Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:18][O:19][C:20]([O:23][Si](C)(C)C)=[CH:21][CH3:22].C(Cl)Cl>CC#N.Cl[Ti](Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:21]([CH3:22])[C:20]([O:19][CH3:18])=[O:23])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: CC=C(OC)O[Si](C)(C)C
Reactant: OC(c1ccccc1)c1ccc2[nH]ncc2c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)C(C)C(c1ccccc1)c1ccc2[nH]ncc2c1
Reaction time: 1 h

Procedure:
To a solution of (1H-indazol-5-yl)(phenyl)methanol (180 mg, 0.71 mmol) and (1-methoxyprop-1-enyloxy)trimethylsilane (0.32 mL, 1.78 mmol) in 10 mL of dry MeCN was added TiCl4 (2.5 mL of 1.0 M DCM solution, 2.5 mmol) and then stirred 1 h. The reaction was incomplete so added 10 mL of DCM and additional (1-methoxyprop-1-enyloxy)trimethylsilane (0.3 mL, 1.7 mmol) After 1 h, the reaction was quenched with MeOH, poured into aqueous sodium bicarbonate and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated. HPLC purification resulted in the resolution of the two diastereomers of methyl 3-(1H-indazol-5-yl)-2-methyl-3-phenylpropanoate which were taken independently to the next step. MS found: (M+H)+=295.
Reaction SMILES: O=[C:2]1[C:7]2[CH:8]=[CH:9][C:10]3[CH2:14][CH2:13][CH2:12][C:11]=3[C:6]=2[O:5][C:4]([C:15]([OH:17])=[O:16])=[CH:3]1.[H][H]>C(O)(=O)C.[Pd]>[O:5]1[C:6]2[C:11]3[CH2:12][CH2:13][CH2:14][C:10]=3[CH:9]=[CH:8][C:7]=2[CH2:2][CH2:3][CH:4]1[C:15]([OH:17])=[O:16]
Reactant: [H][H]
Reactant: O=C(O)c1cc(=O)c2ccc3c(c2o1)CCC3
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)C1CCc2ccc3c(c2O1)CCC3
Yield: 106.9 %

Procedure:
A mixture of intermediate (3-a) (0.09 mol) in acetic acid (200 ml) was hydrogenated with palladium on activated carbon (1 g) as a catalyst. After uptake of hydrogen (3 eq.), the catalyst was filtered off. The solvent was evaporated. The residue was vacuum dried, yielding 21 g of (±)-2,3,4,7,8,9-hexahydrocyclopenta[h]-1-benzopyran-2-carboxylic acid (interm. 4-a).
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[OH-].[K+:10]>O>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[K+:10].[K+:10]
Reactant: O=C(O)/C=C/C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])/C=C/C(=O)[O-]

Procedure:
A mixture of 100 g of fumaric acid, 201 g of a 48% aqueous solution of caustic potash and 1370 g of water was subjected to reaction conducted in the same manner as illustrated in Example 10 to obtain an aqueous solution of potassium fumarate having a pH value of 10.5 and containing 10.3% by weight of a solid matter. To this aqueous solution of potassium fumarate was added an aqueous solution of 308 g of silver nitrate in 300 g of water to effect a double decomposition reaction in the same manner as illustrated in Example 10 whereby 275 g of silver fumarate was obtained which had a silver content of 61.3% by weight.
Reaction SMILES: [OH:1][OH:2].[F:3][C:4]([F:9])([F:8])[C:5]([OH:7])=O>O>[F:3][C:4]([F:9])([F:8])[C:5]([O:1][O:2][C:5](=[O:7])[C:4]([F:9])([F:8])[F:3])=[O:7]
Reactant: O=C(O)C(F)(F)F
Reactant: OO
Solvent: O
Product: O=C(OOC(=O)C(F)(F)F)C(F)(F)F

