Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C@@H:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C@H:5]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:4]1>C(O)C.[H][H].[Pt](=O)=O>[CH3:1][N:2]([CH3:24])[C@@H:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[C@H:5]([O:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:4]1
Reactant: CN(C)[C@@H]1CCc2ccccc2[C@H](Oc2ccc([N+](=O)[O-])cc2)C1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCO
Product: CN(C)[C@@H]1CCc2ccccc2[C@H](Oc2ccc(N)cc2)C1
Reaction time: 0.5 h
Yield: 107.1 %

Procedure:
370 mg of platinum dioxide were added to a solution of 3.7 g of cis N,N-dimethyl-5-[4-nitrophenoxy]-6,7,8,9-tetrahydro-benzocycloheptene-7-amine in 200 ml of ethanol and one liter of hydrogen was bubbled therethrough for 30 minutes with stirring. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure to obtain 3.6 g of cis N,N-dimethyl-5-[4-aminophenoxy]-6,7,8,9-tetrahydro-5H-benzocycloheptene-7-amine in the form of an orange oil. The said oil was dissolved in 20 ml of ethyl acetate and a solution of ethyl acetate saturated with gaseous hydrogen chloride was added thereto to adjust the pH to 1. The mixture stood for one hour at room temperature and was then vacuum filtered to obtain 4.1 g of the dihydrochloride of the cis compound in the form of colorless crystals melting at ≈260° C.
Reaction SMILES: [C:1](F)(F)([C:12](F)(F)[C:13](F)(F)F)[C:2](F)(F)[C:3](F)(F)[C:4](F)(F)F.[Br:21]/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1([Zn]I)C=CC=CC=1>CC#N.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1(/[CH:22]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:12]=[CH:13][CH:4]=[CH:3][CH:2]=1.[Br:21]/[CH:22]=[CH:23]/[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Br/C=C/c1ccccc1
Agent: I[Zn]c1ccccc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: C(=C/c1ccccc1)\c1ccccc1
Reaction time: 24 h

Procedure:
FC-72 (10 mL) was charged to the U-tube (F-phase), a solution of (E)-bromostyrene (130 μL, 1.0 mmol) in MeCN (1 mL) was charged to the S-phase of the U-tube and a solution of Pd(PPh3)4 (23 mg, 0.02 mmol) in toluene (1.5 mL) was charged to the P-phase of the U-tube. After PhZnI (0.5 M in THF, 1.0 mL) was added to the P-phase, each phase was stirred for 1 day. The mixture in the P-phase was decanted into water, extracted with ether, dried over MgSO4 and then evaporated. However, trans-stilbene was not obtained in the P-phase and (E)-bromostyrene was recovered from the S-phase.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[F:7][C:8]([F:18])([F:17])[O:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[F:7][C:8]([F:17])([F:18])[O:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:2](=[O:3])[O:4][CH2:5][CH3:6]
Reactant: Nc1ccccc1OC(F)(F)F
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Nc1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
Ethyl chloroformate (4.4 mL, 0.046 mol) was added to a mixture of 2-(trifluoromethoxy)aniline (8.25 g, 0.0466 mol), sodium carbonate (15 g, 0.14 mol), 1,4-dioxane (70 mL) and water (70 mL) at 0° C. and the reaction mixture stirred at room temperature overnight. The reaction mixture was then washed with ether, acidified (pH 3) and the product extracted into EtOAc (3×40 mL). The combined extracts were washed with water (40 mL) and brine (40 mL), dried over Na2SO4 and the solvent removed in vacuo to give the desired product in a 84% yield. 1H NMR (400 MHz, CDCl3): δ 1.33 (t, J=5.2 Hz, 3H), 4.25 (q, J=6.8 Hz, 2H), 6.91 (br, 1H), 7.04 (m, 1H), 7.23 (m, 1H), 7.28 (m, 1H) and 8.2 (m, 1H). MS (ES+): m/z 250.12 [MH+].
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].CS(O[CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])(=O)=O>C1(C)C=CC=CC=1>[CH2:1]([NH:3][CH2:11][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26]#[N:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:9])[CH3:2]
Reactant: CCN
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: Cc1ccccc1
Product: CCNCC(C)N1c2ccccc2Sc2ccc(C#N)cc21
Reaction time: 24 h

