Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][N:32]3[CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[C:24](F)=[N:25][CH:26]=1>C1COCC1.C(Cl)Cl.[Cl-].[Na+].O>[Cl:20][C:21]1[CH:22]=[C:23]([C:28]2[N:36]=[C:35]([CH3:37])[N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][N:32]3[CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][O:39]2)[C:24]([NH:9][C:6]2[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:25][CH:26]=1
Reactant: Cc1nc(-c2cc(Cl)cnc2F)c2ncn(C3CCCCO3)c2n1
Reactant: COc1ccc(N)cn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(Cl)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reaction time: 0.33 h
Yield: 90.8 %

Procedure:
A solution of 6-methoxypyridin-3-amine (0.357 g, 2.88 mmol) (Source: Aldrich) in THF (10 mL) was treated with lithium bis(trimethylsilyl)amide (5.03 mL, 5.03 mmol) (Source: Aldrich) and the mixture was stirred under an inert atmosphere for 20 minutes. Then 6-(5-chloro-2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (0.500 g, 1.438 mmol) was added to the mixture and the mixture was stirred overnight. The reaction mixture was diluted with DCM and brine solution. The organic layer was collected by extracting the aqueous layer with DCM (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The crude was purified by ISCO Silica-Gel Chromatography, Teledyne ISCO, Lincoln, Nebr., (120 gram column), using a gradient of 10-60% EtOAc/DCM over 37 minutes. The fractions with desired material were combined and concentrated to give 5-chloro-N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (0.590 g, 1.306 mmol, 91% yield) as a yellow solid. m/z (ESI, +ve) 452 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 9.76 (s, 1H); 8.40 (s, 1H); 8.23 (s, 1H); 8.16 (s, 2H); 7.19 (s, 1H); 6.75 (d, J=8.80 Hz, 1H); 5.80 (d, 1H); 4.14 (d, 1H); 3.91 (s, 4H); 3.76 (t, 1H); 2.83 (s, 3H); 1.46-2.25 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:24][NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32](C)=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:9][C:10]([NH:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1.[OH-:36].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:24][NH:25][S:26]([C:29]2[CH:34]=[CH:33][C:32]([O:36][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:9][C:10]([NH:12][C:13]2[CH:23]=[CH:22][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCOC(=O)c1ccc(NC(=O)CC(CNS(=O)(=O)c2ccc(C)cc2)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CC(CNS(=O)(=O)c1ccc(Oc2ccccc2)cc1)c1ccc(Cl)cc1)Nc1ccc(C(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of ester 38 (0.065 g, 0.107 mmol) in methanol (1.5 ml) and THF (1.5 ml) was stirred in presence of NaOH 1M (1 ml) for 2 h at 80° C. After cooling to rt, the solution remaining was concentrated in vacuo. HCl 1M (1.5 ml) was added and the formed white solid was filtered, washed with water (10 ml) and dried. The pure acid 40 was obtained without further need for purification (0.050 g, 0.088 mmol, 83%), mp 119-121° C. 1H NMR (400 MHz, CD3OD) δ 2.61 (1H, dd, J 8.4, 14.8 Hz, H—CHCO), 2.82 (1H, dd, J 6.0, 14.8 Hz, H—CHCO), 3.09 (1H, dd, J 7.8, 13.4 Hz, H—CHNH), 3.16 (1H, dd, J 6.4, 13.2 Hz, H—CHNH), 6.99 (2H, d, J 9.2 Hz), 7.06-7.08 (2H, m), 7.17-7.24 (5H, m), 7.47.44 (2H, m), 7.54 (2H, d, J 9.2 Hz), 7.72 (2H, d, J 8.8 Hz), 7.91 (2H, d, J 9.2 Hz). 13C NMR (400 MHz, CD3OD) δ. νmax (pure sample)/(cm−1) 3359 (st) (OH), 1686 (st) (C═O), 1595 (st) (C═O), 1530 (st), 1487 (st), 1410 (md), 1318 (md), 1246 (st), 1150 (st) 1092 (md). MS (API-ES): m/z 563 [M+H]+ (100%), HRMS (API-ES) m/z found 563.10436 [M−H]−.
