Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[N:3]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[CH:19]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: O=Cc1c(Cl)n(-c2cccc(Cl)c2)c2ccccc12
Yield: 70 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 3-chlorophenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(3-chlorophenyl)-1H-indole-3-carboxaldehyde (70% yield) as a cream solid. ESI/MS 290 (M+H); RT 3.55 min; NMR 10.13 (1H, s); 8.21 (1H, d); 7.84 (1H, d); 7.74 (3H, m); 7.38 (2H, m); 7.16 (1H, d, J=9 Hz).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH-:12].[Na+].[CH2:14]=O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:14][OH:12]
Reactant: C=O
Reactant: [OH-]
Reactant: Oc1ccnc2ccccc12
Agent: [Na+]
Product: OCc1cnc2ccccc2c1O
Temperature: 45 °C

Procedure:
A mixture of 4-hydroxyquinoline (5.0 g), aqueous sodium hydroxide solution (1M, 42 mL) and formaldehyde solution (37% in water, 6 mL) was heated at 45° C. for 18.5 hours. The reaction mixture was filtered, acidified with 2N HCl (21 mL) and extracted with ethyl acetate. The aqueous layer was chilled to afford 4-hydroxy-3-hydroxymethylquinoline (2.0 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=3)=[CH:6][N:5]2[CH:21]=1.[OH2:22].[C:23]1([CH3:33])C=CC(S(O)(=O)=O)=CC=1>C(O)CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[NH:8][C:7]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([O:20][CH2:33][CH2:23][OH:22])([CH3:19])[CH3:18])=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:21]=1
Reactant: CC(C)(O)c1ccc(-c2cn3cc(F)cc3c(=O)[nH]2)cc1
Reactant: O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCCO
Product: CC(C)(OCCO)c1ccc(-c2cn3cc(F)cc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a suspension of 28.6 mg (0.10 mmol) 7-fluoro-3-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-2H-pyrrolo[1,2-a]pyrazin-1-one in 0.45 ml ethane-1,2-diol is added 1.7 mg (0.01 mmol) toluene-4-sulfonic acid monohydrate. The reaction mixture is stirred for 5 days at ambient temperature. The reaction mixture is partitioned between water and ethylacetate. The organic phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column with cyclohexane/ethyl acetate as eluent to afford 7-fluoro-3-{4-[1-(2-hydroxy-ethoxy)-1-methyl-ethyl]-phenyl}-2H-pyrrolo[1,2-a]pyrazin-1-one as white powder; HPLC/MS 2.17 min (B), [M+H] 331; 1H NMR (400 MHz, DMSO-d6) δ [ppm] 10.99 (s, 1H), 7.68-7.61 (m, 3H), 7.55-7.50 (m, 2H), 7.48 (dd, J=3.4, 1.9 Hz, 1H), 6.77 (d, J=1.9 Hz, 1H), 4.55 (t, J=5.6 Hz, 1H), 3.50 (q, J=5.5 Hz, 2H), 3.19 (t, J=5.6 Hz, 2H), 1.50 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26]4[CH:25]=[CH:24][N:23]=[C:22]([C:27]#[N:28])[C:21]=4[N:20]=[CH:19]3)=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].C[O-].[Na+].[CH3:36][NH:37]C>CO.C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:11][C:12]2[CH:13]=[CH:14][C:15]([N:18]3[C:26]4[CH:25]=[CH:24][N:23]=[C:22]([C:27]([NH:37][CH3:36])=[NH:28])[C:21]=4[N:20]=[CH:19]3)=[CH:16][CH:17]=2)=[CH:4][C:3]=1[C:29]([F:30])([F:31])[F:32]
Reactant: N#Cc1nccc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CNC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNC(=N)c1nccc2c1ncn2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 30 %

Procedure:
In 5 mL of methanol, 12 mg (0.026 mmol) of 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-[4-(4-cyanoimidazo-[4,5-c]pyridin-1-yl)phenyl]urea prepared in Example 91 was dissolved, and one drop (a catalytic amount) of a 28% methanol solution of sodium methylate was added thereto and the solution was stirred at room temperature for six hours. The reaction solution was neutralized with one drop of acetic acid, and then 50 μL of a dimethylamine 40% methanol solution was added thereto and the mixture solution was further stirred at room temperature for 14 hours. The solvent was distilled under reduced pressure, and the residue was separated by reversed phase high-pressure liquid chromatography (C18 Column, acetonitrile:water=55:45, 0.05% trifluoroacetic acid). The fraction containing a target product was concentrated, and then trifluoroacetic acid was replaced with hydrochloric acid to obtain 4.2 mg (30%) of 1-{4-[3-(4-chloro-3-(trifluoromethyl)phenyl)ureido]phenyl}-N-methyl-1H-imidazo[4,5-c]pyridine-4-carboxamidine hydrochloride (Table 1, Compound No. 94) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1>[OH-].[Na+]>[CH:12]1([NH:15][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: Clc1ccnc2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: c1ccc2c(NC3CC3)ccnc2c1
Temperature: 180 °C
Reaction time: 16 h
Yield: 42.2 %

