Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([CH:19](O)[CH:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:21]#[N:22])[C:10]2=[O:30])[CH:5]=[C:6]([Cl:8])[CH:7]=1.FC(F)(F)C(O)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>ClCCl>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([CH:19]=[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:21]#[N:22])[C:10]2=[O:30])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: N#CC(c1cccnc1)C(O)c1cc2cccnc2n(-c2cc(Cl)cc(Cl)c2)c1=O
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#CC(=Cc1cc2cccnc2n(-c2cc(Cl)cc(Cl)c2)c1=O)c1cccnc1
Reaction time: 1 h
Yield: 90.4 %

Procedure:
3 g of 3-[1-(3,5-dichlorophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-3-hydroxy-2-(3-pyridyl)propionitrile, prepared in Example 77, are suspended in 20 ml of dichloromethane. After the addition of 1.05 ml of trifluoroacetic acid (2 eq), a yellow solution is obtained which becomes bright yellow with a rise in temperature after the addition of 1.44 ml of trifluoroacetic anhydride (1.5 eq). This solution is stirred for one hour and water is then added; the organic phase is decanted, washed with a 10% solution of sodium bicarbonate and then water and dried over magnesium sulfate. After concentration under vacuum, the solid obtained is washed with ether and dried to give 2.6 g of 3-[1-(3,5-dichlorophenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-2-(3-pyridyl)prop-2-enenitrile in the form of a bright yellow solid melting at 261° C. Yield 91%.
Reaction SMILES: [C:1]1(=[O:12])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH2:2]1.[Br:13]Br>C(O)(=O)C>[Br:13][CH:2]1[C:1](=[O:12])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3]1
Reactant: BrBr
Reactant: O=C1CC=CC2=C1CCCCC2
Solvent: CC(=O)O
Product: O=C1C2=C(C=CC1Br)CCCCC2
Reaction time: 4 h

Procedure:
2-bromobenzocycloheptan-1-one was prepared by dissolving benzocycloheptan-1-one (25.15 g, 0.157 mol) in acetic acid (200 mL, 99.8%) in a 500 mL three neck flask. Bromine (25.15 g, 0.157 mol) and acetic acid (10 mL) were placed in a dropping funnel. The bromine was slowly added dropwise to the flask over 4 hours at room temperature. The reactor was kept under a static blanket of nitrogen throughout. Then the reaction was held at room temperature for an additional four hours. The reaction mixture was washed with water (200 mL×2) and dried over sodium sulfate. A brown colored liquid (30.2 g) as a crude product was obtained after filtration from the sodium sulfate. The purity of the product was 96.4% by GC (area %).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[O:22][CH3:21])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: COc1ccccc1O
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: COc1ccccc1OCCCOc1ccc(C[C@H](OC)C(=O)O)cc1

Procedure:
The title compound was prepared from (2S)-3-[4-(3-bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 284, Step 2) and 2-methoxy-phenol via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a colorless oil. MS (ES) for C20H24O6 [M+NH4]+: 378.4.
Reaction SMILES: [CH:1]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22]#[C:23][CH2:24][CH2:25][OH:26])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C=O)C.[Cu]I>[CH:1]([N:14]1[C:15]2[C:16](=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH:22]=[C:23]1[CH2:24][CH2:25][OH:26])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCC#Cc1cc(Cl)ccc1NC(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: OCCc1cc2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1

Procedure:
A solution of the crude 4-[2-(benzhydryl-amino)-5-chloro-phenyl]-but-3-yn-1-ol (25.5 g) and CuI (2.7 g, 14.1 mmol) in DMF (200 mL) was heated at 125° C. for 24 hours. The reaction mixture was filtered through celite and rinsed with EtOAc. The filtrate was concentrated, redissolved in EtOAc, washed with water (3×) and brine, and dried over MgSO4. Silica gel column chromatography (30% EtOAc/hexanes) yielded the desired 2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethanol as a yellow solid (14.5 g, 73% over 2 steps).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[C:10]([N:24]([CH3:26])[CH3:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[C:10]([N:24]([CH3:25])[CH3:26])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1-c1ccccc1F
Agent: [Pd]
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1-c1ccccc1F

