Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH:6]([CH3:8])[CH2:5][NH:4][C:3]1=[O:9].C(N(CC)CC)C.[CH2:17]([O:24][C:25](ON1C(=O)CCC1=O)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([O:24][C:25]([N:7]1[CH:6]([CH3:8])[CH2:5][NH:4][C:3](=[O:9])[C@@H:2]1[CH3:1])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1CNC(=O)[C@H](C)N1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CNC(=O)[C@H](C)N1C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of (3S, 5RS)-3,5-dimethyl-piperazin-2-one (24.3 mmol) in 100 mL of methylenechloride is added triethylamine (8.45 mL, 60.75 mmol) and N-(benzyloxycarbonyloxy)succinimide (12.1 g, 48.6 mmol). After stirring overnight, the CH2Cl2 is removed, and the crude mixture is chromatographed (50% EtOAc/Hexane). (2S, 6RS)-2,6-Dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (3.3 g, 52% yield over three steps) is isolated as a white powder. MS C14H18N2O3 MS m/z: 263.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[C:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1>[C:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:1][C:2]2[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)(=[O:12])[CH3:11]
Reactant: Nc1cc(Br)cnc1Cl
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2cc(Br)cnc2Cl)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
To a 150 mL, round-bottomed flask was added 3-amino-5-bromo-2-chloropyridine (1 g, 5 mmol, Asymchem Laboratories, Morrisville, N.C.) and pyridine(10 mL). To this solution, 4-acetylbenzenesulfonyl chloride (2 g, 10 mmol, Sigma-Aldrich Corporation, St. Louis, Mo.) was added, the mixture was stirred at 25° C. for 15 h and at 100° C. for additional 2 h. The mixture was concentrated in high vacuo. The result brown oil was suspended in methanol (200 mL)-H2O (5 mL). To this suspension, K2CO3 (2 g, 14.4 mmol) was added and the mixture was stirred at 25° C. for 15 h. The methanol was removed in vacuum; the residue was treated with H2O. Filtration provided 4-acetyl-N-(5-bromo-2-chloropyridin-3-yl)benzenesulfonamide (0.5 g) as a brown solid. The filtrate was extracted by MeOH-DCM (10%) to provide additional 1.1 g of 4-acetyl-N-(5-bromo-2-chloropyridin-3-yl)benzenesulfonamide as a white solid. MS (ESI positive ion) m/z: 391 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 2.57 (s, 3H), 7.51-7.56 (m, 2H), 7.81 (d, J=8.41 Hz, 2H), 7.98 (d, J=8.41 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH:5]([N:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][NH:31]C(OC(C)(C)C)=O)=[CH:26][CH:25]=1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].Cl.O1CCOCC1>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([N:11]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:30][NH2:31])=[CH:28][CH:29]=1)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH3:22])[C:4]([O:3][CH2:1][CH3:2])=[O:39])[CH3:10]
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CNC(=O)OC(C)(C)C)cc1)C(C(=O)OCC)C(=O)OCC
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCCN(CCC)CCCCN(Cc1ccc(CN)cc1)C(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.2 %

Procedure:
The compound (421 mg) obtained in Example 89-1 was dissolved in anhydrous ethanol (4.0 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (4.00 ml) and the whole was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off. The resultant was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (338 mg) as a pale-yellow oily substance.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1O)([O-:3])=[O:2].S(Cl)([Cl:20])=O.CN(C)C=O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=[C:6]([N+:14]([O-:16])=[O:15])[C:5]=1[Cl:20])([O-:3])=[O:2]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Yield: 86.6 %

