Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Mg]Br.[F:4][C:5]([F:10])([F:9])[C:6]([OH:8])=[O:7].[Cl:11][C:12]1[N:13]=[CH:14][N:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:41]=[C:27]4[CH:28]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)[CH2:29][C:30](=[O:33])[CH2:31][CH2:32][N:26]4[N:25]=3)=[CH:19][C:18]=2[O:42][CH3:43])[CH:16]=1.[C:44](O)(C(F)(F)F)=O>C1COCC1.[Cu]I>[F:4][C:5]([F:10])([F:9])[C:6]([OH:8])=[O:7].[Cl:11][C:12]1[N:13]=[CH:14][N:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:41]=[C:27]4[C@@H:28]([C:34]5[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=5)[CH2:29][C@@:30]([CH3:44])([OH:33])[CH2:31][CH2:32][N:26]4[N:25]=3)=[CH:19][C:18]=2[O:42][CH3:43])[CH:16]=1
Reactant: COc1cc(Nc2nc3n(n2)CCC(=O)CC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Agent: [Cu]I
Agent: C[Mg]Br
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1cc(Nc2nc3n(n2)CC[C@](C)(O)C[C@@H]3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 17 %

Procedure:
A 25 mL round bottom flask was charged with copper (I) iodide (8.16 mg, 0.043 mmol) in THF (1 mL), and cooled to 0° C. A solution of methylmagnesium bromide (1.53 mL, 2.142 mmol, 1.4 M in THF) was added dropwise to the stirred solution and stirred for 20 min. To solution of methyl cuprate was added 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (100 mg, 0.214 mmol, from example 137) in THF (1 mL) and the reaction was stirred at 0° C. for an additional 2 h. The resulting mixture was quenched slowly with saturated ammonium chloride, and the aqueous layer was washed with EtOAc (×3). The combined organic layers were then washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (21.6 mg, 17% yield) as a TFA salt. LC-MS (M+H)+ 483.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 10.36 (1 H, br. s.), 9.30 (1 H, br. s.), 8.05 (1 H, s), 7.22-7.33 (2 H, m), 7.08-7.20 (6 H, m), 4.62-4.76 (2 H, m), 4.34-4.46 (1 H, m), 3.82-3.92 (3 H, m), 2.16-2.34 (2 H, m), 2.04-2.14 (1 H, m), 1.92-2.04 (1 H, m), 1.43-1.53 (3 H, m).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:16][C:17]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:18]=1[NH2:19]>C(O)(C)C>[ClH:2].[F:16][C:17]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:18]=1[NH:19][C:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1
Reactant: COC(=O)Oc1cc(N)c(F)cc1C
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc([N+](=O)[O-])ccc23)c(F)cc1C
Temperature: 50 °C
Yield: 440.3 %

Procedure:
A solution of 4-chloro-7-nitroquinazoline hydrochloride (2.46 g, 10 mmol) and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (2.2 g, 1 mmol), (prepared as described for the starting material in Example 12), in isopropanol (25 ml) was heated at 50° C. for 1 hour. The mixture was allowed to cool, the precipitated solid was collected by filtration recrystallised from methylene chloride/methanol/isopropanol to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-nitroquinazoline hydrochloride (1.8 g, 45%) as a yellow solid.
Reaction SMILES: Br[CH:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)=O.[NH2:21][C:22]1[S:23][CH:24]=[CH:25][N:26]=1>CN(C=O)C>[C:15]1([C:2]2[N:26]3[C:22]([S:23][CH:24]=[CH:25]3)=[N:21][C:3]=2[C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1nccs1
Reactant: COC(=O)c1ccc(C(=O)C(Br)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-c2nc3sccn3c2-c2ccccc2)cc1