Procedure:
The title compound was prepared from (2-dimethylamino-2′-fluoro-5-nitro-biphenyl-4-yl)-carbamic acid tert-butyl ester (Example C2) (4.54 g, 12.1 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a light brown solid (3.324 g).
Reaction SMILES: [H-].[Na+].Cl.Cl.[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[NH:11])=[CH:8][CH:7]=1.CN(C)[CH:17]=[CH:18][C:19]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25])=O>C(O)C>[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]2[N:12]=[C:19]([C:21]3[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=3)[C:24]#[N:25])[CH:18]=[CH:17][N:11]=2)=[CH:8][CH:7]=1
Reactant: N=C(N)c1ccc(N)cc1
Reactant: CN(C)C=CC(=O)c1cccc(C#N)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cccc(-c2ccnc(-c3ccc(N)cc3)n2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
Part A. A flask containing absolute ethanol (10 mL) is cooled to 0° C., and sodium hydride (42 mg, 60% w/w with mineral oil, 1.05 mmol) is added. After stirring for 0.5 h., the solution is treated with 4-aminobenzamidine dihydrochloride (104 mg, 0.50 mmol) and the mixture is allowed to stir for 5 min. Then, 3-(3-dimethylamino-acryloyl)-benzonitrile (100 mg, 0.50 mmol) is added, and the resulting mixture is heated to reflux for 3 h. then cooled to ambient temperature and stirred for 60 h. The mixture is evaporated, and the resulting mixture is triturated with diethyl ether and filtered. The filtrate is evaporated to afford a yellow oil, which is separated by column chromatography (1:1 ethyl acetate-hexane) to afford the product, 3-[2-(4-amino-phenyl)-pyrimidin-4-yl]-benzonitrile (76 mg, 56%). 1H NMR (300 MHz, CDCl3): δ 8.75 (1H, d, J=6 Hz), 8.49 (1H, t, J=2 Hz), 8.37-8.31 (3H, m), 7.75 (1H, dt, J=8, 2 Hz), 7.59 (1H, t, J=8 Hz), 7.40 (1H, d, J=6 Hz), 6.76 (2H, d, J=9 Hz), 4.03 (2H, br s). 13C NMR (CDCl3): δ 164.6, 160.8, 158.0, 149.2, 138.2, 133.6, 131.0, 130.7, 129.8 (2C), 129.5, 127.2, 118.5, 114.5 (2C), 113.0, 112.9. MS (ES+): m/e 274 (20), 273 (100).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc3ccccc3o2)CC1

Procedure:
A mixture of 52.5 mmol 2-chlorobenzoxazol, 53.6 mmol piperazine-1-carboxylic acid tert-butyl ester and 63 mmol of potassium carbonate in 60 ml of acetonitrile was refluxed for 16 hours. The reaction mixture was conentrated, diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated to yield the title compounds as a slightly orange solid. MS (m/e): 304.2 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[OH:10].[CH2:11](N(CC)CC)[CH3:12].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(Cl)(=O)C>C1(C)C(C)=CC=CC=1>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]2[N:1]=[C:11]([CH3:12])[O:10][C:3]=2[CH:4]=1
Reactant: Cc1cc(Br)cc(O)c1N
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1C
Product: Cc1nc2c(C)cc(Br)cc2o1

Procedure:
To 1.5 g (7.42 mmol) 2-amino-5-bromo-3-methyl-phenol in 30 mL xylene is added 1.15 mL (8.19 mmol) triethylamine, 0.68 g (2.70 mmol pyridinium p-toluenesulfonate and 0.55 mL (7.74 mmol) acetyl chloride. The mixture is refluxed for 3 d. Subsequently the solvent is removed in vacuo, and the residue is treated with 50 mL ethylacetate. The mixture is extracted twice with water. The combined aq. layers are extracted with ethylacetate. The combines organic layers are dried and concentrated to yield the desired product.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][CH2:15][C:16]3[CH:20]=[C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[O:18][N:17]=3)=[CH:13][C:8]=2[O:7][CH:6]=1.[OH-].[Li+]>>[F:30][C:27]([F:28])([F:29])[C:24]1[CH:25]=[CH:26][C:21]([C:19]2[O:18][N:17]=[C:16]([CH2:15][O:14][C:12]3[CH:11]=[CH:10][C:9]4[C:5]([CH2:4][C:3]([OH:31])=[O:2])=[CH:6][O:7][C:8]=4[CH:13]=3)[CH:20]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)Cc1coc2cc(OCc3cc(-c4ccc(C(F)(F)F)cc4)on3)ccc12
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1coc2cc(OCc3cc(-c4ccc(C(F)(F)F)cc4)on3)ccc12