Procedure:
180 grams (0.75 moles) of 2,6-dinitro-4-tert-butylphenol thus prepared was placed in a mixture of 113 grams (0.95 moles) thionyl chloride, 55 grams (0.76 moles) dimethylformamide and 300 ml. of dry toluene. The mixture was stirred and heated to reflux temperature for 15 hours after which time the thionyl chloride, DMF and toluene were removed under reduced pressure until a slush remained. Hexane was then added to the reaction vessel, the mixture cooled and filtered. The product was then recrystallized from boiling hexane to give 168 grams 2,6-dinitro-4-tert-butylchlorobenzene in the form of light yellow needles melting at 114° - 116° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[CH:11][CH3:12])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.[Pd]>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: CC=C1CCc2ccc(Br)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC1CCc2ccc(Br)cc21
Yield: 89.2 %

Procedure:
6-Bromo-1-ethylidene-indan 41a (3.07 g, 13.7 mmol) was dissolved in 80 mL of ethyl acetate followed by addition of palladium on carbon (0.61 g) at room temperature. The mixture was hydrogenated for 5 hours in a hydrogenator under 3 atm. of hydrogen. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered to remove palladium on carbon and the filter cake was washed with ethyl acetate (10 mL×3). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound 6-bromo-1-ethyl-indan 41b (2.75 g, 88.7%) as a light yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[H-].[Na+].[C:12]1([S:22](Cl)(=[O:24])=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>O1CCCC1>[CH3:1][C:2]1([CH3:9])[N:6]([S:22]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:24])=[O:23])[C:5](=[O:7])[N:4]([S:22]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:24])=[O:23])[C:3]1=[O:8]
Reactant: CC1(C)NC(=O)NC1=O
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)C(=O)N(S(=O)(=O)c2cccc3ccccc23)C(=O)N1S(=O)(=O)c1cccc2ccccc12
Reaction time: 0.5 h
Yield: 6 %

Procedure:
5,5-Dimethylimidazolidine-2,4-dione (1.28 g) was dissolved in tetrahydrofuran (20 mL), and sodium hydride (60%, in oil) (0.25 g) was added at 0° C. under ice-cooling. After stirred for 30 minutes, 1-naphthalenesulfonyl chloride (2.38 g) was added at 0° C., and the mixture was stirred at room temperature overnight. After the solvent was distilled off, ethyl acetate (150 mL) was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, an aqueous saturated sodium bicarbonate solution and a saturated brine in turn. After drying over anhydrous magnesium sulfate, the solvent was distilled off. Further purification by silica gel chromatography (hexane:ethyl acetate=2:1) afforded 160 mg of white crystals.
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[NH:8][C:9](=O)[C:10]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:13][C:11]=2[N:12]=1)[CH:2]([CH3:4])[CH3:3].N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:38]>C(Cl)(Cl)Cl>[Cl:38][C:9]1[C:10]2[CH:16]=[CH:15][C:14]([C:17]3[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=3)=[N:13][C:11]=2[N:12]=[C:7]([CH2:6][O:5][CH2:1][CH:2]([CH3:4])[CH3:3])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)COCc1nc2nc(-c3ncccc3C(F)(F)F)ccc2c(=O)[nH]1
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Product: CC(C)COCc1nc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1

