Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:18])/[CH:4]=[CH:5]/[N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:17])[CH:13]=2)[N:8]=[CH:7]1.Cl.C(O)(=O)C=C>O>[OH:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6](/[CH:5]=[CH:4]/[C:3]([OH:18])=[O:2])[C:15]2=[O:16]
Reactant: COC(=O)/C=C/n1cnc2ccc(O)cc2c1=O
Agent: C=CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)/C=C/n1cnc2ccc(O)cc2c1=O

Procedure:
A mixture of 8.35 g. of trans-3-(6-hydroxy-4-oxo-4H-quinazolin-3-yl)-2-propenoic acid methyl ester and 500 ml. of 6 N hydrochloric acid was stirred and refluxed for 15 minutes. After cooling, water was added and the resultant solid was filtered to yield 6.33 g., m.p. 294°-296°; of trans-3-hydroxy-4-oxo-4H-quinazolin-3-yl)-2-propenoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:12]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[C:7]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: O=C1CCc2cc(Cl)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: COC(C)(C)OC
Product: CC=CCC1Cc2cc(Cl)ccc2C1=O
Yield: 36 %

Procedure:
A solution of 25 g of 5-chloro-1-indanone, 31 ml of 3-buten-2-ol and 250 mg of p-toluenesulfonic acid in 31 ml of 2,2-dimethoxy-propane and 250 ml of anhydrous toluene was boiled under reflux for 17 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 11.9 g (36%) of (RS)-2-(2-buten-1-yl)-5-chloro-1-indanone were obtained as a yellow oil.
Reaction SMILES: C([Mg]Cl)(C)C.[Li+].[Cl-].Br[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[CH:14](=[O:17])[CH2:15][CH3:16].[Cl-].[NH4+]>C1COCC1>[S:10]1[CH:11]=[CH:12][N:13]=[C:9]1[CH:14]([OH:17])[CH2:15][CH3:16]
Reactant: CCC=O
Reactant: Brc1nccs1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(O)c1nccs1
Temperature: 0 °C

Procedure:
A 1.3 M solution of i-PrMgCl.LiCl (2.65 mL, 3.44 mmol) under an atmosphere of argon was cooled to −15° C. and treated with a solution of 2-bromothiazole (0.56 g, 3.4 mmol) in anhydrous THF (1 mL). The reaction mixture was then allowed to warm to 0° C. over 15 minutes. Propionaldehyde (0.25 mL, 3.4 mmol) was added and the solution was allowed to warm to room temperature over 18 hours. The solution was poured into saturated aqueous ammonium chloride (50 mL) containing crushed ice. The aqueous layer was extracted with EtOAc (50 mL) and washed with saturated aqueous sodium bicarbonate (100 mL). The aqueous layer was again extracted with EtOAc (50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The material was purified by silica gel chromatography eluting with a gradient of 0-10% methanol in dichloromethane to afford 1-thiazol-2-yl-propan-1-ol.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:7]1)[CH3:2].[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH2:32]Cl>>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH2:32][N:18]1[CH2:17][CH2:16][CH:15]([C:8]2[C:9]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH:7]=2)[CH2:20][CH2:19]1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: CCOCCn1cc(C2CCNCC2)c2cccnc21
Product: CCOCCn1cc(C2CCN(CCOc3ccccc3C(=O)OC)CC2)c2cccnc21

Procedure:
This compound was prepared following the procedure described in example 4, part E, starting with 0.98 g (3.58 mmol) of 1-(2-ethoxyethyl)-3-piperidin-4-yl-1H-pyrrolo[2,3-b]pyridine and 0.92 g (4.29 mmol) of 2-(2-chloroethoxy)benzoic acid methyl ester. After standard work-up and purification, 0.58 g (36% of yield) of the expected product were obtained.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2].[H][H]>C(O)C.[Pd]>[C:1]([CH2:3][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=Cc1ccccc1CC#N
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccccc1CC#N

