Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[CH2:34][CH2:35][CH2:36][NH2:37]>>[CH2:5]([C@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:2]([OH:1])[CH2:3][NH:37][CH2:36][CH2:35][CH2:34][C:28]1[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=1[CH3:26])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H]1CO1
Reactant: Cc1ccc(CCCN)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccc(CCCNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)c(C)c1

Procedure:
A stirred mixture of tert-butyl (1S)-1-[(2S)-oxiranyl]-2-phenylethylcarbamate (V, 247 mg, 0.939 mmol), sodium carbonate (299 mg, 2.82 mmol), and 3-(2,4-dimethylphenyl)propylamine (VI, 628 mg, 2.82 mmol) is heated at reflux overnight. The reaction mixture is cooled to 20–25 degrees C. and concentrated under reduced pressure. Purification by flash column chromatography (silica; methylene chloride/methanol/ammonium hydroxide, 98/2/1) gives tert-butyl (1S,2R)-1-benzyl-3-{[3-(2,4-dimethylphenyl)propyl]amino}-2-hydroxypropylcarbamate (VII), NMR (300 MHz, CD3OD): δ 7.22–7.16, 3.81, 3.18, 2.77, 2.54, 2.15, 2.13, 1.89 and 1.23.
Reaction SMILES: [CH2:1]1[O:6][C:4](=[O:5])[C@H:3]([OH:7])[C@H:2]1[OH:8].[NH3:9]>CO>[O:5]=[C:4]([NH2:9])[C@@H:3]([C@H:2]([CH2:1][OH:6])[OH:8])[OH:7]
Reactant: N
Reactant: O=C1OC[C@H](O)[C@H]1O
Solvent: CO
Product: NC(=O)[C@H](O)[C@@H](O)CO
Temperature: 0 °C

Procedure:
A solution of 5.50 g (46.57 mmoles) L-threonolactone in 100 mL MeOH, previously saturated with anhydrous NH3 at 0° C., was kept at room temperature for 48 h in a pressure bottle. The solvent was evaporated in vacuo, the residual oil re-evaporated from absolute EtOH, and the resulting solid crystallized from boiling EtOH. The crystals were collected after cooling at 0° C., washed with EtOH-Et2O (1:1 parts by volume), then with Et2O, and dried at 40° C./0.005 mm Hg to give 6.023 g (95.7%) of analytically pure product L-threonamide, m.p. 105°-107° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]#[C:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[S:6][CH:7]=1.[NH:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[CH3:21][O:20][C:12]1[CH:11]=[C:10]([C:9]#[C:8][C:5]2[S:6][CH:7]=[C:3]([CH2:2][N:22]3[CH2:28][CH2:27][CH2:26][N:25]([CH2:2][C:3]4[N:4]=[C:5]([C:8]#[C:9][C:10]5[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=5)[S:6][CH:7]=4)[CH2:24][CH2:23]3)[N:4]=2)[CH:15]=[C:14]([O:16][CH3:17])[C:13]=1[O:18][CH3:19]
Reactant: C1CNCCNC1
Reactant: COc1cc(C#Cc2nc(CCl)cs2)cc(OC)c1OC
Product: COc1cc(C#Cc2nc(CN3CCCN(Cc4csc(C#Cc5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenylethynyl)-thiazole (126 mg) and homopiperazine (19 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([CH3:10])([CH3:9])[C:5](OC)=[O:6].[C:11](#[N:13])[CH3:12].Cl>C1COCC1.O>[F:3][C:4]([CH3:10])([CH3:9])[C:5](=[O:6])[CH2:12][C:11]#[N:13]
Reactant: CC#N
Reactant: COC(=O)C(C)(C)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(F)C(=O)CC#N
Temperature: 70 °C
Yield: 69.7 %

