Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[N:19][N:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[N:19][N:18]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nnc(N3CCN(c4ccc(O)cc4)CC3)c3ccccc23)cc1
Reaction time: 7 h
Yield: 19.6 %

Procedure:
35 mmol of 1-(4-hydroxyphenyl)piperazine dihydrobromide, 35 mmol of 1-chloro-4-(4-tolyl)phthalazine and 52.5 mmol of K2CO3 in 110 ml of absolute N,N-dimethylformamide (DMF) were reacted by the same procedure as described in Example 18. The subsequent stirring time was 2 hours at 90° C. and 7 hours at 105° C. The DMF was then removed by distillation in vacuo. The residue remaining was taken up in CH2Cl2 /water. After thorough mixing, the phases were separated, the aqueous solution was extracted a further three time with CH2Cl2, and the CH2Cl2 extracts were combined and, after drying using MgSO4, were evaporated in vacuo. The residue was mixed with 70 ml of CH2Cl2, and the substance produced in crystalline form during this procedure was filtered off under suction. This solid (1.7 g) was 1,2-dihydro-4-(4-tolyl)phthalazin-1-one, a byproduct. The filtrate was concentrated to a volume of 40-50 ml, whereupon further substance crystallized out, which was filtered off under suction. This component (4.65 g) was boiled briefly with 15 ml of methanol, and, after cooling (<10° C.), filtered off under suction and dried. At this point, 2.72 g of pure 1-(4-hydroxyphenyl)-4-[4-(4-tolyl)phthalazin-1-yl]piperazine, melting point 265°-66° C., were obtained,
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:11]1[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13]2[S:19][C:20]3[CH2:21][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:24][C:25]=3[C:12]=12>>[C:17]([C:16]1[C:11]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=2)=[C:12]2[C:25]3[CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][C:20]=3[S:19][C:13]2=[N:14][CH:15]=1)#[N:18]
Reactant: Nc1ccc(Cl)c(Cl)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(Nc4ccc(Cl)c(Cl)c4)c23)C1

Procedure:
In analogy to Example 54A, the title compound was synthesized from 3,4-dichloroaniline (116 mg, 0.72 mmol) and tert-butyl 4-chloro-3-cyano-5,8-dihydrothieno[2,3-b:5,4-c′]dipyridine-7(6H)-carboxylate (250 mg, 0.72 mmol) from Example 53A to yield 207 mg (61%).
Reaction SMILES: N1C=C(CC[NH:8][CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)N=C1.[CH3:19][C:20]1[C:21]([CH:27]=O)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:19][C:20]1[C:21]([CH2:27][NH:8][CH:9]2[C:18]3[N:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH2:12][CH2:11][CH2:10]2)=[N:22][CH:23]=[C:24]([CH3:26])[CH:25]=1
Reactant: Cc1cnc(C=O)c(C)c1
Reactant: c1cnc2c(c1)CCCC2NCCc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CNC2CCCc3cccnc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of [2-(1H-imidazol-4-yl)-ethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine and 3,5-dimethyl-pyridine-2-carbaldehyde in CH2Cl2 with NaBH(OAc)3 gave COMPOUND 380 as a yellow oil. 1H NMR (CDCl3) δ 1.60 (m, 1H), 1.90 (m, 2H), 2.05 (m, 2H), 2.11 (s, 3H), 2.18 (s, 3H), 2.47 (m, 1H), 2.75 (m, 2H), 2.90 (m, 2H), 3.77 (d, 1H, J=12.0 Hz), 4.04 (m, 2H), 6.65 (s, 1H), 7.04 (t, 2H, J=6.0 Hz), 7.31 (d, 1H, J=9.0 Hz), 7.55 (s, 1H), 8.09 (s, 1H), 8.43 (d, 1H, J=3.0 Hz). 13C NMR (CDCl3) δ 18.2, 18.4, 22.1, 23.2, 23.6, 29.7, 51.4, 55.1, 61.1, 122.1, 124.8, 130.4, 133.0, 134.9, 135.0, 137.1, 139.1, 146.4, 154.3, 158.3. ES-MS m/z 362 [M+H]+. Anal. Calcd. for C22H27N5.0.4H2O.0.3 CH2Cl2: C, 73.10; H, 7.53; N, 19.37. Found: C, 67.69; H, 7.28; N, 17.64.
Reaction SMILES: [OH:1][C:2]1[N:11]=[C:10]([N:12]([NH2:18])C(OCC)=O)[C:9]2[C:4](=[CH:5][C:6]([CH3:20])=[C:7]([CH3:19])[CH:8]=2)[N:3]=1.CN(C)[CH:23]=[O:24]>>[CH3:20][C:6]1[C:7]([CH3:19])=[CH:8][C:9]2[C:10]3[N:11]([C:23](=[O:24])[NH:18][N:12]=3)[C:2](=[O:1])[NH:3][C:4]=2[CH:5]=1
Reactant: CN(C)C=O
Reactant: CCOC(=O)N(N)c1nc(O)nc2cc(C)c(C)cc12
Product: Cc1cc2[nH]c(=O)n3c(=O)[nH]nc3c2cc1C
Temperature: 25 °C

