Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH:3]([CH3:13])[O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1.FC(F)(F)C(O)=O.[H][H]>CO.[Pd]>[NH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH:3]([CH3:13])[C:2]([F:15])([F:1])[F:14])=[CH:10][N:9]=1
Reactant: CC(Oc1ccc(C#N)nc1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CC(Oc1ccc(CN)nc1)C(F)(F)F

Procedure:
Add (±)-5-(2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carbonitrile (810 mg, 3.7 mmol), 10% Pd/C (Degussa type E101, 50% water by wt, 300 mg), and trifluoroacetic acid (4 mL) in methanol (50 mL) to a pressure vessel. Pressurize the vessel to 40 psi with hydrogen for 0.25 h. Filter the mixture through Celite® and wash the cake with warm ethanol followed by DCM under a nitrogen atmosphere. Concentrate in vacuo to obtain the crude product as a trifluoroacetic acid salt. Prepare the free base with SCX ion chromatography, then purify by chromatography on silica gel eluting with DCM/2M ammonia in methanol (20:1) to obtain the title compound (676 mg, 82%). GC-MS m/z: 220 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:10]1[CH2:11][S:12][CH:13]=[C:14]2[C:18]([O:20]CC(Cl)(Cl)Cl)=[O:19])=[O:7])([CH3:4])(C)C.Cl.[C:27](O)(=O)[CH3:28]>CN(C)C=O.O.[Zn]>[CH2:1]([O:5][C:6]([NH:8][C@H:9]1[C:16](=[O:17])[N:15]2[C@@H:10]1[CH2:11][S:12][CH:13]=[C:14]2[C:18]([OH:20])=[O:19])=[O:7])[CH2:4][CH2:27][CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@H]1C(=O)N2C(C(=O)OCC(Cl)(Cl)Cl)=CSC[C@H]12
Reactant: CC(=O)O
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N[C@H]1C(=O)N2C(C(=O)O)=CSC[C@H]12
Reaction time: 3 h

Procedure:
To a solution of 43 mg (0.1 mmole) of trichloroethyl cis-7-t-butoxycarbonylamino-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate in 6 ml of dimethylformamide and 6 ml of acetic acid is added over a 1.5 hr period 250 mg (3.8 mmole) zinc dust. The mixture is stirred vigorously for 3 hrs and then diluted with 50 ml of water. The mixture is acidified with dilute HCl, filtered and extracted with ethyl acetate. The organic phase is extracted with 5% NaHCO3 which is acidified and reextracted into ethyl acetate. The final extracts are washed with brine, dried, and evaporated to give cis-7-butoxycarbonylamino-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=1.[CH3:22][C:23]1[CH:37]=[CH:36][C:26]([CH:27](O)[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:22][C:23]1[CH:37]=[CH:36][C:26]([CH:27]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[O:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])=[CH:10][CH:9]=2)=[CH:25][CH:24]=1
Reactant: Cc1ccc(C(O)c2ccc(C)cc2)cc1
Reactant: O=C(CCc1ccc(OCCSCCO)cc1)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(OCCSCCOc2ccc(CCC(=O)C(F)(F)F)cc2)c2ccc(C)cc2)cc1
Yield: 94.2 %

Procedure:
A solution of 4-[4-[2-(2-hydroxyethylthio)ethoxy]phenyl]-1,1,1-trifluoro-2-butanone (1.20 g, 3.72 mmol), 4,4′-dimethylbenzhydrol (0.95 g, 4.47 mmol) and p-toluenesulfonic acid (0.035 g) in toluene (20 ml) was heated under reflux for 15 min. The cooled reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo and chromatography of the residue on silica gel (elution with a gradient of ethyl acetate 20-40% in hexane) gave 1.81 g (94%) of the title material as an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11].[C:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18](=[O:21])[CH2:19]Br)=[CH:16][CH:15]=1)#[N:13]>CC#N>[CH3:1][C:2]1[N:10]=[C:5]2[N:6]([CH2:19][C:18]([C:17]3[CH:22]=[CH:23][C:14]([C:12]#[N:13])=[CH:15][CH:16]=3)=[O:21])[CH:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[CH3:11]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: Cc1[nH]c2ncccc2c1C
Solvent: CC#N
Product: Cc1nc2n(CC(=O)c3ccc(C#N)cc3)cccc-2c1C