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[CH2:22](O)[CH:23]=[CH2:24]>>[CH2:24]([O:14][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([OH:1])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:23]=[CH2:22]
Reactant: CCCCCCC(O)CCCCCCCCCCC(=O)O
Reactant: C=CCO
Product: C=CCOC(=O)CCCCCCCCCCC(O)CCCCCC
Yield: 78 %

Procedure:
In analogy to A(2), 200 gm of 12-hydroxystearic acid were esterified with 300 ml of allyl alcohol. The 12-hydroxystearic acid allyl ester was obtained in a yield of 78%, and was distilled over in the high-vacuum at about 160° C. to 180° C.
Reaction SMILES: [CH3:1][C@@H](CC)C(OC[C@@H]1CC(=C(C)C)C1(C)C)=O.[C:18]([C@H:21]1[CH2:24][C@@H:23]([C:25]([OH:27])=[O:26])[C:22]1([CH3:29])[CH3:28])(=[O:20])[CH3:19].C[Mg]Cl>>[OH:20][C:18]([C@H:21]1[CH2:24][C@@H:23]([C:25]([OH:27])=[O:26])[C:22]1([CH3:29])[CH3:28])([CH3:1])[CH3:19]
Reactant: CC(=O)[C@H]1C[C@@H](C(=O)O)C1(C)C
Reactant: CC[C@H](C)C(=O)OC[C@@H]1CC(=C(C)C)C1(C)C
Agent: C[Mg]Cl
Product: CC(C)(O)[C@H]1C[C@@H](C(=O)O)C1(C)C

Procedure:
A method for making [(R)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate (2), said method comprising (or consisting essentially of or consisting of) reacting (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid [(cis)-pinononic acid] with methyl magnesium chloride to form (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3) or reacting (1R,3S)-3-acetyl-2,2-dimethylcyclobutanecarboxylic acid [(cis)-pinononic acid] with methyl lithium, and then methyl magnesium chloride to form (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3); reacting (1R,3S)-3-(1-hydroxy-1-methylethyl)-2,2-dimethylcyclobutanecarboxylic acid (3) with phosphorus oxychloride to form (1R,5S)-4,4,6,6-tetramethyl-3-oxabicyclo[3.1.1]heptan-2-one (4); reacting (1R,5S)-4,4,6,6-tetramethyl-3-oxabicyclo[3.1.1]heptan-2-one (4) with p-toluenesulfonic acid to form (R)-2,2-dimethyl-3-(1-methlethylidene)cyclobutanecarboxylic acid (5); reacting (R)-2,2-dimethyl-3-(1-methlethylidene)cyclobutanecarboxylic acid (5) with lithium aluminum hydride to form [(R)-(−)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methanol [(R)-maconelliol] (6), and reacting [(R)-(−)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methanol (6) with oxalyl chloride and (S)-2-methylbutanoic acid to form [(R)-2,2-dimethyl-3-(1-methylethylidene)cyclobutyl]methyl (S)-2-methylbutanoate [(R)-maconelliyl (S)-2-methylbutanoate] (2).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:22][CH:23]2[CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24]2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[C:12]1[NH:20][C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=1.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35].CO>C(Cl)Cl>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[NH:25]1[CH2:24][CH:23]([NH:22][C:3]2[C:2]([CH3:1])=[N:11][C:10]3[C:5]([N:4]=2)=[C:6]([C:12]2[NH:20][C:19]4[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=4[CH:13]=2)[CH:7]=[CH:8][CH:9]=3)[CH2:26]1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CN(C(=O)OC(C)(C)C)C1
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CNC1
Yield: 40.8 %

Procedure:
A solution of tert-butyl 3-((3-methyl-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxalin-2-yl)amino)azetidine-1-carboxylate (98.0 mg, 0.218 mmol) and TFA (1.0 mL, 12.98 mmol) in DCM (2.0 mL) was stirred at 25° C. for 1 h. MeOH (2 mL) was added, and the mixture was concentrated in vacuo. The residue was partitioned between 5% MeOH/DCM (80 mL) and saturated aq. NaHCO3 (50 mL). The aq. layer was separated and concentrated in vacuo. Sonication of the residue with 5% MeOH/DCM (80 mL, then 2×40 mL) and concentration of the combined organic layers provided a yellow-orange oil. This oil was triturated