Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.C(OC([N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1)C)C.C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[NH:25]1[CH:29]=[C:28]([C:3]2[C:2]([F:1])=[CH:7][N:6]=[C:5]3[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[CH:10][C:4]=23)[CH:27]=[N:26]1
Reactant: CCOC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1ccc2c(I)c(F)cnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)c(F)cnc21
Temperature: 110 °C
Reaction time: 1 h
Yield: 68.7 %

Procedure:
A mixture of 5-fluoro-4-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (7.20 g, 18.4 mmol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.36 g, 20.1 mmol), tetrakis(triphenylphosphine)palladium(0) (1.06 g, 0.918 mmol) and sodium carbonate (5.84 g, 55.1 mmol) in 1,4-dioxane (50 mL) and water (25 mL) was stirred at 110° C. under nitrogen for 1 hour. After being cooled to room temperature, the mixture was diluted with EtOAc, washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatograpgy on silica gel eluting with 10-30% EtOAc/hexanes. The purified intermediate was added into a mixture solution of THF (8.0 mL), water (30 mL) and hydrogen chloride (30 mL, 100 mmol). The resulting suspension was stirred at room temperature for 2 hours. The mixture was adjusted to pH=9-10 with 6 N NaOH and extracted with EtOAc (2×). The combined extracts were washed with water, brine and dried over anhydrous Na2SO4. After filtration and concentration, the residue was added into a mixture solvents of hexane and EtOAc (9/1, 50 mL). The solid formed was filtered to give 4.2 g (69%) of 4-(1H-pyrazol-4-yl)-5-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine as a light green solid. LC/MS found: 333.2 (M+H)+.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:58][CH3:59])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([O:52][Si](C)(C)C)[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:36][CH3:37])=[CH:31][C:30]=2[CH3:60])[CH:28]=1>O1CCCC1.C(OCC)(=O)C>[CH3:19][O:20][C:21](=[O:61])[CH2:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([CH2:36][CH3:37])([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[C:45][C:46]4([OH:52])[CH2:47][CH2:48][O:49][CH2:50][CH2:51]4)=[C:40]([CH3:57])[CH:39]=3)[CH2:58][CH3:59])=[CH:31][C:30]=2[CH3:60])[CH:28]=1
Reactant: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCOCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC2(O)CCOCC2)c(C)c1)c1ccc(-c2cncc(CC(=O)OC)c2)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 79.7 %

Procedure:
Tetrabutylammonium fluoride (1 M solution in tetrahydrofuran, 0.316 mL, 0.316 mmol) was added to a solution of [5-(4-{1-ethyl-1-[3-methyl-4-(4-trimethylsilanyloxy-tetrahydro-pyran-4-ylethynyl)-phenyl]-propyl}-2-methyl-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 132-(1); 62.9 mg, 0.105 mmol) in tetrahydrofuran (3 mL), and the mixture was stirred at 0° C. for 10 minutes. Then, the reaction mixture was diluted with ethyl acetate and was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (44.0 mg, 80%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[NH:33][C:31]4[C:32]5[C:23](=[N:24][NH:25][C:26](=[O:34])[C:27]=5[CH:28]=[CH:29][CH:30]=4)[CH:22]3[C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)=[CH:17][CH:16]=2)[CH2:10][CH:9]1[CH3:42])=O)(C)(C)C>Cl.C(#N)C>[F:41][C:38]1[CH:37]=[CH:36][C:35]([CH:22]2[C:23]3=[N:24][NH:25][C:26](=[O:34])[C:27]4[CH:28]=[CH:29][CH:30]=[C:31]([C:32]=43)[NH:33][CH:21]2[C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH:9]([CH3:42])[CH2:10]3)=[CH:16][CH:17]=2)=[CH:40][CH:39]=1
Reactant: CC1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC#N
Product: CC1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CCN1
Reaction time: 2 h
Yield: 0.1 %

