Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([O:19][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:21][OH:22])=[C:11]2[O:12][C:13]=1[CH3:14].[H-].[Na+].[CH3:28]I.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([O:19][CH:20]([CH2:21][O:22][CH3:28])[CH2:23][CH2:24][CH3:25])=[C:11]2[O:12][C:13]=1[CH3:14]
Reactant: CCCC(CO)Oc1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCC(COC)Oc1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Reaction time: 3 h

Procedure:
To a stirring solution of (±)-2-[3-(2,4-dichloro-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazol-7-yloxy]-pentan-1-ol (60 mg, 0.157 mmol) in THF (1.565 ml) at RT is added NaH (6.26 mg, 0.157 mmol). After 10 mins MeI (10.77 μl, 0.172 mmol) is added and the reaction mixture is stirred for a further 3 hours. An additional 1.leq of MeI (10.77 μl, 0.172 mmol) is added and reaction continued for 1 hour whereupon it is added to sat. ammonium chloride (50 ml) and the product extracted into EtOAc (60 ml). The organics are washed with brine, dried over MgSO4 and concentrated in vacuo. The crude reaction products are purified by ISCO combiflash chromatography, eluting with 0 to 100% (iso-hexane/EtOAc) on a 12 g SiO2-column to give (±)-3-(2,4-Dichloro-phenyl)-7-(1-methoxymethyl-butoxy)-2,6-dimethyl-pyrazolo[5,1-b]oxazole as a solid; MS: m/z 397.20 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.58 (2H, m), 7.41 (1H, dd), 4.03 (1H, m), 3.58 (2H, m), 3.44 (3H, s), 2.33 (3H, s), 2.30 (3H, s), 1.76 (2H, m), 1.57 (2H, m), 1.00 (3H, t).
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].[Cl:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[CH:20]([NH:22][CH:23]1[CH2:25][CH2:24]1)[CH2:19][CH2:18]2.C(N(CC)CC)C.CCCCCCC.C(OCC)(=O)C>O1CCCC1>[Cl:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:21]=1[CH:20]([N:22]([CH:23]1[CH2:25][CH2:24]1)[C:9]([C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[F:1])=[O:10])[CH2:19][CH2:18]2
Reactant: Clc1cccc2c1C(NC1CC1)CC2
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Cc1nn(C)c(F)c1C(=O)N(C1CC1)C1CCc2cccc(Cl)c21
Reaction time: 3 h
Yield: 0.1 %

Procedure:
At ambient temperature, a solution of 0.19 g (1.06 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride in 3 ml of tetrahydrofurane is added dropwise to a solution of 0.20 g (0.96 mmol) of 7-chloro-N-cyclopropyl-2,3-dihydro-1H-inden-1-amine and 0.15 ml triethylamine in 8 ml tetrahydrofurane. The reaction mixture is stirred for 3 hrs at reflux. The solvent is removed under vacuum and 10 ml of water are then added to the residue. The watery layer is extracted three times with ethyl acetate (3×20 ml); the combined organic layers are dried over magnesium sulphate and concentrated in vacuum. Column chromatography (gradient n-heptane/ethyl acetate) yields 0.26 mg (73% yield) of N-(7-chloro-2,3-dihydro-1H-inden-1-yl)-N-cyclopropyl-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide as an orange oil (M+1=348).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][CH2:8][CH2:9][OH:10])=[S:6].[O:11]=[CH:12][C:13]([Cl:16])([Cl:15])[Cl:14]>>[Cl:14][C:13]([Cl:16])([Cl:15])[CH:12]([N:4]([CH2:3][CH2:2][OH:1])[C:5]([N:7]([CH:12]([OH:11])[C:13]([Cl:16])([Cl:15])[Cl:14])[CH2:8][CH2:9][OH:10])=[S:6])[OH:11]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: OCCNC(=S)NCCO
Product: OCCN(C(=S)N(CCO)C(O)C(Cl)(Cl)Cl)C(O)C(Cl)(Cl)Cl
Temperature: 80 °C

