Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([N:17]4C=C[N:19]=[CH:18]4)=[O:16])=[C:10]3[CH2:9][N:8]([CH3:22])[C:7](=[O:23])[C:6]=2[CH:24]=1.[CH:25]1(C(=NO)N)[CH2:27][CH2:26]1>CN(C)C=O>[CH:25]1([C:18]2[N:17]=[C:15]([C:14]3[N:13]=[CH:12][N:11]4[C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=5[C:7](=[O:23])[N:8]([CH3:22])[CH2:9][C:10]=34)[O:16][N:19]=2)[CH2:27][CH2:26]1
Reactant: CN1Cc2c(C(=O)n3ccnc3)ncn2-c2ccc(F)cc2C1=O
Reactant: NC(=NO)C1CC1
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3nc(C4CC4)no3)ncn2-c2ccc(F)cc2C1=O

Procedure:
6.5 g (20 mmol) of 1-[(8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepin-3-yl)carbonyl]imidazole are stirred at 100° for 1 hour together with 2.2 g (22 mmol) of cyclopropanecarboxamidoxime in 25 ml of N,N-dimethylformamide. The mixture is then evaporated to dryness, 50 ml of glacial acetic acid are added to the residue and the mixture is heated to reflux for 1 hour. The mixture is again evaporated to dryness in vacuo and the residue is dissolved in methylene chloride. The methylene chloride solution is washed twice with sodium bicarbonate solution, subsequently dried with magnesium sulphate and evaporated. By recrystallization from methylene chloride/ethyl acetate there is obtained 3-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-8-fluoro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 216°-217°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C@H:16]([O:29][CH2:30][CH3:31])[C:17](N[C@H](C2C=CC=CC=2)CO)=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:32]S(O)(=O)=O.[OH-].[Na+]>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C@H:16]([O:29][CH2:30][CH3:31])[C:17]([OH:18])=[O:32])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)N[C@@H](CO)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 80 °C
Reaction time: 15 h

Procedure:
(2S)-3-[4-(benzyloxy)phenyl]-2-ethoxy-N-[(1R)-2-hydroxy-1-phenylethyl ]propanamide (4.3 kg, 10.2 mol) were dissolved in dioxane (30 L) and diluted with deionized water (35 L). To this opaque reaction mixture, H2SO4 (19.2 kg, 192 mol) was added. The reaction temperature was raised to 80° C. and kept at 80° C. for 15 hours. The reaction mixture was extracted twice with TBME (64 L, 70 L) at room temperature. The combined organic phases were extracted twice with 1 M NaOH (2×20 L, 2×20 mol). The aqueous phases were acidified with H2SO4 (24 L, 24 mol), extracted with TBME (40 L) and the organic phases dried with saturated NaCl solution. The solution was concentrated to yield 64 L concentrate which contained 2.9 kg, 100% (GLC 68% area (2S)-3-[4-(benzyloxy) phenyl]-2-ethoxypropanoic acid and 28% area (2S)-2-ethoxy-(4-hydroxyphenyl) propanoic acid).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C@:8]2([CH2:19][F:20])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28](O)=[O:29])=[N:26][CH:27]=1.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1.CO>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:15])[F:16])[CH2:13][C@:8]([C:4]2[CH:3]=[C:2]([NH:1][C:28](=[O:29])[C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][N:26]=3)[CH:7]=[CH:6][CH:5]=2)([CH2:19][F:20])[N:9]=1
Reactant: NC1=N[C@](CF)(c2cccc(N)c2)C[C@@H](C(F)(F)F)O1
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: C1CCOC1
Product: NC1=N[C@](CF)(c2cccc(NC(=O)c3ccc(Cl)cn3)c2)C[C@@H](C(F)(F)F)O1
Temperature: 25 °C
Yield: 63.3 %