Procedure:
A mixture of 4-chloroquinoline (13.9 g) and cyclopropyl amine (9.7 g) was heated at 180° C. under stirring for 16 hours. After cooling, a solution of sodium hydroxide 1N (200 ml) was added. After extraction with dichloromethane (200 ml), the organic layer was separated and dried over sodium sulfate. The solvent was removed under reduce pressure to afford an oil, which was crystallized in acetonitrile (50 ml). Cyclopropyl-quinolin-4-yl-amine (6.6 g; 42% yield) was obtained after filtration.
Reaction SMILES: [CH2:1]([CH:3]1[C:11]2[C:10](O)=[N:9][CH:8]=[N:7][C:6]=2[CH2:5][S:4]1)[CH3:2].C(C1SC2C(O)=NC=NC=2C1)C.O=P(Cl)(Cl)[Cl:27]>ClCCCl.C(N(C(C)C)CC)(C)C>[Cl:27][C:10]1[C:11]2[CH:3]([CH2:1][CH3:2])[S:4][CH2:5][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: CCC1SCc2ncnc(O)c21
Reactant: O=P(Cl)(Cl)Cl
Agent: CCC1Cc2ncnc(O)c2S1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC1SCc2ncnc(Cl)c21
Yield: 28 %

Procedure:
To a solution of a mixture of 5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidin-4-ol and 6-ethyl-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (2.32 g, 12.8 mmol) in 1,2-dichloroethane (50 mL) and diisopropylethylamine (4 mL) was added POCl3 (4 mL), and the mixture was refluxed overnight. The solvent was removed and the residue was purified by silica gel chromatography, eluting with Hexane/ethyl acetate (9:1-4:1) to give 4-chloro-5-ethyl-5,7-dihydrothieno[3,4-d]pyrimidine (0.49 g, 28%). 1H NMR (CDCl3, 400 MHz) δ 8.73 (s, 1H), 4.44 (m, 1H), 4.32-4.00 (m, 2H), 2.08 (m, 1H), 1.75 (m, 1H), 0.93 (m, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][C:38]=1[CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH2:28][CH2:29][C:30](OC)=[O:31])=[CH:24][CH:23]=1.[C:45]([O-:50])(=[O:49])[C:46]([O-:48])=[O:47]>C1COCC1>[C:45]([OH:50])(=[O:49])[C:46]([OH:48])=[O:47].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:36]=[CH:37][C:38]=1[CH2:39][N:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1)[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])=[CH:24][CH:23]=1
Reactant: O=C([O-])C(=O)[O-]
Reactant: COC(=O)CCCOc1ccc(-c2cc3ccccc3n2Cc2ccc(CN3CCCC3)c(OC)c2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(Cn2c(-c3ccc(OCCCCO)cc3)cc3ccccc32)ccc1CN1CCCC1
Product: O=C(O)C(=O)O
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield in two steps from LAH reduction of methyl 4-[4-[1-[3-methoxy-4-[(1-pyrrolidinyl)methyl]benzyl]indol-2-yl]phenoxy]butyrate (free base of Example 8) in THF at 0° C. for 1 h, followed by oxalate formation as previously described.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH:14]2[CH2:19][CH2:18][CH:17]([C:20](N)=[O:21])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.[OH-:23].[K+].O.Cl>C(O)CO>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([C:20]([OH:21])=[O:23])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1
Reactant: NC(=O)C1CCC([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: O=C(O)[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Temperature: 180 °C

