Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:21]([CH2:22][OH:23])[N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:21]([CH2:22][O:23][S:41]([CH3:40])(=[O:43])=[O:42])[N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)C1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCn2c(nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)C1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 2-{[(4-fluorobenzyl)amino]carbonyl}-3-hydroxy-9-(hydroxymethyl)-4-oxo-4,6,7,9-tetrahydro-8H-pyrazino[1,2-a]pyrimidine-8-carboxylate in dry CHCl3, triethylamine (2 eq.) was added and mixture was stirred ten minutes at room temperature. Methanesulfonyl chloride (1.5 eq.) was slowly added and the resulting mixture was aged at room temperature for 1.5 hours to afford tert-butyl 2-{[(4-fluorobenzyl)amino]carbonyl}-3-hydroxy-9-{[(methylsulfonyl)oxy]methyl}-4-oxo-4,6,7,9-tetrahydro-8H-pyrazino[1,2-a]pyrimidine-8-carboxylate as the main product (monitored by LC-MS). MS (ES) C22H27FN4O8S requires 526. Found: 527 (M+H+). The reaction mixture was concentrated under vacuum at 30° C. and the solvent switched to dry acetonitrile. The insoluble material was filtered off and to the filtrated 5 equivalents of N-benzylmethylamine were added. The mixture was warmed at 110° C. upon microwave irradiation for 30 minutes then stirred at room temperature for further 36 hours. The mixture was concentrated by rotary evaporation and the resulting residue, dissolved in the minimum amount of MeOH, was carefully acidified with some drops of glacial acetic acid applied on cation-exchange resin. The resin was washed with MeOH and the crude product was eluted with 1M ammonia in methanol. The pooled eluants were concentrated to dryness under reduced pressure to get tert-butyl 9-{[benzyl(methyl)amino]methyl}-2-{[(4-fluorobenzyl)amino]carbonyl}-3-hydroxy-4-oxo-4,6,7,9-tetrahydro-8H-pyrazino[1,2-a]pyrimidine-8-carboxylate as a brown oil. MS (ES) C29H34FN5O5 requires 551. Found: 552 (M+H+).
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][OH:30])=[C:27]([CH3:33])[CH:26]=1>>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][O:30][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:27]([CH3:33])[CH:26]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Br)ccc1CO
Agent: c1c[nH]cn1
Product: Cc1cc(Br)ccc1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
Tert-butylchlorodiphenylsilane (13.06 g) and imidazole (9.7 g) were added to a solution of 4-bromo-2-methylbenzyl alcohol (9.55 g) in N,N-dimethylfocmamide (80 ml) at 5° C. and the mixture was allowed to warm to room temperature, and stirred for 18 hours. The mixture was extracted with ethyl acetate and the extract was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give 1-bromo-4-(tert-butyldiphenylsilyloxymethyl)-3-methylbenzene (20.5 g) as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[S:10][C:9]([NH:11][C:12]([N:14]2[C:30]3[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=3)[C:16]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)[CH2:15]2)=[O:13])=[N:8][CH:7]=1.[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1>>[Cl:31][C:27]1[CH:26]=[C:25]2[C:16]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)[CH2:15][N:14]([C:12](=[O:13])[NH:11][C:9]3[S:10][C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][S:35]([CH:32]4[CH2:34][CH2:33]4)(=[O:37])=[O:36])=[CH:7][N:8]=3)[C:30]2=[CH:29][CH:28]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCN)s1)c1ccc(Cl)cc12
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCNS(=O)(=O)C3CC3)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 3, with the exceptions that the methyl 1-((5-((3-aminopropyl)thio)thiazol-2-yl)carbamoyl)-5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate obtained in Example 176 was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that cyclopropanesulfonyl chloride was used instead of acetyl chloride.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][C:8](C(O)=O)=[C:7]2[OH:15].[C:16](C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCOCC>[CH2:1]([C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[N:9][CH:8]=[C:7]2[OH:15])[CH3:16]
Reactant: Cc1cccc2c(O)c(C(=O)O)nnc12
Reactant: O=C(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: CCc1cccc2c(O)cnnc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A mixture of 0.7 g of 53D and 2.8 g of benzophenone was heated at 180°-210° C. until no more gas evolved (30 minutes). The mixture was cooled to 0° C., diluted with ether and filtered. The solid was slurried with hot 5 N aqueous sodium hydroxide solution and filtered. The filtrate was acidified with 12 N hydrochloric acid, allowed to cool and stand overnight at room temperature, and filtered. The resulting solid was dried under reduced pressure, and flash chromatographed on silica gel, using a 1:1 v:v mixture of ethyl acetate and methylene chloride as eluent, to give 8-ethyl-4-hydroxycinnoline (53E), as a solid, m.p.: 160°-161° C.
Reaction SMILES: [CH3:1][C:2]([CH3:42])([CH3:41])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([CH:21]=[C:22]([C:25]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:26])[C:23]#[N:24])=[CH:17][CH:16]=3)[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]([CH3:42])([CH3:41])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([CH:21]=[C:22]([C:25]([N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:26])[C:23]#[N:24])=[CH:19][CH:20]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCCCC4)cc3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCCCC4)cc3)nc12
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.7 %