Procedure:
To 98.4 g (0.6 mole) of 1,3-bis(2-hydroxyethyl)-thiourea at 65° C. was slowly added 182 g (1.24 moles) of chloral while the temperature was maintained below 75° C. by means of external cooling. The reaction mixture was vigorously stirred and heated at 80° C. for 1 hour. On cooling 275 g of a viscous syrupy product was isolated.
Reaction SMILES: [BrH:1].[CH3:2][O:3][C:4]1[N:9]=[CH:8][C:7]([CH:10]([OH:13])[CH2:11][CH3:12])=[C:6]([CH3:14])[CH:5]=1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.[Cu](Br)Br>[Br:1][CH:11]([CH3:12])[C:10]([C:7]1[CH:8]=[N:9][C:4]([O:3][CH3:2])=[CH:5][C:6]=1[CH3:14])=[O:13]
Reactant: CCC(O)c1cnc(OC)cc1C
Reactant: Br
Agent: Br[Cu]Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1cc(C)c(C(=O)C(C)Br)cn1
Temperature: 70 °C

Procedure:
To a stirred suspension of copper (II) bromide (499 mg, 2.23 mmol, 2 eq.) in EtOAc is added HBr (33% in acetic acid, 0.368 ml, 2.25 mmol, 2 eq.) followed by 1-(6-methoxy-4-methyl-pyridin-3-yl)-propan-1-ol (200 mg, 1.12 mmol, 1 eq.). The mixture is heated at 70° C. for 12 hrs. After cooling to RT the mixture is poured into 2M Na2CO3 (50 ml) and extracted with EtOAc (2×50 ml). The combined extracts are washed successively with 2M Na2CO3, water and brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting crude residue is purified by column chromatography on silica gel eluting with 10% EtOAc/iso-hexane to yield 2-bromo-1-(6-methoxy-4-methyl-pyridin-3-yl)-propan-1-one as a clear oil. MS: m/z 257.9 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 1.90 (d, 3H), 2.50 (s, 3H), 4.0 (s, 3H), 2.33 (s, 3H), 5.20 (q, 1H), 6.65 (s, 1H), 8.65 (s, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[N+:19]([O-])([OH:21])=[O:20]>>[C:1]([NH:4][C:5]1[C:14]([N+:19]([O-:21])=[O:20])=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(C(F)(F)F)cc1NC(C)=O
Product: COC(=O)c1ccc(C(F)(F)F)c([N+](=O)[O-])c1NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To an ice-cooled nitric acid (fuming) (20 ml) was added methyl 2-(acetylamino)-4-(trifluoromethyl)benzoate (7.30 g, 0.028 mol) portionwise and stirred for 30 min. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extracts were washed with aqueous saturated sodium bicarbonate and water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a 30% ethyl acetate/n-hexane to give 3.20 g (0.010 mol, 38%) of the title compound as a yellow powder.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([CH3:11])([CH3:10])[C:7]([O-:9])=[O:8])[C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]1=2.BrC1C=CC(C(C)(C)C(OCC)=O)=CC=1>>[S:1]1[CH:5]=[C:4]([C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8])[C:3]2[CH:12]=[CH:13][CH:14]=[CH:15][C:2]1=2
Reactant: CC(C)(C(=O)[O-])c1csc2ccccc12
Agent: CCOC(=O)C(C)(C)c1ccc(Br)cc1
Product: CC(C)(C(=O)O)c1csc2ccccc12

Procedure:
The title compound was prepared according to the method of Example 22B substituting the product of Example 49B for the product of Example 22A.
Reaction SMILES: C[O:2][C:3]1[CH:28]=[CH:27][C:6]2[N:7]([C:10]3[CH:19]=[CH:18][C:17]4[C:12](=[C:13]([N:20]5[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]5)[CH:14]=[CH:15][CH:16]=4)[N:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[NH2:26][CH:23]1[CH2:24][CH2:25][N:20]([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:12]=2[N:11]=[C:10]([N:7]2[C:6]4[CH:27]=[CH:28][C:3]([OH:2])=[CH:4][C:5]=4[N:9]=[CH:8]2)[CH:19]=[CH:18]3)[CH2:21][CH2:22]1
Reactant: COc1ccc2c(c1)ncn2-c1ccc2cccc(N3CCC(N)CC3)c2n1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: NC1CCN(c2cccc3ccc(-n4cnc5cc(O)ccc54)nc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[2-(5-Methoxy-benzoimidazol-1-yl)-quinolin-8-yl]-piperidin-4-ylamine (500 mg, 1.10 mmol) was dissolved in 10 mL of DCM under an atmosphere of dry N2. To this solution was added boron tribromide (300 mL, 3.30 mmol) and the mixture was stirred overnight at ambient temperature. Then an additional 200 mL of borontribromide was added and the mixture was stirred for two hours. The reaction mixture was then poured over crushed ice and the pH of the resulting solution was adjusted to 9 with the careful addition of sodium carbonate (Na2CO3). The slurry was filtered and the solid was washed with water followed by Et2O and then dried under vacuum to give 1-[8-(4-Amino-piperidin-1-yl)-quinolin-2-yl]-1H-benzoimidazol-5-ol as a yellow solid. C.I. m/z 360 [M+1]; 1H NMR (DMSO) δ 9.07 (s, 1 H), 8.76 (d, J=8.9 Hz, 1 H), 8.48 (d, J=8.9 Hz, 1 H), 8.10 (d, J=8.9 Hz, 1 H), 7.56 (d, J=7.4 Hz, 1 ), 7.45 (m, 1 H), 7.26 (d, J=7.4 Hz, 1 H), 7.01 (d, J=2.2 Hz, 1 H), 6.95 (dd, J=2.2, 8.9 Hz, 1 H), 3.72 (m, 2 H), 2.76 (m, 3 H), 1.88 (m, 2 H), 1.65 (m, 2 H).
Reaction SMILES: [O:1]1[CH2:4][CH:3]([C@H:5]([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=5)[N:21]([CH3:29])[N:20]=4)[N:17]=3)[N:12](COCC[Si](C)(C)C)[CH:11]=2)=[O:9])[CH3:6])[CH2:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[O:1]1[CH2:2][CH:3]([C@H:5]([NH:7][C:8]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([C:19]4[C:27]5[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=5)[N:21]([CH3:29])[N:20]=4)[N:17]=3)[NH:12][CH:11]=2)=[O:9])[CH3:6])[CH2:4]1
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C1COC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)C1COC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 64.5 %