with Et2O, the supernatant was drawn off, and the precipitated residue was taken up in 5% MeOH/DCM, filtered, and dried in vacuo to provide a yellow foam. Purification of this foam by reversed-phase HPLC (Phenomenex Gemini C18 column (150×30 mm, 10 μm), 35 mL/min, 5-100% ACN/H2O+0.1% TFA) furnished 2-(3-(azetidin-3-ylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (41.0 mg, 0.089 mmol, 41% yield) as a red-brown solid: 1H NMR (400 MHz, MeOH-d4) δ ppm 11.47 (1H, br. s.), 7.78 (1H, d, J=7.2 Hz), 7.69 (1H, d, J=8.0 Hz), 7.45 (1H, t, J=8.0 Hz), 7.34 (1H, d, J=2.0 Hz), 5.21 (1H, quin, J=7.5 Hz), 4.43-4.51 (2H, m), 4.18-4.28 (2H, m), 3.63 (2H, t, J=7.0 Hz), 3.01 (2H, t, J=7.0 Hz), 2.64 (3H, s). 19F NMR (376 MHz, MeOH-d4) δ ppm −77.58 (3F, s). m/z (ESI, +ve) 349.1 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:49][O:50][C:51](=[O:59])[C:52]1[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][CH:53]=1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[CH3:49][O:50][C:51](=[O:59])[C:52]1[CH:57]=[CH:56][C:55]([NH:58][C:8](=[O:9])[CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:19])([F:20])[F:21])[CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:54][CH:53]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(F)c(C(F)(F)F)c2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 12.7 %

Procedure:
A solution of 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (prepared as in Example 87, 202 mg, 0.66 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (294 mg, 0.66 mmol), and 6-amino-nicotinic acid methyl ester (111 mg, 0.73 mmol) in N,N-dimethylformamide (3.32 mL) at 25° C. was treated with N,N-diisopropylethylamine (0.24 mL, 1.39 mmol). The reaction mixture was stirred at 25° C. for 12 h. At this time, the reaction was poured into water (50 mL) and extracted into ethyl acetate (3×35 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 80/20 hexanes/ethyl acetate) afforded 6-[3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionylamino]-nicotinic acid methyl ester (36.7 mg, 12.6%) as a white foam: EI-HRMS m/e calcd for C22H22F4N2O3 (M+) 438.1566, found 438.1568.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:13]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([F:20])[CH:15]=2)=[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][N:7]2[N:6]=1)=O.[C:21]([NH2:24])(=[S:23])[CH3:22].[OH-].[NH4+]>CN(C)C=O>[F:20][C:16]1[CH:15]=[C:14]([C:13]2[C:5]([C:3]3[N:24]=[C:21]([CH3:22])[S:23][CH:2]=3)=[N:6][N:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=23)[CH:19]=[CH:18][N:17]=1
Reactant: O=C(CBr)c1nn2ccccc2c1-c1ccnc(F)c1
Reactant: CC(N)=S
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1nc(-c2nn3ccccc3c2-c2ccnc(F)c2)cs1
Temperature: 60 °C
Yield: 94.5 %

Procedure:
To a solution of 2-bromo-1-[3-(2-fluoro-4-pyridinyl)pyrazolo[1,5-a]pyridin-2-yl]ethanone (250 mg, 0.75 mmol) in N,N-dimethylformamide (15 mL) was added thioacetamide (67 mg, 0.90 mmol). After heating at 60° C. for 3 hours, the reaction was cooled to room temperature. An ammonium hydroxide solution was used to adjust the pH to 9. The resultant solution was extracted with ethyl acetate. The organics were combined and washed with water, brine and dried over magnesium sulfate. Filtration and concentration gave 3-(2-fluoro-4-pyridinyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrazolo[1,5-a]pyridine (220 mg, 95%) as a pale yellow solid. 1H NMR (CDCl3): δ 8.56 (d, 1H), 8.23 (d, 1H), 7.61 (d, 1H), 7.30 (s, 1H), 7.27 (m, 2H), 7.05 (s, 1H), 6.89 (m, 1H), 2.76 (s, 3H). MS m/z 311 (M+1).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[NH:14][C@H:15]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[C:16]([N:18]1[CH2:21][C:20]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[CH2:19]1)=[O:17])(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:14][C@H:15]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[C:16]([N:18]1[CH2:21][C:20]([O:29][CH2:30][CH2:31][CH2:32][CH3:33])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[CH2:19]1)=[O:17]
