Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][C:5]1[CH:43]=[CH:42][CH:41]=[CH:40][C:6]=1[CH2:7][CH2:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]([NH:19][C:20]2[CH:39]=[CH:38][C:23]([CH2:24][N:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]3)=[CH:22][CH:21]=2)[N:10]=1.O.[OH-].[Li+:47]>C1COCC1.O>[C:34]([O:33][C:31]([N:28]1[CH2:27][CH2:26][N:25]([CH2:24][C:23]2[CH:38]=[CH:39][C:20]([NH:19][C:11]3[N:10]=[C:9]([CH2:8][CH2:7][C:6]4[CH:40]=[CH:41][CH:42]=[CH:43][C:5]=4[CH2:4][C:3]([O-:44])=[O:2])[C:14]([C:15]([F:16])([F:17])[F:18])=[CH:13][N:12]=3)=[CH:21][CH:22]=2)[CH2:30][CH2:29]1)=[O:32])([CH3:37])([CH3:35])[CH3:36].[Li+:47]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)[O-])n3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
tert-Butyl 4-(4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I96) (120 mg, 0.196 mmol) was dissolved in THF (4 mL), and a solution of lithium hydroxide hydrate (25 mg, 0.59 mmol) in water (1 mL) was added. The mixture was stirred at room temperature for 18 hours then concentrated and the residue evaporated twice from toluene to give the title compound (I97) as a tan solid which was used without purification. LCMS Method C: rt 5.17 min; m/z 600.2 [M-Li+2H]+; 544.1 [M-tBu-Li+3H]+; m/z 598.2 [M-Li]−.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[C:5]([C:25](O)=[O:26])[CH:4]=[N:3]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.CCCP(=O)=O>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[C:6]([C:7]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=[C:11]3[CH:10]=2)=[O:24])=[C:5]([C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:26])[CH:4]=[N:3]1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Reactant: C1COCCN1
Agent: CCCP(=O)=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 44.5 %

Procedure:
A mixture of 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (100 mg, 276 μmol), morpholine (240 μl, 2.76 mmol) and propylphosphonic anhydride (50% in ethyl acetate, 407 μl, 690 μmol) in tetrahydrofurane (7 ml) is stirred for 3 hours at 70° C. The mixture is diluted with ethyl acetate and washed with sat. aqueous sodium hydrogencarbonate solution and brine. The organic layer is separated, dried with magnesium sulfate and the solvent is evaporated. The residue (76 mg white foam) is triturated with diethylether and ethyl acetate affording 1-methyl-4-(morpholine-4-carbonyl)-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1H-pyrazole-5-carboxamide (53 mg, 44.5%) as a white solid. mp.: 203-207° C. MS: m/z=432.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].Cl[CH2:23][C:24]1[O:28][N:27]=[C:26]([CH2:29][CH3:30])[CH:25]=1>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:23][C:24]3[O:28][N:27]=[C:26]([CH2:29][CH3:30])[CH:25]=3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: CCc1cc(CCl)on1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1cc(CN2C[C@@H]3COCCN3c3nc(Cl)ncc32)on1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x5 using (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 100 mg, 0.441 mmol) in DMSO (5 mL), sodium tert-butoxide (50.9 mg, 0.529 mmol) and 5-(chloromethyl)-3-ethylisoxazole (70.7 mg, 0.485 mmol) (120 mg, 81%). ESI-MS m/z [M+H]+ calc'd for C15H18ClN5O2, 336.12; found 336.3.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:12])[CH:8]=[CH:9][CH2:10][OH:11].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl.O1CCCC1>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:11][CH2:10]/[CH:9]=[CH:8]\[CH2:7][OH:12]
Reactant: OCC=CCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: OC/C=C\COC1CCCCO1
Temperature: 0 °C
Reaction time: 48 h
Yield: 481.9 %