Procedure:
0.7 g (2.1 mM) of methyl 4-[bromo(phenyl)acetyl]benzoate and 2-aminothiazole (2.5 eq) are stirred in 20 ml DMF at 90° C. for 6 h. The DMF is evaporated and the crude product is purified by column chromatography.
Reaction SMILES: [CH2:1]([O:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][C:7](=[O:12])[CH2:6][C:5]1([CH3:14])[CH3:13])[CH3:2].[C:15](#[N:17])[CH3:16].C([Li])CCC>C1COCC1>[CH2:1]([O:3][N:4]1[C:5]([CH3:13])([CH3:14])[CH2:6][C:7]([CH2:16][C:15]#[N:17])([OH:12])[CH2:8][C:9]1([CH3:11])[CH3:10])[CH3:2]
Reactant: CCON1C(C)(C)CC(=O)CC1(C)C
Reactant: CC#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCON1C(C)(C)CC(O)(CC#N)CC1(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3 g 1-Ethoxy-2,2,6,6-tetramethyl-piperidin-4-one is dissolved in 20 ml dry THF and 0.93 g acetonitrile are added. The mixture is cooled to −78° C. and 9.4 ml n-butyllithium (1.6 M solution in hexane) are added over a period of 30 min. Stirring is continued at −78° C. for 1 h, then the cooling bath is removed. After 2 h stirring at room temperature, the reaction mixture is diluted with MTBE and quenched with ammonium chloride solution. The organic phase is washed with water and brine, dried over sodium sulfate, and the solvent is removed in vacuo. The residue obtained is recrystallized from toluene to obtain the product as colorless crystals. 1H-NMR (CDCl3, 300 MHz): δ 3.78 (q, 2H), 2.43 (s, 2H), 1.93 (s, OH), 1.81 (2 d, 4H), 1.68 (d, 2H), 1.37 (s, 6H), 1.16 (s, 6H), 1.13 (t, 3H). C13-NMR (CDCl3, 75 MHz): δ 117.3, 72.5, 70.0, 58.8, 48.3, 34.8, 33.9, 21.1, 13.2. MS: m/z=241.0 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[S:5]([CH:9]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:10](O)=[O:11])([OH:8])(=[O:7])=[O:6]>CN(C)C=O.CCOCC>[S:5]([CH:9]([C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)[C:10]([Cl:3])=[O:11])([OH:8])(=[O:7])=[O:6]
Reactant: O=C(O)C(c1ccc([N+](=O)[O-])cc1)S(=O)(=O)O
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)C(c1ccc([N+](=O)[O-])cc1)S(=O)(=O)O
Yield: 81.3 %

Procedure:
6.58 Grams (5.7 × 10-2M) of thionyl chloride, 2 ml. of ether and 2 drops of dimethylformamide were added to 1.5 g. (5.7 × 10-3M) of α-sulfo-α-(p-nitrophenyl)acetic acid to allow to react for 14.5 hours at room temperature. The reaction product was subjected to the evaporation to dryness under reduced pressure to obtain a crude desired product. Yield 81.3%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.[C:13](C1NC=CN=1)([C:15]1N[CH:17]=[CH:18][N:19]=1)=[O:14].N1CCOCC1>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([N:19]3[CH2:15][CH2:13][O:14][CH2:17][CH2:18]3)=[O:12])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Solvent: ClCCl
Solvent: C1COCCN1
Product: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
Indole-6-carboxylic acid (0.60 g, 3.7 mmol) was dissolved in DCM (15 mL) and carbonyl diimidazole (0.63 g, 3.9 mmol) was added and the reaction mixture was refluxed under N2 for 30 min. The mixture was allowed to cool to room temperature before morpholine (0.39 g, 4.5 mmol) was added and the reaction mixture was refluxed for 16 hours. The mixture was allowed to cool to room temperature before it was washed in sequence with HCl (50 mL, 1 N in water), NaOH (50 mL, 1 N in water) and brine (50 mL). The organic phase was dried with MgSO4, and the solvent was removed in vacuo to give 0.74 g of (1H-indol-6-yl)-morpholin-4-yl-methanone.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[C:5]([CH3:16])=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=1.[C:22]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:31]=1)([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([C:26]1[CH:27]=[C:28]([C:2]2[N:6]([S:7]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)(=[O:9])=[O:8])[C:5]([CH3:16])=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=2)[CH:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:31]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cc(B(O)O)cc(C(C)(C)C)c1
Reactant: CCOC(=O)c1cc(Br)n(S(=O)(=O)N2CCCCC2)c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n(S(=O)(=O)N2CCCCC2)c1C
Temperature: 100 °C
Yield: 61.4 %

