Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH3:66][O:67][C:68](=[O:77])[C:69]1[CH:74]=[CH:73][C:72]([CH2:75][NH2:76])=[CH:71][CH:70]=1>C(Cl)Cl>[CH3:66][O:67][C:68](=[O:77])[C:69]1[CH:74]=[CH:73][C:72]([CH2:75][NH:76][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10]2)=[O:30])=[CH:71][CH:70]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of rac (2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (150 mg, 0.26 mmol) in methylene chloride (10 mL), HATU (Aldrich, 177 mg, 0.46 mmol) was added followed by the addition of DIPEA (0.36 mL, 2.06 mmol) and 4-aminomethyl-benzoic acid methyl ester hydrochloride salt (Aldrich, 104 mg, 0.52 mmol). The mixture was stirred at rt for overnight. The reaction was quenched with addition of water. The mixture was extracted with methylene chloride (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on an ISCO machine (40 g column, 5-15% EtOAc/hexanes) to give a white solid. 119 mg.
Reaction SMILES: [C:1]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[C:1]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1COCCN1
Reactant: O=C1CCCCCCCCCCC1
Agent: C1=C(/N2CCOCC2)CCCCCCCCCC/1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(N2CCOCC2)CCCCCCCCCC1

Procedure:
A 100 mL three neck round bottom flask, equipped with a stir bar, thermometer and a Dean-Stark trap, was charged with 10 g (55 mmoles) of cyclododecanone, 6.7 g (77 mmoles) of morpholine, 40 mL of anhydrous toluene and a catalytic amount of p-toluenesulfonic acid monohydrate. The reaction mixture was refluxed for 48-77 hours. The toluene was removed under vacuum, and the reaction mixture was vacuum distilled to give 5.7 g of N-morpholino-1-cyclododecene (at 160°-168° C./0.5mm) as a 95% pure clear liquid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O-:14])(=[O:13])[CH2:10][CH2:11][CH3:12].[K+].C(OC(=O)CCC)(=O)CCC>>[CH2:11]([C:10](=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]([OH:14])=[O:13])[CH3:12]
Reactant: O=Cc1ccccc1
Reactant: CCCC(=O)[O-]
Agent: CCCC(=O)OC(=O)CCC
Agent: [K+]
Product: CCC(=Cc1ccccc1)C(=O)O

Procedure:
Benzaldehyde was condensed with potassium butyrate and butyric anhydride according to the procedure as outlined in the patent to Archer, U.S. Pat. No. 2,931,830 to give α-ethyl cinnamic acid, mp 104°-104.8° C.
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Cl[C:44]1[N:45]=[CH:46][C:47]2[C:52]([CH:53]=1)=[CH:51][CH:50]=[CH:49][C:48]=2[Cl:54].[NH2:55][C:56]1[N:57]=[C:58]([O:64][C@@H:65]2[CH2:69][CH2:68][NH:67][CH2:66]2)[C:59]([C:62]#[N:63])=[N:60][CH:61]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CN(C=O)C.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]>[Cl:54][C:48]1[CH:49]=[CH:50][CH:51]=[C:52]2[C:47]=1[CH:46]=[N:45][C:44]([NH:55][C:56]1[N:57]=[C:58]([O:64][C@@H:65]3[CH2:69][CH2:68][NH:67][CH2:66]3)[C:59]([C:62]#[N:63])=[N:60][CH:61]=1)=[CH:53]2
Reactant: Clc1cc2cccc(Cl)c2cn1
Reactant: N#Cc1ncc(N)nc1O[C@@H]1CCNC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#Cc1ncc(Nc2cc3cccc(Cl)c3cn2)nc1O[C@@H]1CCNC1
Temperature: 130 °C
Reaction time: 0.17 h
Yield: 4 %