Procedure:
A solution of 2,3-dimethylpyrrolo[2,3-b]pyridine (146 mg, 1 mmol) and p-cyanophenacyl bromide (248 mg, 1.1 mmol) in 3 ml CH3CN was refluxed for 1.5 h. The mixture was allowed to cool and the precipitated product filtered off and washed with a small volume of ice cold CCl4 affording 313 mg (85%) pure title compound as the hydrobromide salt.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][C:35](Cl)=[O:36])=[CH:29][CH:28]=1>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:35](=[O:36])[CH2:34][CH2:33][C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CCc1ccc(Cl)cc1
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)CCc2ccc(Cl)cc2)N(c2nnc(C(C)(C)C)s2)C1=O

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)- 3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. β-(4-Chlorophenyl)propionyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl- 1,3,4-thiadiazol-2-yl)-3-methyl-6-[β-(4-chlorophenyl)propionyloxy] -2 (1H)-pyrimidinone as the residue.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:20][CH2:19][C:18]([OH:32])([C:21](=[O:31])[NH:22][CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:24])[CH2:17][CH2:16]1)(C)(C)C>ClCCl>[NH2:14][CH:15]1[CH2:20][CH2:19][C:18]([OH:32])([C:21]([NH:22][CH:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH3:24])=[O:31])[CH2:17][CH2:16]1
Reactant: CC(NC(=O)C1(O)CCC(NC(=O)OC(C)(C)C)CC1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(NC(=O)C1(O)CCC(N)CC1)c1ccccc1

Procedure:
Trifluoroacetic acid (1.5 ml) was added to a solution of crude [4-hydroxy-4-(1-phenyl-ethylcarbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (320 mg) in dichloromethane (6.0 ml). The reaction was judged to be complete by LCMS in less than 90 minutes. The reaction was diluted with dichloromethane and quenched to pH 12 using 5N sodium hydroxide. The crude product was extracted with two volumes of dichloromethane, dried over sodium sulfate, filtered and concentrated to 4-amino-1-hydroxy-cyclohexanecarboxylic acid (1-phenyl-ethyl)-amide (210 mg). LCMS M+H=263.2.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:18])[O:9][C:10]3[C:15]([C:16]=2[OH:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]1([CH2:25][CH:26]([CH3:29])[CH2:27]Cl)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>CCCCCC>[N:19]1([CH2:25][CH:26]([CH3:29])[CH2:27][O:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[O:9][C:8](=[O:18])[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=c1oc2ccccc2c(O)c1-c1ccccc1
Reactant: CC(CCl)CN1CCCCC1
Solvent: CCCCCC
Product: CC(COc1c(-c2ccccc2)c(=O)oc2ccccc12)CN1CCCCC1
Yield: 77.5 %

