Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[C:2]1([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10][N+:9]=2[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][Mg]Br.[Cl-].[NH4+]>C(OCC)C>[CH3:25][C:8]1([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][N:9]1[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: c1ccc(C[N+]2=C(c3ccccc3)c3ccccc3CC2)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [I-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC1(c2ccccc2)c2ccccc2CCN1Cc1ccccc1

Procedure:
To a suspension of 1-phenyl-2-benzyl-3,4-dihydroisoquinolinium iodide (1.0 g) in diethyl ether (10 ml) was added 3 M diethyl ether solution of methylmagnesium bromide (4.5 ml). The mixture was refluxed for 30 minutes with stirring and then poured into saturated ammonium chloride aqueous solution and extracted with ethyl acetate. The separated organic layer was washed with water, sodium chloride aqueous solution and dried over magnesium sulfate and evaporated in vacuo. The residue was crystallized from n-hexane to give 1-methyl-1-phenyl-2-benzyl-1,2,3,4-tetrahydroisoquinoline (0.64 g).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].Cl[C:8]1[N:9]([CH2:31][CH:32]2[CH2:34][CH2:33]2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:13]=[C:12]([C:23]1[C:24]([CH3:30])=[N:25][C:26]([NH2:29])=[N:27][CH:28]=1)[N:11]=2>CS(C)=O>[NH2:29][C:26]1[N:25]=[C:24]([CH3:30])[C:23]([C:12]2[N:11]=[C:10]3[C:15]([N:16]=[C:8]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[N:9]3[CH2:31][CH:32]3[CH2:34][CH2:33]3)=[C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[N:13]=2)=[CH:28][N:27]=1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Reactant: CN(C)CCN
Solvent: CS(C)=O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(NCCN(C)C)n(CC3CC3)c2n1
Temperature: 150 °C
Reaction time: 3 h
Yield: 54.4 %

Procedure:
N,N-Dimethylethylenediamine (110 mg, 1.3 mmol) and dimethyl sulfoxide (700 μl) were added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.26 mmol) and the resulting mixture was stirred at 150° C. for 3 hours. The reaction mixture was partitioned with ethyl acetate and water, the organic layer was concentrated, and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (64 mg, 52%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[BH-](OC(C)=O)(OC(C)=O)O[C:30](C)=O.[Na+].[OH-].[Na+]>CO.C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:30])[C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:27]=[CH:26][C:21]4[NH:22][C:23](=[O:25])[O:24][C:20]=4[CH:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=c1[nH]c2ccc([C@H]3CC[C@H](NCCCc4ccc(Cl)cc4)CC3)cc2o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CN(CCCc1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6-{trans-4-[3-(4-chlorophenyl)-propylamino]-cyclohexyl}-3H-benzoxazol-2-one (655 mg, 1.7 mmol) in MeOH (20 mL) and CH2Cl2 (25 mL) was added p-formaldehyde (0.70 mL of a 37 wt % solution in H2O, 8.5 mmol). The reaction mixture was warmed to dissolve compound the amine, and then stirred at room temperature for 15 minutes. NaBH(OAc)3 was added and stirring was continued for 12 hours. The reaction mixture was brought to pH 8 with solid NaOH, concentrated under reduced pressure, and purified by flash chromatography (silica, 95:4.5:0.5 CH2Cl2:MeOH:NH4OH). Formation of the HCl salt, followed by recrystallization (MeOH:Et2O) gave 6-(trans-4-{[3-(4-chlorophenyl)propyl]-methylamino}-cyclohexyl)-3H-benzoxazol-2-one (461 mg, 66%), as a white solid: mp 267-271° C.; IR (KBr): 2949, 1769, 1494, 1452 cm−1; 1H NMR (500 MHz, DMSO-d6): δ 11.50 (s, 1H), 10.39 (s, 1H), 7.37 (d, J=8 Hz, 2H), 7.30 (d, J=8 Hz, 2H), 7.16 (s, 1H), 7.00 (br s, 2H), 3.33-3.26 (m, 1H), 3.18-3.10 (m, 1H), 3.04-2.95 (m, 1H), 2.69 (d, J=5 Hz, 3H), 2.68-2.62 (m, 2H), 2.58-2.51 (m, 1H), 2.18-1.98 (m, 4H), 1.93-1.87 (m, 2H), 1.69-1.51 (m, 4H); HRMS-APCI (m/z): [M+H]+ calcd for C23H27ClN2O2, 399.1839; found, 399.1831; HPLC: method A, 6.35 minutes (98.6%); method B. 11.82 minutes (99.1%); Anal. Calcd for C23H27ClN2O2.HCl.0.25H2O: C, 62.80; H, 6.53; N, 6.37. Found: C, 62.94; H, 6.57; N, 6.21.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.CC1C=CC(S(O[CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=O)=O)=CC=1>>[CH2:25]([O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCc2ccccc2)cc1
Reactant: OC1CCOCC1
Product: c1ccc(COCCOCCOC2CCOCC2)cc1
Yield: 85.3 %