Procedure:
A mixture of tris(dibenzylideneacetone)dipalladium(0) (23 mg, 0.025 mmol) and 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (29 mg, 0.05 mmol) in toluene (1.5 mL) was degassed under a stream of nitrogen gas with stirring for 10 minutes. 3,8-Dichloroisoquinoline (50 mg, 0.252 mmol), (R)-5-amino-3-(pyrrolidin-3-yloxy)pyrazine-2-carbonitrile (85 mg, 0.278 mmol) in DMF (0.5 mL) and caesium carbonate (165 mg, 0.505 mmol) were added and the mixture was degassed for a further 5 minutes, then heated at 130° C. for 30 minutes in a microwave reactor. Upon cooling, the mixture was diluted with methanol and isolated by SPE using a MP-TsOH cartridge, washing with methanol and then eluting with 2 M ammonia in methanol. The combined basic fractions were concentrated in vacuo. Preparative HPLC gave (R)-5-(8-chloroisoquinolin-3-ylamino)-3-(pyrrolidin-3-yloxy)pyrazine-2-carbonitrile (3.8 mg, 0.01 mmol, 4%). 1H NMR (d4-MeOD) δ 9.42 (d, 1H, J=0.9 Hz), 8.52 (s, 1H), 8.32 (d, 1H, J=5.3 Hz), 7.85 (d, 1H, J=8.3 Hz), 7.66-7.62 (m, 1H), 7.59-7.57 (m, 1H), 5.89-5.86 (m, 1H), 3.67-3.65 (m, 2H), 3.50-3.46 (m, 2H), 2.52-2.47 (m, 2H). LC-MS (2) Rt=2.65 min; m/z (ESI−) 365 (M−H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH:12][C:13]2[N:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])[N:16]=[C:15]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:14]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:29](B(O)O)[CH3:30].C(Cl)Cl.C1(C)C=CC=CC=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[C:25]([C:15]1[CH:14]=[C:13]([NH:12][C:5]2[CH:4]=[CH:3][C:2]([CH2:29][CH3:30])=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[N:16]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CCB(O)O
Reactant: COC(=O)c1cc(Br)ccc1Nc1cc(C(C)(C)C)nn1-c1ccccc1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCc1ccc(Nc2cc(C(C)(C)C)nn2-c2ccccc2C)c(C(=O)OC)c1
Temperature: 85 °C
Yield: 37.5 %

Procedure:
To a mixture of methyl 5-bromo-2-{[3-tert-butyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzoate (Example 234, 1.15 g, 4.13 mmol), ethylboronic acid (1.16 g, 15.7 mmol), and Pd(dppf)Cl2.CH2Cl2 (114 mg, 0.16 mmol) was added toluene (20 mL) and dioxane (5 mL). The resulting solution was degassed under nitrogen for 30 min, followed by addition of sodium bicarbonate (2 M aq solution, 15 mL). The mixture was then heated to 85° C. for 16 h. The reaction mixture was allowed to cool to rt. The solvent was removed under reduced pressure, and the residue was purified by silica gel flash chromatography using 0 to 10% ethyl acetate in hexanes to afford 606 mg (61%) of the title compound. 1H NMR (300 MHz, CD2Cl2) δ 9.17 (s, 1H), 7.68 (s, 1H), 7.22-7.33 (m, 6H), 6.08 (s, 1H), 3.70 (s, 3H), 2.51 (q, 2H), 2.05 (s, 3H), 1.30 (s, 9H), 1.14 (t, 3H). ES-MS m/z 392.2 (MH+); HPLC RT (min) 4.62.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]1[O:30][C@H:29]([CH2:31][O:32]C(=O)C2C=CC=CC=2)[C@@H:19]([O:20]C(=O)C2C=CC=CC=2)[C@H:9]1[O:10]C(=O)C1C=CC=CC=1)=[O:6].C[O-].[Na+]>CO>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]1[O:30][C@H:29]([CH2:31][OH:32])[C@@H:19]([OH:20])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(NCCCl)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
The crystals of 1-(2-chloroethyl)-3-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) urea (3.0 g) obtained in step (1) above were partially dissolved in methanol (100 ml) and to the resulting suspension was added an 0.2 N methanolic solution of sodium methoxide (8 ml). Dissolution of the crystals in the methanol was completed by stirring the mixture at room temperature for 10 minutes. The resulting solution was stored in the cold for 7 days and then treated with 2 ml of a cation exchange resin "Amberlite" IR-120 (H+ form) (Amberlite is a trademark of Rohm and Haas Co.) to remove the sodium cation. The cation exchange resin was filtered off and the filtrate was concentrated in vacuo. The resulting residue was dissolved in water (100 ml) and washed three times with ethyl ether (50 ml each). The aqueous layer was concentrated in vacuo and the residue was crystallized from methanol to give 1-(2-chloroethyl)-3-(β-D-ribofuranosyl) urea (1.06 g) as crystals. Yield 81%.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][OH:12])=[CH:2]1.CN1CCOCC1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>O>[N+:30]([C:27]1[CH:26]=[CH:25][C:24]([O:23][C:21](=[O:22])[O:12][CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[CH:29][CH:28]=1)([O-:32])=[O:31]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCCc1c[nH]c2ccccc12
Solvent: O
Solvent: CN1CCOCC1
Product: O=C(OCCc1c[nH]c2ccccc12)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.9 %

