Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.[CH3:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[CH2:24][C:23](=O)[CH2:22][CH2:21]2.C(N(CC)C(C)C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O.C(O)(=O)C>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:25]=1[CH2:24][CH:23]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1)[CH2:22][CH2:21]2
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: COc1cccc2c1CC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNC2CCc3cccc(OC)c3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15 g (74.4 mmol) of methyl 4-(aminomethyl)benzoate hydrochloride, 13.8 g (78.1 mmol) of 8-methoxy-3,4-dihydronaphthalen-2(1H)-one [for the preparation, see WO 2005/012291-A1, Example 45], 14.3 ml (81.8 mmol) of N,N-diisopropylethylamine, 4.7 ml of acetic acid and 20.5 g (96.7 mmol) of sodium triacetoxyborohydride were suspended in 600 ml of dichloromethane and stirred at RT overnight. The reaction mixture was then concentrated and the residue was stirred with ethyl acetate and water at RT for 1 h. The resulting precipitated solid was filtered off with suction. The filtrate phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried and concentrated. The solid obtained above (18.2 g) and the residue of the organic phase (12.9 g) were combined and once more stirred in a mixture of dichloromethane, water and saturated potassium carbonate solution (pH 12) until everything had gone into solution. The organic phase was then separated off, dried and concentrated. The title compound was obtained in the form of the residue.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([F:35])=[C:25]([C:28]5[O:32][C:31]([CH:33]=O)=[CH:30][CH:29]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][S:37]([CH2:40][CH2:41][NH2:42])(=[O:39])=[O:38]>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([F:35])=[C:25]([C:28]5[O:32][C:31]([CH2:33][NH:42][CH2:41][CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:30][CH:29]=5)[CH:26]=4)[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cc2F)o1
Reactant: CS(=O)(=O)CCN
Product: CS(=O)(=O)CCNCc1ccc(-c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cc2F)o1

Procedure:
Prepared according to Procedure D from 5-(4-(1-Benzyl-1H-indazol-5-ylamino)-7-fluoro-quinazolin-6-yl)-furan-2-carbaldehyde (0.6 equiv) and 2-methanesulphonyl-ethylamine (1 equiv). δ 1H NMR (400 MHz, DMSO-d6) 10.16(s, 1H), 8.91(d, 1H), 8.46(s, 1H), 8.11(s, 2H), 7.65(m, 3H), 7.26(m, 5H), 6.93(m, 1H), 6.54(d, 2H), 5.65(s, 2H), 3.89(s, 2H), 3.28(m, 2H), 2.99(m, 5H). ESI-MS m/z 569(M−1).
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)=[N:13][CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>[C].[Pd].C(O)C>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:14]2[C:9](=[O:8])[NH:10][CH:11]=[CH:12][N:13]=2)=[CH:17][CH:18]=1)[CH3:23]
Reactant: CCc1ccc(Cc2nccnc2OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(Cc2ncc[nH]c2=O)cc1
Reaction time: 18 h
Yield: 40.6 %

Procedure:
Next, a mixture of 2-benzyloxy-3-(4-ethylbenzyl)pyrazine (420 mg, 1.38 mmol), 10% palladium carbon (40 mg) and ethanol (5 mL) was stirred under a hydrogen atmosphere for 18 hours. After filtration to remove the insoluble materials, the filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=1:2) to give 3-(4-ethylbenzyl)-1H-pyrazin-2-one (120 mg, 40%) as a yellow crystal.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[ClH:15].[CH3:16][O:17][C:18](=[O:21])[CH2:19][NH2:20].C(N(CC)C(C)C)(C)C.[CH3:31][O:32][C:33]1[CH:40]=[CH:39][C:38]([O:41][C:42]([F:45])([F:44])[F:43])=[CH:37][C:34]=1[CH:35]=O>ClCCl.C(O)(=O)C>[ClH:15].[CH3:16][O:17][C:18](=[O:21])[CH2:19][NH:20][CH2:35][C:34]1[CH:37]=[C:38]([O:41][C:42]([F:43])([F:44])[F:45])[CH:39]=[CH:40][C:33]=1[O:32][CH3:31]
Reactant: COc1ccc(OC(F)(F)F)cc1C=O
Reactant: COC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNCc1cc(OC(F)(F)F)ccc1OC
Reaction time: 8 h
Yield: 64.5 %

