Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][NH2:10]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CN
Reactant: Clc1ccnc(Cl)n1
Solvent: ClCCl
Product: CNc1ccnc(Cl)n1
Temperature: 5 °C
Reaction time: 12 h
Yield: 88.6 %

Procedure:
To a solution of 17.0 g (0.11 mole) of 2,4-dichloropyrimidine in 150 ml of dichloromethane was added methylamine (0.25 mole, 20 ml of 40% methanol solution) at such a rate that the temperature of the solution was maintained at 5° C. After the addition, the solution was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure, and extracted with dichloromethane. The dichloromethane layer was dried over an anhydrous sodium sulfate, and concentrated under reduced pressure to give 14.0 g (purity 80%) of 2-chloro-4-methylaminopyrimidine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5](Br)=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[H][H]>[Pd].C(OCC)(=O)C.CO>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[CH:5]=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCNc1nc(N)nc(Cl)c1Br
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCNc1ccnc(N)n1

Procedure:
A solution of tert-butyl 2-(2-amino-5-bromo-6-chloropyrimidin-4-ylamino)ethylcarbamate (Example 1A, 18.60 g, 0.0507 mole), triethylamine (135.0 mL, 0.9686 mole), and 10% palladium on charcoal (7.40 g) in 1:1 ethyl acetate/methanol (500 mL) was treated with hydrogen (60 psi) for two days. Insoluble material was removed by filtration through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and dilute aqueous sodium hydroxide. The organic layer was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give tert-butyl 2-(2-aminopyrimidin-4-ylamino)ethylcarbamate as a white, amorphous solid (12.7 g, 98.8% yield). 1H NMR (300 MHz, CD3Cl3) δ ppm 1.44 (s, 9H), 3.27-3.37 (m, 2H), 3.37-3.47 (m, 2H), 5.00 (sbr, 2H), 5.28 (sbr, 1H), 5.52 (sbr, 1H), 5.78 (d, J=6 Hz, 1H), 7.76 (d, J=6 Hz, 1H). MS (DCl—NH3) m/z=254 (M+H)+.
Reaction SMILES: [CH:1]12[CH:9]([CH2:10][C:11](Cl)=[O:12])[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.[NH2:14][N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]1[CH:26]([CH3:28])[CH3:27]>>[CH:1]12[CH:9]([CH2:10][C:11]([NH:14][N:15]3[C:24](=[O:25])[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=[C:16]3[CH:26]([CH3:28])[CH3:27])=[O:12])[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2
Reactant: O=C(Cl)CC1C2CCCC1CCC2
Reactant: CC(C)c1nc2ccccc2c(=O)n1N
Product: CC(C)c1nc2ccccc2c(=O)n1NC(=O)CC1C2CCCC1CCC2

Procedure:
The product from Example 56D and 3-amino-2-isopropylquinazolin-4(3H)-one (Aldrich) were processed using the method described in Example 42C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.20 (d, J=6.7 Hz, 3 H) 1.24 (d, J=6.7 Hz, 3 H) 1.43-1.59 (m, 4 H) 1.65-1.95 (m, 10 H) 1.97-2.08 (m, 1 H) 2.51-2.56 (m, 2 H) 3.02-3.14 (m, 1 H) 7.53 (t, J=6.9 Hz, 1 H) 7.67 (d, J=8.3 Hz, 1 H) 7.79-7.89 (m, 1 H) 8.11 (dd, J=7.9, 1.5 Hz, 1 H) 10.94 (s, 1 H); MS (ESI+) m/z 368 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][C@@H:4]([OH:7])[C@H:3]1[OH:8].[Cl:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[C:13](Cl)=[CH:12][C:11]=1[Cl:20].C(N(CC)CC)C>C(O)(C)(C)C>[Cl:9][C:10]1[C:11]([Cl:20])=[CH:12][C:13]([NH:1][C@@H:2]2[CH2:6][CH2:5][C@@H:4]([OH:7])[C@H:3]2[OH:8])=[C:14]([N+:16]([O-:18])=[O:17])[CH:15]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Reactant: N[C@@H]1CC[C@@H](O)[C@H]1O
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1N[C@@H]1CC[C@@H](O)[C@H]1O