Procedure:
Ethyl o-(cyanomethyl)cinnamate (75.1 g., 0.35 mole) is dissolved in ethanol (300 ml.) and hydrogenated at a pressure of 1 atmosphere and room temperature over 2.5 g. of a 5% palladium on charcoal catalyst. When the theoretical amount of hydrogen (0.35 mole) has been absorbed, the catalyst is filtered off and the ethanol removed by distillation at reduced pressure to yield ethyl o-(cyanomethyl)hydrocinnamate.
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[N:8][CH:9]=1.[C:17]1([C:23](=[N:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C=CCO[C@H](C1C2C(=CC=CC=2)N=CC=1)[C@H]1[N+]2(CC3C4C(=CC=CC=4)C=C4C=3C=CC=C4)C[C@H](C=C)[C@@H](CC2)C1.[Br-].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>ClCCl>[C:17]1([C:23](=[N:30][C@@H:31]([CH2:3][C:4]2[CH:9]=[N:8][C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:16])=[CH:6][CH:5]=2)[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: Cc1ccccc1-c1ccc(CBr)cn1
Agent: Br
Agent: C=CCO[C@H](c1ccnc2ccccc12)[C@@H]1C[C@@H]2CC[N+]1(Cc1c3ccccc3cc3ccccc13)C[C@@H]2C=C
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(C[C@H](N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)cn1
Temperature: -78 °C
Reaction time: 10 h
Yield: 100 %

Procedure:
To a stirred mixture of 800 mg (2.33 mmol) of 5-(bromomethyl)-2-o-tolylpyridine hydrobromide, 689 mg (2.33 mmol, 1.0 equivalent) of tert-butyl 2-(diphenylmethyleneamino)acetate and 141 mg (0.233 mmol, 0.1 equivalent) of O-allyl-N-(9-anthracenylmethyl)cinchonidinium bromide in 14 mL of dichloromethane at −78° C. under argon was added 1.687 mL (5.83 mmol, 2.5 eq) of 2-t-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine over 5 min. The reaction mixture was stirred at −78° C. for 10 h and then allowed to warm to room temperature in situ. The mixture was directly purified by silica gel chromatography using ethyl acetate/dichloro-methane (1:4) as eluant (5×10 cm column), to give tan oil, 1.10 g, 100% yield.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]([SH:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([S:20][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)S
Reactant: O=Cc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1ccccc1C=O
Temperature: 50 °C
Yield: 40.3 %

Procedure:
2-fluoro-benzaldehyde (2.00 g, 16.1 mmol), potassium carbonate (2.45 g, 17.7 mmol) and 2-methyl-2-propanethiol (17.1 mmol) were dissolved in 10.0 mL DMF in a 50 mL round-bottomed flask under dry nitrogen, topped with a reflux condenser. The reaction mixture was heated to 50° C. for 4 days. After cooling, the mixture was added to 50 ml of saturated potassium carbonate solution and extracted with 3×50 mL portions of ether. The extracts were dried with magnesium sulfate and evaporated. The crude product was further purified by chromatography on silica gel using 2:1 dichloromethane/n-hexane as eluent to give a yellow oil (1.26 g, 40%). 1H NMR (200 MHz, CDCl3): δ 1.26 (s, 9H), 7.43-7.63 (m, 3H), 7.96 (dd, J1=6.9, J2=2.5, 1H), 10.76 (s, 1H) ppm.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[C:15]1[C:16]2[N:17]([CH:21]=[CH:22][N:23]=2)[CH:18]=[CH:19][N:20]=1>C(NC(C)C)(C)C.CN1C(=O)CCC1.C(OCC)(=O)C>[N:23]1[CH:22]=[CH:21][N:17]2[CH:18]=[CH:19][N:20]=[C:15]([N:1]3[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]3)[C:16]=12
Reactant: Clc1nccn2ccnc12
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2nccn3ccnc23)C1
Temperature: 100 °C
Yield: 94.9 %

Procedure:
To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (80.2 g, 0.43 mol, 1.1 eq) in 75 mL of diisopropylamine and 34 mL of NMP was added portionwise 8-chloroimidazo[1,2-a]pyrazine (60 g, 0.39 mol, 1 eq). The reaction mixture was heated at 100° C. for 4 h and was then diluted with 1.2 L of ethyl acetate. The organic layer was washed with H2O and brine, dried with Na2SO4 and concentrated to give (S)-tert-butyl (1-(imidazo[1,2-a]pyrazin-8-yl)pyrrolidin-3-yl)carbamate (111.7 g, 0.37 mol, 94%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21]C)([CH3:20])[CH3:19])[CH:15]=[C:14]([C:23]([CH2:26]C)([CH3:25])[CH3:24])[C:13]=1[OH:28])([O-])=O.[N+](C1C=CC([Cl:38])=CC=1N=NC1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1O)([O-])=O>>[Cl:38][C:7]1[CH:8]=[CH:9][C:4]2=[N:1][N:11]([C:12]3[CH:17]=[C:16]([C:18]([CH3:21])([CH3:19])[CH3:20])[CH:15]=[C:14]([C:23]([CH3:24])([CH3:26])[CH3:25])[C:13]=3[OH:28])[N:10]=[C:5]2[CH:6]=1
Reactant: CCC(C)(C)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)CC)c1
Reactant: CC(C)(C)c1cc(N=Nc2cc(Cl)ccc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Product: CC(C)(C)c1cc(-n2nc3ccc(Cl)cc3n2)c(O)c(C(C)(C)C)c1
Yield: 68.2 %