Procedure:
Sodium triacetoxyborohydride (5.6 g) was added portionwise to a mixture of glycine methyl ester hydrochloride (1.63 g), N,N-diisopropylethylamine (2.27 ml) and 2-methoxy-5-(trifluoromethoxy)benzaldehyde (3.8 g) in a mixture of dichloromethane (30 ml) and acetic acid (3 drops) at 0° C. and the whole was stirred at 5° C.˜room temperature overnight. The mixture was partitioned between ethyl acetate and 2N sodium hydroxide. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (2:1). The fractions containing the objective compound were collected and evaporated under reduced pressure and treated with 4N hydrogen chloride in ethyl acetate solution to give N-[2-methoxy-5-(trifluoromethoxy)benzyl]glycine methyl ester hydrochloride (2.76 g) as a colorless powder.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](C1[N-]C=CN=1)=[O:12].[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[NH:26][C:27]1[NH:28][CH2:29][CH2:30][N:31]=1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([N:31]1[CH2:30][CH2:29][N:28]=[C:27]1[NH:26][C:20]1[C:21]([Cl:25])=[CH:22][CH:23]=[CH:24][C:19]=1[Cl:18])=[O:12]
Reactant: Clc1cccc(Cl)c1NC1=NCCN1
Reactant: O=C(c1ccc2ccccc2n1)c1ncc[n-]1
Product: O=C(c1ccc2ccccc2n1)N1CCN=C1Nc1c(Cl)cccc1Cl
Yield: 84.4 %

Procedure:
Using the process described in Example 57, 5.36 g (24 millimoles) of quinolin-2-oyl-imidazolide and 4.6 g (20 millimoles) of 2-(2',6'-dichlorophenylamino)-2-imidazoline give 6.5 g of pure 1-(quinolin-2-oyl)-2-(2',6'-dichlorophenylamino)-2-imidazoline of melting point 193.5°-196° C.; the material is identical with the product obtained according to Example 45.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:11][CH:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][CH3:27])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:10]2[CH2:11][N:8]([C:4]3[CH:3]=[C:2]([NH:20][C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([NH:26][CH3:27])=[O:25])[CH:7]=[CH:6][CH:5]=3)[CH2:9]2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(OC2CN(c3cccc(Br)c3)C2)cc1
Reactant: CNC(=O)c1cccc(N)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CNC(=O)c1cccc(Nc2cccc(N3CC(Oc4ccc(F)cc4)C3)c2)c1
Temperature: 100 °C
Yield: 23.3 %

Procedure:
To a solution of 1-(3-bromophenyl)-3-(4-fluorophenoxy)azetidine (400 mg, 1.24 mmol) and 3-amino-N-methylbenzamide (187 mg, 1.24 mmol) in toluene (4 mL, 3 mmoL) was added cesium carbonate (180 mg, 1.86 mmol) and degassed for 15 min. Pd2(dba)3 (56 mg, 0.062 mmol) and BINAP (38 mg, 0.062 mmol) were added and the mixture was heated in the microwave for 30 min at 100° C. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×30 mL) and water (2×30 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure then purified by silica gel column chromatography to provide 3-((3-(3-(4-fluorophenoxy)azetidin-1-yl)phenyl)amino)-N-methylbenzamide (113 mg, 23%) as a solid. Observed mass (M+1): 393.1
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[S:29]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[CH2:38][CH2:39][CH2:40][C:41](O)=[O:42])(=[O:31])=[O:30].Cl.CN(C)CCCN=C=NCC.Cl.Cl.[N:58]1([CH2:63][CH2:64][O:65][C:66]2([C:72]3[CH:73]=[N:74][CH:75]=[CH:76][CH:77]=3)[CH2:71][CH2:70][NH:69][CH2:68][CH2:67]2)[CH2:62][CH2:61][CH2:60][CH2:59]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:23]=1[S:29]([N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[CH2:38][CH2:39][CH2:40][C:41]([N:69]1[CH2:70][CH2:71][C:66]([C:72]2[CH:73]=[N:74][CH:75]=[CH:76][CH:77]=2)([O:65][CH2:64][CH2:63][N:58]2[CH2:59][CH2:60][CH2:61][CH2:62]2)[CH2:67][CH2:68]1)=[O:42])(=[O:30])=[O:31]
Reactant: c1cncc(C2(OCCN3CCCC3)CCNCC2)c1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(Cl)c1S(=O)(=O)N1CCCCC1CCCC(=O)N1CCC(OCCN2CCCC2)(c2cccnc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61 %

