36]>CO>[O:1]=[C:2]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:17])([CH3:16])[CH3:18])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@@:3]21[CH2:34][C:21]1=[N:22][C:23]3[CH:24]=[CH:25][C:26]([C:30]([NH:35][NH2:36])=[O:31])=[CH:27][C:28]=3[CH:29]=[C:20]1[CH2:19]2
Reactant: COC(=O)c1ccc2nc3c(cc2c1)C[C@@]1(C3)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Reactant: NN
Solvent: CO
Product: C[Si](C)(C)CCOCN1C(=O)[C@]2(Cc3cc4cc(C(=O)NN)ccc4nc3C2)c2cccnc21
Temperature: 70 °C

Procedure:
To a solution of methyl (2S)-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[cyclopenta[b]quinoline-2,3′-pyrrolo[2,3-b]pyridine]-7-carboxylate from Step G (317 mg, 0.667 mmol) in MeOH (1 mL) was added hydrazine (1.0 mL, 32 mmol). The reaction was sealed and then heated to 70° C. for 18 hours. After cooling to ambient temperature, the bulk of the solvent was removed in vacuo. The residue was diluted with DCM (50 mL) and water (20 mL). The organics were then successively washed with water, half-saturated brine and brine before being dried over sodium sulfate. The organics were then filtered, concentrated in vacuo to give the title compound. MS: m/z=476 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:11][CH2:10][C@H:9]1[C:23](O)=[O:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][C:28]=1[O:34][CH3:35].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH2:11][CH2:10][C@H:9]1[C:23](=[O:24])[NH:31][C:30]1[CH:32]=[CH:33][C:27]([Cl:26])=[C:28]([O:34][CH3:35])[CH:29]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc([C@H]2CC[C@@H](C(=O)O)N2C(=O)OC(C)(C)C)cc1OC
Reactant: COc1cc(N)ccc1Cl
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(NC(=O)[C@@H]2CC[C@H](c3ccc(OC)c(OC)c3)N2C(=O)OC(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A solution of (2S,5R)5-(3,4-dimethoxy-phenyl)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.50 g, 7.11 mmol, 1.0 equivalent), 4-chloro-3-methoxyaniline (1.12 g, 7.11 mmol, 1.0 equivalent), PyBrop coupling reagent (3.98 g, 8.54 mmol, 1.2 equivalents), and DIEA (1.86 ml, 10.7 mmol, 1.5 equivalents) in dichloromethane (35 ml) was allowed to stir at room temperature overnight. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (100 ml) and washed with 1N NaOH (3×100 ml). The organic extract was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude oil was filtered through a layer of silica and eluted with ethyl acetate:hexanes (1:1). The filtrate was concentrated in vacuo to afford (2S,5R)2-(4-chloro-3-methoxy-phenylcarbamoyl)-5-(3,4-dimethoxy-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.48 g, 7.09 mmol, 100% yield). Analysis H1 NMR (400 MHz, CDCl3): 7.59 (1H, broad s), 7.23 (1H, m), 6.85–6.60 (4H, m) 4.64 (2H, m), 3.00 (3H, s), 3.83 (3H, s), 3.56 (3H, broad s), 2.62 (1H, broad m), 2.36 (1H, m), 2.11–1.89 (2H, m), 1.22 (9H, broad s). MS (LC-MS): Calculated for C25H31ClN2O6 490.19, found 491.15 (M+H)+.