Procedure:
(±)-(1R*,2S*,3R*)-3-Amino-1,2-cyclopentanediol (7.10 g, 50.0 mmol), 1,2,4-trichloro-5-nitrobenzene (11.67 g, 50.0 mmol as 97%, Aldrich), triethylamine (10 mL) and t-butanol (50 mL) were refluxed under nitrogen for 7 hours. Volatiles were removed in vacuo and the black residue chromatographed on silica gel. Title compound was eluted with methanol:chloroform/1:24 as an orange solid (6.45 g, 42%). Crystallization of such a sample from ethanol-water gave title compound as yellow needles, m.p. 137°-140° C.; 1H-NMR (DMSO-d6) δ: 8.26 and 7.49 (both s, 1 each, 2 aromatic CH), 8.06 (d, J=7.0 Hz, 1, NH), 5.04 (d, J=6.1 Hz, 1, OH), 4.65 (d, J=4.1 Hz, 1, OH), 4.0-3.7 (m, 3,2 OCH and NCH), 2.2-2.1, 2.0-1.8, 1.7-1.3 (all m, 4, 4 CH).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:27])=[O:26])[C:6]2[CH:7]=[C:8]([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15]([O:17]CC)=[O:16])=[CH:11]3)[CH2:3][CH2:2]1.C(O)C.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH2:4][N:5]([S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:27])=[O:26])[C:6]2[CH:7]=[C:8]([O:20][CH2:21][CH2:22][O:23][CH3:24])[CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15]([OH:17])=[O:16])=[CH:11]3)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc2cc(OCCOC)cc(N(CC3CC3)S(=O)(=O)c3ccccn3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCOc1cc(N(CC2CC2)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 103 %

Procedure:
To a mixture of ethyl 7-[(cyclopropylmethyl)(pyridin-2-ylsulfonyl)amino]-5-(2-methoxyethoxy)-1H-indole-2-carboxylate (650 mg), ethanol (10 mL) and tetrahydrofuran (10 mL) was added 2N aqueous sodium hydroxide solution (3.43 mL) at room temperature, and the mixture was stirred at 50° C. for 5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and 1N aqueous hydrochloric acid. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated under reduced pressure to give the title compound (630 mg, yield 99%) as a colorless amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]2[C:13](O)=[O:14])=[O:10])=[CH:5][CH:4]=1.ClC(OCC)=O.[BH4-].[Na+].Cl>O1CCCC1.C(N(CC)CC)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([N:11]2[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]2[CH2:13][OH:14])=[O:10])=[CH:20][CH:21]=1
Reactant: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COC(=O)N2C[C@H](O)C[C@H]2CO)cc1
Reaction time: 0.33 h