Procedure:
It is possible to use a lower concentration of hydrogen peroxide. For example, from a commercially available 30% solution of hydrogen peroxide in water it is possible to produce an 8% (mole) solution of bis(trifluoroacetyl) peroxide (BPFAP) in trifluoroacetic acid. This solution was obtained when 30% H2O2 (1.77 g, 15.6 mmol H2O2) was added dropwise into a well-stirred solution of RfCOOK (6.8 mg, 0.047 mmol) in freshly distilled bis(trifluoroacetyl) anhydride (21 g, 100 mmol) at 0° C. After adding the H2O2, the reaction mixture was stirred for 10 minutes (min) at 0° C. The concentration of BPFAP was measured by 19F NMR spectra.
Reaction SMILES: C[Al](C)C.C[Si]([N:9]=[N+:10]=[N-:11])(C)C.[C:12]([C:14]1[CH:15]=[C:16]([C:21]2[O:25][N:24]=[C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][N:27]=3)[N:22]=2)[CH:17]=[C:18]([F:20])[CH:19]=1)#[N:13]>C1(C)C=CC=CC=1>[F:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]2[N:22]=[C:21]([C:16]3[CH:15]=[C:14]([C:12]4[NH:13][N:11]=[N:10][N:9]=4)[CH:19]=[C:18]([F:20])[CH:17]=3)[O:25][N:24]=2)=[N:27][CH:28]=1
Reactant: N#Cc1cc(F)cc(-c2nc(-c3ccc(F)cn3)no2)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2noc(-c3cc(F)cc(-c4nnn[nH]4)c3)n2)nc1
Temperature: 80 °C
Yield: 36 %

Procedure:
To a mixture of 2 M trimethylaluminum (0.45 mL, 0.9 mmole, toluene) with toluene (1 mL) at 10° C., trimethylsilyl azide (0.11 g mL, 0.9 mmole) was added, followed by the addition of 5-(3-cyano-5-fluorophenyl)-3-(5-fluoro-pyrid-2-yl)-1,2,4-oxadiazole. The reaction was heated at 80° C. for 2 hours and then quenched with 6 N hydrochloride (2 mL) and solid was collected by filtration. The product was recrystallized with dimethylformamide to give 59 mg (36%) of 3-(5-fluoro-pyrid-2-yl)-5-[3-fluoro-5-(1H-tetraazol-5-yl)-phenyl]-1,2,4-oxadiazole. 1H-NMR (DMSO-d6), δ (ppm): 8.83 (d, 1H), 8.70 (s, 1H), 8.31 (m, 1H), 8.10 (m, 0.2H), 8.04 (dt, 1H).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[O:9]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10]1.[Si:17]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39](Cl)[N:40]=2)[CH:37]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>C(O)C.C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[Si:17]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([C:11]3[CH:12]=[CH:13][O:9][CH:10]=3)[N:40]=2)[CH:37]=1)([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccccc1-c1ccc2nc(Cl)cn2c1
Reactant: OB(O)c1ccoc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OCc1ccccc1-c1ccc2nc(-c3ccoc3)cn2c1
Temperature: 115 °C
Yield: 99.1 %