Procedure:
Using tetrahydro-4-pyranol (0.784 mL, 8.23 mmol) and 2-[2-(benzyloxy)ethoxy]ethyl 4-methylbenzenesulfonate (1.92 g, 5.48 mmol) synthesized in Reference Example 6 (6a), the desired title compound (1.31 g, yield 85%) was obtained by the same method as in Reference Example 2 (2a).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[CH2:15][C:16](=[O:30])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>>[ClH:32].[C:21]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([NH:17][C:16](=[O:30])[CH2:15][C:14](=[O:31])[N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CC(=O)Nc2ccc(-c3ccccc3)cc2)CC1
Agent: Cl
Product: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
HCl (10 mL) was added to 4-[2-(biphenyl-4-ylcarbamoyl)-acetyl]-piperazine-1-carboxylic acid tert-butyl ester (1.3 g, 3.1 mmol) and the resulting mixture was stirred for 30 minutes, then concentrated. The residue was washed with diethyl ether and dried to afford 1.0 g (90%) of N-Biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[F:22])=[CH:10][C:9]=1[N+:23]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=2[F:22])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(F)c1-c1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Product: COc1cccc(F)c1-c1ccc(NC(=O)OC(C)(C)C)c(N)c1

Procedure:
Prepared from (2′-fluoro-6′-methoxy-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example B16) by catalytic hydrogenation with Pd/C according to the general procedure G (method a). Obtained as a light purple foam (577 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](I)[CH:11]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[C:22]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH2:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)#[CH:23]>>[NH2:33][S:30]([C:27]1[CH:28]=[CH:29][C:24]([C:22]#[C:23][C:10]2[CH:11]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:9]=2[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]3)=[CH:25][CH:26]=1)(=[O:31])=[O:32]
Reactant: C#Cc1ccc(S(N)(=O)=O)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C#Cc3ccc(S(N)(=O)=O)cc3)c2OC1C(F)(F)F

Procedure:
Ethyl 6-chloro-8-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in U.S. Pat. No. 6,271,253 B1 Example 73, Step 2 was reacted with 4-ethynylbenzene sulfonamide prepared as in Step 2 via a method similar to that described in Example 21f, Step 1 to give the product: ESHRMS m/z 503.0686 (M+NH4, C21H15ClF3O5SNH4, Calc'd 503.0655).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(OCC)(=O)C.CN(C)C=O>[CH2:25]([O:24][C:22]([CH2:21][O:1][N:2]=[C:3]([C:11](=[O:13])[CH3:12])[C:4]([O:6][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:5])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)C(=NO)C(=O)OC(C)(C)C
Reactant: O=C(CCl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)C(=NOCC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 7 h
Yield: 95.3 %

Procedure:
To a suspension of tert-butyl 2-hydroxyimino-3-oxobutyrate (56.4 g) and potassium carbonate (62.4 g) in ethyl acetate (300 ml) and N,N-dimethylformamide (60 ml) was added benzyl chloroacetate (60 g), and the mixture was stirred at 40° C. for 7 hours. The reaction mixture was poured into ice-water (1000 ml), and the separated organic layer was washed twice with a saturated aqueous solution of sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave tert-butyl 2-benzyloxycarbonylmethoxyimino-3-oxobutyrate (96.3 g) as an oil.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].N#N.[OH-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[CH2:19]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: OCCOCCOCCOCCO
Reactant: CCCCCCCCBr
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCOCCOCCOCCOCCO
Temperature: 60 °C

Procedure:
Tetraethyleneglycol (1243 g, 6.40 mol) was heated at 100° C. for 30 minutes with stirring and vigorous N2 bubbling, then cooled to 60° C. A 50% NaOH solution (70.4 g, 0.88 mol) was added and the resulting solution was heated at 100°-105° C. for 30 minutes with N2 bubbling. The solution was cooled to 60° C., bromooctane (154 g, 0.80 mol) was added, and the reaction was heated at 100°-110° C. for 24 hours. The reaction solution was cooled, added to ice water and extracted twice with methylene chloride. The combined extracts were washed with 10% NaOH, water and brine; dried, treated with charcoal, and filtered through a thin silica gel pad. The solvent was removed in vacuo; the residual product (155 g, 63%) was a pale yellow oil.
Reaction SMILES: [OH-:1].[Na+].BrBr.[CH3:5][C:6]1[O:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1>O>[CH3:5][C:6]1[O:10][C:9]([C:11]([OH:1])=[O:12])=[CH:8][CH:7]=1
Reactant: Cc1ccc(C=O)o1
Reactant: [OH-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)O)o1
Reaction time: 0.75 h
Yield: 60.6 %

