Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:6]([OH:17])[CH:5]=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CC(C)=O>[OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[C:6]([O:17][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:5]=[CH:4][C:3]=1[C:18](=[O:20])[CH3:19]
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1ccc(O)c(CCCc2ccccc2)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c(CCCc2ccccc2)c1O

Procedure:
A mixture of 6.69 g (24.7 mmol) of 1-[2,4-dihydroxy-3-(3-phenylpropyl)phenyl]ethanone, from the preceding example, 5.35 g (31.3 mmol) of benzyl bromide, 14.9 g (0.108 mol) of anhydrous potassium carbonate, 115 mL of dry N,N-dimethylformamide, and 230 mL of acetone was stirred and refluxed for 8 hr. After being cooled, the slurry was filtered with suction and the solids washed well with acetone. The filtrate and washes were combined and concentrated under reduced pressure to give a yellow oil which was chromatographed on silica gel. There was obtained 5.57 g (62.6%) of the desired monoether as a pale-yellow solid. Recrystallization of a sample from hexane-ethyl acetate gave the title compound as colorless needles, mp 115°-116° C.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]([OH:9])=O)[S:5][CH:6]=1.[CH3:10][S:11]([NH2:14])(=[O:13])=[O:12].N12CCCN=C1CCCCC2>O1CCCC1>[Br:1][C:2]1[N:3]=[C:4]([C:7]([NH:14][S:11]([CH3:10])(=[O:13])=[O:12])=[O:9])[S:5][CH:6]=1
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1nc(Br)cs1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CS(=O)(=O)NC(=O)c1nc(Br)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Bromo-1,3-thiazole-2-carboxylic acid (1.0 g, 4.8 mmol) were initially charged in tetrahydrofuran (10 ml). N,N′-Carbonyldiimidazole (1.17 g, 7.2 mmol) was added and the reaction mixture was heated under reflux for 1 h. Methanesulphonamide (0.69 g, 7.2 mmol) was added and, after 10 min, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.10 g, 7.2 mmol). The reaction mixture was stirred at room temperature for 16 h and then the solvent was removed under reduced pressure. The residue was taken up in water and acidified with hydrochloric acid. The precipitated product was filtered off with suction. This gave 1.18 g (84% of theory) of 4-bromo-N-(methylsulphonyl)-1,3-thiazole-2-carboxamide.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8]([CH:39]=[C:40]([CH3:42])[CH:41]=1)[O:9][C:10]1[N:15]([CH2:16][C:17]2[CH:22]=[C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:20]=[C:19]([F:33])[CH:18]=2)[C:14](=[O:34])[NH:13][C:12](=[O:35])[C:11]=1[CH:36]([CH3:38])[CH3:37].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>O.CC(C)=O>[F:33][C:19]1[CH:18]=[C:17]([CH2:16][N:15]2[C:10]([O:9][C:8]3[CH:7]=[C:6]([CH:41]=[C:40]([CH3:42])[CH:39]=3)[CH:2]=[O:1])=[C:11]([CH:36]([CH3:37])[CH3:38])[C:12](=[O:35])[NH:13][C:14]2=[O:34])[CH:22]=[C:21]([NH:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[N:20]=1
Reactant: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C5OCCO5)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(CNc2cc(Cn3c(Oc4cc(C)cc(C=O)c4)c(C(C)C)c(=O)[nH]c3=O)cc(F)n2)cc1
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of 6-(3-[1,3]dioxolan-2-yl-5-methyl-phenoxy)-1-[2-fluoro-6-(4-methoxy-benzylamino)-pyridin-4-ylmethyl]-5-isopropyl-1H-pyrimidine-2,4-dione (714 mg, 1.24 mmol), PPTS (62 mg, 0.25 mmol), and water (5 drops) in acetone (10 ml) was heated under reflux for 3 hr. After cooling to room temperature, the mixture was evaporated in vacuo and the residue was purified by silica gel column chromatography (eluent, EA: hexanes (from 1:1 to 2:3)) to afford 548 mg (83%) of a white solid. 1H NMR (200 MHz, CD3OD/CDCl3) δ 1.00 (6H, d, J=7.4 Hz), 2.30 (3H, s), 2.58 (1H, m), 3.71 (3H, s), 4.19 (2H, s), 4.65 (2H, s), 5.78 (1H, s), 5.86 (1H, s), 6.76-6.80 (3H, m), 7.02 (1H, s), 7.11-7.16 (2H, s), 7.32 (1H, s), 9.78 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].O[CH2:11][CH2:12][C@H:13]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[O:9][CH2:11][CH2:12][C@H:13]([N:15]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:25])[CH3:14]
Reactant: C[C@H](CCO)N1C(=O)c2ccccc2C1=O
Reactant: Oc1c(Cl)cccc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](CCOc1c(Cl)cccc1Cl)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 301.7 %