Procedure:
A mixture of (4S,6S)-4-(3-aminophenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (0.080 g, 0.275 mmol) and 5-chloro-2-pyridinecarboxylic acid (0.048 g, 0.302 mmol) in THF/MeOH (3/1.2 mL) was stirred at room temperature and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (0.089 g, 0.302 mmol) was added. The reaction mixture was stirred for 30 min. The reaction was quenched with saturated NaHCO3 solution and extracted with dichloromethane. The combined organic layers were dried over Na2SO4, filtered, concentrated. The crude material was purified by column chromatographed on silica gel using 10-50% EtOAc/hexane to afford a white solid as N-(3-((4S,6S)-2-amino-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)phenyl)-5-chloropicolinamide (0.075 g, 0.174 mmol, 63.4% yield). MS m/z=430.9 [M+H]+. Calculated for C18H15ClF4N4O2: 430.8
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:10]2[C:18]3[C:13](=[C:14]([O:19][CH3:20])[CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:11]=2)=[CH:8][N:9]=1)=O.[BH4-].[Na+]>CO.O1CCCC1>[CH:22]1([CH2:21][N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[C:10]([C:7]3[S:6][C:5]([CH2:3][OH:2])=[N:9][CH:8]=3)=[CH:11]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1ncc(-c2cn(CC3CCCCC3)c3c(OC)cccc23)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc2c(-c3cnc(CO)s3)cn(CC3CCCCC3)c12
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 5-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)thiazole-2-carboxylic acid methyl ester (418 mg, 1.09 mmol) in methanol (10 ml) and tetrahydrofuran (10 ml) was added sodium borohydride (83 mg, 2.18 mmol) portionwise over 2 minutes. The reaction was stirred for a further 1 h and then quenched with aqueous hydrochloric acid (1M; 10 ml). The mixture was poured into a separating funnel, diluted with dichloromethane (50 ml) and washed with water (20 ml). The combined organic layers were dried, filtered and the solvent removed in vacuo to leave a yellow oil. The oil was purified by flash column chromatography using 50-100% (v/v) diethyl ether in heptane to give [5-(1-cyclohexylmethyl-7-methoxy-1H-indol-3-yl)thiazol-2-yl]-methanol (308 mg, 0.86 mmol) as an off-white foam.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH:15]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[S:23][C:24]3[C:33]4[N:32]=[C:31]([NH:34][C:35]5[CH:40]=[CH:39][CH:38]=[C:37]([S:41](=[O:44])(=[O:43])[NH2:42])[CH:36]=5)[N:30]=[CH:29][C:28]=4[CH:27]=[CH:26][C:25]=3[N:45]=2)=[O:21])[CH2:16]1)(C)(C)C>ClCCl>[NH2:14][CH:15]1[CH2:19][CH2:18][N:17]([C:20]([C:22]2[S:23][C:24]3[C:33]4[N:32]=[C:31]([NH:34][C:35]5[CH:36]=[C:37]([S:41]([NH2:42])(=[O:43])=[O:44])[CH:38]=[CH:39][CH:40]=5)[N:30]=[CH:29][C:28]=4[CH:27]=[CH:26][C:25]=3[N:45]=2)=[O:21])[CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)c2nc3ccc4cnc(Nc5cccc(S(N)(=O)=O)c5)nc4c3s2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(C(=O)c2nc3ccc4cnc(Nc5cccc(S(N)(=O)=O)c5)nc4c3s2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 ml) was added to a suspension of {1-[8-(3-Sulfamoyl-phenylamino)-thiazolo[4,5-h]quinazoline-2-carbonyl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (87 mg, 0.15 mmol) in dichloromethane (1 ml). The reaction mixture was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure and the residue was purified by reverse phase preparative HPLC [Waters Delta-Pak C18, 15 uM, 100 A column, gradient 10%-100% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 10 minutes at 25 mL/min] to afford the title compound as a yellow solid. MS (ES+) 470, (ES−) 468. δH (d6 DMSO) 2.0-2.5 (4H, m), 3.70-4.05 (3H, m), 4.31-4.44 (2H, m), 7.37 (2H, s), 7.52 (1H, d), 7.60 (1H, t), 8.02-8.13 (6H, m), 8.69 (1H, s), 9.55 (1H, d), 10.57 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>COCCOC.O>[Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:15])[CH:9]([CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)n1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1cccc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.9 %

Procedure:
To a solution of ethyl 3-(6-chloro-2-pyridyl)-3-oxopropionate (7.6 g, 33.4 mmol) in 1,2-dimethoxyethane (50 ml) was added sodium hydride (60% in oil, 1.34 g, 33.4 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hrs. To the reaction solution was dropwise added a solution of 4-trifluoromethylbenzyl bromide (7.98 g, 33.4 mmol) in 1,2-dimethoxyethane (50 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (200 ml), saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene) to give ethyl 3-(6-chloro-2-pyridyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (13.0 g, 100%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:12])=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH2:18][CH3:19])=[O:6]
Reactant: Cc1cc(Cl)c(Cl)cc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc(Cl)c(Cl)cc1C
Yield: 97 %