Procedure:
Ethylamine (18.75 cc) is added to a solution of 2-(2-cyano-10-phenothiazinyl)-1-propyl methanesulphonate, D series (10 g) in toluene (100 cc), and this mixture is brought to a temperature in the region of 105° C. for 24 hours. After cooling, the reaction mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residue is taken up with ethyl ether (250 cc) and extracted successively with N-aqueous hydrochloric solution (2×100 cc). The combined aqueous phases are alkalinized with caustic soda (d=1.33) to pH 13 and extracted with ethyl ether (2×200 cc). The combined organic phases are washed successively with distilled water (50 cc) and with saturated aqueous sodium chloride solution (50 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. 10-(1-Ethylamino-2-propyl)-2-phenothiazinecarbonitrile, D series (5 g) is thereby obtained in the form of an orange oil. This product is dissolved at a temperature in the region of 60° C. in ethanol (17 cc), and this solution is poured into a solution of fumaric acid (1.9 g) in ethanol (17 cc) at the same temperature, crystallization is then primed and the mixture is left for 16 hours at a temperature in the region of 20° C. The solid is drained, washed with ethanol (2×2 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. 10-(1-Ethylamino-2-propyl)-2-phenothiazinecarbonitrile acid fumarate, D series (4 g) is thereby obtained in the form of a yellow solid, m.p. 208° C.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.CON(C)[C:20](=[O:25])[CH2:21][CH:22]([CH3:24])[CH3:23]>>[CH3:23][CH:22]([CH3:24])[CH2:21][C:20]([C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1)=[O:25]
Reactant: Brc1ccc2nc(-c3ccccc3)oc2c1
Reactant: CON(C)C(=O)CC(C)C
Product: CC(C)CC(=O)c1ccc2nc(-c3ccccc3)oc2c1

Procedure:
The preparation is carried out analogously to Example 29a from 6-bromo-2-phenyl-benzoxazole and N-methoxy-3,N-dimethyl-butyramide.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.[C:13]([O:21][CH2:22][C@@H:23]1[CH2:27][C@@H:26]([N:28]=[N+:29]=[N-:30])[C@H:25](OC)[O:24]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C>[C:13]([O:21][CH2:22][C@@H:23]1[CH2:27][C@@H:26]([N:28]=[N+:29]=[N-:30])[C@H:25]([N:8]2[C:6]3[N:7]=[C:2]([NH2:1])[NH:3][C:4](=[O:12])[C:5]=3[S:10][C:9]2=[O:11])[O:24]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CO[C@@H]1O[C@H](COC(=O)c2ccccc2)C[C@H]1N=[N+]=[N-]
Reactant: Nc1nc2[nH]c(=O)sc2c(=O)[nH]1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: [N-]=[N+]=N[C@@H]1C[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(=O)sc2c(=O)[nH]c(N)nc21
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
To a suspension of 5-amino-3,6-dihydrothiazolo[4,5-d]pyrimidine-2,7-dione (730 mg, 3.97 mmol) in ACN (15 mL) was added BSA (2.8 mg, 13.8 mmol). The resulting reaction mixture was then stirred at 70° C. under argon for 0.5 hour to form a clear solution. After the solution was cooled to room temperature, [(2S,4R,5R)-4-azido-5-methoxy-tetrahydrofuran-2-yl]methyl benzoate (compound 33a, crude, 1.1 g, 3.97 mmol) and TMSOTf (4.4 g, 19.5 mmol) were added in sequence. After being heated with stirring at 70° C. for 14 hours, the solvent was removed in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3 solution (30 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (30 mL) twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 500 mg crude product of [(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-azido-tetrahydrofuran-2-yl]methyl benzoate (compound 33b) as a yellow solid. MS obsd. (ESI+) [(M+H)+]: 430.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1.O>[Br:8][C:6]1[CH:7]=[C:2]([C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH:3]=[N:4][CH:5]=1
Reactant: Brc1cncc(Br)c1
Reactant: OB(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Brc1cncc(-c2cccnc2)c1
Temperature: 120 °C
Yield: 47.9 %