Procedure:
To a solution of 2,6-dichlorophenol (14.9 mg, 0.0910 mmol) in THF (1.5 mL) was added (R)-2-(4-hydroxybutan-2-yl)isoindoline-1,3-dione (20 mg, 0.091 mmol) and triphenylphosphine (47.9 mg, 0.182 mmol) and the reaction mixture was cooled to 0° C. in an ice/water bath. DIAD (0.035 mL, 0.18 mmol) was added drop wise and the reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was allowed to warm to rt and stirred at rt for 16 h. The reaction mixture was concentrated under vacuum to yield a yellow oil that was purified by flash chromatography. Intermediate 8A (0.10 g, 96% yield) was isolated as a clear oil. LC-MS (ESI) 365 (M+H), RT=2.84 min (Method A).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[CH:8]1)[C:2]#[CH:3].[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1I>>[CH3:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[C:3]#[C:2][CH2:1][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[CH:8]1
Reactant: Cc1cccc(C)c1I
Reactant: C#CCOCCn1cnc2c(N)nc3ccccc3c21
Product: Cc1cccc(C)c1C#CCOCCn1cnc2c(N)nc3ccccc3c21
Yield: 8 %

Procedure:
Using the general method of Example 7, 1-[2-(2-propynyloxy)ethyl]-1H-imidazo[4,5-c]quinolin-4-amine (0.50 g, 1.88 mmol) was reacted with 2,6-dimethyl iodobenzene (0.61 g, 2.63 mmol). The crude product was purified by column chromatography eluting with 95/5 dichloromethane/methanol to provide 0.056 g of 1-(2-{[3-(2,6-dimethylphenyl)-2-propynyl]oxy}ethyl)-1H-imidazo[4,5-c]quinolin-4-amine as a solid, m.p. 200-201° C.
Reaction SMILES: [N+](C1C=CC(COC([N:12]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([C@@H:23]3[CH2:27][C@H:26]([S:28][C:29]4[C@H:30]([CH3:53])[C@@H:31]5[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]5[C:33]=4[C:34]([O:36]CC4C=CC([N+]([O-])=O)=CC=4)=[O:35])[CH2:25][N:24]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:22])[CH2:17][CH2:16]2)[CH3:14])=O)=CC=1)([O-])=O>O1CCCC1.O>[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21]([C@@H:23]2[CH2:27][C@H:26]([S:28][C:29]3[C@H:30]([CH3:53])[C@@H:31]4[C@@H:48]([C@H:49]([OH:51])[CH3:50])[C:47](=[O:52])[N:32]4[C:33]=3[C:34]([OH:36])=[O:35])[CH2:25][NH:24]2)=[O:22])[CH2:19][CH2:20]1)(=[NH:12])[CH3:14]
Reactant: CC(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Solvent: O
Solvent: C1CCOC1
Product: CC(=N)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)CC1
Yield: 38 %