Procedure:
A mixture of compound 4b (2.1 g, 5.0 mmol), (3,5-di-tert-butylphenyl)boronic acid (1.9 g, 8.1 mmol), Na2CO3 (1.9 g, 17.9 mmol) and Pd(PPh3)4 (100 mg) in dioxane (50 mL) and H2O (15 mL) was heated to 100° C. for 1 h, evaporated and dissolved in EA. The mixture was washed with water (4×80 mL) and brine, dried with Na2SO4, concentrated and purified by CC to afford compound 4c (1.5 g, 61%) as a right red oil.
Reaction SMILES: [C:1]([C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].C(N(CC)CC)C.[H][H]>CO.[Ni]>[NH2:2][CH2:1][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[N:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccc(Cl)n2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CN)(c2cccc(Cl)n2)CC1

Procedure:
A solution of tert-butyl 4-cyano-4-(6-chloropyridin-2-yl)piperidine-1-carboxylate (0.82 mmol) in methanol (20 mL) with triethylamine (1 mL) was reacted with Raney nickel (0.5 mL of 50% slurry in water) under 40 psi hydrogen for 5 hours. The catalyst was filtered off and washed thoroughly with methanol. Evaporation of the solvent afforded the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:15]([SH:26])=[N:14][CH:13]=2)([CH3:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[Br:27][C:28]1[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:27][C:28]1[CH:37]=[CH:36][C:35]([CH2:38][S:26][C:15]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([O:24][CH3:25])[CH:18]=3)[C:12]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)([CH3:11])[CH3:10])=[CH:13][N:14]=2)=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31]
Reactant: COc1cc(-n2c(C(C)(C)c3ccc(Cl)c(Cl)c3)cnc2S)ccc1F
Reactant: COC(=O)c1cc(CBr)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(CSc2ncc(C(C)(C)c3ccc(Cl)c(Cl)c3)n2-c2ccc(F)c(OC)c2)ccc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
A mixture of 5-(2-(3,4-dichlorophenyl)propan-2-yl)-1-(4-fluoro-3-methoxyphenyl)-1H-imidazole-2-thiol (700 mg, 1.7 mmol, 1.0 eq), methyl 2-bromo-5-(bromomethyl)benzoate (630 mg, 2.0 mmol, 1.2 eq) and potassium carbonate (350 mg, 2.6 mmol, 1.5 eq) in acetone (9 mL) was stirred at room temperature 1 h. The solids were filtered and the organics were concentrated and purified (silica, 0 to 60% EtOAc/Hex) to afford the title compound (900 mg, 83%). MS (EI) m/z 638.9 (MH+).
Reaction SMILES: Cl.COC[O:5][C:6]1[CH:7]=[CH:8][C:9]([N+:25]([O-:27])=[O:26])=[C:10]([CH:24]=1)[O:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]>CO>[OH:5][C:6]1[CH:7]=[CH:8][C:9]([N+:25]([O-:27])=[O:26])=[C:10]([CH:24]=1)[O:11][C:12]1[CH:23]=[CH:22][CH:21]=[CH:20][C:13]=1[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17]
Reactant: COCOc1ccc([N+](=O)[O-])c(Oc2ccccc2OCC(=O)OC)c1
Agent: Cl
Solvent: CO
Product: COC(=O)COc1ccccc1Oc1cc(O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 64.7 %