Procedure:
Compound 6 (see WO2009/009756) was prepared as follows: a mixture of 3,5-dibromopyridine (10.6 g, 44.7 mmol), pyridin-3-ylboronic acid (5.50 g, 44.7 mmol), palladium(II) acetate (0.550 g, 2.45 mmol), triphenylphosphine (2.50 g, 9.53 mmol), potassium phosphate tribasic (19.0 g, 89.5 mmol), H2O (45 mL) and 1,4-dioxane (200 mL) was degassed with argon for 2 h. while stirring. The reaction mixture was then maintained under argon at reflux (120° C.) while stirring for 1.5 h. Upon confirming consumption of the starting material by TLC (SiO2, 7:3 dichloromethane-acetone), the reaction was cooled to RT and poured over ethyl acetate (about 400 mL). The organic phase was then washed with saturated NaHCO3, H2O and brine, dried over MgSO4, filter and concentrated in vacuo. The crude product was purified via flash chromatography (SiO2, 4:1 dichloromethane-acetone) to provide Compound 6 (5.03 g, 48%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][O:14][C@@H:15]3[CH2:20][CH2:19][CH2:18][C@H:17]([OH:21])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1>C(OC=C)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][O:14][C@H:15]3[CH2:20][CH2:19][CH2:18][C@@H:17]([OH:21])[CH2:16]3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CO[C@@H]1CCC[C@H](O)C1
Solvent: C=COC(C)=O
Product: Cc1oc(-c2ccc(F)cc2)nc1CO[C@H]1CCC[C@@H](O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
25 g of rac-cis-3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol are dissolved in 320 ml of vinyl acetate, and 1.3 g of Chirazyme L-2 Lyo (Boehringer Mannheim) are added. The mixture is stirred at room temperature for three hours (checked by LC-MS for 40–45% conversion) and the enzyme is then filtered off and washed with ethyl acetate, and the solvent is removed under reduced pressure. The residue is purified by flash chromatography on silica gel (n-heptane/ethyl acetate=3:1). This gives 8 g of (1 R, 3S)-3-[2-(4-fluorophenyl)-5-methyloxazyol-4-ylmethoxy]cyclohexyl acetate as a colorless oil. C19H22FNO4 (347.39), MS (ESI): 348 (M+H+). The acetate is taken up in 170 ml of methanol and, after addition of 27 ml of 2N aqueous sodium hydroxide solution, stirred at room temperature for one hour. Most of the solvent is removed under reduced pressure. After addition of in each case 150 ml of water and ethyl acetate, the organic phase is washed with sodium chloride solution. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure. This gives 6.7 g of 3-(1R,3S)-3-[2-(4-fluorophenyl)-5-methyloxazol4-ylmethoxy]cyclohexanol as a yellowish solid. C17H20FNO3 (305.35), MS (ESI): 306 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([OH:24])=[CH:11][CH:10]=3)[CH3:2].[OH-].[K+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:24][CH2:27][CH:29]1[O:31][CH2:30]1)=[CH:11][CH:10]=3)[CH3:2]
Reactant: ClCC1CO1
Reactant: CCn1ncc2c(NCC3CCCCC3)c3cc(O)ccc3nc21
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(OCC4CO4)ccc3nc21
Reaction time: 0.5 h

Procedure:
A mixture of 1-ethyl-6-hydroxy-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (6 g), KOH (5 g), and DMSO (70 ml) is stirred for 30 minutes and then epichlorohydrin (1.5 ml) is added. The reaction mixture is stirred overnight and then is partitioned between CH2Cl2 and water. The organic layer is then separated, dried and evaporated to dryness. The residue is purified by column chromatography on silica gel eluting with ethyl acetate, followed by crystallization from hexane/ether to afford 1.0 g of 1-ethyl-6-(2,3-epoxypropoxy)-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 160°-163° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl.N12CCCN=C1CCCCC2>CCOC(C)=O>[CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[C:22]([F:21])([F:31])[F:32])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: FC(F)(F)c1ccccc1CCl
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(Cc3ccccc3C(F)(F)F)CC2)nn1
Temperature: 60 °C
Yield: 72 %