Procedure:
5.10 g of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[4-(N-4-nitrobenzyloxycarbonylacetimidoyl)piperazin-1-ylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 100 ml of a 6:4 by volume mixture of tetrahydrofuran and water, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2.5 hours in the presence of 5.0 g of 10% w/w palladium-on-charcoal. The catalyst was filtered off, and the filtrate was washed with diethyl ether and then concentrated by evaporation under reduced pressure. The resulting residue was purified by reverse phase column chromatography through 250 ml of Cosmo Sil 75C18 -PREP (a trade mark for a product of Nacalai Tesque), using water, 5% v/v aqueous acetonitrile and 7% v/v aqueous acetonitrile, in that order, as the eluent. Those fractions containing the title compound were combined, concentrated by evaporation under reduced pressure and lyophilized to give 940 mg of the title compound, as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].[CH3:12][NH:13][CH2:14][C:15]1([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([N:13]([CH3:12])[CH2:14][C:15]1([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:6]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CNCC1(N2CCN(C)CC2)CCCCC1
Solvent: c1ccccc1
Product: CN1CCN(C2(CN(C)C(=O)c3ccc(Cl)c(Cl)c3)CCCCC2)CC1
Yield: 23.5 %

Procedure:
A solution of 3,4-dichlorobenzoylchloride (0.61 g.,) in benzene (10 ml) was added dropwise over 25 mins. to a stirred solution of 1-[1-(methylaminomethyl)cyclohexyl]-4-methyl piperazine (1) (0.65 g.,). The mixture was then heated on a steambath for 1 hr. and the mixture was evaporated to dryness. The residue was dissolved in hot light petroleum (60°-80°) and decolourised with charcoal. The solid which separated was crystallised from light petroleum (60°-80°) to give 3,4-Dichloro-N-methyl-N-[[1-(4-methyl-1-piperazinyl)cyclohexyl]methyl]benzamide (0.27 g., 23%) m.p. 126°-129°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]1[NH:14][C:15]3[CH:20]=[C:19]([CH3:21])[C:18]([CH3:22])=[CH:17][C:16]=3[N:10]1[C:9]2=[O:23])([O-:3])=[O:2].[O:24]=[C:25]([CH2:32]Cl)[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[C:27]([CH2:26][C:25](=[O:24])[CH2:32][N:14]1[C:11]2=[N:12][C:13]3[C:8]([C:9](=[O:23])[N:10]2[C:16]2[CH:17]=[C:18]([CH3:22])[C:19]([CH3:21])=[CH:20][C:15]1=2)=[CH:7][CH:6]=[CH:5][C:4]=3[N+:1]([O-:3])=[O:2])([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1cc2[nH]c3nc4c([N+](=O)[O-])cccc4c(=O)n3c2cc1C
Product: CCOC(=O)CC(=O)Cn1c2cc(C)c(C)cc2n2c(=O)c3cccc([N+](=O)[O-])c3nc12

Procedure:
6-(3-Carboethoxy-2-oxopropyl)-4-nitro-8,9-dimethylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with 4-nitro-8,9-dimethylbenzimidazo[2,1-b]quinazolin-12(6H)one and ethyl 3-oxo-4-chlorobutyrate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].N1C2C(=CC=CC=2)[C:15](CC(O)=O)=[CH:14]1>>[C:3]1([CH2:9][C:10]([O:12][CH2:14][CH3:15])=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Product: CCOC(=O)Cc1ccccc1

Procedure:
I-3. Other helper inducers we have so for discovered such as 2,4-dichlorophenyl acetic acid, and indole-3-acetic acid were obtained from Sigma Chemical Company.
Reaction SMILES: [NH:1]([C:5]1[S:6][C:7]([C:10]([OH:12])=O)=[CH:8][N:9]=1)[C:2]([NH2:4])=[NH:3].Cl.[NH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:15]1>>[NH:1]([C:5]1[S:6][C:7]([C:10]([N:14]2[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:15]2)=[O:12])=[CH:8][N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: N=C(N)Nc1ncc(C(=O)O)s1
Reactant: CCOC(=O)COCC1CCCNC1
Agent: Cl
Product: CCOC(=O)COCC1CCCN(C(=O)c2cnc(NC(=N)N)s2)C1