Procedure:
To a stirred suspension of 60% NaH/mineral oil (12.48 g, 0.31 mol) in dry THF at 75° C. was added dropwise methyl 2-fluoro-2-methylpropanoate (24 g, 0.2 mol) in dry acetonitrile (16 mL, 0.31 mol) over the course of 45 min. The resulting pale yellow suspension was heated at 70° C. overnight, whereupon analysis by TLC indicated a single new product. After cooling to rt, the mixture was poured into water, acidified to pH˜2 with 2N HCl, and extracted with diethyl ether (1 L). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-30% EtOAc in petroleum ether to afford 4-fluoro-4-methyl-3-oxopentanenitrile as a colorless oil (18 g, 72% yield). LC-MS (ESI) m/z 128 (M−H)+.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[CH:32]1([NH:36][C:3](=[O:5])[CH:2]([OH:1])[C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:16]=[C:15]([C:17]4[O:21][N:20]=[C:19]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:18]=4[C:28]([F:30])([F:31])[F:29])[O:14][N:13]=3)=[CH:10][CH:11]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NC1CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NC1CCC1)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 23.9 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 20 mg, 0.046 mmol), cyclobutanamine (4.95 mg, 0.070 mmol), HATU (22.92 mg, 0.060 mmol), and 4-methylmorpholine (18.76 mg, 0.185 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 12 min, 20 mL/min, 220 nM, product retention=14.17 min) to provide (R/S)-N-cyclobutyl-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (7 mg, 0.011 mmol, 23.93% yield): LCMS=485.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.12-8.23 (2 H, m), 7.53-7.73 (7 H, m), 5.09 (1 H, s), 4.15-4.42 (1 H, m), 2.28 (2 H, dddd, J=10.07, 4.90, 4.62, 2.86 Hz), 1.98-2.13 (2 H, m), 1.70-1.79 (2 H, m); HPLC peak RT=10.4 min (Method A).
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C(O)(=O)C.C([BH3-])#N.[Na+].[CH2:14]([O:16][C:17](=[O:27])[C:18]([CH:25]=O)([CH3:24])[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH3:15]>C(O)C>[CH2:14]([O:16][C:17](=[O:27])[C:18]([CH2:24][NH:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)([CH3:25])[CH2:19][CH2:20][CH:21]([CH3:22])[CH3:23])[CH3:15]
Reactant: CCOC(=O)C(C)(C=O)CCC(C)C
Reactant: NC1CCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(CCC(C)C)CNC1CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.8 %

Procedure:
Cyclobutylamine (1.23 mL, 14.4 mmol), glacial acetic acid (1.5 mL), and sodium cyanoborohydride (1.81 g, 28.8 mmol) were added sequentially to a solution of crude rac-2-formyl-2,5-dimethyl-hexanoic acid ethyl ester (prepared as described in Example 19c; 2.88 g, 14.4 mmol) in ethanol (40 mL) at 25° C. 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 (self-packed glass column, gradient elution: 20-30% ethyl acetate in hexanes) to afford rac-2-cyclobutylaminomethyl-2,5-dimethyl-hexanoic acid ethyl ester (1.76 g, 6.89 mmol, 48%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ: 0.87 (3H, d, J=3.0 Hz), 0.88 (3H, d, J=4.0 Hz), 0.99-1.07 (1H, m), 1.17 (3H, s), 1.26 (3H, t, J=7.5 Hz), 1.42-1.68 (4H, m), 2.43 (1H, d, J=11.7 Hz), 2.73 (1H, d, J=11.7 Hz), 3.15-3.23 (1H, m), 4.13 (2H, q, J=7.0 Hz).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:24]([O:27][C:28]1[CH:29]=[C:30]([CH:36]=[CH:37][CH:38]=1)[CH:31]=[CH:32][C:33](O)=[O:34])(=[O:26])[CH3:25].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:24]([O:27][C:28]1[CH:29]=[C:30]([CH:31]=[CH:32][C:33]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=2)=[O:34])[CH:36]=[CH:37][CH:38]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Oc1cccc(C=CC(=O)O)c1
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1cccc(OC(C)=O)c1
Yield: 95.8 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.0 g), triethylamine (1.4 mL), 3-acetoxycinnamic acid (2.0 g), WSC.HCl (1.9 g), and methylene chloride (60 mL), to give the captioned compound (3.1 g, 96%) as an oily product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:27]([CH:28]=1)[C:8]1[N:9]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[C:10](=[O:17])[C:11]3[C:16]([C:7]=1[N:6]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3.[C:29]([O:32][CH2:33][CH2:34]Br)(=[O:31])[CH3:30].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:9]2[C:8]3[N:27]4[CH:28]=[C:2]([O:1][CH2:34][CH2:33][O:32][C:29](=[O:31])[CH3:30])[CH:3]=[CH:4][C:5]4=[N:6][C:7]=3[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:17])=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: CC(=O)OCCBr
Reactant: O=c1c2ccccc2c2nc3ccc(O)cn3c2n1-c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCOc1ccc2nc3c4ccccc4c(=O)n(-c4ccc([N+](=O)[O-])cc4)c3n2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 66.3 %