Procedure:
To a 20 ml vial, 3-[4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxymethyl)-pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]-2-(piperidine-1-carbonyl)prop-2-enenitrile (0.04 ml, 0.04 mmol) was dissolved in DCM (3 ml) and the reaction mixture was cooled to 0° C. TFA (2 ml, 0.0238 mole) was added drop wise at 0° C. and there reaction mixture was stirred for 3 h at room temperature. The solvent was evaporated and the residue was neutralized by NaHCO3 to pH 7-8 and the aq. layer was extracted with EtOAc. The organic layer was evaporated and the residue was dissolved in methanol. HCl and water were added and the solution was stirred at RT overnight and then neutralized with NaHCO3 to pH7-8. The crude product which precipitated was filtrated, washed with water and dried. The crude product was dissolved in a mixture of EtOAC and CH2Cl2, loaded on TLC plate and flashed with EtOAc:hexane=85:15 to yield 0.014 g of 3-[4-[[7-(2,2-dimethylpropanoyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]-2-(piperidine-1-carbonyl)prop-2-enenitrile.
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[C:21]([OH:23])=[O:22])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.[Pt]=O>[C:1]1([S:7]([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[C:12]=2[C:21]([OH:23])=[O:22])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2)ccc2ccccc12
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2)ccc2c1CCCC2
Reaction time: 80 h

Procedure:
A mixture of Example 42C (0.087 g, 0.27 mmol), and platinum oxide (0.056 g, 0.25 mmol) in acetic acid (7.5 mL) was shaken in a reactor pressurized with 60 psi of H2 at 25° C. for 80 hours and filtered. The filtrate was concentrated and the concentrate was purified by C18 reverse-phase HPLC with acetonitrile/water/0.1% trifluoroacetic acid to provide the desired-product. MS (ESI(+)) m/e 332 (M+H)+, 349 (M+NH4)+, 354 (M+Na)+; (ESI(−) m/e 330 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.74 (m, 2H), 7.63 (m, 1H), 7.56 (m, 2H), 6.98 (d, 1H), 6.63 (d, 1H), 2.65 (m, 4H), 1.66 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][O:20][C:21]3[CH:25]=[CH:24][O:23][N:22]=3)[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[C:26]([O:29][CH2:30][C:31](Cl)=[O:32])(=[O:28])[CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][O:20][C:21]3[CH:25]=[CH:24][O:23][N:22]=3)[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:31](=[O:32])[CH2:30][O:29][C:26](=[O:28])[CH3:27])[CH2:10][CH2:9]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Fc1cc(C2=NOC(COc3ccon3)C2)ccc1N1CCNCC1
Product: CC(=O)OCC(=O)N1CCN(c2ccc(C3=NOC(COc4ccon4)C3)cc2F)CC1