Procedure:
1-Hydroxybenzotriazole hydrate (HOBT) (0.022 g, 0.168 mmol, 0.3 eq.) and N-ethyl-diisopropylamine (0.285 ml, 1.68 mmol, 3 eq.) were added to a solution of 4-(1-(2-chloro-6-methylphenylsulfonyl)piperidin-2-yl)butanoic acid (0.252 g, 0.7 mmol, 1.25 eq.) in methylene chloride (7 ml). The mixture was cooled to 0° C., 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (0.161 g, 0.84 mmol, 1.5 eq.) was added and the mixture was stirred for 15 min. 3-(4-(2-(Pyrrolidin-1-yl)ethoxy)piperidin-4-yl)pyridine dihydrochloride (0.195 g, 0.56 mmol, 1 eq.) was then added. The reaction mixture was stirred at room temperature for 72 h. For working up, sat. sodium bicarbonate solution was added to the mixture and the mixture was diluted with ethyl acetate. The phases were separated, and the aqueous phase was extracted 2× with ethyl acetate. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography [Alox Neutral (25 g), ethyl acetate 100%→ethyl acetate/methanol 95:5]. The desired product was obtained as a yellow-white solid in a yield of 61% (0.212 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:19][S:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([S:20][CH3:19])=[CH:22][CH:23]=3)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:17][CH:18]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Reactant: CSc1ccc(C(=O)O)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(SC)cc2)cc1
Yield: 90.3 %

Procedure:
Using the procedure described in Example 55, Part B, N1-(4-methoxybenzoyl)-1,2-benzenediamine (772 mg, 3.19 mmol) was reacted with 4-(methylthio)benzoic acid (772 mg, 4.59 mmol) to yield 1.13 g (91%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]3[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[C:5]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.O[C@@H:36]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]([O:39][CH2:40][CH3:41])=[O:38].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]3[CH2:18][CH2:19][CH:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:21][CH2:22]3)=[CH:11][CH:10]=2)[C:5]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C@H:36]([CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Reactant: CCCCCC1CCC(COc2ccc(CCn3c(C)ccc3-c3ccc(O)cc3)cc2)CC1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCC1CCC(COc2ccc(CCn3c(C)ccc3-c3ccc(O[C@H](Cc4ccccc4)C(=O)OCC)cc3)cc2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 48.7 %

Procedure:
To a solution of 4-(5-methyl-1-{2-[4-(4-pentylcyclohexylmethoxy)phenyl]ethyl}-1H-pyrrol-2-yl)phenol (830 mg, 1.81 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (526 mg, 2.71 mmol) and triphenylphosphine (711 mg, 2.71 mmol) in toluene (1 ml) was added 1,1′-(azodicarbonyl)dipiperidine (684 mg, 2.71 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 560 mg (yield: 48.7%)
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH2:16]([O:18][C:19]1[N:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:22]2[CH:23]=[N:24][C:19]([O:18][CH2:16][CH3:17])=[CH:20][CH:21]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CCOc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOc1ccc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)cn1

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 6-ethoxypyridin-3-ylboronic acid (0.337 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 18 h to give 4-chloro-2-(6-ethoxypyridin-3-yl)-5,7-difluoro-3-methylquinoline as a white solid. Mass Spectrum (ESI) m/e=335.0 (M+1).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)=O.[CH2:18]([NH:25][CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>>[CH2:18]([N:25]([CH2:1][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CNCc1ccccc1
Reactant: O=CC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CN(Cc1ccccc1)CC1CCN(c2ccc([N+](=O)[O-])cc2)CC1