Procedure:
Following the method of Shapiro et al. (Khim. Geterotsikl. Soedin. 1982, 11, 1463), to a stirred solution of 80.3 g (2.00 mol) sodium hydroxide in 330 ml water at 0-5° C. was added dropwise 18 ml (0.35 mol) bromine. 25 ml (0.25 mol) 5-methyl-2-furfural was then added dropwise over 90 minutes and stirring continued for a further 45 minutes at 0-5° C. The reaction mixture was then extracted with ether and the phases separated. The aqueous phase was acidified to pH 1 with concentrated hydrochloric acid and the resulting precipitate collected by filtration and dried in vacuo to afford 19.1 g (60%) 5-methyl-2-furoic acid as a beige crystalline solid. 1H NMR δ (CDCl3, 250 MHz): 8.00-6.60 (1H, v. br. s), 7.24 (1H, d, J=3.4 Hz), 6.17 (1H, d, J=3.4 Hz), 2,42 (3H, s).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[OH:8][C:9]1[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)=[C:18]([CH3:19])[C:13]=2[O:12][C:11](=[O:27])[CH:10]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([O:3][CH2:4][C:5]([C:10]1[C:11](=[O:27])[O:12][C:13]2[C:18]([CH3:19])=[C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][O:22]3)[CH:16]=[CH:15][C:14]=2[C:9]=1[OH:8])=[O:7])[CH3:2]
Reactant: Cc1c(OC2CCCCO2)ccc2c(O)cc(=O)oc12
Reactant: CCOCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCOCC(=O)c1c(O)c2ccc(OC3CCCCO3)c(C)c2oc1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.21 ml of ethoxy acetic acid is added to a solution containing 5.00 g of 4-hydroxy-8-methyl-7-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-1-benzopyran-2-one, 7.30 g of 4-dimethyl-aminopyridine and 3.816 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride. This mixture is agitated for 16 hours at ambient temperature. After diluting with dichloromethane, washing is carried out with an aqueous solution of sodium dihydrogen phosphate then with brine. After drying over magnesium sulphate, filtering and evaporating to dryness, the product obtained is triturated in a hexane-ethyl acetate mixture (4-1). The product obtained is separated and dried. In this way 5.40 g of sought product is obtained.
Reaction SMILES: CC1C=C(N2CCN(CCOC3C=CC=CC=3)C2=O)SC=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.[Cl:48][C:49]1[N:54]=[CH:53][C:52]([CH2:55][NH2:56])=[CH:51][CH:50]=1>>[Cl:48][C:49]1[N:54]=[CH:53][C:52]([CH2:55][NH:56][C:41]([C:39]2[S:40][C:36]([N:33]3[CH2:34][CH2:35][N:31]([CH2:30][C:29]4[CH:28]=[CH:27][C:26]([F:25])=[CH:47][CH:46]=4)[C:32]3=[O:45])=[CH:37][C:38]=2[CH3:44])=[O:42])=[CH:51][CH:50]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(Cl)nc1
Yield: 80 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (6-chloropyridin-3-yl)methanamine, the title compound was obtained as a colorless solid in 80% yield: 1H NMR (300 MHz, CDCl3) δ 8.36 (d, J=1.5 Hz, 1H), 7.68 (dd, J=8.2, 2.4 Hz, 1H), 7.30-7.23 (m, 3H), 7.08-6.99 (m, 2H), 6.13 (t, J=5.8 Hz, 1H), 6.09 (s, 1H), 4.55 (d, J=5.8 Hz, 2H), 4.43 (s, 2H), 3.84-3.76 (m, 2H), 3.48-3.40 (m, 2H), 2.48 (s, 3H); MS (ES+) m/z 459.1 (M+1).
Reaction SMILES: O[CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1.S(Cl)([Cl:14])=O>>[Cl:14][CH2:2][N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[N:4]1
Reactant: O=S(Cl)Cl
Reactant: OCn1nnc2ccccc21
Product: ClCn1nnc2ccccc21