Procedure:
3 mg of palladium acetate, 11 mg of 2-(dicyclohexyl)phosphino-2′,6′-dimethoxy-1,1′-biphenyl, 270 mg of K3PO4, 110 mg of 3-furanboronic acid and a few drops of ethanol are placed in a reactor containing a mixture of 240 mg of 6-[2-[(tert-butyldimethylsilanyl)oxymethyl]phenyl]-2-chloroimidazo[1,2-a]pyridine in 2 ml of toluene degassed beforehand under an argon stream. The reactor is closed and heated at 115° C. for 16 h. After cooling, the reaction mixture is filtered through celite, washed with dichloromethane and then concentrated under reduced pressure. The residue is purified by silica gel chromatography, elution being carried out with a dichloromethane/methanol mixture. 258 mg of compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[O:31][C:28]1[CH:29]=[CH:30][C:25]([N:22]2[CH2:23][CH2:24][N:19]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:20][CH2:21]2)=[CH:26][CH:27]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Oc3cc(Cl)ccc3[N+](=O)[O-])cc2)CC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 89.1 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (2.63 g, 15 mmols), 4-(4-tert-butoxycarbonylpiperazin-1-yl)phenol (4.18 g, 15 mmols), potassium carbonate (2.07 g, 15 mmols) and N,N-dimethylformamide (50 ml) was stirred at 100° C. for 12 hours. The reaction mixture was cooled, poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give a crystal of tert-butyl 4-[4-(5-chloro-2-nitrophenoxy)phenyl]piperazine-1-carboxylate (5.8 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](O)=O>>[CH3:15][O:16][C:17]1[C:27]([O:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:18]=1/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: COc1cccc(C=CC(=O)O)c1OC
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(OC)c3OC)nc2n(CC)c1=O
Yield: 46 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.0 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.52 g (12.1 mmol) of 2,3-dimethoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylsulfoxide/water to give 1.72 g (yield 46%) of Compound 66 as a white powder.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[O:8][C:9]1[C:21]([CH:22]2[CH2:24][CH2:23]2)=[CH:20][C:12]([C:13]([O:15]C(C)(C)C)=[O:14])=[C:11]([F:25])[CH:10]=1.[C@@H]12C[C@@H](CC1)C[C@H]2OC1C(C2CC2)=CC(C(OC(C)(C)C)=O)=C(F)C=1>>[C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[CH2:3][C@H:2]2[O:8][C:9]1[C:21]([CH:22]2[CH2:24][CH2:23]2)=[CH:20][C:12]([C:13]([OH:15])=[O:14])=[C:11]([F:25])[CH:10]=1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(O[C@@H]2C[C@@H]3CC[C@H]2C3)cc1F
Product: O=C(O)c1cc(C2CC2)c(O[C@@H]2C[C@@H]3CC[C@H]2C3)cc1F
Yield: 57 %

Procedure:
Following the procedure as described in Example 283 step 3 and making variations as required to replace tert-butyl 4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoate with tert-butyl 4-((1S,2R,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-cyclopropyl-2-fluorobenzoate. Purification by silica gel column chromatography (2:1 hexanes:ethyl acetate (+0.2% acetic acid v/v)) gave the title compound as a colorless solid (0.50 g, 57%): 1H NMR (300 MHz, DMSO-d6) δ 12.76 (br s, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.76 (d, J=13.2 Hz, 1H), 4.80-4.70 (m, 1H), 2.59-2.52 (m, 1H), 2.25-2.18 (m, 1H), 2.15-2.03 (m, 1H), 2.02-1.79 (m, 2H), 1.61-1.48 (m, 1H), 1.45-1.17 (m, 4H), 0.97-0.82 (m, 3H), 0.60-0.50 (m, 2H); MS (ES+) m/z 291.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:21])[N:4]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([NH:15][CH3:16])=[O:14])[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[F:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH2:38]Br>O>[F:35][C:36]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:37]=1[CH2:38][O:8][C:7]1[CH:6]=[C:5]([CH3:9])[N:4]([C:10]2[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=2[CH3:20])[C:13]([NH:15][CH3:16])=[O:14])[C:3](=[O:21])[C:2]=1[Br:1]
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CNC(=O)c1ccc(C)c(-n2c(C)cc(O)c(Br)c2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CNC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 30 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
3-(3-bromo-4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide (9) (1 kg, 2.85 moles), potassium carbonate (0.43 kg, 3.11 moles), 1-methyl-2-pyrrolidinone (4.0 L) and 2,4-difluorobenzyl bromide (0.71 kg, 3.42 moles) were mixed together and heated at 30° C. for 2 hours. The reaction mixture was diluted with water (12.5 L) over a period of 30 to 60 minutes and then stirred for 30 to 60 minutes. The product was filtered and washed with water. (−)-3-(4-(2,4-difluorobenzyloxy)-3-bromo-6-methyl-2-oxopyridin-1(2H)-yl)-N,4-dimethylbenzamide (1) (1.36 kg, 95% purity, greater than 99% ee) was obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[CH:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=1>C(OCC)(=O)C.C(O)C.[Pd]>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:2]1
Reactant: CCOC(=O)C=Cc1cnc2ccccc2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC1CNc2ccccc2C1
Reaction time: 1 h
Yield: 26.3 %