Procedure:
9.2.1 g (421 mmol) of the 3,4-dichloro-6-methylbenzoic acid obtained in the above step (2) was dissolved in 550 ml of ethanol as both an esterifying agent and a solvent, 20 ml of concentrated sulfuric acid as an acid catalyst was added, and the mixture was refluxed under heat for 7 hours. The ethanol was distilled off under reduced pressure, ice water was added, and the mixture was extracted with ethyl acetate twice. The resultant organic layer was consecutively washed with a sodium carbonate aqueous solution and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 103.4 g (yield 97%) of ethyl 3,4-dichloro-6-methylbenzoate as a crude product.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.N#N.[CH2:12]1[CH2:22][O:21][C:20]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=2[O:13]1.Cl>O.CO>[Cl:1][C:2]1[N:7]=[C:6]([NH:17][C:16]2[CH:18]=[CH:19][C:20]3[O:21][CH2:22][CH2:12][O:13][C:14]=3[CH:15]=2)[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(c1)OCCO2
Agent: Cl
Agent: N#N
Solvent: O
Solvent: CO
Product: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
The reaction flask equipped with a magnetic stirring bar and a rubber septum (to prevent loss of 2,4-dichloro-5-fluoropyrimidine and N2 inlet was charged with 3,4-ethylenedioxyaniline (34 g, 225 mmol), MeOH (100 mL), H2O (300 mL) and 2,4-dichloro-5-fluoropyrimidine (25 g, 150 mmol). The reaction mixture was stirred at room temperature for 1 h, diluted with H2O (1.5 liter), acidified with 2N HCl (200 mL) and sonicated. The solid obtained was filtered, washed with H2O and dried to obtain 33 g (78%) of the desired product, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine (R926087). 1H NMR (CDCl3): δ 8.02 (1H, d, J=3 Hz), 7.25 (d, 1H, J=1.2 Hz), 6.98 (dd, 1H, J=2.4 and 8.1 Hz), 6.85 (d, 1H, J=5.7 Hz), 4.27 (m, 4H); 19F NMR (CDCl3): −44570; LCMS: ret. time: 26.70 min.; purity 100%; MS (m/e): 283 (MH+).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)[CH:2]([CH3:4])[CH3:3].[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31])#[N:23].C(N(CC)C(C)C)(C)C>ClCCl>[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:6][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:13]=2)=[CH:10][CH:11]=1)(=[O:32])=[O:31])#[N:23]
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Reactant: CC(C)CNCc1ccc(-c2cccc(S(C)(=O)=O)c2)s1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1ccccc1C#N

Procedure:
In analogy to example 13, step 2, isobutyl-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-amine (example 15, step 2) was reacted with 2-cyanobenzenesulfonyl chloride and N,N-diisopropyl ethyl amine in dichloromethane to give 2-cyano-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 505.8 ([M+NH4]+)
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[C:13]([F:34])=[CH:14][C:15]([F:33])=[C:16]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[C:21]=3[Cl:31])[CH:17]=1)[N:5]=2.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1.O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:31][C:21]1[C:22]([C:26]2([C:29]#[N:30])[CH2:28][CH2:27]2)=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])=[N:10][C:9]3=[CH:8][CH:7]=2)[C:13]([F:34])=[CH:14][C:15]=1[F:33])=[O:32]
Reactant: O=C(Cl)C1CC1
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(N)sc5n4)c(F)cc3F)c2Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(NC(=O)C6CC6)sc5n4)c(F)cc3F)c2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.1 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2,4-difluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (0.17 g, 0.33 mmol) and N,N-dimethylpyridine-4-amine (0.12 g, 1.00 mmol) in pyridine (2 mL) was added dropwise cyclopropanecarbonyl chloride (0.11 g, 1.00 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (88 mg, 47%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=O.Cl.[NH2:11][OH:12].[OH-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[N:11][OH:12]
Reactant: NO
Reactant: O=Cc1cnccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: ON=Cc1cnccc1Cl
Temperature: 0 °C
Yield: 85.3 %