Procedure:
A mixture of compound 10 (1.0 equiv., 0.806 mmol, 0.300 g), 2-bromoethyl acetate (2.0 equiv., 1.611 mmol, 0.269 g) and K2CO3 (3.0 equiv., 2.417 mmol, 0.334 g) in dry DMF (5 ml) was stirred at 60° C. for 4 h. Water was added to the reaction mixture and the aqueous layer was extracted with dichloromethane. The combined organic layers were dried with MgSO4 and concentrated in vacuo. Purification by column chromatography (dichloromethane/methanol 97.2:2.5) afforded 6-(4-nitrophenyl)-9-[2-[(1-oxoethyl)oxy]-ethoxy]-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (73) (0.245 g, yield=66%, purity (LC)=97%).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][CH:21]=[CH:22][Sn](CCCC)(CCCC)CCCC)[CH3:19]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][CH:11]=[N:12][C:13]=2[CH:19]=[CH:18][O:20][CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: Ic1ncnc2c1ncn2Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCOC=Cc1ncnc2c1ncn2Cc1ccccc1
Temperature: 100 °C

Procedure:
A mixture of 9-benzyl-6-iodopurine (7) (1.00 g, 2.8 mmol), bis(triphenylphosphine)palladium(II) chloride (0.208 g, 0.02 mmol) and ethoxyvinyl(tributyl)tin (2.07 g, 3.8 mmol) in dry DMF (4 mL) was heated under N2 at 100° C. for 6 h. TLC indicated completion of reaction. DMF was distilled off under reduced pressure and the resulting residue was redissolved in EtOAc (50 mL) and filtered through a pad of celite. The solvent (EtOAc) was distilled off and the residue obtained purified by flash chromatography. Yield 0.393 g, (47%). Mp 114-115° C. 1H NMR (CDCl3): δ 1.55 (t, 3H, CH3, J=7.5 Hz), 4.13 (q, 2H, CH2, J=13.7 Hz), 4.99 (d, 1H, CH, J=3 Hz), 5.48 (s, 2H, benzylic CH2), 6.16 (d, 1H, CH, J=3 Hz), 7.30-7.38 (m, 5H, Ar—H), 8.09 (s, 1H, purine C8—H), 9.07 (s, 1H, purine C2—H). 3C NMR (CDCl3): δ 14.3, 47.3, 63.7, 94.7, 127.8, 127.8, 128.6, 129.1, 129.2, 130.3, 135.0, 144.4, 152.1, 152.3, 152.4, 155.4.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]([NH2:21])[C:18]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:21][C:19]1[C:18]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH3:30])=[O:31])=[CH:17][N:16]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:20]=1
Reactant: COc1ccccc1C(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc1N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1C(=O)c1cnc(NC2CCNCC2)nc1N
Temperature: 0 °C
Reaction time: 1 h
Yield: 285.8 %

Procedure:
4-[4-Amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid tert-butyl ester (1.96 g, Example 10) was dissolved in dichloromethane (25 mL), cooled to 0° C. and treated with trifluoroacetic acid (12.5 mL). After stirring 1 hour at 0° C., the reaction mixture was concentrated in vacuo to give 4.29 g of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone as the trifluoroacetic acid salt. A portion of the crude product was purified on HPLC and then neutralized with sodium carbonate, washed with brine and dried to give [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(2-methoxy-phenyl)-methanone free base. HRMS, observed: 328.1771; Calcd for (M+H)+: 328.1768.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)=[CH:10]2)=[CH:5][C:4]([C:23]([OH:25])=O)=[CH:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.C([O:55][C:56](=[O:70])[C@@H:57]([NH:60][S:61]([C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)(=[O:63])=[O:62])[CH2:58][NH2:59])(C)(C)C.N1C(C)=CC(C)=CC=1C>>[C:64]1([S:61]([NH:60][C@@H:57]([CH2:58][NH:59][C:23]([C:4]2[CH:5]=[C:6]3[N:11]([C:2](=[O:1])[CH:3]=2)[CH:10]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]2[N:18]=[CH:19][CH:20]=[CH:21][N:22]=2)[CH:8]=[CH:7]3)=[O:25])[C:56]([OH:70])=[O:55])(=[O:62])=[O:63])[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cc(=O)n2cc(OCCCNc3ncccn3)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1cc(C)nc(C)c1
Product: O=C(NC[C@H](NS(=O)(=O)c1ccccc1)C(=O)O)c1cc(=O)n2cc(OCCCNc3ncccn3)ccc2c1
Reaction time: 0.75 h
Yield: 90.9 %