Procedure:
A mixture of ethyl β-(3-quinolyl)acrylate (100 mg, 0.44 mmol) and 50 mg of 10% Pd/C in ethyl acetate/ethanol (3 ml/1 ml) was hydrogenated under hydrogen (55 psi) for 1 h. The mixture was filtered through celite, the residue was washed with methylene chloride, and the combined organic layer was concentrated in vacuo. Upon chromatographic purification on 20 cm silica column (ethyl acetate/hexane, 1/8-1/2), 49 mg (50%) of ethyl 3-(3-quinolyl)propionate (KUO-1953-136B) and 27 mg (26%) of ethyl 3-(1,2,3,4-tetrahydro-3-quinolyl)propionate was isolated.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:28])[C:6]([NH:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][C:23]([Cl:27])=[CH:22][CH:21]=2)=[O:17])([CH3:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[Cl:27][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18]([C:16]([NH:15][C:6]([CH3:14])([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([OH:28])=[O:4])=[O:17])=[CH:26]2
Reactant: COC(=O)C(C)(Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(Cc1ccccc1)(NC(=O)c1cc2cc(Cl)ccc2[nH]1)C(=O)O
Reaction time: 1 h

Procedure:
Aqueous 2N LiOH (0.10 ml, 0.50 mmol) was added to a solution of (2RS)-[(5-chloro-1H-indole-2-carbonyl)-amino]-2-methyl-3-phenyl-propionic acid methyl ester (132 mg, 0.36 mmol) in tetrahydrofuran (8 ml) at 25° C. The resulting solution was stirred for 1 hour, concentrated and the residue dissolved in ethyl acetate and water (15 ml). The pH was adjusted to 1 with 2 N HCl at 0° C. The organic layer was separated, washed with water, brine and dried giving a foam which was used without further purification (129 mg, 102%): HPLC (60/40) 4.42 minutes (99%); TSPMS 357/359 (MH+, 100%);
Reaction SMILES: [O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH2:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].B>>[OH:15][CH:4]([CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14])[CH2:3][C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)=[O:1]
Reactant: O=C(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: B
Product: O=C(CC(O)Cc1cc(F)c(F)cc1F)N1CCn2c(nnc2C(F)(F)F)C1

Procedure:
Optionally, 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-one or its derivative is reduced by using a suitable borane containing reducing agent as earlier, in absence or presence of an acid in a suitable solvent to get 3-hydroxy-1-(3-(trifluoromethyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-4-(2,4,5-trifluorophenyl) butan-1-one.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][N:14]([CH2:28][CH3:29])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH2:28]([N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]=1)[CH2:13][C@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)[CH3:29]
Reactant: CCN(C[C@H]1CCCN1C(=O)OC(C)(C)C)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C[C@H]1CCCN1)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (R)-2-{[ethyl-(3-phenoxy-phenyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester (0.162 g, 0.41 mmol) in dichloromethane (3 ml) was added trifluoroacetic acid (1 ml) and the mixture was stirred for 3 h at room temperature. Aqueous sodium hydroxide solution (4N) was added until basic pH and the mixture was extracted with ethyl acetate (2 times 30 ml). The combined organic layers were dried with magnesium sulphate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: ethyl acetate) to yield a colourless oil, (0.043 g, 36%); MS (ISP): 297.5 ((M+H)+.).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17](OCC)=[O:18])=[C:4]2[CH2:3]1.[BH4-].[Li+].Cl>O1CCCC1>[OH:18][CH2:17][C:16]1[N:15]=[CH:14][N:5]2[C:6]3[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=3[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][C:4]=12
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1Cc2c(CO)ncn2-c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
21.5 g (75.4 mmol) of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate are dissolved in 250 ml of hot absolute tetrahydrofuran (filtered over Alox basic I) under an argon atmosphere while stirring, cooled to ca 30° C. and treated dropwise with a solution of 1.66 g (75.4 mmol) of lithium borohydride in 25 ml of absolute tetrahydrofuran. The mixture is heated to boiling under reflux for 6 hours, cooled to room temperature and decomposed with 50 ml of 3 N aqueous hydrochloric acid. The mixture is stirred at 60° C. for a further 2 hours and the tetrahydrofuran is removed in vacuo. The residue is made alkaline with concentrated ammonia and left to stand in an ice-bath for 2 hours. The crude product is filtered off under suction, washed with a large amount of water and recrystallised from ethanol. There is obtained 4,5-dihydro-3-(hydroxymethyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 224°-226° C.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([Cl:13])=[N:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.Cl.[F:15][C:16]1[CH:17]=[C:18]([CH:28]([NH2:30])[CH3:29])[CH:19]=[N:20][C:21]=1[O:22][CH2:23][C:24]([F:27])([F:26])[F:25]>>[Cl:13][C:12]1[C:3]2[CH2:2][N:30]([CH:28]([C:18]3[CH:19]=[N:20][C:21]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[C:16]([F:15])[CH:17]=3)[CH3:29])[C:5](=[O:7])[C:4]=2[CH:9]=[CH:10][N:11]=1
Reactant: COC(=O)c1ccnc(Cl)c1CBr
Reactant: CC(N)c1cnc(OCC(F)(F)F)c(F)c1
Agent: Cl
Product: CC(c1cnc(OCC(F)(F)F)c(F)c1)N1Cc2c(ccnc2Cl)C1=O
Yield: 47 %