Procedure:
(5RS)-3-(3-Fluoro-4-piperazin-1-ylphenyl)-5-isoxazol-3-yloxymethyl-4,5-dihydroisoxazole (175 mg, 0.51 mM) was treated with acetoxyacetyl chloride using essentially the conditions of Example 16, to give the desired product after chromatography and precipitation (163 mg).
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:7]=1N.[BrH:18]>S(=O)(=O)(O)O.C(O)(=O)C.O>[Cl:5][C:6]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[CH:10]=[CH:9][C:7]=1[Br:18]
Reactant: Br
Reactant: Nc1ccc(OC(F)(F)F)cc1Cl
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)Oc1ccc(Br)c(Cl)c1
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (16.31 g) in concentrated sulphuric acid was added dropwise to a solution of 2-chloro-4-trifluoromethoxyaniline (50 g) in acetic acid, while maintaining the temperature below 10° C. The mixture was stirred at 5°-10° C. for 0.5 hours then added slowly to a mixture of cuprous bromide (33.9 g) in aqueous hydrobromic acid (200 ml) and ice. The mixture was stirred at room temperature for 0.5 hours and left to stand overnight. The mixture was diluted with water and extracted with dichloromethane, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-chloro-4-trifluoromethoxybromobenzene (63.64 g) as a brown oil which was not further purified.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[C:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=O)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]>>[C:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)=[CH:26][CH:25]=1)(=[O:23])[CH3:22]
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: CC(=O)c1ccc(-c2nc(Cn3ccc4c(C(F)(F)F)c(C#N)ccc43)no2)cc1

Procedure:
Synthesized as described in Example 72 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 4-acetylbenzoic acid: MS (ESI): m/z 411 (M+1).
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[Cl:9][C:10]([Cl:16])=[CH:11][CH:12]=[C:13]([CH3:15])[CH3:14]>S([O-])([O-])(=O)=O.[Cu+2]>[CH3:14][C:13]1([CH3:15])[CH:12]([CH:11]=[C:10]([Cl:16])[Cl:9])[CH:3]1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CC(C)=CC=C(Cl)Cl
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Product: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C

Procedure:
Thus, for example, in Pesticide Science (1974) 5, 791-799 it is shown that the reaction between ethyl diazoacetate and 1,1-dichloro-4-methylpenta-1,3-diene in the presence of copper sulfate to produce ethyl 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropanecarboxylate, results in a product which is contaminated with up to 20% of ethyl fumarate and maleate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([NH:20][C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:35]([O:37][CH3:38])=[O:36]>[H-].[Na+].O1CCCC1>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:30]([F:31])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([N:20]([C:21]4[N:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:35](=[O:36])[O:37][CH3:38])=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1ncccn1
Reactant: COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(C(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C)c1ncccn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.9 %

Procedure:
In 0.02 g of 55% oily sodium hydride suspended in 3 mL of tetrahydrofuran, a solution of 0.17 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-methyl-N-(2-pyrimidinyl)benzoic acid amide synthesized similarly to Step 5 of Synthetic Example 1 in 3 mL of tetrahydrofuran was added dropwise. After the completion of the addition dropwise, it was continued to stir at the same temperature for 10 minutes, then 0.05 g of methyl chloroformate was added, and continued to stir at the same temperature for 1 hour. After the completion of the reaction, the reaction mixture was poured in 10 mL of ice water, extracted with ethyl acetate (10 mL×2), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate to obtain 0.11 g of the aimed product as colorless resinous substance.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20])[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C1C=CC2N(O)N=NC=2C=1>C1(C)C=CC=CC=1>[C:9]([O:8][C:6]([N:5]1[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][C:3](=[O:2])[CH2:4]1)=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)CN(Cc1ccccc1N)C(=O)OC(C)(C)C
Agent: On1nnc2ccccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(=O)Nc2ccccc2C1
Temperature: 100 °C

Procedure:
To a solution of [(2-amino-benzyl)-tert-butoxycarbonyl-amino]acetic acid methyl ester (640 mg, 2.18 mmol) in toluene (30 mL), was added HOBT (177 mg, 1.31 mmol). The reaction mixture was heated at 100° C. for 24 h. After the completion of reaction, as confirmed by TLC, the solvent was removed in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 7:13 EtOAc:Pet. Ether) to afford pure 2-oxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester: (350 mg, 61%) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Oc1ccc(Cl)nc1
Product: Oc1ccc(-c2ccc(C(F)(F)F)cc2)nc1