Procedure:
The title compound was prepared in the manner analogous to example 24 using {6-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethoxy]-benzofuran-3-yl}-acetic acid methyl ester (80A) and lithium hydroxide. mp 201° C. (decompose); IR (thin film) cm−1: 1711, 1600, 1433, 1319, 1228, 1143; 400 MHz 1H NMR (DMSO-d6) 12.40 (br s, 1H), 8.08 (d, 2H, J=8.1 Hz), 7.86 (d, 2H, J=8.1 Hz), 7.74 (s, 1H), 7.45 (d, 1H, J=8.6. Hz), 7.35 (s, 1H), 7.30 (d, 1H, J=2.0 Hz), 6.93 (dd, 1H, J=6.3, 2.2 Hz), 5.27 (s, 2H), 3.60 (s, 2H); MS m/z 416 (M−1). Anal. Calc'd for C21H14F3NO5: C, 60.44; H, 3.38; N, 3.36; found: 60.49; H, 3.23; N, 3.34.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[S:10][C:11]3[CH2:12][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][C:16]=3[C:3]=12.[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:30][N:31]1[C:39]2[C:34](=[CH:35][C:36]([NH2:40])=[CH:37][CH:38]=2)[CH:33]=[N:32]1>>[C:8]([C:7]1[C:2]([NH:40][C:36]2[CH:35]=[C:34]3[C:39](=[CH:38][CH:37]=2)[N:31]([CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[N:32]=[CH:33]3)=[C:3]2[C:16]3[CH2:15][CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:12][C:11]=3[S:10][C:4]2=[N:5][CH:6]=1)#[N:9]
Reactant: Nc1ccc2c(cnn2Cc2ccccn2)c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Cl)c23)C1
Product: CC(C)(C)OC(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc5c(cnn5Cc5ccccn5)c4)c23)C1

Procedure:
In analogy to Example 54A, the compound was synthesized from tert-butyl 4-chloro-3-cyano-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate from Example 53A (220 mg, 0.63 mmol) and 1-(pyridin-2-ylmethyl)-1H-indazol-5-amine from Example 61A (141 mg, 0.63 mmol) to yield 177 mg (52%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])[NH2:6].C(N(CC)CC)C.[C:22](OC(=O)C)(=[O:24])[CH3:23]>CN(C)C=O>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])[NH:6][C:22](=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@@H](N)CCCNC(=N)N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCCNC(=N)N)NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 148.5 %

Procedure:
To a solution of 2.0 gm (8.9 mMol) arginine methyl ester hydrochloride and 1.5 gm (14.8 mMol) triethylamine in dimethylformamide (150 ml) was added 776 mg (7.4 mMol) acetic anhydride dropwise at 0° C. The reaction mixture was stirred at room temperature for 1 hour and then the volatiles removed under reduced pressure. The residue was purified using silica gel chromatography, eluting with ethyl acetate containing 0-50% methanol, to give N-acetyl arginine methyl ester as a crystalline solid (2.53 g).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[C:6]([F:30])=[C:7]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[C:23]([C:25](OCC)=[O:26])[CH:22]=[N:21]3)=[N:18][CH:19]=2)=[O:13])[C:8]([Cl:11])=[CH:9][CH:10]=1)[CH2:3][CH3:4].CC(C[AlH]CC(C)C)C.C1COCC1>C1COCC1>[NH2:1][C@@H:2]([C:5]1[C:6]([F:30])=[C:7]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH:24]=[C:23]([CH2:25][OH:26])[CH:22]=[N:21]3)=[N:18][CH:19]=2)=[O:13])[C:8]([Cl:11])=[CH:9][CH:10]=1)[CH2:3][CH3:4]
Reactant: CCOC(=O)c1cnn(-c2ccc(C(=O)c3c(Cl)ccc([C@H](N)CC)c3F)cn2)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: CC[C@@H](N)c1ccc(Cl)c(C(=O)c2ccc(-n3cc(CO)cn3)nc2)c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 10.8 %

Procedure:
To ethyl 1-[5-({3-[(1R)-1-aminopropyl]-6-chloro-2-fluorophenyl}carbonyl)pyridin-2-yl]-1H-pyrazole-4-carboxylate (Example 41) (0.154 g, 0.358 mmol) in THF (4 ml) at 0° C. was added 1M DiBAL-H/THF (0.78 ml, 0.787 mmol) stirred at 0° C. for 15 minutes allowed to warm to ambient, further 1M DiBAL-H/THF (0.78 ml, 0.787 mmol) added left further 30 minutes at ambient. Reaction quenched with Rochelles salt and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated, purified by Prep HPLC to give {1-[5-({3-[(1R)-1-aminopropyl]-6-chloro-2-fluorophenyl}carbonyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.015 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]2)=[C:4]([O:14][CH3:15])[CH:3]=1.[C:16]1([CH:22]([N:24]2[CH:28]=[N:27][C:26]([NH2:29])=[N:25]2)[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:15][O:14][C:4]1[CH:3]=[C:2]([NH:29][C:26]2[N:27]=[CH:28][N:24]([CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:23])[N:25]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: COc1cc(Br)ccc1-n1cnc(C)c1
Reactant: CC(c1ccccc1)n1cnc(N)n1
Product: COc1cc(Nc2ncn(C(C)c3ccccc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 43 starting with 1-(4-bromo-2-methoxy-phenyl)-4-methyl-1H-imidazole and 1-(1-phenyl-ethyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a white solid (Yield=66%). MS ISP (m/e): 375.3 (100) [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22]Br)[CH3:20].Cl>CN(C)C=O>[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22][O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1)[CH3:20]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: CCCCC(CC)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1ccc(C(=O)OC)c(O)c1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 70.3 %