Procedure:
To a solution of trans-1-p-methoxybenzyloxycarbonyl-4-hydroxyproline (105.5 g: 357.5 mmole) in tetrahydrofuran (1 liter), triethylamine (54.8 ml) is added. After adding ethyl chloroformate (35.9 ml) dropwise at -30° C., the mixture is stirred for 20 minutes. To the reaction mixture, a solution of sodium borohydride (33.25 g) in water (120 ml) is added dropwise at a temperature in the range of -15° to -5° C., neutralized with conc. hydrochloric acid, and concentrated in vacuo. To the residue, ethyl acetate is added, washed with brine, dried over magnesium sulfate, and concentrated in vacuo to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-hydroxy-pyrrolidine-2-methanol.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([O:19]C)=[O:18])[N:12]=2)=[C:7]([CH3:21])[C:6]=1[CH:22]1[C:35]2[C:34](=[O:36])[CH2:33][C:32]([CH3:38])([CH3:37])[CH2:31][C:30]=2[O:29][C:28]2[CH2:27][C:26]([CH3:40])([CH3:39])[CH2:25][C:24](=[O:41])[C:23]1=2.ClCCl.CCCCCC>C1COCC1.CO>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([OH:19])=[O:18])[N:12]=2)=[C:7]([CH3:21])[C:6]=1[CH:22]1[C:35]2[C:34](=[O:36])[CH2:33][C:32]([CH3:37])([CH3:38])[CH2:31][C:30]=2[O:29][C:28]2[CH2:27][C:26]([CH3:40])([CH3:39])[CH2:25][C:24](=[O:41])[C:23]1=2
Reactant: COC(=O)c1nccc(-c2ccc(OC)c(C3C4=C(CC(C)(C)CC4=O)OC4=C3C(=O)CC(C)(C)C4)c2C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(-c2ccnc(C(=O)O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
A 1 M aqueous solution of sodium hydroxide (466 μL, 0.466 mol) was added to a solution of the methyl 4-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]pyrimidine-2-carboxylate obtained in Example 75-3 (206 mg, 0.388 mmol) in THF (0.5 mL) and methanol (0.5 mL) at room temperature. The mixture thus obtained was stirred at the same temperature as above for 15 minutes. Thereafter, the solvent was distilled away under reduced pressure, and water was then added to the residue. The mixed solution was washed with diethyl ether, and 1 M-hydrochloric acid was then added to the water layer thus obtained, so that it was converted to an acidic aqueous solution. The resulting solution was extracted with ethyl acetate twice. The organic layer thus obtained was washed with brine, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then solidified with dichloromethane and hexane to obtain the title compound (158 mg, yield: 79%).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19](Cl)[CH:20]=[CH:21][CH3:22].[I-].[Li+].C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH3:11][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH2:19]/[CH:20]=[CH:21]/[CH3:22])[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:18]
Reactant: CC(C(=O)OCc1ccccc1)c1ccccc1
Reactant: CC=CCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C=C/CC(C)(C(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
A solution of 2-phenyl-propionic acid benzyl ester (2.0 g, 8.32 mmol), crotyl chloride (1.02 mL, 9.99 mmol), and lithium iodide (1 g) in tetrahydrofuran (15 mL) at 0° C. was treated dropwise with the lithium hexamethyldisilazide (9.99 mL, IM in tetrahydrofuran, 9.99 mmol). The reaction was allowed to warm to 25° C. and stirred for 18 hours. The solvent was removed in vacuo and the residue was partitioned between water and ethyl acetate. The aqueous phase was extracted three times with ethyl acetate and the ethyl acetate layers were combined, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane, then 10% ethyl acetate in hexane, and 20% ethyl acetate in hexane to give the title compound (2.43 g, 99%). 1H NMR (300 MHz, CDCl3): δ ppm 1.55 (m, 6 H) 2.68 (m, 2 H) 5.10 (m, 2 H) 5.21 (m, 1 H) 5.45 (m, 1 H) 7.26 (m, 10 H). MS (ESI+) m/z 312 (M+NH4)+.
Reaction SMILES: [C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:28])[CH:19]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[CH3:20])=[CH:13][CH:12]=2)[CH2:7]1)(=[O:3])[CH3:2].Br[CH2:30][CH:31]1[CH2:33][CH2:32]1>>[C:1]([CH2:4][NH:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:28])[CH:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[CH:23][CH:22]=3)[CH3:20])=[CH:15][CH:16]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)CNC1CCN(c2ccc(NC(=O)C(C)c3ccc(O)cc3)cc2)C1
Reactant: BrCC1CC1
Product: CC(=O)CNC1CCN(c2ccc(NC(=O)C(C)c3ccc(OCC4CC4)cc3)cc2)C1

Procedure:
N-{4-[3-(Acetylmethylamino)pyrrolidin-1-yl]phenyl}-2-(4-hydroxyphenyl)propionamide was reacted with bromomethylcyclopropane by method H. This resulted in the product with the molecular weight of 435.57 (C26H33N3O3); MS(ESI): 436 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[C:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2[NH:27][N:26]=[N:25][N:24]=2)[CH:20]=[CH:21][CH:22]=1>>[Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]4[NH:27][N:26]=[N:25][N:24]=4)[CH:18]=3)(=[O:13])=[O:12])=[C:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2c(Cl)cccc12
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3nnn[nH]3)c2)sc2c(Cl)cccc12
Yield: 49.8 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from 7-chloro-3-methylbenzothiophene-2-sulfonyl chloride (Intermediate 6) (30 mg, 0.10 mmol) and 5-(3-amino-phenyl)tetrazole (34 mg, 0.21 mmol) giving 20.2 mg (50%) of the title compound. MS (ESI+) calcd for C16H12ClN5O2S2 405.012094, found 405.012294.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:15])[CH3:14].[Si:24]([N:31]1[C@H:34]([CH2:35][CH:36]=[O:37])[C@@H:33]([C@H:38]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH3:39])[C:32]1=[O:48])([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]>O1CCCC1>[Si:24]([N:31]1[C@H:34]([CH2:35][CH:36]([OH:37])[CH2:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@@H:33]([C@H:38]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43])[CH3:39])[C:32]1=[O:48])([C:27]([CH3:30])([CH3:28])[CH3:29])([CH3:26])[CH3:25]
Reactant: CC(=O)OCc1ccccc1
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N([Si](C)(C)C(C)(C)C)[C@@H]1CC(O)CC(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
n-Butyllithium (1.81 mmol) is added by syringe to a solution of diisopropylamine (1.81 mmol) in 9 ml of freshly distilled tetrahydrofuran at -78° C. The resulting solution is stirred for 15 min at -78° C. Benzyl acetate (1.81 mmol) is then added dropwise by syringe and the resulting solution is stirred at -78° C. for 20 min. A solution of (3S, 4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(2-oxoethyl)azetidin-2-one (1.64 mmol) in 3 ml of anhydrous tetrahydrofuran is added slowly by syringe. The reaction mixture is stirred at -78° C. an additional 15 min and then quenched by addition of saturated aqueous ammonium chloride solution. Ethyl acetate (50 ml) is added and the organic phase is separated, washed with water (2×10 ml) and brine and dried over magnesium sulfate. Removal of solvents in vacuo gives a white solid which is chromatographed on a short silica gel column (40% ether in petroleum ether) to yield (3S,4R)-1-(t-butyldimethylsilyl)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-(3-benzyloxycarbonyl-2-hydroxypropyl)azetidin-2-one n.m.r. (CDCl3) δ7.32(s,5), δ5,1(s,2), δ4.0(m,3), δ2,4-3,8(m,4),δ2.0(m,2), δ1.25(overlapping d,3), δ0.95(s,9), δ0.9(s,9), δ0.3(s,6), δ0.18(s,6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-])=O)[C:3]=1[O:15][CH3:16].Cl>CO.[Pd]>[Cl:1][C:2]1[C:3]([O:15][CH3:16])=[C:4]([CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[NH2:12]
Reactant: COc1c(Cl)cc(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1c(N)cc(C(F)(F)F)cc1Cl
Yield: 101.1 %