Procedure:
4.0 g (17.1 mmol) of 4-formyl-1-(4-nitrophenyl)piperidine, 2.1 g (17.1 mmol) of N-benzyl-N-methylamine, 1.0 g (17.1 mmol) of acetic acid and 1.1 g (17.1 mmol) of sodium cyanoborohydride were reacted as in Example 1.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]([CH3:26])[C:20]=3[CH3:27])[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]([CH3:26])[C:20]=3[CH3:27])[CH:13]=[N:12]2)[C:8]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(C)c(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)c1C
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: Cc1ccc(C)c(Oc2cnn(C(CC3CCCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)c(=O)c2)c1C
Yield: 93 %

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[6-oxo-4-(2,3,6-trimethyl-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 66) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2,3,6-trimethyl-phenoxy)-6H-pyridazin-1-yl]-propionamide as a white solid (1.27 g, 93%); ES+-HRMS m/e calcd for C28H37N5O4 [M+H+] 508.2919 found 508.2921. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.98-1.18 (m, 1H), 1.04 (s, 3H), 1.05 (s, 3H), 1.23-1.79 (m, 8H), 1.83-1.98 (m, 1H), 2.01 (s, 3H), 2.06 (s, 3H), 2.17-2.32 (m, 1H), 2.25 (s, 3H), 3.89 (s, 2H), 4.68 (s, 1H), 5.37-5.50 (m, 2H), 6.39 (d, J=2.1 Hz, 1H), 7.01-7.19 (m, 2H), 7.52 (d, J=2.1 Hz, 1H), 8.19 (d, J=2.7 Hz, 1H), 10.83 (s, 1H).
Reaction SMILES: [C:1]([CH:3]([OH:18])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:5]=1)#[N:2].[CH3:19][C:20]1([CH3:35])[C@@H:22](/[CH:23]=[CH:24]\[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@H:21]1[C:32](O)=[O:33]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:19][C:20]1([CH3:35])[C@@H:22](/[CH:23]=[CH:24]\[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[C@H:21]1[C:32]([O:18][C@H:3]([C:1]#[N:2])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=1)=[O:33]
Reactant: N#CC(O)c1ccc(F)c(Oc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2ccc(F)c(Oc3ccccc3)c2)C1(C)C
Temperature: 20 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
A solution of 30 g of (RS)α-cyano-3-phenoxy-4-fluoro-benzyl alcohol, 300 mg of 4-dimethylamino-pyridine and 50 ml of methylene chloride was added all at once at -5° C. to a solution of 30 g of (1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropane-carboxylic acid in 100 ml of methylene chloride and the mixture was stirred at 0° C. for 30 minutes and at 20° C. for 3 hours. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 n-hexane-ethyl acetate mixture to obtain 53.9 g of (S)α-cyano-3-phenoxy-4-fluoro-benzyl(1R,cis,Z)2,2-dimethyl-3-[3-oxo-3-tert.-butoxy-1-propenyl]-cyclopropanecarboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)=[CH:11][C:10]=1[O:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[C:31]#[N:32].C1(O)C=CC=CC=1.N(C)(C)C>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:19][N:18]([C:28]3[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=3)[C:31]#[N:32])[C:17](=[O:20])[CH2:16]2)=[CH:11][C:10]=1[O:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cccc(Br)c1
Reactant: O=C1CC(c2ccc(OCc3ccccc3)c(OC3CCCC3)c2)CN1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)C
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: N#Cc1cccc(N2CC(c3ccc(OCc4ccccc4)c(OC4CCCC4)c3)CC2=O)c1
Reaction time: 24 h
Yield: 74 %