Procedure:
When in Example 1, the 2-nitro-2'-hydroxy-3',5'-di-tert-amylazobenzene was replaced by an equivalent amount of 2-nitro-5-chloro-2'-hydroxy-3',5'-di-tert-butylazobenzene, the above noted product was obtained in a yield of 68.2%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[Cl-].[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OCc1ccccc1)c1ccc(F)cc1

Procedure:
A mixture of 4-fluorobenzoic acid (5.0 g, 36 mmol) in CH2Cl2 was treated with oxallyl chloride (6.2 mL, 72 mmol) and a catalytic amount of DMF. The mixture was stirred until the evolution of gas stopped and then concentrated under reduced pressure. The residue was re-dissolved in CH2Cl2 and the solution was added in a drop wise manner to a mixture of benzyl alcohol (3.9 g, 36 mmol), diisopropyl ethyl amine (12.6 mL, 72 mmol) and a catalytic amount of DMAP in CH2Cl2. After stirring overnight the reaction mixture was concentrated and the residue was passed through a silica gel plug with 10% Et2O in hexanes. The intermediate 4-fluoro benzoic acid benzyl ester obtained from the above procedure was dissolved in DMSO (25 mL). Followed addition of piperazine (14 g, and the mixture was heated in a sealed tube at 120° C. overnight. Next morning the reaction mixture was partitioned between EtOAc and water. The water layer was basified to pH 12 with solid NaOH, extracted once again with EtOAc and the combined EtOAc layer was dried over Na2SO4, filtered and concentrated to afford the product (8.5 g, Yield: 80%). HRMS m/z calcd for C18H20N2O2 [M+H]: 297.1598. Found: 297.1597.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:4]=2[S:3]1(=[O:14])=[O:13].[Br:15]N1C(=O)CCC1=O>CC(C)C#N>[Br:15][CH2:12][C:10]1[CH:9]=[CH:8][C:5]2[C:6](=[O:7])[N:2]([CH3:1])[S:3](=[O:13])(=[O:14])[C:4]=2[CH:11]=1
Reactant: Cc1ccc2c(c1)S(=O)(=O)N(C)C2=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)C#N
Product: CN1C(=O)c2ccc(CBr)cc2S1(=O)=O
Yield: 23.7 %

Procedure:
Using a procedure analogous to that described in Preparation 8, from 2,6-dimethyl-1,1-dioxo-benzo[d]isothiazole-3-one (2 g), N-bromosuccinimide (1.7 g) and 2,2'-azo-bis(2-methyl-propionitrile (10 mg) was obtained 650 mg of the title compound. m.p. 153°-154° C.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(O)(=O)C.C(OCC)(=O)C>ClC(Cl)C>[CH2:13]([N:10]1[CH2:9][CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: C1=C(c2ccccc2)CCNC1
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: C1=C(c2ccccc2)CCN(Cc2ccccc2)C1
Yield: 50 %

Procedure:
1,2,3,6-Tetrahydro-4-phenylpyridine (410 mg, 2.6 mmol), benzaldehyde (300 mg, 2.9 mmol), sodium triacetoxyborate (1.1 g, 5.2 mmol) and acetic acid (1.5 ml, 26 mmol) were stirred in dichloroethane at a room temperature for 14 hours. To the reaction solution was added ethyl acetate, and the resulting solution was washed with sodium hydroxide aqueous solution (1 N) and saturated brine and dried with anhydrous sodium sulfate. Then the solvent was evaporated under a reduced pressure. Thereafter, the resulting residue was separated and purified by a silica gel column chromatography to obtain 330 mg of the title compound (1.3 mmol, 45% in yield).
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([CH3:13])[CH:5]=1)([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH2:33][CH2:34][C:35]1[C:36]([OH:43])=[N:37][C:38]([CH3:42])=[CH:39][C:40]=1[CH3:41]>ClCCl>[OH:43][C:36]1[C:35]([CH2:34][NH:33][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][C:6]=2[CH3:13])=[C:40]([CH3:41])[CH:39]=[C:38]([CH3:42])[N:37]=1
Reactant: Cc1cc(C(C)C)ccc1C(=O)O
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)C)cc2C)c(O)n1
Temperature: 20 °C
Reaction time: 13 h
Yield: 35.6 %