Procedure:
42 g of crude 4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanecarboxamide were suspended in 500 ml of ethylene glycol while gassing with argon and then treated with 19 g of solid potassium hydroxide. The mixture was heated to 180° C. (bath temperature) for 5 hours while stirring. After cooling the reaction mixture was poured into 500 ml of water, acidified to pH about 3 with 10 percent hydrochloric acid and extracted three times with 300 ml of methylene chloride each time. The combined organic phases were washed once with 500 ml of 1 percent hydrochloric acid and twice with 500 ml of water each time, dried over magnesium sulfate, filtered and evaporated. The dark brown crude product (41 g) was purified by chromatography on silica gel with ethyl acetate. Crystallization of the product obtained (36 g) from acetone gave 13.8 g of pure trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanecarboxylic acid. Working-up of the mother liquor gave a further 2.5 g of pure product.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:29]([N:31]([CH2:41][C:42]1[C:43]2[CH:50]=[CH:49][CH:48]=[CH:47][C:44]=2[S:45][CH:46]=1)[C@@H:32]([CH3:40])[CH:33]([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36])=[O:30])[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[S:45]1[CH:46]=[C:42]([CH2:41][N:31]([C@@H:32]([CH3:40])[CH:33]([O:34][CH2:35][CH3:36])[O:37][CH2:38][CH3:39])[C:29](=[O:30])[C@@H:20]([NH:19][C:14](=[O:16])[CH2:13][N:11]([CH3:12])[NH:10][C:8](=[O:9])[NH:7][CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:18][CH:17]=2)[CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:43]2[CH:50]=[CH:49][CH:48]=[CH:47][C:44]1=2
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 88 mg (0.32 mmol) was coupled with (S)-tert-butyl 3-amino-4-((benzo[b]thiophen-3-ylmethyl)-((S)-1,1-diethoxypropan-2-yl)amino)-4-oxobutanoate (Compound IV-18) 100 mg (0.22 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1]([SH:4])[CH:2]=[CH2:3].[CH:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13](=[N:19][O:20][CH2:21][CH2:22]Br)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:12]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([S:4][CH2:22][CH2:21][O:20][N:19]=[C:13]([C:11]1[N:12]=[C:8]([NH:7][CH:5]=[O:6])[S:9][CH:10]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:2]=[CH2:3]
Reactant: CCOC(=O)C(=NOCCBr)c1csc(NC=O)n1
Reactant: C=CCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCSCCON=C(C(=O)OCC)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 81.6 %

Procedure:
Allyl mercaptan (2.12 g.) was added dropwise to a stirred suspension of ethyl 2-(2-formamidothiazol-4-yl)-2-(2-bromoethoxyimino)acetate (syn isomer, 5 g.) and potassium carbonate (3.95 g.) in N,N dimethylformamide (50 ml.) under ice cooling and stirred at the same temperature for 10 minutes and further at room temperature for 5 hours. After adding water (300 ml.) to the resultant solution, the mixture was extracted with ethyl acetate three times. The extracts were washed twice with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The oily residue was subjected to column chromatography on silica gel and eluted with chloroform. The eluate was concentrated in vacuo to give ethyl 2-(2-allylthioethoxyimino)-2-(2-formamidothiazol-4-yl)acetate (syn isomer, 4.0 g.), mp. 62° to 64° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]([C:11](=O)[C:12]#[C:13]C)=[C:4]2[CH:3]=1.[N+]([O-])(O)=O.[C:27]1([NH:33][C:34]([NH2:36])=[NH:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[C:10]([C:11]3[CH:12]=[CH:13][N:36]=[C:34]([NH:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:35]=3)=[C:4]2[CH:3]=1
Reactant: N=C(N)Nc1ccccc1
Reactant: CC#CC(=O)c1c(-c2ccc(F)cc2)nn2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O=[N+]([O-])O
Product: Fc1ccc(-c2nn3ccc(Cl)cc3c2-c2ccnc(Nc3ccccc3)n2)cc1
Temperature: 150 °C
Yield: 35.8 %