Procedure:
A mixture of tert-butyl-4-(4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzyl)-2-methylpiperazine-1-carboxylate (70 mg, 0.123 mole) in 2 ml of HCl-acetonitrile was stirred for 2 hours. Concentrated and the residue was purified by prep-HPLC to afford the title produce as a white solid (30 mg, yield 52%). 1H-NMR (400 MHz, DMSO-d) δ (ppm): 0.87 (d, J=6.4 Hz, 3H), 1.49 (t, J=10 Hz, 1H), 1.83 (t, J=10 Hz, 1H), 2.55 (m, 2H), 2.64 (m, 2H), 2.75 (m, 1H), 3.32 (s, 3H), 4.34 (d, J=9.2 Hz, 1H), 4.72 (d, J=9.2 Hz, 1H), 6.97-7.01 (m, 2H), 7.13-7.24 (m, 7H), 7.37-7.41 (m, 2H), 7.55-7.59 (m, 1H), 12.15 (s, 1H); LC-MS (ESI) m/z: 470 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1>CCOC(C)=O.[Cl-].[Zn+2].[Cl-]>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([O:23][CH3:24])[CH:20]=[CH:21][C:22]=1[C:5]([C:4]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:3]=1[O:2][CH3:1])=[O:6]
Reactant: COc1cc([N+](=O)[O-])ccc1C(=O)Cl
Reactant: COc1cccc(OC)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)c2ccc([N+](=O)[O-])cc2OC)c(OC)c1
Temperature: 150 °C

Procedure:
2-Methoxy-4-nitro-benzoyl chloride (392) (0.5 g, 2.32 mmol), 1,3-dimethoxy-benzene (393) (0.962 g, 6.96 mmol) and zinc (II) chloride (0.063 g, 0.46 mmol) were combined. The mixture was heated to 150° C. for 30 minutes. TLC indicated product formation. The mixture was diluted with EtOAc (200 mL), washed with aqueous HCl (100 mL, 1.0 M), NaHCO3 (aqueous saturated, 100 mL) and brine (100 mL) via extraction, dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography on silica gel using a gradient of hexane and EtOAc (eluting with 15–100% EtOAc/hexane in 30 minutes) gave the desired product along with the corresponding o-acylated product (10:1 ratio by NMR). Recrystallization from acetone followed by filtration under reduced pressure gave the desired product (394) as yellow cubic crystals (0.618 g, 2.0 mmol, >99% pure, 84% yield). 1H NMR (400 MHz, Acetone-d6): δ 3.53 (s, 3H), 3.78 (s, 3H), 3.85 (s, 3H), 6.58 (d, 1H, J=2.4 Hz), 6.64 (dd, 1H, J=8.4 Hz, 2 Hz), 7.44 (d, 1H, J=8 Hz), 7.63 (d, 1H, J=9.2 Hz), 7.81 (d, 1H, J=2 Hz), 7.84 (dd, 1H, J1=8.4 Hz, J2=2.4 Hz).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:37]C(=O)OCC2C3C=CC=CC=3C3C2=CC=CC=3)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1>>[NH2:37][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:7][CH:8]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Yield: 99.5 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl (S)-3-(4-tert-butoxyphenyl)-1-(((S)-1,1-diethoxypropan-2-yl)(naphthalen-1-ylmethyl)amino)-1-oxopropan-2-ylcarbamate (Compound III-2) 1.34 g (1.84 mmol) was treated with piperidine and purified on silica gel column chromatography (n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound 928 mg (99%).
Reaction SMILES: [CH2:1]([N:19]1[C:27](=O)[CH:26]2C(C[CH:23]=[CH:24][CH2:25]2)[C:20]1=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[CH:31]([OH:33])[CH3:32].[BH4-].[Na+].Cl>O>[OH:33][CH2:31][CH:32]1[CH:27]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:20]=[O:29])[CH2:26][CH:25]=[CH:24][CH2:23]1
Reactant: CC(C)O
Reactant: CCCCCCCCCCCCCCCCCCN1C(=O)C2CC=CCC2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCCCCCCCCCCCCN(C=O)C1CC=CCC1CO
Temperature: 25 °C
Reaction time: 46 h