Procedure:
In the same manner as described in Example 4, from 2-guanidino-thiazole-5-carboxylic acid and ethyl (RS)-(piperidin-3-ylmethoxy)-acetate hydrochloride there is obtained ethyl (RS)-[1-(2-guanidino-thiazole-5-carbonyl)-piperidin-3-ylmethoxy]-acetate, m.p. 156° C., MS: 370 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]1([OH:16])[CH2:15][CH2:14][CH2:13][CH2:12]1.[H-].[Na+]>C1COCC1>[CH:11]1([O:16][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: OC1CCCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OC2CCCC2)nc1
Temperature: 0 °C
Reaction time: 0.01 h
Yield: 4.3 %

Procedure:
To a solution of 2-chloro-5-nitropyridine (7.01 g, 44.4 mmol) in THF (30 mL) and cyclopentanol (3.9 g, 45.3 mmol) was added sodium hydride (1.3 g, 54.2 mmol) portionwise with stirring over ˜30 sec with ice-bath cooling at 0° C. After stirring at 0° C. for 5 min, the ice bath was removed and the reaction was stirred at rt for 3 h. It was then concentrated in vacuo and the residue was dissolved in DCM and washed extensively with 1 M NaHCO3 and then dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash column chromatography (silica gel, 9:1 Hexane:Ethyl Acetate) to obtain pure 2-cyclopentyloxy-5-nitro-pyridine (0.4 g, 4%). 1H-NMR (300 MHz, CDCl3): δ 9.07 (s, 1H), 8.32 (m, 1H), 6.74 (d, 1H), 5.53 (m, 1H), 2.00 (m, 2H), 1.81 (m, 4H), 1.66 (m, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][C:7]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:24])=O>C(Cl)Cl>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([CH2:12][Cl:24])[CH:9]=[CH:8][C:7]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCOc1cc(CO)ccc1-c1cccc(OC)c1
Solvent: ClCCl
Product: CCCCOc1cc(CCl)ccc1-c1cccc(OC)c1
Reaction time: 8 h

Procedure:
To a stirred solution of T13.2 (530 mg, 1851 μmol) in DCM (15 mL) at 23° C. was added thionyl chloride (270 μL, 3702 μmol). The resulting mixture was stirred overnight and was then concentrated and then purified by silica gel chromatography (0 to 10% EtOAc/hexanes) to provide T13.
Reaction SMILES: C(O)(=O)C(O)=[O:3].[CH3:7][N:8]1[C@@H:24]2[CH2:25][C:13]3[CH:14]=[CH:15][C:16]([O:28][CH3:29])=[C:17]4[O:18][C@H:19]5[C:20]([O:26]C)=[CH:21][CH:22]=[C:23]2[C@:11]5([C:12]=34)[CH2:10][CH2:9]1.[OH-].[Na+]>O.C(O)(=O)C.OO>[CH3:7][N:8]1[C@@H:24]2[CH2:25][C:13]3[CH:14]=[CH:15][C:16]([O:28][CH3:29])=[C:17]4[O:18][CH:19]5[C:20]([CH:21]=[CH:22][C@:23]2([OH:3])[C@:11]5([C:12]=34)[CH2:10][CH2:9]1)=[O:26]
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Reactant: O=C(O)C(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 2 °C
Yield: 82 %