Procedure:
The title compound is prepared in 47% yield (104 mg, colorless amorphous solid) from methyl 3-(bromomethyl)-2-chloroisonicotinate (150 mg, 0.57 mmol) and 1-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanamine hydrochloride (156 mg, 0.57 mmol, Amine-7, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[CH:8]1[C:13]([OH:14])=[CH:12][C:11]2[O:15][C:16]3[C:22](=[N:23][C:10]=2[CH:9]=1)[CH:21]=[CH:20][C:18](=[O:19])[CH:17]=3.C(=O)([O-])[O-].[K+].[K+].O>COCCOCCN(CCOCCOC)CCOCCOC.O1CCOCC1>[CH3:5][O:14][C:13]1[CH:8]=[CH:9][C:10]2[N:23]=[C:22]3[C:16]([O:15][C:11]=2[CH:12]=1)=[CH:17][C:18](=[O:19])[CH:20]=[CH:21]3
Reactant: O=c1ccc2nc3ccc(O)cc3oc-2c1
Reactant: COS(=O)(=O)OC
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2nc3ccc(=O)cc-3oc2c1
Reaction time: 2 h
Yield: 59.5 %

Procedure:
12.1 ml of dimethyl sulphate were added at room temperature while stirring well to a suspension of 20.0 g (85.0 mmol) of resorufin, 17.6 g of freshly powdered potassium carbonate and 10 drops of tris-[2-(2-methoxyethoxy)ethyl]amine in 150 ml of dioxan. The reaction mixture was subsequently stirred at 100° for 2 hours, cooled and then treated with 150 ml of water. The solid was filtered off, washed with water and dried over phosphorus pentoxide. 11.5 g (59.5%) of resorufin methyl ether of m.p. 240°-244° (dec.) were obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:11][C:12]([O:14]C(C)(C)C)=O)[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[NH:20]([C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C@H:21](C(O)=O)[CH:22]([CH3:24])[CH3:23].C(OC([C@@]1(NC([C@@H]2C[C@@H](OC3C4C(=CC(OC)=CC=4)N=C(C4C=CC=CC=4)C=3)C[C@H]2C(=O)N[C@H](C(=O)N[C@@H](C2CCCCC2)C(=O)NC)C(C)(C)C)=O)C[C@H]1C=C)=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:19])[C@@H:4]([NH:11][C:12](=[O:14])[C@@H:21]([NH:20][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH:22]([CH3:24])[CH3:23])[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)C1CCCCC1
Agent: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)NC)C1CCCCC1)C(C)(C)C)C(=O)OCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C1CCCCC1
Yield: 94.4 %