Procedure:
1-Chloro-2-methoxy-3-nitro-5-trifluoromethylbenzene (3.46 g, 13.5 mmol) was dissolved in MeOH (74 mL). Hydrochloric acid (2M, 13 mL, 26 mmol) and Pd/C (10%, 0.44 g) was added. Hydrogenation at atmospheric pressure and at room temperature for 1 h 30 min, filtration and evaporation of the solvent gave a crude product. Purification by flash chromatography (SiO2, CH2Cl2 -hexarne 1:2 followed by EtOAc-NH3 100:0.1) yielded the title compound (3.08 g) as an oil. 1H NMR (CDCl3): 7.00 (J 1.8 Hz, 1 H), 6.85 (d, J=1.95 Hz, 1 H), 4.11 (br s, 2 H), 3.87 (s, 3 H). MS (EI, 70 eV): m/z (rel. int.) 227/225 (M+, 17/58).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C(O[C:14](=O)[CH:15]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.ClCCl.C(O)C.C(O)(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([CH2:14][NH:32][CH2:31][C:30]1[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=1)[CH2:21][CH:22]([CH3:23])[CH3:24])[CH3:20]
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)C(CC(C)C)C(=O)OCC
Agent: CC(C)C[Al+]CC(C)C
Agent: [BH3-]C#N
Agent: [H-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(CNCc1ccc(F)cc1)CC(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.7 %

Procedure:
Diisobutylaluminum hydride (35.2 mL of a 1.0 M solution in toluene, 35.2 mmol) was added over 5 min to a solution of 2-isobutyl-malonic acid diethyl ester (3.81 g, 17.6 mmol) in dichloromethane (33 mL) at −78° C. The reaction mixture was stirred at that temperature for 4 h, and then was quenched with saturated aqueous ammonium chloride (35 mL). The cold bath was removed, 1.0 M aqueous hydrochloric acid solution (90 mL) and DL-tartaric acid (4.25 g) were added sequentially, and the mixture was allowed to warm to 25° C. over 1.5 h with vigorous stirring. The biphasic mixture was then partitioned between 1.0 M aqueous hydrochloric acid solution (350 mL) and dichloromethane (350 mL). The organic layer was dried over sodium sulfate and was concentrated in vacuo to afford crude product (2.20 g, 12.8 mmol, 73%). This material was dissolved in ethanol (40 mL) at 25° C. and 4-fluorobenzylamine (1.46 mL, 12.8 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.61 g, 25.6 mmol) were added sequentially. The mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo. The residue was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The combined organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0-70% ethyl acetate in hexanes) to afford rac-2-[(4-fluoro-benzylamino)-methyl]-4-methyl-pentanoic acid ethyl ester (0.995 g, 3.54 mmol, 28%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.89 (3H, d, J=6.2 Hz), 0.91 (3H, d, J=6.0 Hz), 1.26 (3H, t, J=7.0 Hz), 1.54-1.61 (1H, m), 2.63-2.68 (2H, m), 2.83 (1H, dd, J1=10.2 Hz, J2=12.2 Hz), 3.72 (1H, d, J=13.3 Hz), 3.77 (1H, d, J=13.2 Hz), 4.13-4.18 (2H, m), 6.96-7.00 (2H, m), 7.23-7.27 (2H, m).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)=[CH:3][CH:2]=1.[C@@H:16]1([NH2:26])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1.[BH4-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][NH:26][C@@H:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][CH2:18][CH2:17]2)=[CH:3][CH:2]=1
Reactant: O=Cc1cccc(Oc2ccncc2)c1
Reactant: N[C@H]1CCCc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1cc(CN[C@H]2CCCc3ccccc32)cc(Oc2ccncc2)c1
Yield: 84.3 %