Procedure:
The titled compound is made in a manner substantially similar to Preparation 28 starting from the 6-chloro-pyridin-3-ol and 4-trifluoromethylphenyl boronic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26](F)[CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.F[C:32]1[CH:33]=[CH:34][C:35](C)=[C:36]([CH:40]=1)[C:37](Cl)=[O:38]>>[CH2:15]1[C:26]2[C:27](=[CH:28][CH:29]=[C:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[C:8]([C:4]5[CH:3]=[C:2]([NH:1][C:37](=[O:38])[C:36]6[CH:40]=[CH:32][CH:33]=[CH:34][CH:35]=6)[CH:7]=[CH:6][CH:5]=5)=[N:9][N:10]5[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=45)[CH:22]=[CH:21][N:20]=3)[CH:25]=2)[CH2:12][CH2:11][NH:10]1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(F)c3)n2)c1
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluorophenyl)-2-pyrimidinamine and 5-fluoro-2-methylbenzoyl chloride in a manner analogous to Example 66. 1H NMR (300 MHz, DMSO-d6): δ 10.48 (s, 1H), 9.80 (s, 1H), 8.85 (d, 1H), 8.47 (d, 1H), 8.32 (d, 1H), 8.07 (s, 1H), 7.84 (d, 1H), 7.77 (m, 1H), 7.53-7.42 (m, 3H), 7.36-7.28 (m, 3H), 7.26-7.18 (m, 2H), 7.13 (m, 1H), 6.71 (m, 1H), 6.60 (d, 1H), 2.32 (s, 3H); HRMS: calc. C31H23N6OF2 (M+H)+ 533.1901 found 533.1904.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:24])[CH:3]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][C:26]1=[O:30]>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:29][CH2:28][CH2:27][C:26]3=[O:30])=[CH:3][C:4]=2[F:24])=[O:9])[CH2:11][CH2:12]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)c(C)c1
Reactant: O=C1CCCN1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3F)CC2)c(C)c1

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (783 mg) described in Preparation Example 116 and pyrrolidin-2-one (0.16 mL) and by the reaction and treatment in the same manner as in Example 1, the title compound (313 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[S:8][C:9](/[CH:12]=[CH:13]/[C:14]([O:16]CC)=[O:15])=[CH:10][N:11]=2)=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[S:8][C:9](/[CH:12]=[CH:13]/[C:14]([OH:16])=[O:15])=[CH:10][N:11]=2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)/C=C/c1cnc(Oc2ccc(Cl)cc2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1cnc(Oc2ccc(Cl)cc2)s1
Temperature: 25 °C

Procedure:
A solution of ethyl trans-3-(2-(4-chlorophenoxy)-5-thiazolyl)propenoate from above in 1:1 1N LiOH:THF (120 mL) was heated at 50° C. for 5 hrs. It was then cooled to r.t. and the THF was stripped off. The aqueous residue was poured into 1:1 ice:conc. HCl (100 mL), the precipitate was collected, taken up in ethylacetate(150 mL), dried with MgSO4 and concentrated to afford trans-3-(2-(4-chlorophenoxy)-5-thiazolyl)propenoic acid as an off-white solid.
Reaction SMILES: C(O[C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[CH:9][CH:8]=1)C.[OH:29][CH2:30][CH2:31][NH:32][CH2:33][CH2:34][OH:35]>C(O)C>[CH2:21]([O:20][C:18](=[O:19])[NH:17][CH2:16][CH2:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4](=[O:28])[N:32]([CH2:33][CH2:34][OH:35])[CH2:31][CH2:30][OH:29])=[CH:12][CH:11]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: OCCNCCO
Reactant: CCOC(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Solvent: CCO
Product: O=C(NCCCCc1ccc(OCC(=O)N(CCO)CCO)cc1)OCc1ccccc1