Procedure:
Dihydropyran (9.1 ml, 100 mmol) was added dropwise to a cooled (0° C.) solution of 2-butene-1,4-diol (8.8 g, 10 mmol) and pyridinium paratoluenesulfonate (0.25 g, 10 mmol) in anhydrous dichloromethane:tetrahydrofuran (2:1). The mixture was stirred two days at 0° C. then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (ethyl acetate:hexane 3:7) to give 8.3 g of the title compound (49%).
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].Br[C@H:7]([CH3:11])[C:8]([OH:10])=[O:9]>C(#N)C>[C:1]([S:3][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: C[C@@H](Br)C(=O)O
Agent: [K+]
Solvent: CC#N
Product: CC(=O)S[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a light green solution of potassium thioacetate (3.94 g, 34.5 mmol) in acetonitrile (150 ml) was added a solution of (R)-2-bromopropanoic acid (4.8 g, 31 mmol) in acetonitrile (12 ml) at room temperature under an argon atomosphere. The resulting white slurry was stirred at room temperature for 2 hours then filtered. The filtrate was concentrated in vacuo. The residue was diluted in ethyl acetate (100 ml), washed with a 10% aqueous solution of potassium bisulfate (50 ml) and brine, dried (sodium sulfate), and concentrated in vacuo. The crude product (4.61 g) was purified by flash chromatography (60 g--Merck silica gel, 1:45:54 acetic acid/ethyl acetate/hexane) to afford 3.7 g of the title product as a light yellow oil; [α]D =-114° (c=0.50, methanol).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:16][CH2:17][N:18]([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[C:14]#[N:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[K+].Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.O>C1(C)C=CC=CC=1>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)([CH2:16][CH2:17][N:18]([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:20])[CH3:21])[C:14]#[N:15])=[CH:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)N(CCC(C#N)c1ccc(-c2ccccc2)cc1)C(C)C
Reactant: Brc1ccccn1
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)N(CCC(C#N)(c1ccc(-c2ccccc2)cc1)c1ccccn1)C(C)C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
A mixture of 50.0 g (0.16 mole) of 2-(4-phenylphenyl)-4-[N,N-bis(1-methylethyl)amino]butanenitrile and 29.7 g of potassium hydride (about 0.26 mole as a 35% dispersion in oil) in 1000 ml of toluene was heated at 65°. A solution of 32 g (0.20 mole) of 2-bromopyridine in 450 ml of toluene was added slowly. After addition was complete, the mixture was stirred an additional 30 minutes, cooled in an ice bath, and treated with 750 ml of water. The toluene layer was separated and extracted with 10% aqueous hydrochloric acid. The acidic aqueous layer was neutralized with a slight excess of aqueous sodium hydroxide and extracted wih dichloromethane. The organic phase was washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness, giving 56.5 g of the title compound as an oil having the expected NMR spectrum. The intermediate nitrile was used without further purification.
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[C:11]1([CH:21]=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[H-].[Na+].[OH-].[Na+]>C(O)C>[C:11]1([CH:21]=[C:3]([CH2:2][C:1]([OH:8])=[O:7])[C:4]([OH:6])=[O:5])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(=O)CCC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(=Cc1cccc2ccccc12)C(=O)O
Yield: 55.7 %

