Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][C:6]([C:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11](=[O:19])(=[O:18])[CH2:10]2)=[O:8])=[CH:5][C:4]=1[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27].[Cl-].[Li+].Cl>CN(C)C=O>[OH:2][C:3]1[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][C:6]([C:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[S:11](=[O:19])(=[O:18])[CH2:10]2)=[O:8])=[CH:5][C:4]=1[C:26]([N:28]1[CH2:29][CH2:30][CH2:31][CH2:32]1)=[O:27]
Reactant: COc1c(C(=O)N2CCCC2)cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc1C(F)(F)F
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(c1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C(F)(F)F)c1O)N1CCCC1
Temperature: 120 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
3-[4-methoxy-3-(pyrrolidine-1-carbonyl)-5-trifluoromethylbenzoyl]-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (715 mg) was dissolved in N,N-dimethylformamide (7 mL), and lithium chloride (649 mg) was added to the solution, and then the mixture was stirred at 120° C. for 2 hours. To the reaction solution, 1N hydrochloric acid was added, and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (654 mg) as a colorless amorphous product.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:30]=[CH:29][O:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:31]([O:33]C)=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O.Cl>O1CCCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][C:26]4[CH:30]=[CH:29][O:28][CH:27]=4)[CH2:23][CH2:22][C:21]([C:31]([OH:33])=[O:32])=[CH:20][C:19]=3[CH:35]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccoc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 103.7 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-1-(3-furylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (310 mg) in a mixture of tetrahydrofuran (21 ml) and methanol (21 ml) was added 1N sodium hydroxide solution (7 ml), and the mixture was stirred at room temperature for 3 days. Then, to the mixture was added water at 0° C., and 1N hydrochloric acid was further added to make acidic (pH=4), and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting solid was washed with hexane to give 7-(4-butoxyethoxyphenyl)-1-(3-furylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (312 mg) as yellow crystals.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]2[CH2:40][CH2:39][C:16]3[N:17](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:18]=[N:19][C:15]=3[CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCCCOCC2CCC3N=CN(C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)C=3C2)C=CC=CC=1>C(O)(=O)C.O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]2[CH2:40][CH2:39][C:16]3[NH:17][CH:18]=[N:19][C:15]=3[CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CCCCOCC2CCc3c(ncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)cc1
Agent: c1ccc(CCCCOCC2CCc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3C2)cc1
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(CCCCOCC2CCc3[nH]cnc3C2)cc1
Temperature: 90 °C

Procedure:
A mixture of 5-(4-phenylbutoxymethyl)-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-(4-phenylbutoxymethyl)-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole (0.50 g, 0.95 mmol) was dissolved in a mixture of acetic acid (5 ml) and water (0.6 ml). The reaction mixture was heated to 90° C. for 2 hours. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 0.27 g of the title compound.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5](=O)[C:6]([F:9])([F:8])[F:7].B.C1COCC1>O1CCCC1>[Cl:1][CH2:2][CH2:3][NH:4][CH2:5][C:6]([F:9])([F:8])[F:7]
Reactant: O=C(NCCCl)C(F)(F)F
Agent: B
Solvent: C1CCOC1
Product: FC(F)(F)CNCCCl

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of N-(2-chloroethyl)-2,2,2-trifluoroacetamide (17.6 g, 100.26 mmol, 1.00 equiv) in tetrahydrofuran (50 mL). This was followed by the addition of BH3.THF (200 mL) dropwise with stirring. The resulting solution was heated to reflux overnight in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 200 mL of H2O. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 15 g (crude) of (2-chloroethyl)(2,2,2-trifluoroethyl)amine as yellow oil. (ES, m/z): 163 [M+H]+
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@H:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:6][N:5]1[CH3:19])([OH:3])=O.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][S:9][C@@H:7]2[CH2:6][N:5]([CH3:19])[C@H:4]([C:1]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)=[O:3])[CH2:8]2)=[CH:12][CH:13]=1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Reactant: CN1CCNCC1
Solvent: CC#N
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CCN(C)CC3)N(C)C2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
700 mg of N,N'-carbonyldiimidazole were added to a suspension of 1.0 g of (2S,4S)-2-carboxy-4-(4-methoxybenzylthio)-1-methylpyrrolidine in 15 ml of dry acetonitrile, and the resulting mixture was stirred at 40° C. for 30 minutes. At the end of this time, the reaction mixture was ice-cooled, and 440 μl of N-methylpiperazine were added to the mixture. The temperature was then allowed to rise to room temperature over a period of 30 minutes. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and the residue was purified by reverse phase column chromatography using LiChroprep RP-8 (trade mark) as stationary phase and 70% v/v aqueous methanol as the eluent, to give 1060 mg of the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C@@H:7]([NH2:29])[CH2:8][S:9][C:10]([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)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[C:31](=N)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[C:1]([O:5][C:6](=[O:30])[C@@H:7]([N:29]=[C:31]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N=C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)N=C(c1ccccc1)c1ccccc1