Procedure:
To 30 ml of dimethylformamide (DMF) were added 5.00 g (29.9 mmol) of methyl 2,4-dihydroxybenzoate and 4.52 g (32.7 mmol) of potassium carbonate, and 6.32 g (32.7 mmol) of 2-ethylhexyl bromide was added thereto dropwise at room temperature. After the dropwise addition, the mixture was stirred at 80° C. for 5.5 hours. The reaction mixture was added to 200 ml of dilute hydrochloric acid and extracted with a 150 ml portion and two 50 ml portions of ethyl acetate. The resulting extract was washed successively with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The resultant crude product was purified by column chromatography to obtain 5.89 g (yield: 78%) of methyl 4-(2-ethylhexyloxy)-2-hydroxybenzoate represented by the following chemical formula (hereinafter referred to as compound 1) as a colorless, clear and oily substance. The analytical results of the product are shown below. ##STR22##
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:11]=2[CH:10]=1)=[O:8].[C:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)#[N:20]>>[CH3:5][O:6][C:7]([C:9]1[C:12]2[CH:13]=[C:14]([OH:17])[C:15]([C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)=[CH:16][C:11]=2[CH:10]=1)=[O:8]
Reactant: COC(=O)C1=Cc2ccc(OC)cc21
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: COC(=O)C1=Cc2cc(C(=O)c3ccc(C#N)cc3)c(O)cc21

Procedure:
In a manner analogous to that described in Example 5, starting from 26.6 g of aluminium trichloride, 9.61 g of 5-methoxybenzocyclobutene-1-carboxylic acid methyl ester and 17.56 g of p-cyanobenzoyl chloride there is obtained 4-(p-cyanobenzoyl)-5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester having a melting point of 113°-114°.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@H:37]([CH2:42][OH:43])[CH2:38][CH:39]([CH3:41])[CH3:40])=[O:35])[CH2:28][C:29]1[N:33]=[CH:32][NH:31][CH:30]=1)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.[BrH:44].C(O)(=O)C>C(OCC)C>[BrH:44].[BrH:44].[C:14]1([CH2:13][C@@H:12]([C:24]([NH:26][C@H:27]([C:34]([NH:36][C@H:37]([CH2:42][OH:43])[CH2:38][CH:39]([CH3:40])[CH3:41])=[O:35])[CH2:28][C:29]2[N:33]=[CH:32][NH:31][CH:30]=2)=[O:25])[NH2:11])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)C[C@@H](CO)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC(C)C[C@@H](CO)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](N)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 0.59 g. (1 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-L-histidyl-L-leucinol (prepared as described in Example 9) were added 10 ml. of a 25% w/v hydrogen bromide/acetic acid solution. The mixture was stirred at room temperature for 30 minutes, after which there were added 100 ml. of anhydrous diethyl ether. The white precipitate thus formed was separated by filtration, thoroughly washed with diethyl ether and dried in a desiccator. There was obtained 0.52 g. of the desired compound as a white powdery solid, melting at 155°-159° C.; [α]24 +21.0° (C=0.5, methanol).
Reaction SMILES: Cl.C1[O:18][C:5]2([CH2:10][CH2:9][C:8]([NH2:17])([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)OC1.I[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]I.C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)C.O.C(O)C>[C:11]1([C:8]2([N:17]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:7][CH2:6][C:5](=[O:18])[CH2:10][CH2:9]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: ICCCCCI
Reactant: NC1(c2ccccc2)CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: O=C1CCC(c2ccccc2)(N2CCCCC2)CC1
Yield: 61 %