Procedure:
To a solution of 2-(1H-indol-3-yl)-ethanol (1600 mg, 9.92 mmol), in N-methyl morpholine (2000 m g, 19.84 mmol), was added p-nitrophenyl chloroformate (4000 mg, 19.84 mmol), and the mixture was stirred for 24 hours at room temperature. Water was added and the mixture extracted with dichloromethane. Evaporation of the solvent gave a residue which was purified by silica gel column chromatography using a mixture of DCM/Hx (3:1) as eluent to produce 1034 mg (32%) of the title compound as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([OH:12])=[CH:7][C:6]=2[Br:13].Br[CH:15]([CH2:25][CH3:26])[C:16]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]#[C:21][CH3:22])=[O:17]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH:15]([CH2:25][CH3:26])[C:16]([NH:18][C:19]([CH3:24])([CH3:23])[C:20]#[C:21][CH3:22])=[O:17])=[CH:7][C:6]=2[Br:13]
Reactant: CC#CC(C)(C)NC(=O)C(Br)CC
Reactant: Oc1cc(Br)c2ncc(Br)cc2c1
Product: CC#CC(C)(C)NC(=O)C(CC)Oc1cc(Br)c2ncc(Br)cc2c1

Procedure:
In a similar procedure, 3,8-dibromo-6-hydroxyquinoline was reacted with 2-bromo-N-(4-methylpent-2-yn-4-yl) butyramide to give 2-(3,8-dibromo-6-quinolinyloxy)-N-(4-methylpent-2-yn-4-yl) butyramide as a colourless gum, 1H NMR (CDCl3) δ: 1.07(3H, t);1.59 (3H, s); 1.60(3H, s); 1.78(3H, s); 1.99-2.06(2H, m); 4.52(1H, t); 6.30(1H, s); 7.00(1H, m); 7.82(1H, dd); 8.21(1H, d); 8.88(1H, m).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[S:5][C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[CH2:20][NH:21]C(=O)C)[N:11]=2)=[C:7]([CH3:9])[N:8]=1)[CH3:2]>CC#N>[NH2:21][CH2:20][C:19]1[CH:18]=[C:17]([NH:16][C:12]2[N:11]=[C:10]([C:6]3[S:5][C:4]([NH:3][CH2:1][CH3:2])=[N:8][C:7]=3[CH3:9])[CH:15]=[CH:14][N:13]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCNc1nc(C)c(-c2ccnc(Nc3cccc(CNC(C)=O)c3)n2)s1
Solvent: CC#N
Product: CCNc1nc(C)c(-c2ccnc(Nc3cccc(CN)c3)n2)s1