Procedure:
3-(4-Pyridinyloxy)benzaldehyde (0.85 g, 4.27 mmol), prepared according to J. Chem. Soc. Perkin Trans 2 (1987) 1867, and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine (0.63 g, 4.29 mmol) were combined in ethanol (10 mL), briefly heated and the solvent removed under reduced pressure. This process was repeated twice more. The residual oil was dissolved in ethanol (5 mL) and stirred with sodium borohydride (0.16 g, 4.23 mmol) overnight at room temperature. The reaction mixture was quenched with water (10 mL) and diluted with diethyl ether (50 mL). The diethyl ether was washed with saturated NaHCO3 solution (3×10 mL), brine (10 mL), dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to provide the title compound as a thick orange liquid (1.19 g, 85% yield).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1Cl)=[O:13])[CH2:8]2.C(N(CC)CC)C.[NH:28]1[CH:32]=[N:31][CH:30]=[N:29]1>>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([CH3:20])[C:18]=1[N:28]1[CH:32]=[N:31][CH:30]=[N:29]1)=[O:13])[CH2:8]2
Reactant: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1Cl
Reactant: c1nc[nH]n1
Solvent: CCN(CC)CC
Product: Cn1ncc(C(=O)NC2C3CC4CC(C3)CC2C4)c1-n1cncn1

Procedure:
Heating a mixture of 5-chloro-1-methyl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (Example 5, 88 mg; 0.30 mmol), triethylamine (0.22 mL; 1.56 mmol) and 1,2,4-triazole (0.21 g; 3.0 mmol) under microwave irradiation for 4 hr according to the procedure described for Example 14 provided after purification by reverse phase HPLC, 1-methyl-5-[1,2,4]triazol-1-yl-1H-pyrazole-4-carboxylic acid adamantan-2-ylamide (11 mg, 11%) as an off-white powder. ES-HRMS m/e calcd for C17H22N6O (M+H+) 327.1928, found 327.1924.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](I)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(C)(C)C.[K+].[CH2:66]1[O:75][C:74]2[CH:73]=[CH:72][C:70]([NH2:71])=[CH:69][C:68]=2[O:67]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.ClCCl>[CH2:66]1[O:75][C:74]2[CH:73]=[CH:72][C:70]([NH:71][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=3)=[CH:69][C:68]=2[O:67]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: COc1cc(I)cc(OC)c1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc(Nc2ccc3c(c2)OCO3)cc(OC)c1OC
Temperature: 100 °C

Procedure:
10 mmol of 3,4,5-trimethoxyiodobenzene, 0.4 mmol of palladium acetate, 0.4 mmol of 2,2′-bis(diphenylphosphino)-1,1′-bi naphthyl and 14 mmol of potassium tert-butanolate are added to 10 mmol of 3,4-methylenedioxyaniline dissolved in toluene. After heating for 15 minutes at 100° C., the reaction mixture is brought to ambient temperature, and then dichloromethane and water are added. The organic phase is subsequently separated off and distilled under reduced pressure. The residue is purified by chromatography on silica, using dichloromethane as eluant, to yield the expected product in the form of an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](F)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[NH2:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.O>CS(C)=O>[C:1]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([N:25]2[CH2:26][CH2:27][CH:22]([NH2:21])[CH2:23][CH2:24]2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NC1CCNCC1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)c1ccc(N2CCC(N)CC2)cc1
Temperature: 120 °C
Reaction time: 17 h

Procedure:
4-fluorobenzoic acid tert-butyl ester (19.6 g, 100 mmol) was dissolved in dimethyl sulfoxide (hereinafter referred to as DMSO) (50 ml), and potassium carbonate (20.7 g, 150 mmol) and 4-aminopiperidine (11.0 g, 110 mmol) were added thereto, followed by stirring at 120° C. for 17 hours. After the reaction mixture was cooled to room temperature, water was added to the mixture, and the precipitate was collected by filtration, thereby obtaining 4-(4-aminopiperidin-1-yl)-benzoic acid tert-butyl ester (23.3 g, 84%) as a milky-white solid.