Procedure:
2-Octadecyl-4,7,3a,7a-tetrahydroisoindole-1,3-dione (5.00 g) was suspended into a mixture of 2-propanol (90 ml) and water (15 ml) and then sodium borohydride (2.34 g) was added thereto. After being stirred for 46 hours at room temperature, the reaction mixture was acidified with dilute hydrochloric acid and then concentrated. The residue was, with chloroform added thereto, washed with dilute hydrochloric acid, water and saturated sodium hydrogencarbonate aqueous solution successively, dried over sodium sulfate anhydride, and concentrated. The residue was purified by silica gel column chromatography (silica gel 80 g, chloroform:methanol=50:1-10:1), thereby yielding the entitled compound (4.32 g) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[C@@H:7]([N:10]1[C@H:15]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C@@H:14]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH2:13][C@@:12]([CH2:31][C:32](O)=[O:33])([CH3:30])[C:11]1=[O:35])[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].Cl.C[N:39](C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C([O-])(O)=O.[Na+].N.CO>CN(C=O)C.O>[NH2:39][C:32](=[O:33])[CH2:31][C@@:12]1([CH3:30])[CH2:13][C@H:14]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[C@@H:15]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[N:10]([C@@H:7]([CH2:8][CH3:9])[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:36])[C:11]1=[O:35]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: Cl
Agent: N
Agent: O=C([O-])O
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CC[C@@H](C(=O)OC(C)(C)C)N1C(=O)[C@@](C)(CC(N)=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid (230 mg, 0.430 mmol; Example 67) in DMF (4.3 mL) was treated with N-(3-dimethyaminopropyl)-N′-ethylcarbodiimide hydrochloride (165 mg, 0.86 mmol), 1-hydroxy-7-azabenzotriazole (117 mg, 0.86 mmol) and NaHCO3 (72.3 mg, 0.861 mmol) successively. After being stirred at rt for 0.5 h, 7 M ammonia in methanol (6.2 mL, 4.30 mmol) was added dropwise and the reaction was stirred overnight. Then, the reaction was diluted (water), extracted (2×EtOAc), and washed (1× saturated NaHCO3, and 2×sat. aq. NaCl solution). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification by RP-HPLC (45 to 70% MeCN/H2O (0.1% TFA), a gradient elution) provided the title compound as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[NH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:15]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[C:24]([O:23][C:22](=[O:28])[NH:21][CH2:20][CH:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:15]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: CC(C)(C)OC(=O)NCC1CCCNC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)NCC1CCCN(c2ccc(C#N)c3ccccc23)C1
Temperature: 60 °C
Reaction time: 96 h
Yield: 71.1 %

Procedure:
1-Cyano-4-fluoronaphthalene (273 mg, 1.60 mmol), tert-butyl (piperidin-3-ylmethyl)carbamate (411 mg, 1.92 mmol) and DBU (25 μl, 0.16 mmol) were dissolved in pyridine (4 mL) and stirred at 60° C. for 4 days. The reaction was worked up in the same way as for 198RL60 followed by purification using silica gel column chromatography eluted with a stepwise gradient of 0-70% ethyl acetate in n-heptane, giving the desired compound (416 mg, 71%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[CH:30]=3)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(Br)n2)c1
Reactant: OB(O)c1cccc(F)c1
Product: CCOC(=O)C=Cc1cccc(NC(=O)c2cccc(-c3cccc(F)c3)n2)c1

Procedure:
The pyridyl bromide (109) (100 mg, 0.27 mmol) was coupled to 3-fluoro-phenylboronic acid (41 mg, 0.29 mmol) using Method E. The residue was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13]S(C2SC3C=CC=CC=3N=2)(=O)=O)[CH2:11][O:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=O)=[CH:41][CH:40]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[C@H:12](/[CH:13]=[CH:43]/[C:42]2[CH:45]=[CH:46][C:39]([F:38])=[CH:40][CH:41]=2)[CH2:11][O:10][C:9]1([CH3:26])[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1[C@H](CS(=O)(=O)c2nc3ccccc3s2)COC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@H](/C=C/c2ccc(F)cc2)COC1(C)C
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 53305.5 %