Procedure:
To a solution of 32.3 g of ethyl succinate and 29.0 g of 1-naphthaldehyde in 320 ml of an absolute ethyl alcohol was added 10.7 g of a 50% sodium hydride (dispersion in mineral oil) under ice-cooling, and the mixture was heated under reflux for 30 minutes. To the reaction mixture was added 230 ml of a 1N-aqueous sodium hydroxide solution, and the mixture was concentrated under reduced pressure. To the residue was added water, and the mixture was extracted with ethyl ether to remove neutral materials. The aqueous layer was acidified with a concentrated hydrochloric acid, and extracted with ethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. To the residue was added benzene, and precipitated crystals were collected by filtration to obtain 26.5 g of 2-(1-naphthylmethylene) succinic acid as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11](=[O:14])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:18][C:19]#[C:20][CH2:21][CH3:22]>CN(C=O)C>[CH2:18]([N:10]1[C:11](=[O:14])[CH:12]=[N:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:9]1)[C:19]#[C:20][CH2:21][CH3:22]
Reactant: CCC#CCCl
Reactant: O=c1cnc(-c2ccc(Cl)cc2)n[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC#CCn1nc(-c2ccc(Cl)cc2)ncc1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The 0.4 g of 3-(4-chlorophenyl)-1,2,4-triazin-6-one (1.9 mmol) was placed in 10 mL of DMF and cooled in an ice bath. Sodium hydride (NaH) (0.8 g of 60% dispersion, 2 mmol) was added, and the reaction mixture was held for 15 minutes. Excess 1-chloro-2-pentyne was added, the bath was removed, and the reaction mixture was allowed to warm to room temperature. Water and ethyl acetate were added. The organic phase was washed with water and brine, dried over magnesium sulfate, filtered and stripped. The crude product was chromatographed on silica gel to give 0.05 g of 1-(2-pentynyl)-3-(4-chlorophenyl)-1,2,4-triazin-6-one.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[CH:7][C:8]=1[C:9]([OH:11])=[O:10])=[O:2].S(=O)(=O)(O)O.OS(O)(=O)=O.O=S(=O)=O.[N+:26]([O-])([OH:28])=[O:27]>>[CH:1]([NH:3][C:4]1[S:5][C:6]([N+:26]([O-:28])=[O:27])=[CH:7][C:8]=1[C:9]([OH:11])=[O:10])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=CNc1sccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: O=CNc1sc([N+](=O)[O-])cc1C(=O)O
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 90 %

Procedure:
51.3 parts of 2-formylaminothiophene-3-carboxylic acid are added to 500 parts of sulphuric acid (sp.gr. 1.84) at a temperature below 10°C, and 56.7 parts of a nitrating mixture (obtained by mixing together 633 parts of 20% oleum and 348 parts of nitric acid of sp.gr. 1.50) are then slowly added, the temperature of the mixture being maintained at -10° to -5°C by external cooling. The mixture is stirred for 5 minutes at -5°C, poured into an ice/water mixture and the precipitated 2-formylamino-5-nitrothiophene-3-carboxylic acid (90% yield) is filtered off, washed with water and dried.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]([CH3:21])[CH:14]=[C:13]2[C:22]1[N:38](S(C2C=CC(C)=CC=2)(=O)=O)[C:25]2=[N:26][CH:27]=[CH:28][C:29]([CH2:30][NH:31][C:32]3[N:33]([CH3:37])[N:34]=[CH:35][CH:36]=3)=[C:24]2[CH:23]=1.[OH-].[K+]>>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]([CH3:21])[CH:14]=[C:13]2[C:22]1[NH:38][C:25]2=[N:26][CH:27]=[CH:28][C:29]([CH2:30][NH:31][C:32]3[N:33]([CH3:37])[N:34]=[CH:35][CH:36]=3)=[C:24]2[CH:23]=1
Reactant: COc1cc2c(-c3cc4c(CNc5ccnn5C)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(-c3cc4c(CNc5ccnn5C)ccnc4[nH]3)cn(C)c2cc1OC
Yield: 49.3 %

Procedure:
[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](2-methyl-2H-pyrazol-3-yl)amine is prepared as described in Example 179a starting with 0.08 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](2-methyl-2H-pyrazol-3-yl)amine trifluoroacetate instead of the [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](4-trifluoromethylsulfanylbenzyl)amine used in Example 179a and 0.62 cm3 of 5N potassium hydroxide. After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 98/02 by volume as eluent), 0.024 g of [2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl](2-methyl-2H-pyrazol-3-yl)amine is obtained, the characteristics of which are as follows:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9](O)=[O:10]>>[CH3:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:9]([Cl:3])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(=O)O)cc1C
Product: Cc1ccc(C(=O)Cl)cc1C
Yield: 94.4 %