Procedure:
Prepared from 3-phenyl-4-hydroxy-coumarin and 3-piperidino-2-methyl-1-chloropropane, according to the method of Example 8. A light yellow solid is obtained. M.P. 86°-87° C. (hexane). Yield 77.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([S:16][CH3:17])=[CH:11][C:10]=2[Cl:18])[CH:5]=[CH:4][N:3]=1.[OH:19]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[C:13]([Cl:15])[C:12]([S:16]([CH3:17])=[O:19])=[CH:11][C:10]=2[Cl:18])[CH:5]=[CH:4][N:3]=1
Reactant: CSc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1Cl
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: CS(=O)c1cc(Cl)c(Oc2ccnc(Cl)c2)cc1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
An amount of 32.6 gm (0.1 mol) of 2-chloro-4-(2,5-dichloro-4-methylmercaptophenoxy)-pyridine, prepared analogously to Example 1, was suspended in 100 ml of glacial acetic acid. The mixture was warmed to 45° to 50° C., and 11 ml (0.11 mol) of 30% H2O2 were added dropwise at such a rate that the internal temperature did not exceed 50° C. The mixture was then stirred for 3 hours at 50° C., after which it was cooled and poured into 300 ml of water. The batch was stirred until crystallization was complete, and the product was recovered by suction filtration, washed with water, dried, and recrystallized from ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=2[NH2:17])=[CH:4][CH:3]=1.C(Cl)(Cl)[Cl:20]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[C:14]([Cl:20])[CH:13]=[C:12]([CH3:16])[C:11]=2[NH2:17])=[CH:6][CH:7]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1cccc(C(=O)Nc2ccc(Cl)cc2)c1N
Product: Cc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cc2)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(4-chlorophenyl)-2-amino-3-methylbenzamide (0.40 g, 1.5 mmol) in chloroform (3 mL) at 0° C. was added SO2Cl2 (0.31 g, 2.3 mmol). The mixture was warmed to ambient temperature and stirred for 1 hour. Concentration of all volatiles in vacuo afforded N-(4-chlorophenyl)-2-amino-3-methyl-5-chlorobenzamide as a yellow solid; NMR (DMSO-d6) 10.2 (s, 1), 7.8 (d, 2), 7.6 (s, 1), 7.4 (d, 2), 7.2 (s, 1), 6.2 (br, 2), 2.1 (s, 3) ppm.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][N:7]=[CH:6][C:5]=2[S:4][CH:3]=1.[F:12][C:13]1[CH:18]=[CH:17][N:16]2[CH:19]=[C:20]([CH2:22][CH2:23]O)[N:21]=[C:15]2[CH:14]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[Br:1][C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:23][CH2:22][C:20]3[N:21]=[C:15]4[CH:14]=[C:13]([F:12])[CH:18]=[CH:17][N:16]4[CH:19]=3)[N:7]=[CH:6][C:5]=2[S:4][CH:3]=1
Reactant: OCCc1cn2ccc(F)cc2n1
Reactant: O=c1[nH]ncc2scc(Br)c12
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=c1c2c(Br)csc2cnn1CCc1cn2ccc(F)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
A mixture of 3-bromothieno[2,3-d]pyridazin-4(5H)-one from Example 3.4 (231 mg, 1 mmol), 2-(7-fluoroimidazo[1,2-a]pyridin-2-yl)ethanol from Example a5 (180 mg, 1.00 mmol) and Ph3P (525 mg, 2.00 mmol) was dissolved in THF (6 mL). Then DEAD (0.317 mL, 2.00 mmol) in THF (1 mL) was added. The resulting mixture was stirred at room temperature under nitrogen overnight. The mixture was concentrated and purified on the ISCO Combiflash system using a 40 g C-18 column using the following gradient: A: Water (0.1% NH4HCO3); B: Methanol; 30% B to 80% B over 20 min (160 mg, yield: 17.7%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:10][C:11]([C:13]1[NH:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([NH:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=1)(=[O:25])=[O:24])=[CH:17][CH:16]=2)=O)[CH2:8][CH3:9].O>O1CCCC1>[CH:32]([C:29]1[CH:28]=[CH:27][C:26]([S:23]([NH:22][C:18]2[CH:19]=[C:20]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH2:11][NH:10][CH2:7][CH2:8][CH3:9])=[CH:21]3)(=[O:24])=[O:25])=[CH:31][CH:30]=1)([CH3:34])[CH3:33]
Reactant: CCCNC(=O)c1cc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCNCc1cc2cc(NS(=O)(=O)c3ccc(C(C)C)cc3)ccc2[nH]1
Temperature: 25 °C
Yield: 24 %