Procedure:
By hydrolysis of N-{3-[4-(2-ethylamino-4-methyl-thiazol-5-yl)-pyrimidin-2-ylamino]-benzyl}-acetamide. Yellow solid. Mp 290-292° C. Anal. RP-HPLC: tR=10.6 min (10-70% MeCN, purity>95%). 1H-NMR (DMSO-D6) δ: 1.31 (t, 3H, J=7.0 Hz, CH3), 2.64 (s, 3H, CH3), 3.54 (m, 2H, CH2), 4.11 (m, 2H, CH2), 7.14 (d, 1H, J=6.0 Hz, pyrimidinyl-H), 7.22 (d, 1H, J=8.0 Hz, Ph-H), 7.45 (t, 1H, J=8.0 Hz, Ph-H), 7.74 (d, 1H, J=8.0 Hz, Ph-H), 7.95 (s, 1H, Ph-H), 8.53 (d, 1H, J=6.0 Hz, pyrimidinyl-H). MS (ESI+) m/z 341.20 [M+H]+ (C17H20N6S requires 340.45).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:13][CH2:14][O:15]C(=O)C)[CH2:9]1)=[O:7].[OH-].[Li+]>CO.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C@@:10]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOC(C)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)N2CC[C@](CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reaction time: 3.5 h

Procedure:
Combine (+)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-acetoxyethyl)pyrrolidine (670 mg, 1.35 mmol) and aqueous lithium hydroxide solution (4.2 mL, 1M) in methanol (15 mL). After 3.5 hours, concentrate in vacuo to give a residue. Dissolve the residue in dichloromethane and extract with 1M hydrochloric acid solution and saturated sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to obtain a residue. The residue was dried under high vacuum for 18 hours to give (S)-1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)pyrrolidine: Rf =0.11 (silica gel, ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([OH:22])[C:5]2[CH2:11][CH:10]([CH2:12][CH2:13][C:14]3[S:18][C:17]([C:19]([OH:21])=O)=[CH:16][CH:15]=3)[CH2:9][NH:8][C:6]=2[N:7]=1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.Cl.[CH2:42]([O:44][C:45](=[O:48])[CH2:46][NH2:47])[CH3:43]>CN(C)C=O>[CH2:42]([O:44][C:45](=[O:48])[CH2:46][NH:47][C:19]([C:17]1[S:18][C:14]([CH2:13][CH2:12][CH:10]2[CH2:9][NH:8][C:6]3[N:7]=[C:2]([NH2:1])[N:3]=[C:4]([OH:22])[C:5]=3[CH2:11]2)=[CH:15][CH:16]=1)=[O:21])[CH3:43]
Reactant: CCOC(=O)CN
Reactant: Nc1nc(O)c2c(n1)NCC(CCc1ccc(C(=O)O)s1)C2
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1ccc(CCC2CNc3nc(N)nc(O)c3C2)s1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 37.8 %

Procedure:
To 0.15 g (0.47 mmol) of 5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]-pyrimidin-6-yl)ethyl]thien-2-ylcarboxylic acid in a three-necked round bottomed flask under an atmosphere of nitrogen were added 3.0 mL of anhydrous dimethylformamide and 0.11 mL (0.99 mmol) of 4-methylmorpholine. To this was then added 0.84 g (0.48 mmol) of 2-chloro-4,6-dimethoxy-1,3,5-triazine. The reaction mixture was stirred at room temperature for 35 minutes and a solution of 0.072 g (0.51 mmol) of glycine ethyl ester hydrochloride in 1.0 mL of anhydrous dimethylformamide was added together with 0.65 mL (5.85 mmol) of 4-methylmorpholine. After 35 minutes, an additional 0.015 g (0.11 mmol) of glycine ethyl ester hydrochloride and 0.2 mL (1.80 mmol) of 4-methylmorpholine was added. The reaction was stirred for 3 hours and concentrated in vacua. The crude mixture then was chromatographed on silica gel eluting with a gradient of 2-12% CH3OH/CHCl3 to give 0.072 g (38%) of N-{5-[2-(2-amino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)ethyl]thien-2-ylcarbonyl}glycine ethyl ester as a white solid. Rf=0.34 (20% CH3OH/CHCl3) m.p.=152°-160° C. (foam, dec.) Mass Spectrum (FD+): M+=405; IR (CHCl3, cm-1)=1046, 1196, 1304, 1464, 1602, 1745, 2363, 2977, 3025, 3619; UV (C2H5OH) λmax =222, 279 (ε=24333, 23816); 1H NMR (300 MHz, DMSOd6) δ1.17 (t, J=6.5 Hz, 3H), 1.52-1.60 (m, 3H), 1.77-1.84 (m, 1H), 2.40-2.44 (m, 1H), 2.72-2.8(m, 3H), 3.14-3-24 (m, 1H), 3.91 (d, J=4.7 Hz, 2H), 4.05-4.12 (m, 2H), 6.24 (s, 2H), 6.89 (s, 1H, 7.57 (s, 1H), 8.80 (s, 1H), 9.66 (s, 1H).
Reaction SMILES: C([O-])(=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.P([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)(O)(O)=O>>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([OH:19])=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(OP(=O)(O)O)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Product: O=[N+]([O-])c1ccc(O)cc1
Reaction time: 0.33 h