Procedure:
78 g of thionyl chloride were added to 50 g of 3,4-dimethylbenzoic acid and the reaction mixture was heated at reflux for 3 hours. The reaction mixture was subsequently concentrated, and the residue was taken up twice in toluene and concentrated again. 53 g of 3,4-dimethylbenzoyl chloride were obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[C:3]([OH:5])=[O:4].[CH3:22]O>OS(O)(=O)=O.O>[CH3:1][C:2]([CH3:21])([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[C:3]([O:5][CH3:22])=[O:4]
Reactant: CC(C)(Cc1cccc(OCc2ccccc2)c1)C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)C(C)(C)Cc1cccc(OCc2ccccc2)c1
Yield: 50 %

Procedure:
A solution of 2,2-dimethyl-3-(3-benzyloxyphenyl)propionic acid (400 mg, 1.4 mmole) in 20 mL of MeOH and 0.5 mL conc. H2SO4 was refluxed for 18 hours. The reaction was cooled, diluted with H2O and extracted with Et2O. The extracts were washed with H2O, three times with aqueous NaHCO3, dried, and the solvent evaporated. The residue was chromatographed over a silica gel column, and elution with a mixture of CH2Cl2, hexane and MeOH (50:50:1) gave the titled compound, 208 mg (50% yield). MS (ESI) 299 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[NH:14][N:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:28][CH2:29][CH2:30][F:31])(=O)=O>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:28][CH2:29][CH2:30][F:31])[N:13]=[N:12]1
Reactant: O=c1[nH]nnn1-c1ccc([N+](=O)[O-])cc1F
Reactant: CS(=O)(=O)OCCCF
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1n(CCCF)nnn1-c1ccc([N+](=O)[O-])cc1F
Temperature: 60 °C
Yield: 60.8 %

Procedure:
A stirred mixture of 28.0 g (0.124 mole) of 1-(2-fluoro-4-nitrophenyl)-1,4-dihydro-5H-tetrazol-5-one, 19.3 g (0.140 mole) of potassium carbonate, and 21.8 g (0.140 mole) of 3-fluoropropyl methanesulfonate in 100 mL of dimethylformamide was heated at 60° C. for approximately 18 hours. The reaction mixture was poured into icewater, and the resultant fixture was extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with methylene chloride, to yield 21.5 g of 1-(2-fluoro-4-nitrophenyl)-4-(3-fluoropropyl)-1,4-dihydro-5H-tetrazol-5-one as a solid, m.p. 86°-89° C.
Reaction SMILES: [CH2:1]([C@@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.[O:24]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[CH3:14][C:13]([CH3:15])([CH3:16])[C@@H:11]([N:7]1[CH2:6][CH2:5][C@@:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH2:1][CH2:2][OH:24])[O:9][C:8]1=[O:10])[CH3:12]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)O1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A solution of (R)-6-allyl-3-((2S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one [Isomer 1] (450 mg, 1.41 mmol) in dry CH2Cl2 (10 mL) was treated with O3 at −78° C. till the mixture turned blue. NaBH4 (157 mg, 4.23 mmol) was added, and the mixture was stirred at rt overnight. The solution was concentrated, and the residue was purified by preparative TLC followed by preparative HPLC to give (S)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one [Isomer 1] (265 mg, 58%). LC-MS Method 2 tR=3.83, min, m/z=669.03; 1H NMR (CDCl3): 0.71 (s, 9H), 1.06-1.11 (d, 3H), 2.07-2.19 (m, 2H), 2.31-2.28 (m, 1H), 2.67-2.76 (m, 1H), 3.12-3.18 (m, 1H), 3.47-3.58 (m, 1H), 3.69-3.78 (m, 1H), 4.38-4.47 (m, 1H), 7.03-7.09 (m, 2H), 7.26-7.33 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([CH3:18])=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH3:20])[CH:14]=3)[C:9]=2[O:21][CH2:22]OC)=[CH:4][CH:3]=1.Cl.O1CCOCC1.FC1[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([CH3:18])=[CH:16][C:11]3[C:10](=[CH:15][CH:14]=[C:13]([O:19][CH3:20])[CH:12]=3)[C:9]=2[O:21][C:22]2[CH:40]=[CH:39][C:36]([CH:37]=[O:38])=[CH:35][CH:34]=2)=[CH:6][CH:7]=1
Reactant: COCOc1c(-c2ccc(F)cc2)c(C)cc2cc(OC)ccc12
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccc(F)cc3)c(C)cc2c1
Yield: 71.6 %