Reactant: CCCCOC1(c2ccccc2F)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCOC1(c2ccccc2F)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
1 ml of trifluoroacetic acid is added to a solution of 94 mg (0.2 mmol) of tert-butyl[(R)-2-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-1-(4-methoxybenzyl)-2-oxoethyl]carbamate in 10 ml of dichloromethane, cooled beforehand to 0° C. After stirring for 1 h 30 at ambient temperature, the reaction medium is evaporated off under a stream of nitrogen. 119 mg of (R)-2-amino-1-[3-butoxy-3-(2-fluorophenyl)azetidin-1-yl]-3-(4-methoxy-phenyl)propan-1-one trifluoroacetate are obtained in the form of a yellow oil with a yield of 100%.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12](N)=[C:11]2[C:6]=1[C:7](=[O:16])[CH2:8][CH2:9][S:10]2)(=[O:3])[CH3:2].N([O-])=O.[Na+].[ClH:21]>O.[Cu]Cl>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:12]([Cl:21])=[C:11]2[C:6]=1[C:7](=[O:16])[CH2:8][CH2:9][S:10]2)(=[O:3])[CH3:2]
Reactant: Cl
Reactant: CC(=O)Nc1ccc(N)c2c1C(=O)CCS2
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(Cl)c2c1C(=O)CCS2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Into a solution of 500 mg of 5-acetylamino-8-amino-4-thiochromanone (described in Japanese Patent Laid-open (ko-kai) 279891/1989) suspended in a mixed solvent of 12 ml of concentrated hydrochloric acid and 3 ml of water cooled to 0° C. was slowly dropped a solution of 153 mg of sodium nitrite in 2 ml of water. The mixture was stirred for 5 minutes, whereupon a solution of copper (I) chloride in 3 ml of concentrated hydrochloric acid was added to it at 0° C. The mixture was allowed to stand at room temperature overnight and stirred for 20 minutes at 70° C. The reaction mixture was extracted with chloroform, the extract was dried over anhydrous magnesium sulfate. After concentration, the residue was subjected to silica gel column chromatography using chloroform as an eluant to obtain fractions containing the target compound. The fractions were concentrated to produce 478 mg of the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:9][C@H:8]([O:10][Si](C)(C)C)[CH2:7][C@H:6]1[C:15]([O:17][Si](C)(C)C)=[O:16])=[O:4].[F-].[Na+]>C(#N)C>[Cl:1][CH2:2][C:3]([N:5]1[CH2:9][C@H:8]([OH:10])[CH2:7][C@H:6]1[C:15]([OH:17])=[O:16])=[O:4]
Reactant: C[Si](C)(C)OC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C)CN1C(=O)CCl
Agent: [F-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)CCl
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.7 %

Procedure:
Anhydrous HF with nitrogen gas was bubbled into a solution of trimethylsilyl (2S,4R)—N-(chloroacetyl)-4-(trimethylsilyloxy)pyrrolidine-2-carboxylate (4.70 g, 15.0 mmol) in 20 ml of acetonitrile in a Teflon container [HF was generated by heating 10 g (100 mmol) of NaF.HF at 215° C. in a Teflon® vessel and carried with nitrogen flow into the solution]. The reaction mixture was then stirred at room temperature for 15 h. The reaction mixture was evaporated to dryness in vacuo. The resulting solid was washed with 100 ml of anhydrous ether and dried in vacuo to yield 2.67 g (yield 92%) of (2S,4R)—N-(chloroacetyl)-4-hydroxypyrrolidine-2-carboxylic acid as a off-white solid: mp 123-124° C. (dec): 1H-NMR (D2O) δ 1.9-2.4 (m, 2H), 3.4-3.7 (m, 2H), 3.9-4.2 (m, 2H), 4.25-4.5 (m, 2H): 13C-NMR (CDCl3) δ 36.65, 41.84, 54.87, 58.36, 69.79, 168.22, 175.30: High Resolution Mass/ESI-APCI method; (M+H)+ 208.0369 (calcd 208.0371 for C7H11ClNO4); (M+Na)+ 230.0189 [calcd 230.0191 for (C7H10ClNO4+Na)].