Procedure:
1.0 g (0.0030 mol) of ethyl 2-hydoxy-6,7-dimethyl-quinazolin-4-yl-carbazate in 57 ml of dimethylformamide was boiled under reflux for 2 hrs. The reaction mixture was cooled to room temperature and then poured on to ice-water. The precipitate was filtered off and dried in a vacuum. There were obtained white crystals which were recrystallized from dimethylformamide/methanol. Yield: 0.43 g (52%) of 8,9-dimethyl-2,3,5,6-tetrahydro-1,2,4-triazolo[4,3-c]quinazoline-3,5-dione as yellowish crystals; m.p. >350° C.
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7](=[O:22])[NH:8][C:9]2[C:10]([CH3:21])=[N:11][O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH3:5])[CH2:3][CH2:2]1.[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:27])[CH3:24]>>[CH2:23]([O:25][C:26]([C:28]1([C:31]2[CH:36]=[CH:35][C:34]([C:17]3[CH:18]=[CH:19][C:14]([C:13]4[O:12][N:11]=[C:10]([CH3:21])[C:9]=4[NH:8][C:7]([O:6][CH:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:5])=[O:22])=[CH:15][CH:16]=3)=[CH:33][CH:32]=2)[CH2:29][CH2:30]1)=[O:27])[CH3:24]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)C1CC1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)C4CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-cyclopropyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester; the isolated material was then purified by preparative HPLC, using a Chiracel OD column (97:3 hexanes:EtOH) to provide enantiomer A and enantiomer B. Enantiomer A had a retention time of 27 minutes, enantiomer B had a retention time of 33 minutes.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][N:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:5](=[O:16])[C:4]1([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.S(Cl)([Cl:31])=O.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:31][CH2:2][CH:3]1[CH2:7][N:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[C:5](=[O:16])[C:4]1([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(Cl)Cl
Reactant: CC(c1ccccc1)N1CC(CO)C(c2ccccc2)(c2ccccc2)C1=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(c1ccccc1)N1CC(CCl)C(c2ccccc2)(c2ccccc2)C1=O

Procedure:
To 34.0 g. (0.09 mole) of 4-(hydroxymethyl)-3,3-diphenyl-1-(1-phenylethyl)-2-pyrrolidinone in 200 ml. of chloroform was added 25.0 g. (0.20 mole) of thionylchloride. To this solution with stirring and ice bath cooling was added dropwise, 20.0 g. (0.26 mole) of dry pyridine maintaining the reaction mixture at 25° C. The solution was refluxed for 1.5 hours, concentrated in vacuo and the residue was dissolved in chloroform. The solution was washed successively with dilute hydrochloric acid solution and dilute sodium hydroxide solution. The chloroform solution was dried, filtered, and concentrated in vacuo. The residue was dissolved in hot isopropyl ether and some isooctane was added. The hot solution was decanted from a gummy residue and the product crystallized from the cooled solution. Seven grams were recrystallized in isopropyl ether to give the product which melted at 115°-120° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]1=[O:15].C(OC([NH:23][CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])=O)(C)(C)C.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(N(CC)CC)C>[ClH:1].[NH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:12]1[CH2:13][CH2:14][C:6]2([C:5](=[O:15])[N:4]([O:3][CH3:2])[C:8](=[O:9])[CH2:7]2)[CH2:10][CH2:11]1)=[O:28]
Reactant: CON1C(=O)CC2(CCNCC2)C1=O
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON1C(=O)CC2(CCN(C(=O)CCCN)CC2)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 58.7 %