Procedure:
A solution of [4-(4-benzyloxycarbonylaminobutyl)phenoxy]acetic acid ethyl ester 23 (0.3 g, 0.78 mmol), 2-(2-hydroxyethylamino)ethanol 24 (0.15 mL, 1.6 mmol), and ethanol (20 mL) was heated at 70° C. for 72 hours. Solvent was evaporated in vacuo. The residue was purified by flash chromatography (silica gel, dichloromethane/methanol, 100:5, v/v) to provide [4-(4-{[N,N-bis-(2-hydroxyethyl)carbamoyl]methoxy}phenyl)-butyl]carbamic acid benzyl ester 25 [0.19 g, 100% based on the recovered starting material (0.13 g)] as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 1.65 (m, 4H), 2.50 (m, 2H), 3.20 (m, 2H), 3.55 (m, 4H), 3.75 (m, 4H), 4.80 (s, 2H), 5.10 (s, 2H), 6.85 (d, 2H), 7.10 (d, 2H), 7.40 (m, 5H). m/z (ESI): 445 [C24H32N2O6+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[C@H:10]([CH2:33][CH2:34][S:35][CH3:36])[NH:11][C:12](=[O:32])[C@H:13]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH:14]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:38]>O1CCOCC1>[ClH:38].[CH2:1]([O:8][C:9](=[O:37])[C@H:10]([CH2:33][CH2:34][S:35][CH3:36])[NH:11][C:12](=[O:32])[C@H:13]([CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)[NH2:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CSCC[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1

Procedure:
17.1 Parts N-t-butoxycarbonyl-L-tryptophyl-L-methionine benzyl ester is dissolved in 200 parts dioxane and treated with a 10 fold excess of 2N hydrochloric acid in dioxane for 10 minutes. Removal of the solvent under reduced pressure affords pure L-tryptophyl-L-methionine benzyl ester hydrochloride.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[C:34]=1[OH:42].[CH2:43]([O:50][C:51](=[O:63])[C@@H:52]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:53]O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>O1CCCC1>[CH2:43]([O:50][C:51](=[O:63])[C@@H:52]([NH:55][C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])[CH2:53][O:42][C:34]1[C:35]([N+:39]([O-:41])=[O:40])=[CH:36][CH:37]=[CH:38][C:33]=1[Cl:32])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=[N+]([O-])c1cccc(Cl)c1O
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](COc1c(Cl)cccc1[N+](=O)[O-])C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 50.9 %

Procedure:
Under an inert atmosphere, a solution of 6.5 g (25 mmol) of triphenylphosphine in 20 ml of tetrahydrofurane was treated with at 0° C. with 3.9 ml (25 mmol) of diethyl azodicarboxylate. Thereupon, 3.0 g (17 mmol) of 2-chloro-6-nitrophenol were added and the reaction mixture was stirred at 0° C. for 15 minutes. Finally, 4.93 g (17 mmol) of (S)-2-tert-butoxycarbonylamino-3-hydroxy-propionic acid benzyl ester were added and the reaction mixture was left to warm to room temperature. After stirring for 18 hours, for the working-up the solvent was evaporated under reduced pressure and the residue triturated in ether at 0° C. The precipitated triphenylphosphinoxide was filtered and washed with ether. The combined filtrates were evaporated to yield 12.8 g of the crude product as a brown-yellow oil. The crude product was purified by chromatography on silica gel using heptane and ethyl acetate as the eluent. There were obtained 3.9 g (50%) of the title compound as a yellow oil, [α]589=−5.96° (c=1.0% in MeOH), MS m/e (%): 468.1 (M+NH4+, 100).
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>C(O)C>[CH:1]([C@@H:14]1[CH2:20][C@@H:19]([OH:18])[C@H:17]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1ccc(F)cc1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@H]3O[C@H]3CO2)cc1
Solvent: CCO
Product: O[C@@H]1C[C@@H](C(c2ccccc2)c2ccccc2)OC[C@H]1NCc1ccc(F)cc1

Procedure:
(1S,4S,6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]-heptane 28a (0.025 g, 0.094 mmol) was reacted with para-fluoro-benzylamine (0.24 g, 1.88 mmol) in ethanol (Procedure E) to yield (2S,4R,5R)-2-benzhydryl-5-(4-fluoro-benzylamino)-tetrahydropyran-4-ol, (−)-29b, 0.032 g (86%, [α]D=(−)77.2, c=1, MeOH).