Procedure:
In a round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-oxetan-3-yl-ethyl)-amide (29 mg, 0.055 mmol) was dissolved in tetrabutylammonium fluoride (1.0 M in THF, 0.56 ml, 0.56 mmol). The light brown reaction mixture was stirred at 70° C. for 4 h then cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with MeOH/CH2Cl2 (0.5% NH4OH) (gradient: 0-5% MeOH) to afford 14 mg (64%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-oxetan-3-yl-ethyl)-amide as a light yellow solid. Optical purity was determined to be 60% ee by chiral HPLC. MS: (M+Na)+=417; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.87 (br. s., 1H), 9.10 (s, 1H), 8.46 (s, 1H), 8.42 (dd, J=8.8, 5.3 Hz, 1H), 8.07 (d, J=8.6 Hz, 1H), 7.71 (dd, J=9.9, 1.8 Hz, 1H), 7.25 (td, J=9.1, 2.0 Hz, 1H), 4.69 (dd, J=7.6, 6.1 Hz, 1H), 4.53-4.65 (m, 2H), 4.50 (t, J=6.1 Hz, 1H), 4.42 (t, J=6.3 Hz, 1H), 4.16 (s, 3H), 3.10-3.23 (m, 1H), 1.24 (d, J=6.6 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[NH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[O-]CC.[Na+]>C(O)C>[NH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:2]1[N:6]=[CH:5][NH:4][N:3]=1
Reactant: NCCCN
Reactant: Clc1nc[nH]n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: NCCCNc1nc[nH]n1
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-1,2,4-triazole (10.3 g., 0.1 m.) and 1,3-diaminopropane (7.4 g., 0.1 m.) in ethanol containing sodium ethoxide is allowed to stand overnight. The solvent is removed to give 3-(3-aminopropylamino)-1,2,4-triazole. This intermediate is reacted with methyl isothiocyanate to give N-methyl-N'-[3-(3-(1,2,4-triazolyl)amino)propyl]thiourea.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([O:7]C1C=CC([N+]([O-])=O)=CC=1)=O.[C:20]1(=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:29])[CH2:21]1.[F-].[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([CH:21]1[C:20](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:29])=[O:7]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)c1cccc(Cl)c1
Reactant: O=C1CC(=O)c2ccccc21
Agent: [F-]
Agent: [K+]
Product: O=C(c1cccc(Cl)c1)C1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 7 h
Yield: 160.4 %

Procedure:
A 25-mL 3-neck round bottom flask was charged with 4-nitrophenyl 3-chlorobenzoate (0.64 g, 2.3 mmol), indane-1,3-dione (0.39 g, 2.7mmol) and (methyl sulfoxide)-d6 (5.0 g). The mixture was heated to 80° C. and potassium fluoride (0.60 g, 10 mmol) was added in a single portion. After stirring at 80° C. for 7 hours, the mixture was cooled, partitioned between diethyl ether-ethyl acetate (1:1, 100 mL) and 1N hydrochloric acid (25 mL). The organic layer was washed with additional portions of 1N hydrochloric acid (3×10 mL), then with brine (10 mL), dried over magnesium sulfate, filtered, and evaporated to leave a brown solid (1.05 g).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C(N(CC)CC)C.[CH:14]1([C:20]#[CH:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CCCCCC>COCCOC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:14]1([C:20]#[C:21][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Brc1nccs1
Reactant: C#CC1CCCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: C(#CC1CCCCC1)c1nccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44 %