Procedure:
To 1-hydroxymethylbenzotriazole (59.6 g), prepared above, kept at ice-bath temp., 175 ml of thionyl chloride was added dropwise as long as a vigorous reaction continued. The reminder was added more rapidly. The mixture was then stirred and refluxed for 90 minutes. Excess thionyl chloride was removed by distillation, the last traces were removed by heating for a short time with 200 ml of methanol. After cooling and collecting on a funnel, the product weighted 45 g. (67%); melting point: 136° C; (lit. 136°-138° C.).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=1)=[O:5].C(N(CC)CC)C.Cl.OC(C)(C)CN1C=CC(NC(=O)[C@@H](N2[CH2:51][C:50]([O:52][C:53]3[CH:58]=[CH:57][CH:56]=[C:55]([Cl:59])[C:54]=3[Cl:60])=[CH:49][C:48]2=[O:61])CC(C)C)=N1>CO>[Cl:60][C:54]1[C:55]([Cl:59])=[CH:56][CH:57]=[CH:58][C:53]=1[O:52][C:50]1[CH2:51][N:2]([C@@H:3]([CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]([NH:6][C:7]2[CH:11]=[CH:10][N:9]([CH2:12][C:13]([OH:16])([CH3:14])[CH3:15])[N:8]=2)=[O:5])[C:48](=[O:61])[CH:49]=1
Reactant: CC(C)(O)Cn1ccc(NC(=O)[C@@H](N)CC2CCCCO2)n1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCO2)N2CC(Oc3cccc(Cl)c3Cl)=CC2=O)n1
Yield: 3.7 %

Procedure:
(S)-2-amino-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydropyran-2-yl)-propionamide hydrochloride (118 mg, 0.30 mmol) was dissolved in methanol (2 mL) and triethylamine (0.2 mL) was added. The mixture was evaporated to dryness. The residue was dissolved in acetonitrile (5 mL). To this solution was added (E)-4-bromo-3-(2,3-dichloro-phenoxy)-but-2-enoic acid ethyl ester (prepared as in Example 77, 109 mg, 0.30 mmol). The mixture was refluxed for 40 h. The mixture was evaporated and the residue was treated with ethyl acetate and water. The layers were separated and the organic layer was dried over sodium sulfate and concentrated to give a crude product (180 mg). One part of the crude product (30 mg) was purified through reverse phase preparative HPLC (acetonitrile in water, 25% to 100% linear gradient) to afford (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-2-yl)-propionamide as a white powder (6 mg): LR-ES-MS m/z calculated for C25H30Cl2N4O5 [M]+ 536, observed [M+H]+ 537; 1H-NMR (CDCl3) δ ppm 1.16 (s, 6H), 1.25-1.73 (m, 5H), 1.73-2.00 (m, 2H), 2.17-2.34 (m, 1H), 3.29-3.49 (m, 2H), 3.88-4.06 (m, 3H), 4.24 (d, J=17.8 Hz, 1H), 4.42 (d, J=17.8 Hz, 1H), 4.89 (s, 1H), 5.02-5.16 (m, 1H), 6.70 (br s, 1H), 7.14-7.23 (m, 1H), 7.28-7.37 (m, 3H), 7.42 (d, J=8.2 Hz, 1H), 8.76 (br s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]3[N:15]=[C:14]([C:16]([O:18]CC)=[O:17])[CH:13]=[CH:12][C:10]=3[CH:11]=[C:3]12.[OH-].[Na+]>C(O)C>[O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]2[C:9]3[N:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:10]=3[CH:11]=[C:3]12
Reactant: CCOC(=O)c1ccc2cc3n(c2n1)CCCNC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1ccc2cc3n(c2n1)CCCNC3=O
Temperature: 50 °C
Reaction time: 5 h
Yield: 84.8 %

Procedure:
To a solution of ethyl 6-oxo-7,8,9,10-tetrahydro-6H-pyrido[3′,2′:4,5]pyrrolo[1,2-a][1,4]diazepine-2-carboxylate (1.84 g, 6.73 mmol) in ethanol (30 mL) is added 1N NaOH solution (16.8 mL, 16.8 mmol). The reaction is stirred at 50° C. for 5 h then is cooled to room temperature. The ethanol is removed in vacuo and the aqueous mixture is acidified to pH 5 with 1N hydrochloric acid. The resulting solid is collected by filtration and dried in vacuo at 50° C. to afford the title compound as a tan solid (1.4 g, quantitative). LCMS: 264.63 (M+H+).
Reaction SMILES: [C:1]12([NH:12][C:13](=[O:26])[CH2:14][N:15]3C(=O)C4=CC=CC=C4C3=O)[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH:5]1[CH2:11][CH:2]2[CH2:3][CH2:4]1.O.NN.C(O)C.[ClH:33]>C1C=CC=CC=1>[ClH:33].[C:1]12([NH:12][C:13](=[O:26])[CH2:14][NH2:15])[CH2:10][CH:6]([CH2:7][CH2:8][CH2:9]1)[CH:5]1[CH2:11][CH:2]2[CH2:3][CH2:4]1
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)NC12CCCC(C1)C1CCC2C1
Agent: Cl
Agent: NN
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: NCC(=O)NC12CCCC(C1)C1CCC2C1
Reaction time: 2 h