Procedure:
A reaction mixture consisting of the free base from 2.88 gm. (0.011 mole) of 4-amino-4-phenylcyclohexanone ethylene ketal hydrochloride (prepared in Example 32, above), 3.47 gm. 1,5-diiodopentane 2.95 gm. potassium carbonate and 25 ml. ethanol is heated at the reflux temperature, with stirring, for eighteen (18) hours. After cooling and removing most of the liquid and voltiles by evaporation under reduced pressure, the residue thus obtained is dispersed in a mixture of 100 ml. of diethyl ether and 10 ml. of water. The ether layer is allowed to separate and is recovered. It is washed with water and with brine, before removing the ether by evaporation under reduced pressure. The residue thus obtained is dissolved in diethyl ether and an amount of 3 N hydrogen chloride in diethyl ether is added so as to form the hydrochloride acid addition salt which precipitates. The salt is collected on a filter and then recrystallized from a mixture of methylene chloride and ethyl acetate. There is thus obtained 2.26 gm. (61% yield) of 4-phenyl-4-(1-piperidinyl)cyclohexanone, ethylene ketal hydrochloride having a melting range from 228° to 231° C. An analytical sample has a melting point at 234° to 235.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:16]=1.C(Cl)Cl.C(Cl)Cl.[OH2:23]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]3[CH2:11][CH2:12][N:13]([C:8]([O:9][CH:5]([CH3:6])[CH3:4])=[O:23])[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:16]=1
Reactant: O
Reactant: Brc1ccc2oc(C3CCNCC3)nc2c1
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(c2nc3cc(Br)ccc3o2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Intermediate 5 (980 mg, 3.31 mmol) was dissolved in DCM (50 mol) and added TEA (0.45 ml, 3.31 mmol). Reaction mixture cooled to 0° C., isopropylchloro formate (2.7 ml, 6.62 mmol) was added and stirred the reaction mixture for 3 h at rt. Work up (DCM/H2O) followed by column purification on 60-120 mesh silica gel using EtOAc and Petether (15:85) as eluent afforded the titled compound (500 mg) as a pale-red solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[CH:32]=[CH:31]C(C#N)=[CH:27][CH:26]=5)[CH2:21][CH2:20]4)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O.[C:35]([OH:38])(=[O:37])[CH3:36]>>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH:19]4[CH2:20][CH2:21][N:22]([C:25]5[CH:32]=[CH:31][C:36]([C:35]([OH:38])=[O:37])=[CH:27][CH:26]=5)[CH2:23][CH2:24]4)[CH2:15][CH2:14]3)=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)O
Reactant: N#Cc1ccc(N2CCC(N3CCN(c4ccc(C5CCCCC5)cc4)CC3)CC2)cc1
Agent: Cl
Solvent: O
Product: O=C(O)c1ccc(N2CCC(N3CCN(c4ccc(C5CCCCC5)cc4)CC3)CC2)cc1
Temperature: 120 °C
Reaction time: 10 h

Procedure:
To a solution of 4-[4-[4-(4-cyclohexylphenyl)piperazin-1-yl]piperidin-1-yl]benzonitrile (1.95 g) in acetic acid (10 ml) was added concentrated hydrogen chloride (20 ml) and the mixture was stirred at 120° C. for 10 hours. The reaction mixture was added to water and the resulting precipitate was collected by filtration to give 4-[4-[4-(4-cyclohexylphenyl)piperazin-1-yl]piperidin-1-yl]benzoic acid (959 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([N+:12]([O-])=O)=[CH:7][CH:6]=2>CO.[Pd]>[NH2:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3]([CH2:2][OH:1])=[CH:11]2
Reactant: O=[N+]([O-])c1ccc2[nH]c(CO)cc2c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2[nH]c(CO)cc2c1
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a solution of 13 (862 mg, 4.49 mmol) in methanol (50 mL) was added 5% Pd/C (50 mg) and the reaction mixture was hydrogenated for 1 h at a pressure of 50 lb/inch2. The reaction mixture was filtered through celite and the celite was washed with methanol. The solvent was removed in vacuo and 707 mg (97% yield) of grey powder 14 was obtained. mp: 159°-160° C. 1H NMR (DMSO-d6, ppm): 10.44 (s, 1 H, NH), 7.01-6.99 (d, 1 H, J=8.5 Hz, Ar--H), 6.60 (d, 1 H, J=2.0 Hz, Ar--H), 6.43-6.40 (dd, 1 H, J=2.4, 8.5 Hz, Ar--H), 5.97 (brs, 1 H, Ar--H), 5.07 (brs, 1 H, OH), 4.50 (brs, 2 H, CH2OH), 4.30 (brs, 2 H, NH2), Anal. (C9H10N2O), C, H, N.