Procedure:
Compound 54 (93 mg, 0.343 mmol) was deprotected and coupled to Z-Val-OH (95 mg, 0.378 mmol) according to the method for the preparation of 39. Flash column chromatography (toluene/ethyl acetate 4:1) gave 55 (131 mg, 94%) as a colorless solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C@@H:6]1[C:11](=[O:12])[O:10][C:8](=[O:9])[CH2:7]1)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH2:21][CH2:20]1.[Cl-].[NH4+]>ClC(Cl)C>[O:19]1[C:23]2[CH:24]=[CH:25][C:26]([C:8](=[O:9])[CH2:7][CH:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:14])[F:13])[C:11]([OH:12])=[O:10])=[CH:27][C:22]=2[CH2:21][CH2:20]1
Reactant: O=C1C[C@H](NC(=O)C(F)(F)F)C(=O)O1
Reactant: c1ccc2c(c1)CCO2
Agent: [Al+3]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(Cl)Cl
Product: O=C(CC(NC(=O)C(F)(F)F)C(=O)O)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 36 h
Yield: 88 %

Procedure:
0.1 mole of the compound obtained in Example 1 and 0.05 mole of aluminum chloride suspended in 100 ml of dichloroethane are added to a solution of 12 ml of dichloroethane containing 0.05 mole of 2,3-dihydrobenzofuran. The mixture is stirred for 36 hours at room temperature and then hydrolyzed with saturated ammonium chloride solution. The mixture is extracted with dichloromethane and the extract washed with water, dried over magnesium sulfate, filtered and concentrated to obtain the expected product.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11].[CH3:12][C:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19](Cl)=[O:20])[CH:14]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C-:1]1([C:19]([CH:15]2[CH2:16][CH2:17][CH2:18][C:13]([CH3:12])=[CH:14]2)=[O:20])[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:6]1[CH:10]=[CH:9][CH:8]=[CH:7]1.[Fe+2:11]
Reactant: CC1=CC(C(=O)Cl)CCC1
Agent: [Fe+2]
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1=CC(C(=O)[c-]2cccc2)CCC1

Procedure:
Prepared from ferrocene, 3-methyl-2-cyclohexen-1-carboxylic acid chloride and aluminium chloride in methylene chloride at 0° C. in a manner analogous to that described in Example 1.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[C:20]([C:33]([F:36])([F:35])[F:34])[CH:19]=3)[N:14]=[C:13]([C:37]#[N:38])[C:12]=2[N:11]=[N:10]1.Cl[CH2:40][C:41]([N:43]([CH3:45])[CH3:44])=[O:42].CCN(C(C)C)C(C)C>CO>[CH3:44][N:43]([CH3:45])[C:41](=[O:42])[CH2:40][N:30]1[CH2:29][CH2:28][CH:27]([CH2:26][CH2:25][O:24][C:21]2[CH:22]=[CH:23][C:18]([C:15]3[N:14]=[C:13]([C:37]#[N:38])[C:12]4[N:11]=[N:10][N:9]([CH3:8])[C:17]=4[CH:16]=3)=[CH:19][C:20]=2[C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31]1
Reactant: Cn1nnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Reactant: CN(C)C(=O)CCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CN1CCC(CCOc2ccc(-c3cc4c(nnn4C)c(C#N)n3)cc2C(F)(F)F)CC1
Temperature: 90 °C

Procedure:
To 1-methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile TFA salt (150 mg) in methanol (2 ml) was added 2-chloro-N,N-dimethylacetamide (67 mg) and DIPEA (0.23 ml). The mixture was heated at 90° C. for 40 minutes, then purified by basic HPLC to give 6-(4-(2-(1-(2-dimethylamino-2-oxoethyl)piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridine-4-carbonitrile which was then converted to HCl salt by lypholising with 1M hydrochloric acid (1 ml) (130 mg).