Procedure:
A mixture of 1.39 g (3.94 millimoles) of N-(1-tricyclo[4.3.1.12,5 ]undecyl)-2-phthalimidoacetamide, 0.30 g (4.37 millimoles) of 80% hydrazine hydrate and 10 ml of ethanol was refluxed under agitation for 4 hours. The reaction temperature was lowered to 60° C., and 5 ml of 10% hydrochloric acid was added and the mixture was agitated for 2 hours. After cooling, the precipitate was recovered by filtration, and the pH of the filtrate was adjusted to 9 with a 5% aqueous solution of sodium hydroxide and the mixture was extracted with diethyl ether. The diethyl ether solution was condensed, and the residue was dissolved in 20 ml of dry benzene and dry hydrogen chloride gas was blown into the solution. The formed white precipitate was recovered by filtration and recrystallized from ethanolacetone to obtain 0.59 g (the yield being 58%) of the intended compound having a melting point of 225° to 229° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[CH:24]1([NH:27][C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34](B3OC(C)(C)C(C)(C)O3)=[C:33]([F:46])[CH:32]=2)=[O:29])[CH2:26][CH2:25]1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CCO.COCCOC>[CH:24]1([NH:27][C:28](=[O:29])[NH:30][C:31]2[CH:36]=[CH:35][C:34]([C:2]3[N:3]=[C:4]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:5]4[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=4[N:7]=3)=[C:33]([F:46])[CH:32]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOCC3)c2C1
Yield: 56 %

Procedure:
A solution of tert-butyl 2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 2) (85 mg, 0.25 mmol), 1-cyclopropyl-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (intermediate 29) (100 mg, 0.31 mmol), [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (10 mg, 0.012 mmol) and sodium carbonate (40 mg, 0.38 mmol) in 2 ml of a 7:3:2 mixture of DME:EtOH:H2O respectively was heated in the microwave at 130° C. for 30 minutes. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and the solvent removed in vacuo. The residue was purified by prep. HPLC at low pH, yielding the title compound (72 mg, 0.14 mmol, 58%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[CH:6][C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Li+].Cl.Cl.[CH3:30][O:31][C:32](=[O:39])[C@H:33]([CH2:35][CH2:36][S:37][CH3:38])[NH2:34].ON1C(=O)C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>CO.C(OCC)(=O)C.N1C=CC=CC=1.C1COCC1>[CH3:30][O:31][C:32](=[O:39])[C@H:33]([CH2:35][CH2:36][S:37][CH3:38])[NH:34][C:3](=[O:2])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[CH3:18])=[CH:6][C:5]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: COC(=O)c1ccc(CNc2cnccc2C)cc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CNc2cnccc2C)cc1-c1ccccc1
Reaction time: 15 h

Procedure:
A solution of the product of Example 280B (446 mg, 1.3 mmol) and aqueous saturated lithium hydroxide (3 mL) in methanol (5 mL) was heated at 60° C. for 15 hours. The reaction mixture was then neutralized with hydrogen chloride (4 N in dioxane, 5 mL). The reaction mixture was concentrated in vacuo to dryness. To the residue was added sequentially L-methionine methyl ester hydrochloride (311 mg, 1.56 mmol), 3-hydroxy 1,2,3-benzotriazin-4(3H)-one (318 mg, 1.95 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodimide (374 mg, 1.95 mmol), THF (10 mL) and pyridine (1 mL). After 15 hours, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was then purified by column chromatography (ethyl acetate) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10].[Cl:14]Cl>ClC(Cl)(Cl)Cl>[Cl:14][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:13])[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(=O)c1ccccc1C
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(=O)c1ccccc1CCl
Yield: 35 %

Procedure:
100 g (0.56 mole) of methyl 2-methylphenylglyoxylate in 600 ml of tetrachloromethane are initially taken. The mixture is then refluxed while being exposed to a 300 W Hg vapor lamp, and 28 g (0.39 mole) of chlorine gas are passed in during this procedure. After a conversion of about 50% (determined by thin-layer chromatography), the reaction is terminated and the mixture is evaporated down. The residue is then subjected to fractional distillation. 29 g of product were obtained as an oil.