Procedure:
2.5N Hydrochloric acid (30 mL) is added to a solution of methyl {o-[5-(methoxymethoxy)-2-nitrophenoxy]phenoxy}acetate (3.35 g, 9.2 mmol) in methanol. The reaction mixture is refluxed for one hour, cooled to room temperature and concentrated in vacuo to give a residue. A solution of the residue in methylene chloride is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain the title product as a yellow liquid (1.9 g) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:30](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[CH3:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(N2CCN(C)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 3 h

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (73 mg, 0.20 mmol) in CH2Cl2 (5 mL) was treated with a 37% aqueous formaldehyde solution (16 μL, 0.22 mmol) and stirred for 5 min after which time solid sodium triacetoxyborohydride (64 mg, 0.30 mmol) was added. The suspension was then stirred for 3 hr then quenched with a saturated aqueous NaHCO3 solution (2 mL). The organic component was separated, dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 5% MeOH/CH2Cl2 as eluant to afford the title compound as a burgundy oil (69 mg, 91%). 1H NMR (CDCl3) 7.33-7.20 (m, 5H), 6.72 (d, J=8.6, 1H), 6.35 (d, J=2.9, 1H), 6.30 (dd, J=8.6, 2.9, 1H), 4.62-4.59 (m, 1H), 3.76 (s, 3H), 3.32-3.22 (m, 2H), 3.13-3.02 (m, 3H), 2.67-2.60 (m, 4H), 2.57 (s, 3H), 1.85-1.77 (m, 6H), 1.61-1.54 (m, 2H). 13C NMR 148.4, 146.1, 144.5, 139.0 (CH), 129.5 (CH), 128.6, 126.4 (CH), 113.2 (CH), 107.8 (CH), 106.2 (CH), 80.4 (CH), 63.7 (CH), 56.8 (CH3), 55.1 (CH2), 55.0 (CH2), 50.2 (CH2), 42.9 (CH3), 36.3 (CH2), 33.0 (CH2), 24.2 (CH2). LC/MS (Method A) 5.10 min, [M+1]+ 381.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH2:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:3]([N+:13]([O-:15])=[O:14])[CH:4]=1)(=[O:10])=[O:9])[CH3:12]
Reactant: CCS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: NCC1CCOCC1
Product: CCS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared according to the procedure described in Step A of Example 5 from 1-chloro-4-(ethylsulfonyl)-2-nitrobenzene (Step C of Example 2) and 4-aminomethyltetrahydropyran (Apollo Scientific Ltd.).
Reaction SMILES: [CH3:1][C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.Cl.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]2[NH:40][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][C:34]=3[N:33]=2)[CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[N:33]1[C:34]2[CH:39]=[CH:38][N:37]=[CH:36][C:35]=2[NH:40][C:32]=1[CH:29]1[CH2:30][CH2:31][N:26]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([C:7]3[C:8]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:9][N:4]4[N:3]=[C:2]([CH3:1])[N:24]=[C:5]4[N:6]=3)=[CH:17][CH:18]=2)[CH2:27][CH2:28]1
Reactant: c1cc2nc(C3CCNCC3)[nH]c2cn1
Reactant: Cc1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: Cc1nc2nc(-c3ccc(CN4CCC(c5nc6ccncc6[nH]5)CC4)cc3)c(-c3ccccc3)cn2n1
Yield: 33.7 %