Procedure:
To a solution of 4-isopropyl-2-methylbenzoic acid (80 mg, 0.45 mmol), 1-hydroxybenzotriozole (91 mg, 0.68 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (130 mg, 0.68 mmol), triethylamine (0.3 mL) in dichloromethane (15 mL) was added 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (69 mg, 0.45 mmol). The reaction mixture was stirred at 20° C. for 13 hours. The mixture was washed with water (20 mL×2). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-isopropyl-2-methylbenzamide as a white solid (50 mg, 36%). LRMS (M+H+) m/z: calcd 312.18. found 312. HPLC Purity (214 nm): 99%. 1H NMR (300 MHz, d6-DMSO): δ 11.45 (s, 1H), 8.00 (t, J=4.8 Hz, 1H), 7.20-7.06 (m, 3H), 5.85 (s, 1H), 4.25 (d, J=4.8 Hz, 2H), 2.91-2.82 (m, 1H), 2.29 (s, 4H), 2.12 (s, 2H), 2.10 (s, 1H), 1.17 (m, 1H) (d, J=6.9 Hz, 6H).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12]([Br:14])[C:11](=[O:15])[NH:10][C:9]1=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29]Br)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][N:10]1[C:11](=[O:15])[C:12]([Br:14])=[CH:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:16])=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: O=c1[nH]c(=O)n(Cc2ccccc2)cc1Br
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCn1c(=O)c(Br)cn(Cc2ccccc2)c1=O
Temperature: 60 °C

Procedure:
To a solution of 1-benzyl-5-bromo-1H-pyrimidine-2,4-dione (1.0 g, 3.6 mmol) in N,N-dimethylformamide (15 mL) was added tetrabutylammonium bromide (46 mg, 0.14 mmol) and sodium hydroxide (160 mg, 3.9 mmol). The suspension was stirred vigorously, heated to 60° C. for 1.5 h and then cooled to ambient temperature. N-tert-butoxycarbonyl-3-bromopropylamine (0.93 g, 3.9 mmol) was added, the reaction was heated to 50° C. for 20 h and then concentrated in vacuo. The residue was taken up in ethyl acetate:water (1:1 100 mL), the layers separated and the aqueous layer extracted with ethyl acetate (3×50 mL). The organic layers were combined and washed with 0.5 M sodium hydroxide (1×50 mL), water (1×50 mL), brine (1×100 mL), dried with magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by pressurized silica gel chromatography (40% ethyl acetate in hexane) to provide 3-(3-tert-butoxycarbonylaminopropyl)-1-benzyl-5-bromo-1H-pyrimidine-2,4-dione.
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]([OH:21])=O)[NH:3][C:4](=[O:17])[NH:5][CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[NH2:22][C@@H:23]([CH2:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[CH:50][CH:49]=1)[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)=[O:25]>>[C:55]([O:54][C:51]1[CH:50]=[CH:49][C:48]([CH2:47][C@H:23]([NH:22][C:19](=[O:21])[CH2:18][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][CH:8]=2)=[O:17])[C:24]([N:26]([C@@H:38]([CH3:46])[CH:39]([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])[CH2:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:53][CH:52]=1)([CH3:58])([CH3:56])[CH3:57]
Reactant: CN(CC(=O)O)NC(=O)NCc1cccc2ccccc12
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1cccc2ccccc12

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(naphthalen-1-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-8) 85 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>CS(C)=O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[CH:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Solvent: CS(C)=O
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Yield: 84.6 %