Procedure:
A mixture of 4-(4-benzyloxy-3-cyclopentyloxyphenyl)pyrrolidin-2-one, 3-bromobenzonitrile, phenol (0.1 mmol), copper acetate (0.15 mmol), arylboronic acid (0.12 mmol), 4 Å Molecular Sieves (“MS”) (p100 mg) and CH2Cl2 (1 mL) was created in a dry round bottom flask. (CH3)3N (0.22 mmol) was added, the flask was sealed, and the mixture was stirred for 24 h. The reaction mixture was then diluted with 10 mL of CH2Cl2 and filtered. The filtrate was washed with saturated NH4Cl, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel or preparative liquid chromatography-mass spectrometry LC-MS to give pure product. Yield: 74%.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][C:15]#[C:16][CH2:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:10]=[CH:9]2)C=CC=CC=1.Cl>C(O)C>[CH:19]1([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][NH:8][CH:12]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: C(#CCCC1CCCCC1)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Solvent: CCO
Product: c1nc(CCCCCCC2CCCCC2)c[nH]1
Temperature: 90 °C
Yield: 34.6 %

Procedure:
1-[1-Triphenylmethyl-1H-imidazol-4-yl]-6-cyclohexyl-3-hexyne (0.629 g, 1.33 mmol) was suspended in ethyl alcohol (3 ml). 2N HCl (25 ml) was added and the reaction mixture heated at 90° C. for 1 hr. The reaction mixture was cooled, filtered through a pad of celite and the filtrate evaporated in vacuo. The residue was dissolved in methanol (20 ml). 10% Pd(C) (0.1 39 g) and ammonium formate (1.5 g) were added, and the reaction mixture heated at 65° C. under N2 for 6.5 hours. The reaction mixture was cooled, filtered through a pad of celite and the methanol filtrate concentrated. The residue was partitioned between CH2Cl2 and 10% NaOH solution (100 ml, 1:1). The CH2Cl2 layer was separated, washed with water (50 ml), dried over MgSO4, filtered and evaporated in vacuo. Purification by flash chromatography using ethyl acetate as eluent gave 108 mgs of final product.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([Cl:12])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[F:13][C:14]1[CH:28]=[CH:27][C:17]([CH2:18][O:19][C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>C(#N)C>[Cl:12][C:10]1[N:9]=[CH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:24][C:23]3[CH:22]=[CH:21][C:20]([O:19][CH2:18][C:17]4[CH:27]=[CH:28][C:14]([F:13])=[CH:15][CH:16]=4)=[CH:26][CH:25]=3)[C:3]=2[CH:11]=1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Reactant: Nc1ccc(OCc2ccc(F)cc2)cc1
Solvent: CC#N
Product: Fc1ccc(COc2ccc(Nc3ncnc4cnc(Cl)cc34)cc2)cc1

Procedure:
4,6-Dichloro-pyrido[3,4-d]pyrimidine (1 g) and 4-(4-fluorobenzyloxy)aniline (1.08 g) in acetonitrile (70 ml) were reacted together as in Procedure A. The product was collected by filtration as a yellow solid (1.83 g); m/z 381 (M+1)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH:29]([CH3:31])[CH3:30])[C@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:15]([CH2:25][C:26](O)=[O:27])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]([CH:29]([CH3:31])[CH3:30])[C@H:12]1[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[C@@H:15]([CH2:25][CH2:26][OH:27])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)N(C(=O)OCc1ccccc1)[C@@H]1CC[C@H](CC(=O)O)N(C(=O)OC(C)(C)C)C1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)OCc1ccccc1)[C@@H]1CC[C@H](CCO)N(C(=O)OC(C)(C)C)C1
Yield: 86.5 %

Procedure:
To a solution of [(2R,5R)-5-[[(benzyloxy)carbonyl](isopropyl)amino]-1-(tert-butoxycarbonyl)-piperidin-2-yl]acetic acid (8.0 g) in tetrahydrofuran (100 mL) was added triethylamine (7.7 mL), and thereto was added ethyl chloroformate (3.5 mL) under ice-cooling. After the mixture was stirred under ice-cooling for one hour, the insoluble materials were removed by filtration. To the filtrate was added dropwise a solution of sodium borohydride (3.5 g) in water (30 mL) under ice-cooling with stirring. Then, the mixture was stirred at room temperature for one hour. To the mixture was added an aqueous potassium hydrogen sulfate solution under ice-cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound (6.7 g) as a colorless oil.