Procedure:
2-Bromo-1,3-thiazole (3.1 g, 19 mmol) and CuI (290 mg, 1.5 mmol) were combined in DME (30 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (13 mL, 95 mmol) and PdCl2(PPh3)2 (530 mg, 0.76 mmol) were added and cyclohexylethyne (2.0 g, 19 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 16 h at which time GC/MS analysis indicated that the reaction was complete. The mixture was filtered through Celite.™., and the filter pad was washed thoroughly with ethyl acetate. The combined filtrates were concentrated in vacuo and the residue was dissolved in ethyl acetate (300 mL), washed with water (300 mL), brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography eluting with hexane then 99:1 hexane:ethyl acetate to afford 2-(cyclohexylethynyl)-1,3-thiazole (1.6 g, 44% yield) as a yellow oil. 1H NMR (CDCl3, 300 MHz) Δ7.76 (d, J=9.0 Hz, 1H), 7.28 (d, J=3.0 Hz, 1H), 2.68-2.59 (m, 1H), 1.91-1.28 (m, 10H). MS (ESI) 191.7 (M+).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:29])[NH:8][C:9](=[O:28])[C:10]=1[CH2:11][C:12]1[C:17]([F:18])=[CH:16][C:15]([C:19]2[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:14][C:13]=1[F:27])[CH2:2][CH2:3][CH3:4].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:29])[N:8]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:9](=[O:28])[C:10]=1[CH2:11][C:12]1[C:13]([F:27])=[CH:14][C:15]([C:19]2[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:16][C:17]=1[F:18])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1c(F)cc(-c2ccccc2C#N)cc1F
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCCc1nc(C)n(-c2ccccc2)c(=O)c1Cc1c(F)cc(-c2ccccc2C#N)cc1F
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′,5′-difluorobiphenyl-2-carbonitrile (1.0 g), phenylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate. The insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (1.21 g, 100%).
Reaction SMILES: [CH:1]1([C:4](=[O:18])[CH:5]([NH:12][C:13](=O)[CH2:14][O:15][CH3:16])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.O=P(Cl)(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:1]1([C:4]2[O:18][C:13]([CH2:14][O:15][CH3:16])=[N:12][C:5]=2[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(NC(=O)COC)C(=O)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nc(COC)oc1C1CC1
Temperature: 0 °C
Yield: 96 %

Procedure:
Ethyl 4-Cyclopropyl-3-[(methoxyacetyl)amino]-4-oxobutanoate (Preparation 121, 25.7 g, 0.1 mol) was dissolved in dry DMF (170 mL). POCl3 (46 g, 0.3 mol) was poured into this solution at 5-15° C., and the mixture was kept this temperature for 60 minutes. The resulting solution was slowly poured in portions into crushed ice (700 g) and stirred until a homogeneous solution was obtained. The solution was neutralized with a 20% aqueous K2CO3 solution to pH 7-8. The product was extracted with ethyl acetate. The organic extract was washed with brine and concentrated in vacuo to give a dark-brown liquid, which was purified by silica gel column chromatography eluting with EtOAc:Hexane 1:1 to afford the title compound as a colourless liquid (96%). Taken directly on to the next step.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][CH2:14][OH:15].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.CCOCC>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]2[O:15][CH2:14][CH2:13][CH2:12][O:8]2)[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: OCCCO
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc(Br)cc1C1OCCCO1
Yield: 84.3 %

Procedure:
A mixture of 5-bromo-o-anisaldehyde (10.0 g, 46,5 mmol), propane-1,3diol (3.90 g, 51.2 mmol) and BF3-Et2O(0.15 ml) in toluene (50 ml) was refluxed in a Dean-Stark apparatus for 3 h. The reaction mixture was cooled, diluted with ether. The organic layer was washed successively with sat. NaHCO3 aq., water and brine, dried (MgSO4), and concentrated in vacuo to give crude product. The residue was distilled to give Compound 38 (10.7 g, 84%) as a colorless oil.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[CH:32]1([NH2:35])[CH2:34][CH2:33]1.C(OCC)(=O)C.O>CS(C)=O.CO>[CH:32]1([NH:35][C:8]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[O:7])[CH2:34][CH2:33]1
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)cc3)c2cc1OC
Reactant: NC1CC1
Solvent: CS(C)=O
Solvent: CO
Solvent: O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)cc3)c2cc1OC
Yield: 80 %