Procedure:
6-Benzyloxy-4,5α-epoxy-3-methoxy-17-methylmorfina-6,8(14)-diene (52.5 g) is dissolved in a solution prepared by dissolving 9.8 g of oxalic acid in 35 ml of water, 10 ml of acetic acid and 21.2 ml of 30% hydrogen peroxide are added. The reaction mixture is stirred at 20° C. until total conversion of the benzyl analogue of thebaine, the reaction mixture is cooled down to 2° C., 8% aqueous solution of NaOH is added with stirring until pH of 9.2. Precipitated crystals of 14-hydroxycodeinone are filtered off, washed with water and dried. The procedure yields ca. 37 g of 14-hydroxycodeinone (82%). Further procedure of preparation of Oxycodone hydrochloride is the same as in Example Ib) and Ic).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[ClH:37].[Cl:38][CH2:39][C:40]1[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=1>CN(C)C=O>[ClH:38].[ClH:37].[CH2:1]([C@@H:8]1[CH2:13][N:12]([CH2:39][C:40]2[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=2)[CH2:11][CH2:10][N:9]1[C:14](=[O:29])[C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCc1cccnc1
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(Cc2cccnc2)C[C@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled mixture of (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]piperazine (0.3 g) and triethylamine (0.39 ml) in dimethylformamide (8 ml) was added 3-(chloromethyl)pyridine hydrochloride (0.12 g). The reaction mixture was stirred at the same temperature for 30 minutes and then at room temperature for 2 hours. Additional triethylamine (0.39 ml) and 3-(chloromethyl)pyridine hydrochloride (0.12 g) were added and the resulting mixture was stirred overnight. The reaction mixture was filtered and the filtrate was concentrated and subjected to a chromatography on a silica gel eluting with a mixture of toluene and ethyl acetate (5:1). The eluent was treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-2-benzyl-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(pyridin-3-yl-methyl)piperazine dihydrochloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH:19]=[C:20]([CH3:22])[CH3:21])[CH2:15][C@H:14]1[CH2:13][S:12][C:11]([NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[N:10]2.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:15][C@H:14]1[CH2:13][S:12][C:11]([NH:23][C:24](=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[N:10]2
Reactant: [H][H]
Reactant: CC(C)=C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1

Procedure:
A solution of N-[(4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(2-methylprop-1-en-1-yl)-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (C28) (42 mg, 95 μmol) in methanol (28 mL) was treated with palladium on activated carbon [10% by weight (dry), 50% water, 224 mg, 105 μmol] and hydrogenated (35 pounds per square inch of hydrogen) for 20 hours. The reaction mixture was filtered through Celite®, and the filter pad was rinsed with methanol (30 mL). The combined filtrates were concentrated in vacuo and purified via silica gel chromatography (Gradient: 0% to 30% ethyl acetate in heptane) to provide the product as an opaque semi-solid. Yield: 10.9 mg, 24.5 μmol, 26%. LCMS m/z 445.2 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 8.24 (br d, J=8 Hz, 2H), 7.48-7.54 (m, 1H), 7.37-7.48 (m, 3H), 6.84-6.96 (m, 2H), 4.11 (dd, J=12.2, 1.5 Hz, 1H), 3.77 (d, J=12.1 Hz, 1H), 3.64-3.72 (m, 1H), 3.09-3.17 (m, 1H), 3.01 (dd, J=12.7, 4.1 Hz, 1H), 2.63 (dd, J=12.7, 2.7 Hz, 1H), 1.86-1.97 (m, 1H), 1.76-1.87 (m, 1H), 1.55-1.65 (m, 2H), 1.23-1.31 (m, 1H), 0.93 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]>ClCCl>[Cl:3][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCCO
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCCCCl
Yield: 88.3 %