Procedure:
Reflux a mixture of 2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-3H-pyrido[2,3-d]pyrimidin-4-one (0.510 g, 1.35 mmol), 2,6-lutidine (0.62 mL), and POCl3 (0.50 mL) in CHCl3 (10 mL) for 16 hours. Cool the mixture and concentrate under reduced pressure. Partition the residue between EtOAc and saturated NaHCO3 solution. Wash the EtOAc portion with additional NaHCO3 and then dry (Na2SO4) and concentrate under reduced pressure. Filter the brown residue through 2 inches of silica gel (1:1 EtOAc/hexanes eluent) and concentrate under reduced pressure to give 4-chloro-2-isobutoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-pyrido[2,3-d]pyrimidine as yellow viscous oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:17]3[C:16]([CH3:18])=[N:15][NH:14][C:13]=3[C:12](=[O:19])[N:11]2[C:20]2[CH:21]=[C:22]([CH3:30])[C:23]3[N:24]([C:26]([CH3:29])=[N:27][N:28]=3)[CH:25]=2)=[CH:6][CH:5]=1.I[CH2:32][CH3:33]>CN(C=O)C.CCOCC>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:17]3[C:13](=[N:14][N:15]([CH2:32][CH3:33])[C:16]=3[CH3:18])[C:12](=[O:19])[N:11]2[C:20]2[CH:21]=[C:22]([CH3:30])[C:23]3[N:24]([C:26]([CH3:29])=[N:27][N:28]=3)[CH:25]=2)=[CH:6][CH:5]=1
Reactant: CCI
Reactant: Cc1n[nH]c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCn1nc2c(c1C)C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
NaH (21.18 mg, 0.529 mmol) was added to a stirred solution of 4-(4-chlorophenyl)-5-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-methyl-4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one (Example 98) (160 mg, 0.407 mmol) in DMF (4 mL) at 0° C. and the resulting mixture was stirred at 0° C. for 30 min. Iodoethane (0.039 mL, 0.489 mmol) was added and the reaction mixture was stirred at RT for 30 min. The reaction was quenched with water, diluted with EtOAc and both phases were separated. The aq. layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude material was purified by preparative achiral SFC (column NH2, gradient 19-24% in 6 min, total 11 min) to afford, after trituration in Et2O, 31 mg, 0.074 mmol, 18% yield) as white solid. tR: 0.88 min (LC-MS 2); ESI-MS: 421 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (t, J=7.2 Hz, 3H) 2.13 (s, 3H) 2.46 (s, 3H) 2.63 (s, 3H) 4.20 (q, J=7.2 Hz, 2H) 6.49 (s, 1H) 7.33-7.40 (m, 5H) 8.46 (s, 1H).
Reaction SMILES: [CH:1]1([N:14]2[CH2:30][CH2:29][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][CH2:19][CH:18]3[OH:28])[CH2:16][CH2:15]2)[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH2:7][CH2:6][CH2:5][CH:4]3[CH2:3][CH2:2]1.[C:31]([O-:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([O-:36])=[O:35].C(O)(=O)/C=C/C(O)=O>C(OCC)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]/[C:34]([OH:36])=[O:35].[CH:1]1([N:14]2[CH2:30][CH2:29][C:17]3([N:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][CH2:19][C:18]3=[O:28])[CH2:16][CH2:15]2)[C:12]2=[C:13]3[C:8](=[CH:9][CH:10]=[CH:11]2)[CH2:7][CH2:6][CH2:5][CH:4]3[CH2:3][CH2:2]1
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: OC1CCN(c2ccccc2)C12CCN(C1CCC3CCCc4cccc1c43)CC2
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOCC
Product: O=C1CCN(c2ccccc2)C12CCN(C1CCC3CCCc4cccc1c43)CC2

Procedure:
Oxidation of 8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,8-diaza-spiro[4.5]decan-4-ol (mixture of diastereoisomers) according to the general method of example 20 and formation of the fumarate with fumaric acid in diethyl ether yielded the title compound, pale brown solid, m.p. 144° C. and MS: m/e=401.5 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:4]([CH3:16])=[N:3]1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:1][N:2]1[C:6]([O:7][C:20]2[CH:21]=[CH:22][N:23]=[C:18]([Cl:17])[N:19]=2)=[C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[C:4]([CH3:16])=[N:3]1
Reactant: Clc1ccnc(Cl)n1
Reactant: Cc1cccc(Oc2c(C)nn(C)c2O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1cccc(Oc2c(C)nn(C)c2Oc2ccnc(Cl)n2)c1
Reaction time: 3 h
Yield: 87.7 %