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH2:20][CH2:19][C:18]([CH2:22][OH:23])([CH3:21])[CH2:17][CH:16]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.B(Cl)(Cl)Cl>C(Cl)Cl>[OH:23][CH2:22][C:18]1([CH3:21])[CH2:19][CH2:20][C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)=[CH:16][CH2:17]1
Reactant: CC1(CO)CC=C(c2ccc(OCc3ccccc3)cc2)CC1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CC1(CO)CC=C(c2ccc(O)cc2)CC1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of [4-(4-benzyloxy-phenyl)-1-methyl-cyclohex-3-enyl]-methanol (102 mg, 0.331 mmol) in DCM (5.0 mL) at −78° C. was added BCl3 (1.0 M in hexanes, 0.5 mL). The reaction mixture was then stirred at −78° C. for 3 h. The mixture was then quenched with aqueous saturated NaHCO3 (30 mL), extracted with ethyl acetate (60 mL), dried over MgSO4 and purified by SiO2 (50˜70% ethyl acetate/Hexanes) to yield 4-(4-hydroxymethyl-4-methyl-cyclohex-1-enyl)-phenol as a liquid.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:20][C:21]1[CH:22]=[C:23]([Mg]Br)[CH:24]=[CH:25][CH:26]=1.BrC1C=C(C=CC=1)OC1CCCCO1>C1COCC1>[OH:1][CH:2]([C:25]1[CH:24]=[CH:23][CH:22]=[C:21]([O:20][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)[CH:26]=1)[CH2:3][CH2:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=CCCc1ccccc1C(=O)O
Reactant: Br[Mg]c1cccc(OC2CCCCO2)c1
Agent: Brc1cccc(OC2CCCCO2)c1
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1CCC(O)c1cccc(OC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At -10° C., a solution of the aldehyde of Step 2 (5.045 g, 28.3 mmol) in 50 mL of THF was added dropwise to 0.57M 3-(2-tetrahydropyranyloxy)phenylmagnesium bromide in THF (120 mL, 68.4 mmol, prepared from 2-(3-bromophenoxy)tetrahydropyran and Mg in THF and filtered to remove the excess of Mg) and the mixture was stirred at r.t. for 30 min. At 0° C., 25% aq NH4OAc was added. The title product was extracted with EtOAc, dried over Na2SO4 and purified by flash chromatography on silica using acetone:toluene:AcOH 5:95:1 and 15:85:1. Yield: 9.74 g, 97%.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1>C(O)C>[CH3:14][C:4]1[CH:3]=[C:2]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([C:16]([F:15])([F:24])[F:25])=[CH:18][CH:19]=2)[N:7]2[N:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[N:10]=[C:6]2[N:5]=1
Reactant: Cc1cc(Cl)n2nc(C(C)C)nc2n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Solvent: CCO
Product: Cc1cc(Nc2ccc(C(F)(F)F)cc2)n2nc(C(C)C)nc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of Intermediate 18 (0.042 g, 0.199 mmol) in ethanol (5 mL), 4-(trifluoromethyl)aniline (ALDRICH, 0.025 mL, 0.199 mmol) was added and the mixture was stirred at room temperature overnight. Solvent was removed in vacuo and the crude mixture was purified by flash chromatography (Si, eluting with Hexane/EtOAc mixtures from 75:25 to 25:75%) to yield the title compound as a white solid.