Procedure:
To a stirred, cooled (−78° C.) solution of (S)-4-(benzothiazole-2-sulfonylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.484 mg) in THF (12 ml) under an argon atmosphere was added slowly a 1 M solution of LiHMDS in THF (1.1 ml). The mixture was warmed to −40° C. and stirring at that temperature was continued for 30 min. The mixture was cooled again to −78° C. and a solution of 4-fluorobenzaldehyde (0.112 g) in THF (3 ml) was then added slowly via a syringe. Stirring at −78° C. was continued for 2 h, and then the reaction mixture was slowly allowed to warm to 0° C. The mixture was quenched by the addition of sat. aq. NH4Cl (15 ml) and H2O (15 ml) and extracted with EtOAc. The aqueous phase was back extracted with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (SiO2; gradient: cyclohexane ->cyclohexane/EtOAc 85:15) to give (R)-4-[(E)-2-(4-fluoro-phenyl)-vinyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.201 g) as colorless viscous oil. MS (ISP): 322.4 ([M+H]+))
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]#[CH:14])[C:5](Cl)=[O:6].[CH:15]1([C@@H:21]([NH2:23])[CH3:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(OCC)(=O)C>[CH:15]1([C@@H:21]([NH:23][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]#[CH:14])=[C:2]([F:1])[CH:3]=2)[CH3:22])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C[C@H](N)C1CCCCC1
Reactant: C#CCOc1ccc(C(=O)Cl)cc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C#CCOc1ccc(C(=O)N[C@@H](C)C2CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a mixture of 5 ml of ethyl acetate and 0.30 g of 3-fluoro-4-(2-propynyloxy)benzoyl chloride were added 0.22 g of (1S)-1-(cyclohexyl)ethylamine and 0.20 g of triethylamine in order at room temperature. The mixture obtained was stirred at room temperature for 1 hour. Then, ethyl acetate was added to the reaction mixture and the mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was washed with hexane to obtain 0.37 g of N-((1S)-1-cyclohexylethyl)-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 37 of the present invention) represented by the formula:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]([OH:16])=O)[CH:10]=2)=[C:5]([F:17])[CH:4]=1)#[N:2].[C:18]([C:22]1[N:26]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([NH:33][CH:34]3[CH2:36][CH2:35]3)[CH2:29][CH2:28]2)[O:24][N:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[N:26]=[C:25]([N:27]2[CH2:28][CH2:29][CH:30]([N:33]([CH:34]3[CH2:36][CH2:35]3)[C:14]([C:11]3[CH:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[F:17])[O:13][N:12]=3)=[O:16])[CH2:31][CH2:32]2)[O:24][N:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: N#Cc1ccc(-c2cc(C(=O)O)no2)c(F)c1
Reactant: CC(C)(C)c1noc(N2CCC(NC3CC3)CC2)n1
Product: CC(C)(C)c1noc(N2CCC(N(C(=O)c3cc(-c4ccc(C#N)cc4F)on3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from 5-(4-cyano-2-fluoro-phenyl)-isoxazole-3-carboxylic acid and [1-(3-tert-butyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-yl]-cyclopropyl-amine following a procedure analogous to that described in Example 18. LC (method 18): tR=1.29 min; Mass spectrum (ESI+): m/z=479 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[O:15]=[C:16]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17]1>C1COCC1>[OH:15][C:16]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:22][CH2:21][CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17]1
Reactant: COc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCCCC(=O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCCCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 69.1 %