Procedure:
In 10 ml of acetonitrile were dissolved 0.220 g (1.00 mmol) of 1,3-dimethyl-4-(3-methylphenoxy)-5-hydroxypyrazole, 0.220 g (1.50 mmol) of 2,4-dichloropyrimidine and 0.210 g (1.50 mmol) of potassium carbonate. Thus obtained solution was stirred for 3 hours with refluxing. After completing the reaction, the reaction solution was poured into water, extracted with ethyl acetate and dried. The organic layer was concentrated. The residue was purified by means of silica gel column chromatography (developing solution: ethyl acetate-hexane (1:1 v/v)) to give 0.29 g of 1,3-dimethyl-4-(3-methylphenoxy)-5-(2-chloropyrimidine-4-yloxy)pyrazole.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.[CH:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:22])[CH:13]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:10][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:22])[CH:13]=2)=[C:3]([CH3:9])[CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1C
Reactant: Cc1cc(O)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNc2ccc(O)cc2C)cc1C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
4-Amino-m-cresol (242 g, 1.96 mol) is added to a slurry of 4-formyl-2-methyl-benzoic acid, methyl ester (350 g, 1.96 mol) and acetic acid (3100 mL) at room temperature. Sodium triacetoxyborohydride (728 g, 3.44 mol) is added portionwise, keeping the temperature below 30° C. using an ice water bath. After overnight stirring, the reaction mixture is concentrated under reduced pressure. The residue is adjusted to pH 5 using aqueous saturated sodium bicarbonate. The resulting solid is filtered off, washed with water, and dried under vacuum overnight to give the title compound (460 g, 82%) as a brown powder. ES/MS m/e 179 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.C([Mg]Br)C.[CH3:15][C:16]1([CH3:24])[C:18]([CH3:20])([CH3:19])[CH:17]1[C:21](Cl)=[O:22]>ClCCl.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([CH:17]3[C:18]([CH3:20])([CH3:19])[C:16]3([CH3:24])[CH3:15])=[O:22])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Reactant: Clc1ccc2cc[nH]c2c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC1(C)C(C(=O)c2c[nH]c3cc(Cl)ccc23)C1(C)C
Yield: 33.2 %

Procedure:
A mixture of 6-chloroindole (0.38 g, 2.5 mmol), ethylmagnesium bromide (1.0 M solution in THF, 3.0 mL, 3.0 mmol), zinc chloride (1.0 M solution in Et2O, 3.0 mL, 3.0 mmol) and the product of Example 1A (3.0 mmol) in 10 mL of dichloromethane was processed as described in Example 1B to provide the title compound (0.23 g, 0.83 mmol, 34% yield). MS (DCI/NH3) m/z 276 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([NH:15][C:16]1[S:20][C:19]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=2[F:28])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:41]2[CH2:46][CH2:45][CH2:44][C@H:43]([NH:47]C(=O)OC(C)(C)C)[CH2:42]2)=[C:34]2[CH:40]=[CH:39][S:38][C:35]2=[N:36][CH:37]=1)=[O:30])=O)(C)(C)C>C(Cl)Cl>[NH2:15][C:16]1[S:20][C:19]([C:21]2[C:22]([F:28])=[CH:23][CH:24]=[CH:25][C:26]=2[F:27])=[N:18][C:17]=1[C:29]([NH:31][C:32]1[C:33]([N:41]2[CH2:46][CH2:45][CH2:44][C@H:43]([NH2:47])[CH2:42]2)=[C:34]2[CH:40]=[CH:39][S:38][C:35]2=[N:36][CH:37]=1)=[O:30]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2sccc2c1N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2sccc2c1N1CCC[C@H](N)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.8 %