Procedure:
A solution of thionyl chloride (6.74 g, 56.6 mmol) in dichloromethane (50 mL) was slowly added to a solution of N-(6-hydroxyhexyl)-3-nitroquinolin-4-amine (14.9 g, 51.5 mmol) in dichloromethane (200 mL). After the addition was complete the reaction mixture was stirred for about an hour and then it was concentrated under reduced pressure. The residue was suspended in water, slurried for about an hour, isolated by filtration, washed with water and then dried to provide 14.0 g of N-(6-chlorohexyl)-3-nitroquinolin-4-amine as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=2)=[CH:14][CH:15]=1)=O)C.[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=2)[CH2:30][CH2:29]1)[CH3:27].O>C1(C)C=CC=CC=1>[CH2:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([NH:41][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[CH:17]=[C:18]([O:24][CH3:25])[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=4)=[CH:14][CH:15]=3)=[O:3])=[N:39][CH:40]=2)[CH2:32][CH2:33]1)[CH3:27]
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2)c2nccnc12
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(OC)cc(OC)c4)c4nccnc34)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 115.1) (100 mg, 0.30 mmol) and 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 26.1; purified by column chromatography) (78 mg, 0.36 mmol, 1.2 equiv) in toluene (2 mL). The reaction mixture was stirred for 1 h at rt, heated to reflux, stirred for 3 h, allowed to cool, poured onto EtOAc and H2O, and filtered through a pad of celite. The filtrate was extracted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) followed by reverse-phase preparative HPLC to afford 54 mg of the title compound as a pale yellow solid. Title compound: ESI-MS: 513.2 [M+H]+; tR=3.54 min (System 1); TLC: Rf=0.29 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:11])=[CH:6][C:7]=1[C:8](O)=[O:9].[CH:12]([NH:15][CH:16](C)C)(C)C.C(Cl)(=O)C(C)(C)C.CNC>ClCCl>[CH3:12][N:15]([CH3:16])[C:8]([C:7]1[CH:6]=[C:5]([Cl:11])[N:4]=[N:3][C:2]=1[Cl:1])=[O:9]
Reactant: O=C(O)c1cc(Cl)nnc1Cl
Reactant: CC(C)NC(C)C
Agent: CC(C)(C)C(=O)Cl
Agent: CNC
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(Cl)nnc1Cl
Reaction time: 0.42 h
Yield: 61.9 %

Procedure:
3,6-Dichloro-pyridazine-4-carboxylic acid (500 mg, 2.59 mmol) was dissolved in dichloromethane (2 mL), treated with di-iso-propylamine (454 μL, 2.59 mmol) and cooled in an ice water bath. Pivaloyl chloride (318 μL, 2.59 mmol) was added and the mixture was stirred for 25 minutes. 2 M dimethylamine (2.59 mL, 5.18 mmol) was added and the reaction was stirred 15 h. The mixture was washed with saturated ammonium chloride (1×), saturated sodium bicarbonate (1×), and dried over sodium sulfate to afford 3,6-dichloro-pyridazine-4-carboxylic acid dimethylamide (353 mg, 62.2%). MS: m/z 220 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[CH:17]=O)=[CH:4][CH:3]=1.P([O-])([O-])(O)=O.[NH4+].[NH4+].[N+:26](CCC)([O-])=O>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[C:11]3[C:17]#[N:26])=[CH:4][CH:3]=1
Reactant: CCC[N+](=O)[O-]
Reactant: O=Cc1c[nH]c2ccc(-c3ccc(Br)cc3)cc12
Agent: O=P([O-])([O-])O
Agent: [NH4+]
Solvent: CC(=O)O
Product: N#Cc1c[nH]c2ccc(-c3ccc(Br)cc3)cc12

Procedure:
A mixture of 33 (1.35 g 4.50 mmol), diammonium hydrogen phosphate (3.19 g, 23.8 mmol), 1-nitropropane (13.61 g, 152.9 mmol) and glacial acetic acid (10 mL) is refluxed overnight. During the reflux period, the pale-yellow mixture becomes dark red. The volatile reactants and solvents were removed under reduced pressure and an excess of water is then added to the dark residue. After a short time the crude 34 precipitated rapidly. It is separated by filtration washed with hexanes and dried under reduced pressure. Compound 34 was obtained as pale yellow solid in 1.19 g. MS (Es−ve) m/z 295.