Procedure:
A mixture of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide (0.255 mmol), 2-trifluoromethylbenzyl chloride (0.255 mmol), and 1,8-diazabicylco[5.4.0]undec-7-ene (0.77 mmol) was stirred and heated at 60° C. overnight. The reaction mixture was then diluted with EtOAc (100 mL) and washed with aqueous saturated NaHCO3 (2×20 mL) and brine (2×20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified by flash chromatography to give the title compound as a white solid (80 mg, 72% yield). 1H NMR (500 MHz, CDCl3) δ 8.00, 7.86, 7.82, 7.65, 7.55, 7.37, 6.95, 3.74-3.79, 3.73, 3.46-3.52, 2.62, 1.65-1.76, 1.52, 0.94. MS (ES+) m/z 436 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.Br[C:22]1[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=[C:26]([Br:28])[N:27]=1.C(N(C(C)C)C(C)C)C>CC(O)C>[Br:28][C:26]1[N:27]=[C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=1
Reactant: Cn1cc(Br)nc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(Br)nc(Nc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)c1=O
Temperature: 100 °C
Reaction time: 15 h
Yield: 44.8 %

Procedure:
A mixture of 197b (500 mg, 1.8 mmol), 3,5-dibromo-1-methylpyrazin-2(1H)-one (530 mg, 2.0 mmol), N-ethyl-N-isopropylpropan-2-amine (1.5 mL, 0.90 mmol), and propan-2-ol (20 mL) was stirred at 100° C. for 15 h. After the reaction was completed, the solvent was removed under reduced pressure to afford 197c as a brown solid (375 mg, 45%). MS-ESI: [M+H]+ 465.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.O[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]2[CH2:40][CH2:39][CH2:38][C@H:37]3[N:32]2[C:33](=[O:56])/[C:34](=[CH:41]/[C:42]2[CH:47]=[CH:46][C:45]([N:48]4[CH:52]=[C:51]([CH3:53])[N:50]=[CH:49]4)=[C:44]([O:54][CH3:55])[CH:43]=2)/[CH2:35][CH2:36]3)=[CH:27][CH:26]=1.O.C(=O)(O)[O-].[Na+].Cl.NO.C([O-])(=O)C.[Na+].C(N1C=CN=C1)([N:73]1C=CN=C1)=O>C(Cl)Cl.C(O)C.C1COCC1.O.C(OCC)(=O)C>[C:24]([C:25]1[CH:30]=[CH:29][C:28]([C@@H:31]2[CH2:40][CH2:39][CH2:38][C@H:37]3[N:32]2[C:33](=[O:56])/[C:34](=[CH:41]/[C:42]2[CH:47]=[CH:46][C:45]([N:48]4[CH:52]=[C:51]([CH3:53])[N:50]=[CH:49]4)=[C:44]([O:54][CH3:55])[CH:43]=2)/[CH2:35][CH2:36]3)=[CH:27][CH:26]=1)#[N:73]
Reactant: COc1cc(/C=C2\CC[C@H]3CCC[C@@H](c4ccc(CO)cc4)N3C2=O)ccc1-n1cnc(C)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CC[C@H]3CCC[C@@H](c4ccc(C#N)cc4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
Dess-Martin periodinane (37 mg) was added to a solution of (E)-(6S*,9aR*)-6-(4-hydroxymethylphenyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]octahydroquinolizin-4-one (20 mg) in methylene chloride (2 mL), and the reaction solution was stirred at room temperature for 30 minutes. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain a crude aldehyde compound. Hydroxylamine hydrochloride (9 mg) and sodium acetate (11 mg) were added to a solution of the resulting crude aldehyde compound in ethanol (3 mL), and the reaction solution was stirred at room temperature for 12 hours. Saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain a crude oxime compound. To a solution of the resulting crude oxime compound in THF (5 mL), 1,1′-carbonyldiimidazole (70 mg) was added, and the reaction solution was heated to reflux for five hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate) to obtain 6 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH2:11][OH:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[CH2:1]([N:3]([CH2:10][CH2:11][O:12][C:13](=[O:15])[CH3:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCN(CCO)c1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CCN(CCOC(C)=O)c1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 49.6 g (300 mmol) of 15 and 50 ml of acetic acid anhydride in a 250 ml-flask, equipped with a CaCl2-tube is stirred overnight at 60° C. Then, the volatile compounds are evaporated and the crude product is distilled under vacuüm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:10][NH:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[K+].I[CH3:32]>CS(C)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][CH2:21][O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH2:10][N:11]([CH3:32])[C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(NCC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1)c1ccccc1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CN(CC(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a solution of N-[2-(3,4-dichlorophenyl)-4-(tetrahydropyran-2-yloxy)butyl]benzamide (3.3 g) in dimethyl sulfoxide (20 mL) was added powdered potassium hydroxide (1.6 g), followed by iodomethane (1.0 mL) after 15 minutes. After 1 hour, the mixture was diluted with water (330 mL) and extracted with dichloromethane. The combined organic extracts were dried and evaporated to give the N-methylbenzamide (3.1 g) as an oil; MS: m/z=352[(M+1)-tetrahydropyranyl].
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:5]1[N:13]2[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]2)=[CH:7][C:6]=1[C:14](OC)=[O:15])=O.[NH2:20][NH2:21]>C(O)C>[F:1][C:2]([F:19])([F:18])[C:3]1[C:5]2[N:13]3[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]3)=[CH:7][C:6]=2[C:14](=[O:15])[NH:21][N:20]=1
Reactant: NN
Reactant: COC(=O)c1cc2ccccn2c1C(=O)C(F)(F)F
Solvent: CCO
Product: O=c1[nH]nc(C(F)(F)F)c2c1cc1ccccn12
Yield: 79 %