Procedure:
2-(4-Fluoro-phenyl)-6-methoxy-1-methoxymethoxy-3-methyl-naphthalene (203) (0.31 g, 0.95 mmol), 4 N HCl/Dioxane (5 mL), 4-fluorobenzaldehyde (0.132 mL, 1.23 mmol), Cs2CO3 (0.838 g, 2.57 mmol) and DMSO (3 mL) were reacted as described above to give 0.263 g (72%) of the title compound (204) as oil. 1H NMR (400 MHz, d-CDCl3): δ 2.24 (s, 3H), 3.93 (s, 3H), 6.69 (d, J=8.8 Hz, 2H), 6.92-6.97 (m, 2H), 7.07-7.15 (m, 4H), 7.59-7.68 (m, 4H), 9.80 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:7][C:8]([CH3:28])=[C:9]([C:24]([O:26][CH3:27])=[O:25])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][N:38]=1>ClCCl>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH:10]1[C:9]([C:24]([O:26][CH3:27])=[O:25])=[C:8]([CH3:28])[NH:7][C:6]([CH2:5][O:4][CH2:3][CH2:2][NH:1][S:43]([C:40]2[CH:41]=[CH:42][C:37]([Cl:36])=[N:38][CH:39]=2)(=[O:45])=[O:44])=[C:11]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1=C(COCCNS(=O)(=O)c2ccc(Cl)nc2)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.8 %

Procedure:
A solution of 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine (409 mg) and triethylamine (202 mg) in dry dichloromethane (20 ml) was stirred under nitrogen and cooled in an ice-bath while a solution of 2-chloro-5-pyridinesulphonyl chloride (212 mg) in dry dichloromethane (10 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature and stirring continued for a further 3 hours. The solvent was evaporated and the residue chromatographed on silica, eluting with dichloromethane. Appropriate fractions were combined and evaporated and the residue recrystallised from ethyl acetate to give the title compound (320 mg), m.p. 140°-140.5° C. Found: C, 51,27; H, 4.63; N, 7.25. C25H27Cl2N3O7 requires C, 51.37; H, 4.66; N, 7.19%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=2)[S:23][C:24]=1[CH2:25][CH2:26][CH2:27]O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:27][CH2:26][CH2:25][C:24]3[S:23][C:22]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][CH:30]=4)=[N:21][C:20]=3[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCCO
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCCOc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 6 b]) was reacted with 3-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propan-1-ol (example 8 c]) in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield (6-{3-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-propoxy}-indol-1-yl)-acetic acid tert-butyl ester as colorless gum.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39]([OH:41])=O)[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH3:46][N:47]1[CH2:52][CH2:51][N:50]([CH:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)[C@H:49]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:48]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH2:37][C:30]1[C:31]([C:33]([F:36])([F:35])[F:34])=[CH:32][C:27]([CH2:26][C@@H:25]([O:24][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:15]3[CH2:14][CH2:13][C:12]4[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=4[NH:10][C:9]3=[O:8])[CH2:17][CH2:18]2)=[O:23])[C:39]([N:56]2[CH2:57][CH2:58][CH:53]([N:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][C@H:49]3[C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:54][CH2:55]2)=[O:41])=[CH:28][C:29]=1[Cl:38]
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Reactant: CCOC(=O)[C@@H]1CN(C)CCN1C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CN(C)CCN1C1CCN(C(=O)[C@@H](Cc2cc(Cl)c(N)c(C(F)(F)F)c2)OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.40 mL (2.88 mmol) triethylamine were added to a mixture of 260 mg (0.46 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 210 mg (0.58 mmol) ethyl(S)-4-methyl-1-piperidin-4-yl-piperazine-2-carboxylate (Example A9f) and 170 mg (0.53 mmol) TBTU in 2.4 mL DMF and the reaction mixture was stirred for 18 h at RT. The reaction mixture was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.