Procedure:
To a stirred solution of 1-bromo-4-methoxybenzene (0.67 mL, 5.4 mmol) in THF (50 mL) at −78° C. was added n-butyllithium (5 mL, 8 mmol) and the reaction mixture was stirred at −78° C. for 2 h. Then was added tert-butyl 3-oxoazepane-1-carboxylate (1.14 g, 5.4 mmol) at −78° C. and the reaction mixture was warmed to room temperature over 12 h. It was then quenched with saturated NH4Cl at 0° C., and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel (24 g) using 10% ethyl acetate in hexane to yield tert-butyl 3-hydroxy-3-(4-methoxyphenyl)azepane-1-carboxylate (1.2 g, 57%) as a colorless gum. LCMS: R.T. 1.03 min. LCMS (ES-API), m/z 204 (M-117).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5](=[N:7][C:8]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:21][O:22][CH3:23])[CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[S:6][C:5](=[N:7][C:8]2[N:13]=[C:12]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:17][CH2:16]3)[CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:21][O:22][CH3:23])[CH:3]=1
Reactant: COCn1cc(Br)sc1=Nc1cccc(CN2CCNCC2)n1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COCn1cc(Br)sc1=Nc1cccc(CN2CCN(C(=O)c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
77 mg (0.217 mmol) of 1-(6-(5-bromo-3-methoxymethyl-3H-thiazol-2-ylideneamino)-pyridin-2-ylmethyl)-piperazine was dissolved in 10 ml of chloroform, 0.363 ml (2.60 mmol) of triethylamine was added thereto, 0.126 ml (1.09 mmol) of benzoyl chloride was gradually dropped thereinto and the mixture was stirred at room temperature for 30 minutes. The resulting mixture was diluted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by a silica gel column chromatography to give 81 mg (0.161 mmol) of the title compound as a white solid.
Reaction SMILES: [Br-].[O:2]1[CH2:7][CH2:6][CH2:5][O:4][CH:3]1[CH2:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC([O-])(C)C.[K+].[F:35][C:36]1[C:41]([F:42])=[C:40]([O:43][CH2:44][CH3:45])[CH:39]=[CH:38][C:37]=1[CH:46]1[CH2:51][CH2:50][C:49](=O)[CH2:48][CH2:47]1>C1COCC1>[F:35][C:36]1[C:41]([F:42])=[C:40]([O:43][CH2:44][CH3:45])[CH:39]=[CH:38][C:37]=1[CH:46]1[CH2:51][CH2:50][C:49](=[CH:9][CH2:8][CH:3]2[O:2][CH2:7][CH2:6][CH2:5][O:4]2)[CH2:48][CH2:47]1
Reactant: c1ccc([P+](CCC2OCCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOc1ccc(C2CCC(=CCC3OCCCO3)CC2)c(F)c1F
Temperature: -30 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
A mixture of 2-(1,3-dioxane-2-yl)-ethyltriphenyl phosphonium bromide (60.4 mmol) and 30 ml of THF was cooled down to −30° C. by use of a refrigerant under a nitrogen flow. To this mixture, t-BuOK (60.4 mmol) was added, and the mixture was stirred for one hour. A solution of the crude 4-(2,3-difluoro-4-ethoxyphenyl)-cyclohexanone (50.3 mmol) dissolved in 100 ml of THF was added dropwise to this mixture while temperature was maintained at −30° C. or below. After completion of the addition, the reaction temperature was gradually elevated to room temperature, and the mixture was stirred for 2 hours. The reaction mixture was filtered with celite, the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: a mixed solvent of ethyl acetate/toluene=3/7), the solvent was distilled off under reduced pressure, and the product was re-crystallized from heptane to form 2-(2-(4-(2,3-difluoro-4-ethoxyphenyl)cyclohexylidene)-ethyl)-1,3-dioxane (36.9 mmol).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][O:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Cl.O.[OH-].[Na+]>CO.O1CCOCC1>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][O:18][CH2:17]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCOC3)c2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCOC3)c2n1
Reaction time: 4 h
Yield: 71.1 %

Procedure:
2-Butoxy-8-methoxy-9-(tetrahydro-2H-pyran-3-ylmethyl)-9H-purin-6-amine (105 mg) was dissolved in methanol (2 mL) and treated with 4N hydrogen chloride in 1,4-dioxane (1 mL). The reaction mixture was stirred for 4 hours and stripped to dryness. Water (2 mL) and methanol (15 mL) were added to the residue and then neutralised by the addition of 2N sodium hydroxide solution. The above was stripped to near dryness (small volume of water remaining) and the solid thus obtained was filtered off under suction (transferred and washed with water (2 mL, 3 times)). The solid was dried under suction before being dried further in vacuo to afford the title compound as a white solid (71.5 mg).