Procedure:
To a suspension of lithium aluminiumhydride (590 mg, 15.54 mmol) in tetrahydrofuran (THF) (40 ml, dried over Al2O3) at −5 to 0° C. a solution of 5-(4-isopropyl-benzenesulfonylamino)-1H-indole-2-carboxylic acid propylamide (1.03 g, 2.59 mmol) in THF (10 ml) was added. After complete addition the mixture was allowed to warm to room temperature and was heated to reflux for 3 h. At 0° C. THF and then water were added. The mixture was dried with Na2SO4. The filtered solution was evaporated and the residue was purified by column chromatography (toluene:THF:methanol, 4:1:1+2.5% triethylamine) to give the product as a yellow powder (240 mg, 24%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[C:11]([N:13]1[CH2:18][CH2:17][C:16]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19]2)[CH2:15][CH2:14]1)=[O:12].Cl>C(Cl)Cl.O1CCOCC1>[N:13]1([C:11](=[O:12])/[CH:10]=[CH:9]/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:1])([F:36])[F:35])[CH2:18][CH2:17][C:16]2([C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][NH:20][CH2:19]2)[CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(/C=C/c1ccccc1C(F)(F)F)N1CCC2(CC1)CNCc1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (E)-tert-butyl 1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)-1H-spiro[isoquinoline-4,4′-piperidine]-2(3H)-carboxylate (64 mg, 0.13 mmol) in CH2Cl2 (2 mL) was added 4 M HCl in dioxane (2 mL). The mixture was stirred at rt for 2 h and concentrated to afford (E)-1-(2,3-dihydro-1H-spiro[isoquinoline-4,4′-piperidine]-1′-yl)-3-(2-(trifluoromethyl)phenyl)prop-2-en-1-one as its hydrochloride salt. LC-MS Method 1 tR=1.26, min, m/z=401.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][C:25]1[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=1.O>CN(C=O)C>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:24][C:25]3[CH:29]=[CH:28][N:27]([CH3:30])[N:26]=3)[C:7](=[O:12])[CH:6]3[CH2:13][O:14][CH2:15][CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1Nc2cnc(Cl)nc2N2CCOCC12
Reactant: Cn1ccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ccc(CN2C(=O)C3COCCN3c3nc(Cl)ncc32)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
To a mixture of 2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (100 mg, 0.416 mmol), K2CO3 (115 mg, 0.831 mmol) in DMF (2 mL) at 0° C., was added 3-(chloromethyl)-1-methyl-1H-pyrazole (54.3 mg, 0.416 mmol). The mixture was stirred at 0° C. for 30 minutes and then at room temperature for overnight. Water was added and the mixture was extracted with EtOAc (2×). The aqueous layer was basified and then extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and evaporated in vacuo to give 2-chloro-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (104 mg) which was used in the next step without further purification. MS [M+H] Found 335
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7]/[C:8](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:9]\[CH:10]=[O:11].Cl>>[OH:11][C@@H:10]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])/[CH:9]=[C:8](\[CH3:7])/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C/C(=C\C=O)c1ccccc1
Reactant: COP([O-])OC
Agent: Cl
Product: COP(=O)(OC)[C@H](O)/C=C(\C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes, then (E)-β-methylcinnamaldehyde (0.40 mmol) was added thereto. After reacting for 81 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S,E)-1-hydroxy-3-methyl-3-phenyl-2-propenylphosphonate as a final product in a yield of 93%. The chemical reaction in this Example is shown in chemical formula 35.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C@H:10]3[C@@:12]4([C:20]5[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=5)[NH:14][C:13]4=[O:22])[CH2:11]3)[CH:8]=2)[CH:3]=[N:2]1.C([O-])([O-])=O.[K+].[K+].[I:29]I>CN(C=O)C>[I:29][C:3]1[C:4]2[C:9](=[CH:8][C:7]([C@H:10]3[C@@:12]4([C:20]5[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=5)[NH:14][C:13]4=[O:22])[CH2:11]3)=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: II
Reactant: Cc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3cn[nH]c3c1)C(=O)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)[C@]1(C[C@H]1c1ccc3c(I)n[nH]c3c1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a solution of (1R,2S)-2-(1H-indazol-6-yl)-5′-methylspiro[cyclopropane-1,3′-indolin]-2′-one (680 mg, 2.35 mmol) in DMF (16 mL) was added K2CO3 (544 mg, 4 mmol), followed by iodine (851 mg, 3.2 mmol). The resulting mixture was stirred for 3 h at rt, cooled to 0° C., quenched with sat. Na2S2O3, diluted with H2O, extracted with EtOAc (50 mL×3) and dried (Na2SO4). Evaporation of solvents and purification by Biotage Isolera (EtOAc/hexane gradient: 10-90%) gave the title compound as a light yellow solid (794 mg, 81%; >98% e.e.). The major (1R,2S)-enantiomer eluted at 9.6 min (Phenomenex Lux 5u Cellulose-2 (150×4.6 mm); isocratic 10% EtOH in n-hexane 1.75 L/min; ambient temperature; Detection: 254, 214 nm). From the racemic reference standard, the retention time of the (1S,2R)-enantiomer was 7.7 min using this method. 1H NMR (400 MHz, DMSO-d6) δ 13.46 (s, 1H), 10.51 (s, 1H), 7.47 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 6.73 (d, J=7.6 Hz, 1H), 5.86 (s, 1H), 3.16 (t, overlapping with trace MeOH residue), 2.32-2.25 (m, 1H), 2.00-1.93 (m, 1H), 1.85 (s, 3H); MS ESI 416.0 [M+H]+, calcd for [C18H14IN3O+H]+ 416.0.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=1.CCN(CC)CC>CC#N>[CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][CH2:19][C:20]([NH:22][CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([CH2:35][C:34]4[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=4)[CH2:26][CH2:25]3)=[O:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)OCC1c2ccccc2-c2ccccc21)NCC1CCN(Cc2ccc(F)cc2)CC1