Procedure:
To a solution of 2-methoxy-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride (1.5 g) in dimethylformamide (100 ml) were added triethylamine (1 ml), 4-(tert-butyloxycarbonylamino)butyric acid (2.03 g), N-hydroxybenztriazole (1.35 g) and dicylohexylcarbodiimide (2.06 g) in sequential additions, and this was followed by stirring at room temperature for 5 hours. The resulting precipitates were then removed. The solvent was evaporated under reduced pressure, and the resulting residual oily substance was dissolved in dichloromethane (50 ml), after which it was washed with a 10% aqueous solution of citric acid and then with water. The organic layer was then dried with anhydrous magnesium sulfate, and this was followed by the evaporation of the solvent under reduced pressure. The resulting residual oil was separated by silica gel column chromatography (eluent; chloroform-acetone-methanol=10:3:2 (v/v)). To the resulting oily substance containing the desired product was added a solution of 6N hydrogen chloride in ethanol (20 ml), and it was kept standing at room temperature for 10 minutes. The solvent was then evaporated under reduced pressure. The resulting oily substance was separated by silica gel column chromatography (eluent; chloroform-methanol-water=14:6:1) to obtain 1.2 g of a noncrystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:13])[C:10](O)=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:13])[C:10]([N:27]=[N+:28]=[N-:29])=[O:11])=[CH:4][CH:3]=1
Reactant: CC(=Cc1ccc(Cl)cc1)C(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=Cc1ccc(Cl)cc1)C(=O)N=[N+]=[N-]
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a solution of 3-(4-chlorophenyl)-2-methyl-acrylic acid (11.2 g, 57 mmol) in 500 mL of acetone at 0° C. is added triethyl amine (9.6 mL, 68 mmol) followed by ethyl chloroformate (6.2 mL, 63 mmol). The solution is allowed to warm to ambient temperatures. After 2 h, sodium azide (5.6 g, 86 mmol) in 35 mL of H2O is added. After addition, the solution is stirred for 2 hours. The solution is diluted with H2O (100 mL). The resulting solid is collected by filtration giving the title compound as a white solid (11.1 g, 50 mmol). 1H NMR (CDCl3, 300 MHz) δ7.67 (s, 1H), 3.38 (m, 4H), 2.10 9s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)[CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.FC1C=C([N+]([O-])=O)C=C(I)C=1>[Pd].C(O)C>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([B:11]2[O:15][C:14]([CH3:16])([CH3:17])[C:13]([CH3:19])([CH3:18])[O:12]2)[CH:3]=1
Reactant: CC1(C)OB(c2cc(F)cc([N+](=O)[O-])c2)OC1(C)C
Agent: [Pd]
Agent: O=[N+]([O-])c1cc(F)cc(I)c1
Solvent: CCO
Product: CC1(C)OB(c2cc(N)cc(F)c2)OC1(C)C