Procedure:
200 mg (0.64 mmol) 4-(2-methyl-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde and 181 mg (0.76 mmol) 2-piperidine-4-yl-3H-imidazo[4,5-c]pyridine hydrochloride salt were treated as described in example 2.0. Additional NaBH(OAc)3 has been added after one, two, three, four and a half, five and a half, and seven and a half hours (two equivalents each). The solvents were evaporated and the usual workup and purification yields 108 mg of the desired compound.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:19])=[O:9])=[N:4][CH:3]=1.[N:25]1[NH:26][C:27]([SH:30])=[N:28][CH:29]=1>>[CH:20]1([C:18]([C:12]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:11]=2[NH:10][C:8]([NH:7][C:5]2[S:6][C:2]([S:30][C:27]3[NH:28][CH:29]=[N:25][N:26]=3)=[CH:3][N:4]=2)=[O:9])=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1ccc(NC(=O)Nc2ncc(Br)s2)c(C(=O)C2CCCC2)c1
Reactant: Sc1ncn[nH]1
Product: Cc1ccc(NC(=O)Nc2ncc(Sc3nnc[nH]3)s2)c(C(=O)C2CCCC2)c1
Yield: 30.1 %

Procedure:
1-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-3-[5-(4H-[1,2,4]triazol-3-ylsulfanyl)-thiazol-2-yl]-urea (129 mg, 30%) was prepared from 1-(5-bromo-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (408 mg, 1 mmol) and 2H-[1,2,4]triazole-3-thiol (202 mg, 2 mmol) following the general procedure Y
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[C:25]([O:29][C:30](=[O:40])[C:31]([CH2:38][NH2:39])([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH3:34])([CH3:28])([CH3:27])[CH3:26]>CO>[C:25]([O:29][C:30](=[O:40])[C:31]([CH2:38][NH:39][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH:9]=2)=[O:4])([CH2:35][CH2:36][CH3:37])[CH2:32][CH2:33][CH3:34])([CH3:26])([CH3:28])[CH3:27]
Reactant: CCCC(CN)(CCC)C(=O)OC(C)(C)C
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Solvent: CO
Product: CCCC(CCC)(CNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Yield: 82.5 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (135 mg) and 2-aminomethyl-2-propyl-pentanoic acid tert-butyl ester (193 mg) in MeOH (2 mL) was microwaved at 120° C. for 2 h. The mixture was cooled, concentrated with HOAc (0.02 mL), the residue was directly column purified to give the desired product (180 mg). LC MS ESI+: 518 (M+1)+.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3](Cl)=[O:4].[NH:10]1[CH2:16][CH2:15][CH2:14][C@H:11]1[CH2:12][OH:13].C([O-])(=O)C.[Na+]>CC(C)=O.O>[Br:1][CH:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([N:10]1[CH2:16][CH2:15][CH2:14][C@H:11]1[CH2:12][OH:13])=[O:4]
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C)CC(Br)C(=O)Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)CC(Br)C(=O)N1CCC[C@H]1CO
Reaction time: 2 h

Procedure:
A solution of (±)-2-bromo-4-methyl-pentanoyl chloride, 21 g (0.099 mol), in 25 ml of acetone is added dropwise with stirring to a solution of 10 g (0.099 mol) of L-prolinol and 16.2 g (0.197 mol) of sodium acetate in a mixture of 150 ml of acetone and 75 ml of water at 0°-5° C. The mixture is stirred and allowed to reach room temperature over two hours, the solvent is evaporated in vacuo and the residue is suspended in 300 ml of chloroform and washed with water, 2×300 ml. The chloroform layer is separated, dried over sodium sulfate, evaporated in vacuo, and the residue is purified by chromatography using silica gel and eluting with dichloromethane-methanol (95:5) to give (2S)-1-(2-bromo-4-methyl-1-oxopentyl)2-pyrrolidinemethanol (2 position on side chain is R,S mixture), 21 g; mp 79°-82°; [α]D25 -54.0° (c 0.6, methanol).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:35]>>[CH2:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][Cl:35])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCCCOCc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCCCOCc1ccc(CCl)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
A mixture of (4-butoxymethyl-phenyl)-methanol (190 mg, 0.98 mmol) described in Manufacturing Example 33-1-3, triphenylphosphine (310 mg, 1.2 mmol) and carbon tetrachloride (3 mL) was stirred under reflux for 7 hours. The reaction mixture was cooled to room temperature, and concentrated under a reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate:heptane=1:15) to obtain the title compound (180 mg, 86%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([CH2:9][CH3:10])[NH:4][N:3]=1.CN(C)[CH:13]=[C:14]([CH3:27])[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=O>>[CH2:9]([C:5]1[C:6]([C:7]#[N:8])=[C:2]2[N:1]=[CH:13][C:14]([CH3:27])=[C:15]([C:17]3[CH:18]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:20]=[CH:21][CH:22]=3)[N:3]2[N:4]=1)[CH3:10]
Reactant: CCc1[nH]nc(N)c1C#N
Reactant: CC(=CN(C)C)C(=O)c1cccc(C(F)(F)F)c1
Product: CCc1nn2c(-c3cccc(C(F)(F)F)c3)c(C)cnc2c1C#N