Procedure:
A mixture of (I) (3.60 g, 13.3 mmol) and excess 85% aqueous hydrazine in ethanol (250 mL) was heated under reflux for 10 minutes (a precipitate formed). After cooling in a freezer overnight, the solid was collected by filtration and dried to give 4-trifluoromethylpyridazino[4,5-b]indolizin-1-one (II, 2.65 g, 79%)
Reaction SMILES: [C:1]12(OCC[O:12]1)[C:9]1[C:4](=[CH:5][C:6]([CH2:10][OH:11])=[CH:7][CH:8]=1)[CH2:3][CH2:2]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].N>O.CC(C)=O>[OH:11][CH2:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[C:1](=[O:12])[CH2:2][CH2:3]2
Reactant: OCc1ccc2c(c1)CCC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCc2cc(CO)ccc21

Procedure:
A solution of Example 332B (8.0 g, 38.7 mmol) and p-toluenesulfonic acid (7.4 g, 38.7 mmol) in a mixture of water (20 mL) and acetone (85 mL) was refluxed for about 1 hour. The mixture was concentrated in vacuum, diluted with water and was neutralized by careful addition of potassium carbonate (2.7 g, 19.4 mmol). The precipitate was filtered off, washed with a minimum of water and diethyl ether and was dried in vacuum to give the above intermediate. MS (DCI/NH3): m/z 180 (M+NH4)+.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1([C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)Cl)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)(C)C>[C:11]([NH:4][CH2:3][CH2:1][OH:2])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: NCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)O
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
A mixture of isopropanol (750 ml), diethylaminc (75 ml), ethanolamine (98%, 62.3 g, 1 mole) and triphenylchloromethane (97%, 143.7 g, 0.50 moles) was stirred at room temperature for 3 hours. The resulting solution was then poured into ice-cold water (4 l) under continuous stirring and the resulting precipitate was filtered off and dried. The crude product was digested in toluene (340 ml), then filtered off and dried in vacuo at 60° C. Thus 130 g (85%) of the pure desired compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](Cl)(=O)C>CO>[CH2:1]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH3:15])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(OCc1ccccc1)C(=O)O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)C(C)(C)OCc1ccccc1
Reaction time: 16 h

Procedure:
2-Benzyloxy-2-methylpropionic acid (4.4 g., 0.0023 mol) was dissolved in 50 ml. of methanol treated with acetyl chloride (1.61 ml., 1.78 g., 0.0023 mol), stirred for 16 hours, stripped to an oil, taken up in 75 ml. ethyl acetate, washed 1×50 ml. saturated NaHCO3 and 1×50 ml. brine, dried over MgSO4 and stripped to yield purified title product as a second oil, 4.22 g.; 1H-nmr 1.5 (s, 6H), 3.8 (s, 3H), 4.5 (s, 2H), 7.3-7.5 (m, 5H).