Procedure:
Combine 1-fluoro-3-iodo-5-nitrobenzene 2-(3-Fluoro-5-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (940 mg, 3.5 mmol), 5% palladium on carbon (˜60% H2O, 200 mg), and anhydrous ethanol (25 mL). Purge and fill the reaction vessel with hydrogen three times. Stir the reaction mixture under 1 atm of hydrogen. When the reaction is complete by LCMS, filter the reaction mixture through celite to remove the catalyst and wash the filter cake with ethanol. Strip to dryness and purify the crude product by flash chromatography (25% ethyl acetate/hexanes) and combine product fractions. Strip to dryness to provide the crude product. LCMS (APCI-pos): mass 238.2 (M+1), Purity by LCMS (UV area percent): 85%. 1HNMR (CDCl3, 400 MHz): δ6.88-6.83 (m, 2H), 6.47-6.43 (m, 1H), 3.55-3.9 (bs, 2H), 1.32 (s, 12H)
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[NH2:32][CH2:33][C@H:34]([OH:36])[CH3:35].CCN=C=NCCCN(C)C.Cl.Cl>ClCCl.CN(C)C1C=CN=CC=1>[OH:36][C@H:34]([CH3:35])[CH2:33][NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: C[C@@H](O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(C(=O)NC[C@@H](C)O)[nH]2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
5-{3-[(1S)-2-Methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrole-2-carboxylic acid (204 mg, 0.458 mmol) synthesized in Example (18a) was dissolved in dichloromethane (10 mL), and (R)-(−)-1-amino-2-propanol (72.0 μmL, 0.914 mmol), WSCI•HCl (130 mg, 0.678 mmol) and 4-dimethylaminopyridine (115 mg, 0.941 mmol) were added, followed by stirring at room temperature for 18 hours under nitrogen atmosphere. 1N hydrochloric acid (10 mL) was added, and the solution was separated with dichloromethane (15 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=60%-100%) to afford the desired product (191 mg, yield 83%) as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:27][N:26]=[C:25]([CH3:28])[C:24]=4[CH2:29]Br)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4].[C:31]1([CH2:37][CH2:38][SH:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[CH2:3]([O:5][C:6]([C:8]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[O:27][N:26]=[C:25]([CH3:28])[C:24]=4[CH2:29][S:39][CH2:38][CH2:37][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:10][CH2:9]1)=[O:7])[CH3:4]
Reactant: SCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CSCCc4ccccc4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60% in mineral oil, 0.070 g, 1.70 mmol) was added to a solution of 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.500 g, 1.13 mmol) and 2-phenylethanethiol (0.15 mL, 1.13 mmol) in DMF. The reaction was stirred at room temperature for 2 hours, and then partitioned between EtOAc and H2O and acidified with 1 N aqueous HCl. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. Analytical LCMS indicated that a mixture of the title compound and the hydrolyzed acid were present, so the crude material was used directly in the hydrolysis step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)=[CH:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[F:26]>[Pd].CO>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:17]2[NH:25][C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:6][C:5]=1[F:26]
Reactant: COC(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1F
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(C(CC2CCCC2)c2cc3cccnc3[nH]2)cc1F
Temperature: 50 °C
Yield: 94.9 %

Procedure:
A mixture of 4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-2-fluoro-benzoic acid methyl ester (250 mg, 0.69 mmol) and 10% palladium on activated carbon (75 mg) in methanol (250 mL) was heated at 50° C. under hydrogen (50 psi) for 16 h. The mixture was cooled to 25° C., the solids filtered off, washed with ethyl acetate and concentrated in vacuo to afford 4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-ethyl]-2-fluoro-benzoic acid methyl ester (240 mg, 95%) as a white solid which was used in the next step without further purification: LC/MS m/e calcd for C22H23FN2O2 [M+H]+ 367.4, observed 367.0.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[CH:16]=2)[CH2:9]1)C1C=CC=CC=1.C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(OC(C)(C)C)=O.ClC(OC(Cl)C)=O>>[CH3:21][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[CH2:14][CH:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: Cc1cccc(CC2CN(Cc3ccccc3)CCO2)c1
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Agent: CC(Cl)OC(=O)Cl
Product: Cc1cccc(CC2CNCCO2)c1