Procedure:
Combine 4-chloropyridine-3-carboxaldehyde (2.75 g, 0.020 mol) with hydroxylamine hydrochloride (1.38 g, 0.021 mol) and ice (50 g) in an ethanol/water (25 mL/25 mL) mixture. Add aqueous sodium hydroxide (2.00 g, 0.049 mol, in 25 mL of water) dropwise and stir for 3 h near ambient temperature. Adjust the mixture to approx. pH 7.0 with aqueous hydrochloric acid and extract with diethyl ether. Dry the combined extracts over sodium sulfate and concentrate in vacuo which leaves the desired crude oxime (2.67 g, 88%). MS(ES): (M+1)+ 156.0, 158.0 m/z.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][C:29]([F:32])([F:31])[CH2:28][N:27]3[C:33](=[O:37])[CH2:34][C:35]#[N:36])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:38]1([CH:41]=O)[CH2:40][CH2:39]1.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@@H:26]3[CH2:30][C:29]([F:31])([F:32])[CH2:28][N:27]3[C:33]([C:34](=[CH:41][CH:38]3[CH2:40][CH2:39]3)[C:35]#[N:36])=[O:37])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CC(F)(F)C[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: O=CC1CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CC(F)(F)C[C@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
A solution of 3-[(2S)-2-[[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl]-4,4-difluoropyrrolidin-1-yl]-3-oxopropanenitrile (120 mg, 0.24 mmol, 1.00 equiv), cyclopropanecarbaldehyde (80 mg, 1.14 mmol, 5.00 equiv), piperidine (41 mg, 0.48 mmol, 2.00 equiv) in ethanol (10 mL) was stirred at 70° C. for 2 h. The resulting mixture was concentrated under vacuum. The residue was purified on Prep-HPLC. Conditions: (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (40% CH3CN up to 100% in 20 min); Detector, 254 nm, to give 24 mg (18%) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].[CH3:12][Si](C=[N+]=[N-])(C)C>CO.ClCCl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:12])=[O:7])=[CH:4][C:3]=1[F:11]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(Br)c(F)c1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(Br)c(F)c1

Procedure:
A solution of 4-bromo-3-fluorobenzoic acid (117 mg, 0.50 mmol) in methanol (1 mL) and dichloromethane (2 mL) at room temperature was slowly treated with 2M trimethylsilyldiazomethane in hexanes until the solution became light yellow. The mixture was concentrated to provide the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:35])[NH:4][N:5]=[CH:6][C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[CH2:23][CH2:22]2)[CH:11]=1.[CH2:36](Br)[CH3:37].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:36]([N:4]1[C:3](=[O:35])[C:2]([Cl:1])=[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)[CH:11]=2)[CH:6]=[N:5]1)[CH3:37]
Reactant: CCBr
Reactant: COc1ccc(CNc2cn[nH]c(=O)c2Cl)cc1OCCN1CCN(Cc2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCn1ncc(NCc2ccc(OC)c(OCCN3CCN(Cc4ccc(F)cc4)CC3)c2)c(Cl)c1=O
Reaction time: 5 h
Yield: 81.3 %

Procedure:
A mixture comprising 500 mg of 4-chloro-5-[3-{2-(4-(4-fluorobenzyl)-piperazin-1-yl)-ethoxy}-4-methoxybenzylamino]-3(2H)-pyridazinone, 130 mg of ethyl bromide, 190 mg of potassium carbonate and 10 ml of 2-butanone, was refluxed under heating with stirring for 5 hours. Inorganic substances were filtered off, and then the solvent was distilled off under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with chloroform. The extract solution was washed with water and a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent: chloroform/ethanol=19/1) to obtain 429 mg of the above-identified compound as a colorless transparent sticky substance.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH2:21]([NH:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH2:21]([N:28]([CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:15]([CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=1)=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1ccc(CCNCc2ccccc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N(CCc2ccccc2)Cc2ccccc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and benzyl-phenethyl-amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C27H29NO5 [M+H]+: 448.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21](O)=[O:22].[NH:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>ClCCl>[O:1]=[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:20][C:21]([N:24]1[CH2:25][CH2:26][CH:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:28][CH2:29]1)=[O:22]
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)CN2CCCC(c3ccccc3)(c3ccccc3)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.31 g, 1 mmol), tert-butyl piperidin-4-ylcarbamate (CAS 73874-95-0, 0.2 g, 1 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.38 g, 1 mmol) in dichloromethane (10 mL) was added diisopropylethylamine (0.7 mL), and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then diluted with dichloromethane and washed with sequentially with 20 mL of 1 N HCl, water, 20 ml, of 1 N NaOH, and water. The organic phase was dried over magnesium sulfate and concentrated in vacuo to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.33 (m, 8H), 7.21 (m, 2H), 4.45 (m, 2H), 4.03 (m, 1H), 3.77 (m, 1H), 3.49 (m, 2H), 3.11 (m, 1H), 2.79 (m, 1H), 2.63 (m, 2H), 1.97 (m, 2H), 1.83 (m, 2H), 1.45 (m, 9H), 1.32 (m, 2H).