Procedure:
As for Example 1, 3-amino-5-ethylpyrazole-4-carbonitrile is reacted with 3-dimethylamino-2-methyl-3'-(trifluoromethyl)acrylophenone to give the product as crystals, m.p. 163°-164° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][C:16]([CH3:21])([N+:18]([O-:20])=[O:19])[CH3:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22]OC(OC)N(C)C>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][C:16]([CH3:21])([N+:18]([O-:20])=[O:19])[CH3:17])[C:10]([O:12][CH3:22])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCC(C)(C)[N+](=O)[O-])C(=O)O
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: COC(=O)[C@H](CCCC(C)(C)[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
(S)-2-t-Butoxycarbonylamino-6-methyl-6-nitroheptanoic acid (3.90 g, 12.81 mmol) was dissolved in dichloromethane (20 ml) and dimethylformamide dimethylacetal (2.6 ml, 19.22 mmol) was added. The mixture was stirred at room temperature for 20 h. Dimethylformamide dimethylacetal (1.74 ml, 12.8 mmol) was added and the mixture was stirred for 4 h. The mixture was washed with 0.5N hydrochloric acid (30 ml), saturated aqueous sodium hydrogencarbonate solution (30 ml) and saturated brine (30 ml). The solvent was evaporated by concentration under reduced pressure to give the objective compound (2.53 g, yield 62%).
Reaction SMILES: B(F)(F)F.S(C)C.C[O:9][C:10](=[O:29])[CH2:11][C:12]1[CH:17]=[C:16]([Br:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)=[C:14]([Br:28])[CH:13]=1>ClCCl>[Br:18][C:16]1[CH:17]=[C:12]([CH2:11][C:10]([OH:29])=[O:9])[CH:13]=[C:14]([Br:28])[C:15]=1[O:19][C:20]1[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=1
Reactant: COC(=O)Cc1cc(Br)c(Oc2ccc(OC)cc2)c(Br)c1
Agent: FB(F)F
Solvent: CSC
Solvent: ClCCl
Product: O=C(O)Cc1cc(Br)c(Oc2ccc(O)cc2)c(Br)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
BF3—SMe2 (24 mL, 228 mmol) was added to a stirred solution of methyl[3,5-dibromo-4-(4-methoxyphenoxy)phenyl]acetate (2.5 g, 5.8 mmol) and dichloromethane (50 mL) at 0° C. The reaction mixture was stirred for 20 hours at room temperature and subsequently quenched with ice water (50 mL). The two layers were separated with a phase separator and the remaining water phase was extracted with ethyl acetate. Filtration through a silica pad gave the crude 3,5-dibromo-4-(4-hydroxyphenoxy)phenylacetic acid. The residue was dissolved in methanol (40 mL) and thionyl chloride (4 mL) was added carefully to the reaction. After 1.5 hours of heating at reflux, the organic phase was removed in vacuo and the residue was dissolved in chloroform. The organic phase was washed with water and concentrated to give methyl[3,5-dibromo-4-(4-hydroxyphenoxy)phenyl]acetate as beige solid (1.8 g, 75%).