Procedure:
To a solution of 1-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-2-butyn-1-one (1.0 g, 3.36 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was added N-phenylguanidine nitrate (1.0 g, 5.0 mmol) and anhydrous potassium carbonate (0.7 g, 5.0 mmol). The resulting mixture was heated at 150° C. for 12 hours and concentrated in vacuo to a syrup. Ethyl acetate and water were added and the phases separated. The organic phase was dried (magnesium sulfate), filtered and concentrated to a solid. This solid was crystallized from acetonitrile to give 500 mg (36%) of 4-[5-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]-N-phenyl-2-pyrimidinamine as a yellow solid. 1H-NMR (CDCl3): δ 8.48 (d, 1H), 8.45 (d, 1H), 8.23 (d,1H), 7.64 (m, 4H), 7.42 (t, 2H), 7.1–7.25 (m, 4H), 6.93 (dd, 1H), 6.52 (d, 1H); 19F-NMR (CDCl3): δ−112.29; MS m/z 416 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[C:5](C1CC(=O)N(O)C1=O)([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]>C(Cl)(Cl)Cl.O>[NH2:1][CH2:2][CH2:3][NH:4][C:5](=[O:6])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCN
Reactant: O=C(OCc1ccccc1)C1CC(=O)N(O)C1=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: NCCNC(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 2-aminoethylamine LVIII (150 mL; 2.25 mol) in chloroform (1.5 L), cooled to 0° C. was added a solution of carbobenzoxy N-hydroxysuccinimide (112.14 g; 0.45 mol) in water (0.5 L) with vigorously stirring for one hour. The solid was filtered and the solution was washed with brine (3×), once with water and dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure and the residue was purified on a silica gel column (100:1→30:1 DCM:MeOH) to yield benzyl 2-aminoethylcarbamate LIX as a colorless viscous oil (350 g; 1.80 mol; 80% yield). 1H NMR (CDCl3) 2.79-2.83 (m, 2H), 3.21-3.28 (m, 2H), 5.10 (s, 2H), 5.19 (brs, 1H), 7.29-7.34 (m, 1H), 7.35-7.38 (m, 4H); ESIMS found for C10H14N2O2 m/z 195.2 (M+H).
Reaction SMILES: [C:1]([O:8][CH:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][C:11]([O:13]C(C)(C)C)=O)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:23][CH2:24][C:25]([NH:27][C@H:28]([C:31]([OH:33])=[O:32])[CH2:29][OH:30])=[O:26]>>[C:1]([O:8][CH:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][C:11]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:31]([OH:33])=[O:32])[CH2:29][OH:30])=[O:26])=[O:13])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)OC(CCCCC)CC(=O)OC(C)(C)C
Reactant: NCC(=O)N[C@@H](CO)C(=O)O
Product: CCCCCC(=O)OC(CCCCC)CC(=O)NCC(=O)N[C@@H](CO)C(=O)O
Yield: 52.3 %

Procedure:
Starting from tert-butyl 3-hexanoyloxyoctanoate (157 mg) prepared by the method described in Preparation 5 and N-glycyl-L-serine (243 mg), N-[N-(3-hexanoyloxyoctanoyl)glycyl]-L-serine (105 mg) was obtained as an oil according to similar manner to that of Example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O.[F:20][C:21]([F:29])([F:28])[C:22](=[O:27])[CH2:23][C:24](=O)[CH3:25].C(O)(C)C>CCCCCCC.C(OCC)(=O)C>[C:8]([C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:24]([CH3:25])[C:23]([C:22](=[O:27])[C:21]([F:29])([F:28])[F:20])=[C:12]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(N)c(C(=O)c2ccccc2)c1
Reactant: CC(=O)CC(=O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC(C)O
Product: Cc1nc2ccc(C(C)(C)C)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 37 %

Procedure:
The title compound was prepared from (2-Amino-5-tert-butyl-phenyl)-phenyl-methanone [example A1] and 1,1,1-trifluoro-2,4-pentanedione according to the procedure of example 1, except that the solvent was isopropanol, the reaction time was of 16 h and heptane/ethyl acetate (1:2) was used. Yield: 37%; MS: m/z=372 (M+H).
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH:7]=[C:8]([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])=[C:12]([CH3:14])[CH3:13])[CH:3]=[CH2:4].N1C=CC=CC=1.P(Br)(Br)[Br:25]>CCCCCC>[Br:25][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:5][CH2:6][CH:7]=[C:8]([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])=[C:12]([CH3:14])[CH3:13]
Reactant: C=CC(C)(O)CCC=C(C)CCC(C)=C(C)C
Reactant: BrP(Br)Br
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC(=CCBr)CCC=C(C)CCC(C)=C(C)C
Reaction time: 0.5 h

Procedure:
To a solution containing 223.9 g. of 3,7,10,11-tetramethyl-1,6,10-dodecatrien-3-ol in 570 ml. of hexane and 22.2 ml. of pyridine there was added dropwise at -7°C. over a period of two hours, 112 g. of phosphorous tribromide in 125 ml. of hexane. The resulting mixture was stirred for 30 minutes. After this, the reaction mixture was poured onto ice water and the reaction mixture was allowed to stand under constant stirring for 30 minutes. After 30 minutes, the reaction mixture was diluted with 1,000 ml. of hexane and the water layer was separated and the hexane layer was washed with water, aqueous sodium bicarbonate and finally with water. After washing, the hexane solution was dried over sodium sulfate and evaporated. There resulted 1-bromo-3,7,10,11-tetramethyl-2,6,10-dodecatriene.
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH2:29][CH:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[OH:36])[O:27][N:26]=4)[N:24]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:44](Br)[CH:45]=[CH2:46].O>CC(C)=O>[CH2:46]([O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH:28]1[O:27][N:26]=[C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:16][CH2:15][N:14]([C:12](=[O:13])[CH2:11][N:5]4[C:6]([CH:8]([F:10])[F:9])=[CH:7][C:3]([CH:2]([F:1])[F:37])=[N:4]4)[CH2:19][CH2:18]3)[S:21][CH:22]=2)[CH2:29]1)[CH:45]=[CH2:44]
Reactant: O=C(Cn1nc(C(F)F)cc1C(F)F)N1CCC(c2nc(C3=NOC(c4ccccc4O)C3)cs2)CC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccccc1C1CC(c2csc(C3CCN(C(=O)Cn4nc(C(F)F)cc4C(F)F)CC3)n2)=NO1
Yield: 55.1 %