Procedure:
4-(6,7-Dimethoxyquinolin-4-yloxy)phenylcarbamic acid phenyl ester (104 mg, 0.250 mmol) and cyclopropylamine (28.5 mg, 0.500 mmol) were stirred in dimethylsulfoxide (1 ml) at room temperature for 2 hours. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with 1N aqueous sodium hydroxide, water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:methanol=15:1), the fraction containing the target substance was concentrated and suspended in ethyl acetate, the suspension was diluted with hexane and the crystals were filtered out, washed with hexane and blow-dried to obtain the title compound (76 mg, 0.200 mmol, 80%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[O:17][CH:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][CH2:14]2)([O-:3])=[O:2].OC1C=C2C(=CC=1)OC(C1C=CC=CC=1)CC2.[OH-].[K+].ClC1C=CC([C:51]#[N:52])=CC=1[N+]([O-])=O>CS(C)=O>[C:51]([C:8]1[CH:7]=[CH:6][C:5]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=1)#[N:52]
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)c([N+](=O)[O-])c1

Procedure:
4-Cyano-2-nitro-1-(2-phenylchroman-6-yloxy)-benzene was prepared as described for 2-nitro-1-(2-phenylchroman-6-yloxy)-benzene in Example 29(a) except that 6-hydroxyflavane (0.453 g) was used in 10 ml of dry DMSO under nitrogen. Also KI (0.498 g) and KOH (0.224 g) and 4-chloro-3-nitro benzonitrile (0.365 mg) were added in similar manner. Product was purified by column chromatography (CH2Cl2:n-heptane/90:10 as the eluant). 1H-NMR (400 MHz; d6-DMSO): δ 8.64 (d, 1H, J=2.0 Hz), 8.06 (dd, 1H, J=8.8 Hz, J=2.1 Hz), 7.08 (d, 1H, J=8.8 Hz), 7.07-6.93 (m, 3H), 5.15 (dd, 1H, J=10.1 Hz, J=2.1 Hz), 3.05-2.91 (m, 1H), 2.82-2.70 (m, 1H), 2.24-2.12 (m, 1H), 2.08-1.92 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[S:39]1[CH2:43][CH2:42][NH:41][CH2:40]1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11](=[O:12])[N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:27])([F:28])[F:26])=[N:20][C:21]([C:22]([N:41]3[CH2:42][CH2:43][S:39][CH2:40]3)=[O:23])=[C:15]2[CH2:14]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CSCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCSC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 89.4 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), thiazolidine (57 mg, 0.6 mmol), triethylamine (0.275 g, 2.72 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.138 g, 0.544 mmol) were dissolved in 10 mL of dichloromethane under stirring. The reaction mixture was stirred at room temperature for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-3-[1-(thiazolidine-3-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 20a (0.15 g, yield 89%) as a white solid.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[CH2:29]([NH:36][C:37]([C:39]1[S:43][C:42]([N:44]2[CH2:48][CH2:47][N:46]([CH2:49][C:50]([O:52]CC)=[O:51])[C:45]2=[O:55])=[N:41][C:40]=1[CH3:56])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:37]([C:39]1[S:43][C:42]([N:44]2[CH2:48][CH2:47][N:46]([CH2:49][C:50]([OH:52])=[O:51])[C:45]2=[O:55])=[N:41][C:40]=1[CH3:56])=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)CN1CCN(c2nc(C)c(C(=O)NCc3ccccc3)s2)C1=O
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCN(CC(=O)O)C2=O)sc1C(=O)NCc1ccccc1
Yield: 89 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 2-(3-(5-(benzylcarbamoyl)-4-methylthiazol-2-yl)-2-oxoimidazolidin-1-yl)acetate, the title compound was obtained as a colorless solid in 89% yield: 1H NMR (300 MHz, CDCl3) δ 7.37-7.27 (m, 5H), 6.06 (t, J=5.4 Hz, 1H), 4.56 (d, J=5.4 Hz, 2H), 4.17-4.07 (m, 4H), 3.70 (t, J=8.1 Hz, 2H), 2.59 (s, 3H); MS (ES+) m/z 258.2 (M+1).