Procedure:
A solution of 4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (1.50 g, 3.49 mmol), 4-fluorobenzyl bromide (0.478 mL, 3.84 mmol), and Et3N (1.47 mL, 10.5 mmol) in CH3CN (200 mL) was stirred at room temperature for 13 h and concentrated. Column chromatography (SiO2, 10% CH3OH/CH2Cl2) afforded 4-[{N-(9fluorenylmethyloxycarbonyl)glycyl}aminomethyl]-1(4-fluorobenzyl)piperidine
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[C:21]([O:25][C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:32][CH:31]=1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Reactant: CC(C)(C)OC(=O)NCc1ccc(B(O)O)cc1
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(CNC(=O)OC(C)(C)C)cc3)ccn2c1=O
Yield: 107.5 %

Procedure:
Methyl 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and (4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-boronic acid (516 mg, 2.06 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (850 mg, 100%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]([CH2:22][C:23]([OH:25])=[O:24])[N:20]=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl[CH2:31][S:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[N:21]([CH2:22][C:23]([O:25][CH2:31][S:32][CH3:33])=[O:24])[N:20]=[C:19]([C:26]([F:29])([F:27])[F:28])[CH:18]=3)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3CC(=O)O)cc2)c1
Reactant: CSCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCOC(=O)Cn1nc(C(F)(F)F)cc1-c1ccc(-c2cccc(S(C)(=O)=O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.6 %

Procedure:
A mixture of compound 38 (0.2 g, 0.471 mmol), chloromethylmethylsulfane (0182 g, 1.89 mmol) and potassium carbonate (0.324 g, 2.36 mmol) in DMF (5 mL) was stirred at room temperature for 1 h, then heated to 100° C. for 10 h. On completion, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL×3). The combined organic layer was washed with saturated brine, dried over sodium sulphate and concentrated. The crude reaction mixture was purificated by prep HPLC to afford 41 (15 mg, 7%). LCMS: 485.20 (M+1)+; 1H NMR (DMSO-d6, 400 MHz) δ 8.26 (s, 1H), 8.06 (d, 1H, J=7.2 Hz), 7.99 (d, 1H, J=8 Hz), 7.93 (d, 2H, J=8.4 Hz), 7.8-7.6 (m, 3H), 6.75 (s, 1H), 5.10-5.25 (m, 2H), 3.45-3.3 (m, 2H), 3.30 (s, 3H), 1.78 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])=[N:11][CH2:10][C:9]2=[O:26])[CH2:4][CH2:3]1.[N+:27]([O-])([O-:29])=[O:28].[K+].C(Cl)Cl>S(=O)(=O)(O)O>[N+:27]([C:17]1[CH:16]=[CH:15][C:14]2[N:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[C:9](=[O:26])[CH2:10][N:11]=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:13]=2[CH:18]=1)([O-:29])=[O:28]
Reactant: CN1CCC(N2C(=O)CN=C(c3ccccc3F)c3ccccc32)CC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: CN1CCC(N2C(=O)CN=C(c3ccccc3F)c3cc([N+](=O)[O-])ccc32)CC1
Temperature: -8 °C
Reaction time: 6 h
Yield: 24.3 %

Procedure:
To conc. sulfuric acid (10 ml) is added 1-(1-methyl-4-piperidinyl)-1,3-dihydro-5-(2-fluorophenyl)-2H-1,4-benzdiazepin-2-one (2.09 g; 5.95 m mol) under cooling at temperature of -8° C. A solution of potassium nitrate (571 mg, 5.95×0.95 m mol) in conc. sulfuric acid (5 ml) is dropwise added to the mixture at the same temperature, which is allowed to stand at -5° C. over a period of 6 hours and then at room temperature over a period of 15 hours. The reaction mixture is poured onto ice (200 g), neutralized with conc. aqueous ammoniac solution, and shaken with methylene chloride. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue is chromatographed on a column of alumina, which is eluted with ethyl acetate. The eluate is concentrated in vacuo and the residue is crystallized from methylene chloride-ether to give 7-nitro-1-(1-methyl-4-piperidinyl)-1,3-dihydro-5-(2 -fluorophenyl)-2H-1,4-benzdiazepin-2-one (544 mg) as crystals melting at 199° to 201° C. (dec.). The yield is 23%.