Procedure:
The scales treated by fixation were moved and weighed. After measurement, the scales were put into a 96-well microplate. To each well, 2001 of 100 mM acetate buffer (pH 5.3) containing 20 mM tartrate and 10 mM para-nitrophenol phosphate (substrate) was added. Reaction was performed at 25° C. for 20 minutes and subsequently terminated by the addition of a 3 M sodium hydroxide aqueous solution (50±1). Then, 1501 of the solution after the completion of reaction was transferred to another microplate. The amount of para-nitrophenol (p-NP) produced by TRAP was measured with a spectrophotometer (405 nm). The osteoclast activity was indicated as the amount of p-NP produced by the decomposition of para-nitrophenol phosphate per g of scale per minute.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:17]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)(=[O:21])[CH:18]([CH3:20])[CH3:19].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:25]2[CH2:26][CH2:27][N:22]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)N1CCC(=O)CC1
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)C(=O)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-isobutyrylpiperidin-4-one (78.4 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was quenched with saturated NaHCO3 solution, the aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM to DCM/MeOH 95:5 gradient as eluent gave 1-{4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}-2-methylpropan-1-one (129 mg, 78%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.18 min, m/z 389.48 (36), 387.46 (M++H, 100). HPLC tr=3.65 min 97.72%) 1H NMR (270 MHz, CDCl3) δ 1.079 (3H, d, J=6.7 Hz, CH3), δ 1.082 (3H, d, J=6.7 Hz, CH3), 1.23 (2H, m, CH2), 1.45 (br s, NH), 1.83 (2H, m, CH2), 2.70 (2H, m, H2), 2.77 (1H, hept, J=6.7 Hz, CHMe2), 3.01 (1H, m, CHNH), 3.80 (2H, m, CH2), 3.83 (1H, m, ½CH2), 4.41 (1H, br d, J=13.4 Hz, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.87 (1H, m, ArH), 7.12 (1H, td, ArH), 7.24 (1H, m, ArH), 7.25 (2H, AA′BB′, ArH) and 7.39 (1H, dd, J=7.4, 1.7 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 19.46, 19.65 (CH2), 30.13 (CH), 32.39, 33.30, 40.43, 43.95, 45.67 (CH2), 53.97 (CH), 118.94, 119.61, 124.54, 127.96, 128.72, 129.84, 130.58, 131.80, 154.35, 156.37 (ArC), and 175.30 (C═O).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:15])[N:6]=1)=[O:4].[F:16][C:17]1[CH:18]=[CH:19][C:20]([O:35][CH3:36])=[C:21]([C:23]([CH3:34])([CH3:33])[CH2:24][C:25]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH:26]=O)[CH:22]=1.C(O)(=O)C.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N:15]=[CH:26][C:25]([OH:32])([C:28]([F:29])([F:31])[F:30])[CH2:24][C:23]([C:21]2[CH:22]=[C:17]([F:16])[CH:18]=[CH:19][C:20]=2[O:35][CH3:36])([CH3:33])[CH3:34])[N:6]=1)=[O:4]
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(F)ccc3OC)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 37, 200 mg (1.0 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester is reacted with 371 mg (1.2 mmol) of 4-(5-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 1.10 ml of concentrated acetic acid in 20 ml of toluene. After chromatography on silica gel with hexane-ethyl acetate (0-100%), 420 mg (85% of theory) of the product is obtained.
Reaction SMILES: CN1C(=O)C(C2N(C3C=CC(C#N)=CC=3)N=CC=2)=C(C)N(C2C=CC=C(C(F)(F)F)C=2)C1=O.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Br:44]N1C(=O)CCC1=O.[Cl-].[NH4+].[Br:54][CH2:55][C:56]1[N:61]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([F:71])([F:70])[F:69])[CH:63]=2)[C:60](=[O:72])[N:59]([CH3:73])[C:58](=[O:74])[C:57]=1[C:75]1[N:79]([C:80]2[CH:87]=[CH:86][C:83]([C:84]#[N:85])=[CH:82][CH:81]=2)[N:78]=[CH:77][CH:76]=1>O1CCCC1>[Br:54][CH:55]([Br:44])[C:56]1[N:61]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([C:68]([F:71])([F:70])[F:69])[CH:63]=2)[C:60](=[O:72])[N:59]([CH3:73])[C:58](=[O:74])[C:57]=1[C:75]1[N:79]([C:80]2[CH:81]=[CH:82][C:83]([C:84]#[N:85])=[CH:86][CH:87]=2)[N:78]=[CH:77][CH:76]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(CBr)n(-c2cccc(C(F)(F)F)c2)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cn1c(=O)c(-c2ccnn2-c2ccc(C#N)cc2)c(C(Br)Br)n(-c2cccc(C(F)(F)F)c2)c1=O
Temperature: 0 °C