Procedure:
TFA (2.0 mL) was added to a solution of tert-butyl {(3S)-1-[5-({[5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazol-4-yl]carbonyl}amino)thieno[2,3-b]pyridin-4-yl]piperidin-3-yl}carbamate (230.7 mg, 0.3359 mmol) in DCM (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.1% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (55.3 mg, 34%). LCMS calc. for C22H21F2N6OS2 (M+H)+: m/z=487.1. found 487.1. 1H NMR (500 MHz, DMSO-d6) δ 9.42 (s, 1H), 7.82 (d, J=6.1 Hz, 1H), 7.65 (s, 2H), 7.60 (d, J=6.2 Hz, 1H), 7.57-7.50 (m, 1H), 7.28 (t, J=8.7 Hz, 2H), 3.23-3.16 (m, 1H), 3.07-3.01 (m, 2H), 2.99-2.91 (m, 1H), 2.90-2.82 (m, 1H), 1.91-1.66 (m, 3H), 1.30-1.13 (m, 1H) ppm.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Br:20]Br.CCN(C(C)C)C(C)C.O[CH2:32][C:33]1[CH:34]=[C:35]([CH:63]=[CH:64][CH:65]=1)[O:36][C:37]([O:39][CH2:40]/[C:41](/[C:53]1[CH:58]=[CH:57][C:56]([S:59]([CH3:62])(=[O:61])=[O:60])=[CH:55][CH:54]=1)=[C:42](/[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)\[C:43]([O:45][CH3:46])=[O:44])=[O:38]>C(Cl)Cl>[Br:20][CH2:32][C:33]1[CH:34]=[C:35]([CH:63]=[CH:64][CH:65]=1)[O:36][C:37]([O:39][CH2:40]/[C:41](/[C:53]1[CH:58]=[CH:57][C:56]([S:59]([CH3:62])(=[O:61])=[O:60])=[CH:55][CH:54]=1)=[C:42](/[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)\[C:43]([O:45][CH3:46])=[O:44])=[O:38]
Reactant: COC(=O)/C(=C(\COC(=O)Oc1cccc(CO)c1)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)/C(=C(\COC(=O)Oc1cccc(CBr)c1)c1ccc(S(C)(=O)=O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 470 mg of Ph3P in 15 mL of CH2Cl2 cooled at 0° C. was added 1.75 mL of a 1.0M Br2 solution in CH2Cl2. After 10 min, 340 μL of Hunig's base was added followed by 798 mg of methyl (2Z)-4-({[3-(hydroxymethyl)phenoxy]carbonyl}oxy)-3-[4-(methylsulfonyl)phenyl]-2-phenylbut-2-enoate dissolved in 20 mL of CH2Cl2. After 15 min at 0° C., the reaction mixture was warmed to rt for 1 h. The reaction was quenched with H2O, extracted twice with EtOAc and washed with brine, dried over sodium sulfate, evaporated, and purified by flash chromatography (10–50% EtOAc/hexane) to afford 786 mg of the title compound as a colorless oil.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].Cl.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([O:28][CH3:29])[CH:20]=3)=[O:18])=[N:15][CH:16]=2)[CH:13]=1>N1C=CC=CC=1.Cl>[CH3:29][O:28][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][C:22]=1[N+:25]([O-:27])=[O:26])[C:17]([C:14]1[N:12]2[CH:13]=[C:8]([NH:7][S:1]([CH3:4])(=[O:3])=[O:2])[CH:9]=[CH:10][C:11]2=[CH:16][N:15]=1)=[O:18]
Reactant: COc1cc(C(=O)c2ncc3ccc(N)cn23)ccc1[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(C(=O)c2ncc3ccc(NS(C)(=O)=O)cn23)ccc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 18 h
Yield: 91.6 %