Procedure:
To a solution of 2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]-1-(4-{4-[5-(2-hydroxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]-1,3-thiazol-2-yl}piperidin-1-yl)ethanone (81 mg) and potassium carbonate (105 mg) in acetone (5 ml) is added, at room temperature, allyl bromide (73 mg). The reaction mixture is stirred at reflux for 5 h. Then the mixture is admixed with water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated. Purification by column chromatography gives 1-[4-(4-{5-[2-(allyloxy)phenyl]-4,5-dihydro-1,2-oxazol-3-yl}-1,3-thiazol-2-yl)piperidin-1-yl]-2-[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]ethanone (48 mg).
Reaction SMILES: [C:1]([C:9]1[NH:13][C:12]([C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30](=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCCl>[C:1]([C:9]1[N:13]2[C:12](=[CH:11][CH:10]=1)[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:20][CH2:30]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)c1ccc(C(=O)c2ccccc2)[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: ClCCCl
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21
Temperature: 25 °C
Yield: 79.9 %

Procedure:
A mixture of triethyl (5-benzoylpyrrol-2-yl)-methanetricarboxylate (2.00 g, 5 mmol), tetra-butylammonium bromide (1.61 g, 5 mmol) and potassium carbonate (19.0 g, 250 mmol) in 1,2-dichloroethane (100 mL) was refluxed for 2 days. The mixture was cooled to room temperature and filtered. The filter cake was washed with methylene chloride. The filtrate and methylene chloride wash solution were combined and concentrated under reduced pressure. The residue was dissolved in diethyl ether, washed with water, dried, and concentrated. The crude product was purified by flash chromatography on flash silica eluting with hexane/ethyl acetate (90:10) to provide 1.42 g (80%) of diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate. The IR and NMR spectral properties were identical to those of the authentic sample.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](Cl)(=[O:22])[C:19](Cl)=[O:20].[CH3:24][O-:25].[Na+]>CCOCC>[CH3:24][O:25][C:18](=[O:22])[C:19]([C:13]1[C:12]2[C:16](=[CH:17][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:10][CH:11]=2)[NH:15][CH:14]=1)=[O:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: c1ccc(COc2ccc3cc[nH]c3c2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOCC
Product: COC(=O)C(=O)c1c[nH]c2cc(OCc3ccccc3)ccc12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 6-benzoxyindole (1.05 g, 4.7 mmol) in ether (8 mL) is added oxalyl chloride (0.45 mL) at 0˜5° C., stirred for 2 hrs. The reaction mixture is cooled to −78° C., sodium methoxide (25% w/w in methanol, 2.4 mL) is added, warmed up to room temperature, quenched by water. Solid product is collected by filtration, washed by water and dried under vacuum.
Reaction SMILES: [CH2:1]1[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[S:9][C:5]=2[CH2:4][CH2:3][O:2]1.[CH2:14](Cl)[CH3:15].[CH2:17]([NH:19][CH2:20][CH3:21])[CH3:18]>>[CH2:17]([N:19]([CH2:14][CH3:15])[CH2:20][CH2:21][CH:1]1[C:6]2[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[S:9][C:5]=2[CH2:4][CH2:3][O:2]1)[CH3:18]
Reactant: c1ccc2c3c(sc2c1)CCOC3
Reactant: CCNCC
Reactant: CCCl
Product: CCN(CC)CCC1OCCc2sc3ccccc3c21

Procedure:
A mixture of 3,4-dihydro-1H-[ 1]benzothieno[3,2-c]pyran-1-ethyl chloride (12.0 g), described in Example 30, and diethylamine (80 ml) is heated under reflux for 48 hr. The excess amine is evaporated and the residue is dissolved in 2N HCl and washed with ether. The acidic solution is rendered basic and extracted with ether. These extracts are evaporated to yield the title compound, nmr (DMSO-d6) δ 3.97 and 5.00.