Procedure:
To a solution of 4-[5-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (prepared in Example 1) (30.0 mg) in tetrahydrofuran (1.0 ml) was added at 0° C. lithium hexamethyldisilazide (0.1 ml: 1M tetrahydrofuran solution) followed by an addition of N-bromosuccinimide (14.4 mg), and the resulting mixture was stirred at 0° C. for a half hour. To the reaction mixture was added saturated aqueous ammonium chloride solution (5 ml) and the mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (10 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-[5-(6,6-dibromomethyl)-3-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (5.4 mg) and 4-[5-(6-bromomethyl)-3-methyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrazol-1-yl]benzonitrile (6.9 mg). 4-(5-(6-(Bromomethyl)-3-methyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]=[O:19])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][Mg+].[Br-]>C1COCC1.O>[CH2:1]([O:8][C@@H:9]1[C@@H:17]([CH:18]([OH:19])[CH3:23])[O:16][C@H:15]2[C@H:11]([N:12]=[C:13]([N:20]([CH3:22])[CH3:21])[S:14]2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C1=N[C@@H]2C[C@H](OCc3ccccc3)[C@@H](C=O)O[C@@H]2S1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)[C@H]1O[C@@H]2SC(N(C)C)=N[C@@H]2C[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.9 %

Procedure:
To a solution of (3aR,5S,6S,7aR)-6-(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-5-carbaldehyde (1.04 g) in anhydrous THF (30 mL) at 0° C. was added a solution of MeMgBr (1.4 M in 1:3 THF/toluene, 5.80 mL, 8.13 mmol) dropwise. The reaction was then stirred at room temperature for 20 h. The mixture was diluted with H2O (50 mL), extracted with EtOAc (2×40 mL). The combined extract was dried over anhydrous Na2SO4. The solvents were evaporated under reduced pressure, and the residue was purified by silica gel column chromatography, eluted with 2%-5% 2 M NH3 MeOH solution in DCM to give 1-((3aR,5R,6S,7aR)-6-(benzyloxy)-2-(dimethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)ethanol (0.840 g, 77%) as a pale yellow foam. MS m/z 337.2 (M+1, 100%); 1H NMR (400 MHz, CDCl3) shown this was a mixture of two diastereomers with a ratio ˜60:40.