Reaction SMILES: N1CCC([CH2:7][C:8]2[S:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)CC1.[OH-].[Na+].C(O[CH2:24][CH3:25])(=O)C>O>[CH2:8]([N:12]([CH2:7][C:8]1[S:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=1)[CH2:11][CH2:24][CH3:25])[CH3:7]
Reactant: CCOC(=O)c1csc(CC2CCNCC2)n1
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCN(CC)Cc1nc(C(=O)O)cs1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl 2-(4-piperidinylmethyl)-1,3-thiazole-4-carboxylate (19 g, 74 mmol) was added a solution of sodium hydroxide (3.6 g, 88.8 mmol) in water (250 ml). The resulting mixture was stirred at room temperature for 18 h, then ethyl acetate was added and the layers were separated. The aqueous phase was acidified with conc. H2SO4 and concentrated to give a brown solid. The solid was recrystallised from methanol/ethyl acetate, then again from DCM/methanol to give the title compound as a light brown solid (16 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:11]1[CH2:16][CH2:15][C:14](=[CH:17][C:18](OCC)=[O:19])[CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.O>[CH2:7]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCN1CCC(=CC(=O)OCC)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCN1CCC(CCO)CC1
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A suspension of lithium aluminum hydride (0.96 g) in THF (90 ml) was ice-cooled, to which was added dropwise a solution of ethyl 1-n-butyl-4-piperidylideneacetate (3.40 g) obtained in Preparation Example 11 in THF (60 ml) over a period of 10 minutes with stirring. The mixture was stirred under ice-cooling for 10 minutes, and then at room temperature for further 2 hours. To the reaction solution were successively added water (4 ml), a 15% aqueous solution of sodium hydroxide (4 ml), water (12 ml), and anhydrous magnesium sulfate, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered off with Celite, and the solvent was distilled off under reduced pressure. To a solution of the residue in ethanol (150 ml) was added platinum (IV) oxide (0.50 g), and the mixture was shaken at room temperature under hydrogen atmosphere at 2 kg/cm2 for 11 hours. The reaction solution was filtered off with Celite, and the solvent was distilled off under reduced pressure to give the title compound (2.76 g) as a yellow oily substance. This compound was used for the subsequent reaction without purification.
Reaction SMILES: [C:1]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][C:16]2[O:20][C:19]([CH2:21][C:22](Cl)=[N:23][OH:24])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C>O1CCCC1>[F:10][C:11]1[CH:27]=[CH:26][C:14]([CH2:15][C:16]2[O:20][C:19]([CH2:21][C:22]3[CH:2]=[C:1]([C:3]4[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=4)[O:24][N:23]=3)=[CH:18][CH:17]=2)=[CH:13][CH:12]=1
Reactant: ON=C(Cl)Cc1ccc(Cc2ccc(F)cc2)o1
Reactant: C#Cc1cccnc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ncccc1-c1cc(Cc2ccc(Cc3ccc(F)cc3)o2)no1
Temperature: 25 °C
Reaction time: 19 h
Yield: 6.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 3-ethynyl-pyridin-2-ylamine (50 mg, 0.423 mmol) described in Manufacturing Example 1-2-3 and (5-(4-fluorobenzyl)-furan-2-yl) acetohydroximoyl chloride (181 mg, 0.677 mmol) described in Manufacturing Example 208-1-5 was added triethylamine (147 μL, 1.06 mmol), which was stirred for 19 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:4 to 1:2) to obtain the title compound (9 mg, 6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=O.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][CH2:6][CH2:5]2
Reactant: COc1ccc(OC)c2c1CCC2=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC)c2c1CCC2
Reaction time: 2 h

Procedure:
To the cooled and stirred suspension of 4,7-Dimethoxyindan-1-one (35 gm, 0.182 mole) in Triethyl silane (105.7 gm, 0.909 mole), added Trifluoroacetic acid (350 ml) at 10-15° C. The stirring was continued at room temperature for 2 hours and quenched into the water. It was extracted with Ethyl acetate. The Ethyl acetate layer was washed with Sodium bicarbonate solution, dried over Sodium sulphate and evaporated to give crude mass which was purified by column chouromatography using 5% Ethyl acetate in hexane (22.5 gm).