Procedure:
To a mixture of 4-oxo-7-[3-(pyrimidin-2-ylamino)-propoxy]-4H-quinolizine-2-carboxylic acid (6.9 mg, 0.020 mmol), was added HATU (9.9 mg, 0.026 mmol), (S)-3-amino-2-benzenesulfonylamino-propionic acid tert-butyl ester hydrochloride (8.1 mg, 0.024 mmol) and collidine (19 μl, 0.140 mmol). The mixture was stirred for 45 minutes, concentrated and flash chromatographed (0-5% methanol in dichiloromethane) to give 10.3 mg (82% yield) of desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=O)[CH2:6][C:7]([C:9]12[CH2:18][CH:13]3[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]3)[CH2:10]1)[CH2:16]2)=O)[CH3:2].O.[NH2:22][NH2:23]>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[NH:22][N:23]=[C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)[CH:6]=1)=[O:20])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)C12CC3CC(CC(C3)C1)C2
Reactant: NN
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cc(C23CC4CC(CC(C4)C2)C3)n[nH]1
Yield: 91.1 %

Procedure:
Preparation C13, Step 2: 4-Adamantan-1-yl-2,4-dioxo-butyric acid ethyl ester 7.80 g, 28 mmol, 1 eq.), hydrazine hydrate (1.36 mL, 28 mmol, 1 eq.) and ethanol (20 mL) were refluxed until reaction was complete by LCMS. Stripped off the ethanol, and extracted (3×) with ethyl acetate (50 mL). The organic layers were combined, dried and stripped to give 7.00 g of 5-adamantan-1-yl-2H-pyrazole-3-carboxylic acid ethyl ester as a yellow solid. MS found: (M+H)+=275.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(O)C>[CH2:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]([CH3:18])([CH3:17])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CC(OCc2ccccc2)CC(C)(C)N1
Reactant: CCOC(=O)CBr
Solvent: CCO
Product: CCOC(=O)CN1C(C)(C)CC(OCc2ccccc2)CC1(C)C

Procedure:
A mixture of 4-benzyloxy-2,2,6,6,-tetramethylpiperidine and 1.67 parts of ethyl α-bromoacetate in 30 parts of ethyl alcohol was heated under reflux conditions for 115 hours. The ethyl alcohol solvent was removed by distillation under reduced pressure and the residue fractionally distilled to give 4-benzyloxy-1-ethoxycarbonylmethyl-2,2,6,6-tetramethylpiperidine having a boiling point of 145°-6° C. at 0.2 m.m. of Hg. and the following elemental analysis by weight:
Reaction SMILES: C[N:2]1CCOCC1.[C:8]1([CH2:14][S:15](Cl)(=[O:17])=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(#N)C>[CH2:14]([S:15]([NH2:2])(=[O:17])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCOCC1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CC#N
Product: NS(=O)(=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 118.1 %

Procedure:
To a solution of 5 (7.54 g, 0.0298 mole; see Example 5) and 4-methylmorpholine (9.04 g, 0.0894 mole, 9.83 mL) in 300 mL of anhydrous acetonitrile at 0° C. under N2 was added α-toluene-sulfonyl chloride (11.36 g, 0.0596 mole) in one portion. The solution was stirred at 0° C. for 1 hour and allowed to warm to and stir at ambient temperature for 19 hours. The solution was filtered and evaporated. The crude residue was purified by flash chromatography on silica gel using a hexane, CH2Cl2 : 4,1 to CH2C12 gradient system and afforded 12.05 g (99% yield) of product 6 as waxy reddish solid, mp 62-63° C. TLC (silica; CH2Cl2), Rf=0.45.
Reaction SMILES: [CH2:1]([C@H:5]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>N1C=CC=CC=1>[CH2:1]([C@H:5]1[CH2:9][CH2:8][CH:7]([O:10][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCC[C@H]1CCC(O)C1
Solvent: c1ccncc1
Product: CCCC[C@H]1CCC(OS(=O)(=O)c2ccc(C)cc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97 %