Procedure:
A mixture of 19.7 g of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 30.1 g of anhydrous piperazine and 100 ml of dimethyl sulphoxide is heated at 135°-140° C. for 2 hours. The solvent is distilled out under high vacuum, and the residue is suspended in H2O, filtered off with suction and washed with water. For further purification, the moist crude product is boiled with 100 ml of water, filtered with suction at room temperature, the solid is washed with H2O and dried to constant weight over CaCl2 in a vacuum oven at 100° C. 19.6 g of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid, of decomposition point 255°-257° C., are obtained; RF value: 0.07.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@@H:14]([CH2:27][CH:28]2[CH2:31][CH2:30][CH2:29]2)[C:15]([O:17]CC2C=CC(OC)=CC=2)=[O:16])[CH2:4]1)=O.[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.C(Cl)Cl.CO.[NH4+].[OH-]>>[C:32]1([CH2:38][CH2:39][CH2:40][CH:41]2[CH2:42][CH2:43][N:44]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C@@H:14]([CH2:27][CH:28]4[CH2:29][CH2:30][CH2:31]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:45][CH2:46]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: c1ccc(CCCC2CCNCC2)cc1
Reactant: COc1ccc(COC(=O)[C@H](CC2CCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=C(O)[C@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2ccccc2)C1
Yield: 63.8 %

Procedure:
The title compound was prepared from 25 mg (0.059 mmol) of 2-(S)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, (4-methoxy)benzyl ester (from EXAMPLE 92, Step C) and 14.3 mg (0.059 mmol) of 4-(3-phenylpropyl)piperidine.HCl using a procedures analogous to those described in EXAMPLE 1, Step J and EXAMPLE 10, Step F to 18.4 mg (64%) of the title compound: RF: 0.48 (90:10:1 v/v/v CH2Cl2/MeOH/NH4OH); 1H NMR (300 MHz, CD3OD) δ 0.99-3.67 (m, 33H), 6.96-7.23 (m, 10H); ESI-MS 489 (M+H); HPLC A: 2.69 min.
Reaction SMILES: C([O:8][C:9]1[CH:23]=[CH:22][C:12]2[CH2:13][CH2:14][N:15]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[CH2:16][CH2:17][C:11]=2[CH:10]=1)C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[CH:18]1([N:15]2[CH2:16][CH2:17][C:11]3[CH:10]=[C:9]([OH:8])[CH:23]=[CH:22][C:12]=3[CH2:13][CH2:14]2)[CH2:21][CH2:20][CH2:19]1
Reactant: c1ccc(COc2ccc3c(c2)CCN(C2CCC2)CC3)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc2c(c1)CCN(C1CCC1)CC2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
7-Benzyloxy-3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E1) (9.22 g, 30 mmol) was dissolved in ethanol (150 ml) and tetrahydrofuran (50 ml). Palladium (1.5 g, 10% on charcoal paste) was added and the reaction mixture was stirred at room temperature under hydrogen (1 atmosphere) for 5 hours. The reaction mixture was filtered through celite and the filtrate concentrated in vacuo. The crude residue was triturated with diethyl ether and filtered to afford the title product (E3); MS (ES+) m/e 218 [M+H]+.
Reaction SMILES: FC(F)(F)C([NH:5]OC(=O)C(F)(F)F)=O.N1C=CC=CC=1.[CH2:21]([N:25]1[C:29](=[O:30])[CH:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]=O)=[CH:34][CH:33]=2)[NH:27][C:26]1=[O:40])[CH2:22][CH2:23][CH3:24]>C1C=CC=CC=1>[CH2:21]([N:25]1[C:29](=[O:30])[CH:28]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:5])=[CH:34][CH:33]=2)[NH:27][C:26]1=[O:40])[CH2:22][CH2:23][CH3:24]
Reactant: CCCCN1C(=O)NC(Cc2ccc(C=O)cc2)C1=O
Reactant: O=C(NOC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCCN1C(=O)NC(Cc2ccc(C#N)cc2)C1=O

Procedure:
The formyl compound (4.3 g., 0.01 mole), N,O-bis (trifluoroacetyl)hydroxylamine (3.6 g., 0.016 mole) and dry pyridine (2.6 ml. 0.032 mole) were mixed in benzene (75 ml) and heated under reflux for 2 hours. After cooling the benzene solution was washed with water (2×50 ml), dried over magnesium sulphate monohydrate and evaporated in vacuo to give an oil which slowly crystallised. This product was further purified by silica gel chromatography and recrystallisation from a small volume of ethyl acetate to give the title compound, yield 2.5 g., m.p. 136° C.