Procedure:
Example 76 was prepared as described for example 27, but using N-benzyl-2-(3-methylbenzyl)-morpholine, intermediate (a) and 1-chloroethyl chloroformate and was isolated as a colorless oil (38.6 mg).
Reaction SMILES: Br.Br.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:17]3[O:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: Clc1nc2ccccc2o1
Reactant: Oc1ccc(N2CCNCC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc(N2CCN(c3nc4ccccc4o3)CC2)cc1
Temperature: 85 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
A mixture of 5.11 g (15 mmol) of 1-(4-hydroxyphenyl)piperazine dihydrobromide, 2.46 g (16 mmol) of 2-chlorobenzoxazole and 2.18 g (15.8 mmol) of powdered K2CO3 in 55 ml of absolute N,N-dimethylformamide was warmed to 85° C., and 345 mg of powdered K2CO3 were added with stirring under a nitrogen atmosphere in each case after 10 minutes, after a further 25 minutes and after a further 60 minutes (total addition of 1.035 g (7.5 mmol) of K2CO3). The mixture was stirred for a further 3 hours at 85° C., the DMF was substantially removed by distillation in an oil-pump vacuum in a rotary evaporator, the crystalline residue was mixed with 50 ml of water, and this mixture was shaken for 15 minutes. The mixture was then filtered under suction and the filter residue was washed with water and dried in vacuo. 4.30 g (97% of theory) of pure 1-(4-hydroxyphenyl)-4-(benzoxazol-2-yl)piperazine, melting point 161°-3° C., were obtained,
Reaction SMILES: CN1C=CN=C1.[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]([N:16]2[C@H:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]1.S(Cl)(C)(=O)=O.[CH3:51][C@H:52]1[CH2:57][N:56]([CH3:58])[CH2:55][CH2:54][N:53]1[C:59]1[N:64]=[C:63]([NH2:65])[CH:62]=[CH:61][N:60]=1>ClCCl>[CH:7]1([CH2:12][C@H:13]([CH2:34][N:35]([CH:44]=[O:45])[O:36][CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:14]([N:16]2[C@H:20]([C:21]([NH:65][C:63]3[CH:62]=[CH:61][N:60]=[C:59]([N:53]4[CH2:54][CH2:55][N:56]([CH3:58])[CH2:57][C@@H:52]4[CH3:51])[N:64]=3)=[O:22])[CH2:19][CH2:18][N:17]2[C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:25])=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: C[C@H]1CN(C)CCN1c1nccc(N)n1
Agent: CS(=O)(=O)Cl
Agent: Cn1ccnc1
Solvent: ClCCl
Product: C[C@H]1CN(C)CCN1c1nccc(NC(=O)[C@@H]2CCN(C(=O)OCc3ccccc3)N2C(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 58.2 %

Procedure:
1-Methylimidazole (133 μl, 1.674 mmol) was added into the solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (300 mg, 0.558 mmol) in dichloromethane (DCM) (4 ml). The resulting solution was cooled to 0° C., and then mesyl chloride (45.4 μl, 0.586 mmol) was added dropwise at 0° C. To the reaction mixture was added 2-[(25)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinamine (127 mg, 0.614 mmol). After stirring for 1 h 40 min at ambient temperature, the reaction solution was purified by RP-HPLC to yield phenylmethyl (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-3-[({2-[(2S)-2,4-dimethyl-1-piperazinyl]-4-pyrimidinyl}amino)carbonyl]-1-pyrazolidinecarboxylate (236 mg, 0.325 mmol, 58% yield). MS (ES+) m/z 515.4 (MH+). MS (ES+) m/z 727.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[CH:8]1([Mg]Cl)[CH2:12][CH2:11][CH2:10][CH2:9]1>O1CCCC1.C1C=CC(P(C2C=CC=CC=2)CCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ni]Cl>[CH:8]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Brc1cccnc1
Reactant: Cl[Mg]C1CCCC1
Agent: Cl[Ni]Cl
Agent: c1ccc(P(CCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cncc(C2CCCC2)c1
Temperature: -5 °C
Yield: 29.5 %

Procedure:
3-Bromopyridine (3.9 ml, 40 mmol) and [1,2-bis(diphenylphosphino)ethane]dichloronickel(II) (160 mg, 0.3 mmol) were dissolved in dry tetrahydrofuran (25 ml) and cooled to −5° C. Cyclopentylmagnesium chloride (2.0M in diethyl ether, 20 ml, 40 mmol) was added dropwise over 5–10 minutes and the reaction was allowed to warm slowly to room temperature. Further cyclopentylmagnesium chloride (2.0M in diethyl ether, 5 ml, 10 mmol) was added. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution. The mixture was partitioned between water and ethyl acetate. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 20–35% ethyl acetate/i-hexane, to give the title compound (1.74 g, 30%).