Procedure:
To a solution cooled with ice, of 94 mg of (1RS,3S)-3-butylcyclopentan-1-ol (prepared in Reference Example 11) in 2 ml of pyridine, 260 mg of p-toluenesulphonyl chloride was added, and the mixture was stirred for 30 min. at the same temperature and for 5 hrs at room temperature. The reaction solution was poured into ice-water. The mixture was extracted with a mixture of pentane and diethyl ether (1:1). The extract was washed with water, dried over magnesium sulphate, and concentrated under ambient pressure at 50° C. to give 190 mg of the title compound having the following physical characteristic.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[C:7]1([CH2:19]O)[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]3[O:16][CH:17]=[CH:18][C:12]=3[C:11]=12>ClCCl.C(=O)([O-])O.[Na+]>[C:7]1([CH2:19][C:5]#[N:6])[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]3[O:16][CH:17]=[CH:18][C:12]=3[C:11]=12
Reactant: OCc1cnn2ccc3occc3c12
Reactant: C[Si](C)(C)C#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: N#CCc1cnn2ccc3occc3c12
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
To a solution of boron trifluoride diethyl ether complex (200 μL, 1.58 mmol) and trimethylsilyl cyanide (280 μL, 2.10 mmol) in dichloromethane (5 mL) was added a solution of furo[3,2-c]pyrazolo[1,5-a]pyridin-1-ylmethanol (100 mg, 0.531 mmol) in dichloromethane (5 mL) under ice-cooling and an argon atmosphere, and the mixture was stirred for 30 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→30/70) to give the title compound (57.1 mg, yield 55%).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[C:20]1[C:21]([NH2:31])=[N:22][CH:23]=[C:24]([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[C:20]1[C:21]([NH2:31])=[N:22][CH:23]=[C:24]([C:26]2[CH:30]=[N:29][N:28]([CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)[CH:27]=2)[CH:25]=1
Reactant: Nc1ncc(-c2cn[nH]c2)cc1-c1nc2ccccc2o1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ncc(-c2cnn(CCN3CCOCC3)c2)cc1-c1nc2ccccc2o1
Temperature: 120 °C
Reaction time: 7 h

Procedure:
4-(2-Chloroethyl)morpholine hydrochloride (101 mg) was added to a stirred solution 3-(1,3-benzoxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine (150 mg, 0.54 mol) and potassium carbonate (164 mg, 1.19 mol) dissolved in DMA (1 ml) over a period of 5 minutes. The resulting solution was stirred at 120° C. for 7 hours. The mixture was filtered. The reaction mixture was purified by preparative HPLC using a Waters X-Terra reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 1% acetic acid) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 3-(1,3-benzoxazol-2-yl)-5-[1-(2-morpholinoethyl)pyrazol-4-yl]pyridin-2-amine (134 mg. NMR Spectrum: (CDCl3) 2.27-2.58 (m, 4H), 2.88 (t, 2H), 3.68-3.77 (m, 4H), 4.30 (t, 2H), 6.90 (bs, 2H), 7.34-7.41 (m, 2H), 7.58-7.63 (m, 1H), 7.73 (s, 1H), 7.74-7.77 (m, 1H), 7.79 (s, 1H), 8.38 (d, 1H), 8.39 (d, 1H); Mass spectrum: M+H+ 391.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>CN(C=O)C>[CH3:9][C:10]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([Cl:1])[C:11]=1[NH2:12]
Reactant: Cc1cccc(N)c1C
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)c(N)c1C
Reaction time: 1 h
Yield: 98 %

Procedure:
used in the preparation of 389 was prepared as follows: N-Chlorosuccinimide (1.00 g; 8.2 mmol) was added to a solution of 2,3-dimethylaniline (1 ml; 8.2 mmol) in 20 ml of DMF in the dark. After stirring 1 hr. in the dark, the reaction mixture was partitioned between EtOAc (100 ml) and water (100 ml). The organic layer was washed with 1N NaOH (100 ml), water (100 ml) and brine (50 ml). Drying (MgSO4) and concentration afforded 1.25 g (99%) of 2,3-dimethyl-6-chloroaniline as a deep red liquid.
Reaction SMILES: [Na].[CH2:2]([C:9]([CH3:11])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12](O)(=O)[CH3:13]>CO>[C:3]1([CH:2]([C:9](=[O:10])[CH2:11][CH2:9][CH2:2][CH2:3][CH2:4][CH2:12][CH3:13])[CH2:5][CH2:6][CH3:7])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)O
Reactant: CC(=O)Cc1ccccc1
Agent: [Na]
Solvent: CO
Product: CCCCCCCC(=O)C(CCC)c1ccccc1
Temperature: 0 °C
Reaction time: 48 h
Yield: 60 %

Procedure:
To a solution prepared from 3 g sodium metal in 100 ml absolute methanol there was added 45 g methyl benzyl ketone. The resulting solution was refluxed for 30 minutes, cooled to 0° C. and 39 g 2-methylene-3-quinuolidinone was added. The solution was stirred at ambient temperature during 48 hours, netralized by the addition of 3 ml acetic acid and the solvents were removed under reduced pressure. There was obtained a crude oil which was extracted with chloroform. After evaporation of the solvent there was obtained 52 g (a yield of 60%) of the desired product, M.P. from acetone, 125.7° C. Treatment with hydrochloric acid gave the corresponding hydrochloride salt, M.P. above 300° C. (dec.).