Procedure:
0.107 ml (1.38 mmol) of mesyl chloride is added to 0.40 g (1.15 mmol) of (6-aminoimidazo[1,5-a]pyridin-3-yl)(3-methoxy-4-nitrophenyl)methanone hydrochloride in 10 ml of pyridine cooled to 5° C. and the mixture is allowed to return to ambient temperature and is stirred for 18 hours. The medium is taken up in 130 ml of 1N hydrochloric acid and extracted with ethyl acetate. The organic phase is washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate and concentrated under reduced pressure. The residue is taken up in isopropyl ether, filtered off, washed with isopropyl ether and then dried. 411 mg of a yellow solid are obtained. Melting point: 249° C.; 1H NMR (d6-DMSO): 3.14 (3H, s), 4.02 (3H, s), 7.39 (1H, d), 7.94 (1H, s), 8.02-8.11 (3H, m), 8.13 (1H, s), 9.88 (1H, s)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][C@@H:9]1[CH:24]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:51]=[CH:50][CH:49]=[CH:48][C:29]=1[CH2:30][NH:31][CH2:32][C:33](=[O:47])[CH:34]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[Na].C(=O)([O-])O.[Na+]>ClCCl.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][C@@H:9]1[CH2:24][N:31]([CH2:30][C:29]1[CH:48]=[CH:49][CH:50]=[CH:51][C:28]=1[O:27][CH3:26])[CH2:32][C:33](=[O:47])[CH:34]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)C[C@@H]1C=O
Reactant: COc1ccccc1CNCC(=O)C(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccccc1CN(CC(=O)C(c1ccccc1)c1ccccc1)C[C@H]1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
Under nitrogen atmosphere, to a solution of (2R)-2-formylpiperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (2.64 g) and 3-(2-methoxybenzylamino)-1,1-diphenylpropan-2-one (3.66 g) in dichloromethane (30 ml) was added acetic acid (0.607 ml) and sodium tritacetoxyborohydride (4.82 g) under ice-cooling, and then it was stirred at room temperature for 3 hours. The reaction mixture was poured into aqueous sodium hydrogen carbonate (100 ml) and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (82 g) using a mixed solvent of hexane and ethyl acetate (3:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give (2S)-2-[[N-(2-methoxybenzyl)-N-(2-oxo-3,3-diphenylpropyl)amino]methyl]piperazine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (3.24 g) as a syrup.
Reaction SMILES: [OH:1][C@@:2]([CH3:11])([CH2:9][OH:10])[C:3]([N:5]([O:7][CH3:8])[CH3:6])=[O:4].O.[CH3:13][C:14]1C=CC(S(O)(=O)=O)=C[CH:15]=1>COC(OC)(C)C>[CH3:8][O:7][N:5]([CH3:6])[C:3]([C@:2]1([CH3:11])[CH2:9][O:10][C:14]([CH3:15])([CH3:13])[O:1]1)=[O:4]
Reactant: CON(C)C(=O)[C@@](C)(O)CO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CON(C)C(=O)[C@]1(C)COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 581.6 %

Procedure:
(S)-2,3-dihydroxy-N-methoxy-N,2-dimethylpropanamide (32 g, 196 mmol) was dissolved in 2,2-dimethoxypropane (241 ml, 1961 mmol, 4-methylbenzenesulfonic acid hydrate (3.73 g, 19.6 mmol) was added, and the reaction was stirred at ambient temperature overnight. The reaction was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate, extracted with CH2Cl2, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica plug (1.5 L, eluting with 25% EtOAc in hexanes) to afford (S)-N-methoxy-N,2,2,4-tetramethyl-1,3-dioxolane-4-carboxamide (23.1 g, 114 mmol, 58.0% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH:15]=[C:16](O)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2].[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:11](=[O:12])[N:10]2[CH:13]([CH3:18])[CH2:14][CH:15]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:9]2=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1cnc2n(c1=O)C(C)CC=C2O
Solvent: CCO
Product: CCOC(=O)c1cnc2n(c1=O)C(C)CC=C2Nc1ccccc1
Yield: 46.1 %

Procedure:
0.5 g. (2.00 mmoles) of 9-hydroxy-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester is dissolved in 5 ml. of anhydrous ethanol. To the solution 0.3 g. (3.00 mmoles) of aniline is added and the solution is heated under reflux for 3 hours. The reaction mixture is then cooled and the precipitated crystals are filtered and washed with some ethanol. 0.3 g. (46.1%) of 9-(phenyl-amino)-6-methyl-4-oxo-6,7-dihydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid ethyl ester is obtained, melting point: 119°-120° C.