Procedure:
In one incarnation of the present invention, as illustrated below, the cysteine derivative is 2(R)-(benzhydrylidene-amino)-3-tritylsulfanyl-propionic acid tert-butyl ester. 2(R)-(Benzhydrylidene-amino)-3-tritylsulfanyl-propionic acid tert-butyl ester can be formed by the following process: (1) 2(R)-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanyl-propionic acid (i.e., (R)-cysteine with Fmoc a protected amino group and with a trityl protected —SH group), is reacted with t-butyl alcohol and dicyclohexyl carbodiimide (DCC) in 4-(dimethylamino)pyridine (DMAP) and tetrahydrofuran (THF) at room temperature to form 2(R)-(9H-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanyl-propionic acid tert-butyl ester; (2) the Fmoc group is removed from the 2(R)-(9H-fluoren-9-ylmethoxycarbonylamino)-3-tritylsulfanyl-propionic acid tert-butyl ester using either diethylamine in dichloromethane or piperidine in dichloromethane to form 2(R)-amino-3-tritylsulfanyl-propionic acid tert-butyl ester; and (3) the 2(R)-amino-3-tritylsulfanyl-propionic acid tert-butyl ester is reacted with benzhydrylideneamine in dichloromethane at room temperature to form 2(R)-(benzhydrylidene-amino)-3-tritylsulfanyl-propionic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:9](=[O:23])[N:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH:11]([CH:12]([CH3:14])[CH3:13])[C:5]2=[CH:4][N:3]=1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH:12]([CH:11]1[C:5]2[C:6](=[N:7][C:2]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:3][CH:4]=2)[N:8]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:9](=[O:23])[N:10]1[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)([CH3:13])[CH3:14]
Reactant: COc1ccc(N2C(=O)N(c3ccccc3)c3nc(Cl)ncc3C2C(C)C)cc1
Reactant: Nc1ccccc1
Product: COc1ccc(N2C(=O)N(c3ccccc3)c3nc(Nc4ccccc4)ncc3C2C(C)C)cc1
Temperature: 100 °C

Procedure:
(±)-7-Chloro-4-isopropyl-3-(4-methoxy-phenyl)-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (22.0 mg; 0.054 mmol) (from Example 11d supra) and aniline (50 μL; 0.55 mmol) (Aldrich) were combined and heated in an oil bath at 100° C. for 1 hour. Upon cooling, the residue was triturated with hexanes and the supernatant was decanted off. The residue was dissolved in ethyl acetate and washed with water and then brine. The organic phase was mixed with silica gel, concentrated and subsequently purification by flash chromatography (Biotage 12M; 40:60 ethyl acetate-hexanes) and crystallization from dichloromethane-ether-petroleum ether gave (±)-4-isopropyl-3-(4-methoxy-phenyl)-1-phenyl-7-phenylamino-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a white solid. (Yield 14.8 mg; 59.1%). Melting Point: 229–235° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([C:26]3[CH:38]=[CH:37][C:29]4[O:30]C(C)(C)[O:32][C:33](=[O:34])[C:28]=4[CH:27]=3)[C:19](=[O:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CCO>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:40]=[CH:39][C:16]([CH2:17][N:18]([C:19](=[O:25])[CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])[C:26]3[CH:38]=[CH:37][C:29]([OH:30])=[C:28]([CH:27]=3)[C:33]([OH:34])=[O:32])=[CH:15][CH:14]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CC(C)(C)C)c3ccc4c(c3)C(=O)OC(C)(C)O4)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCc1ccc(C#Cc2ccc(CN(C(=O)CC(C)(C)C)c3ccc(O)c(C(=O)O)c3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-butylphenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)-3,3-dimethylbutanamide and aqueous NaOH (1M) in the presence of EtOH as a white powder (36%). 1H NMR (McOD, 300 MHz) δ 7.53 (d, J=2.4 Hz, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H), 7.22 (d, J=8.0 Hz, 2H), 7.09 (dd, J=8.8, 2.4 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H). 4.91 (s, 2H), 2.66 (t, J=7.7 Hz, 2H), 2.13 (s, 2H), 1.64 (m, 2H), 1.40 (m, 2H), 1.01 (s, 9H), 0.97 (t, J=7.5 Hz, 3H). M− (ESI): 496.4. HPLC, Rt: 5.56 min (Purity: 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1.OC1C(C#N)=CNC(=O)C=1.CS(O[CH:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]1)(=O)=O.CS(OC1CCN(C2N=CC(CCC)=CN=2)CC1)(=O)=O>>[Cl:1][C:2]1[C:3]([O:18][CH:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)=[CH:4][C:5](=[O:17])[N:6]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([F:16])[CH:9]=2)[CH:7]=1
Reactant: N#Cc1ccc(-n2cc(Cl)c(O)cc2=O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: CCCc1cnc(N2CCC(OS(C)(=O)=O)CC2)nc1
Agent: N#Cc1c[nH]c(=O)cc1O
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(=O)n(-c3ccc(C#N)c(F)c3)cc2Cl)CC1

Procedure:
The intermediate was prepared according to the procedures described in Example 221 substituting 4-(5-chloro-4-hydroxy-2-oxopyridin-1(2H)-yl)-2-fluorobenzonitrile for 4-hydroxy-6-oxo-1,6-dihydropyridine-3-carbonitrile and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate for 1-(5-propylpyrimidin-2-yl)piperidin-4-yl methanesulfonate in Step B. MS (ESI) 392 (M+H).
Reaction SMILES: [S:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=[CH:10][C:4]=2[S:3]1.[CH3:13]CN(CC)CC.CI>CCO>[CH3:13][S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1
Reactant: N#Cc1ccc2sc(=S)[nH]c2c1
Reactant: CCN(CC)CC
Solvent: CCO
Solvent: CI
Product: CSc1nc2cc(C#N)ccc2s1
Yield: 97.3 %

Procedure:
To a solution of 2-thioxo-2,3-dihydrobenzothiazole-5-carbonitrile (260 mg, 1.35 mmol) in EtOH (10.8 mL) was added Et3N (137 mg, 1.35 mmol) and methyliodide (192 mg, 1.35 mmol). The mixture was heated at reflux for 1 h. The volatiles were evaporated and the residue was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give 2-methylsulfanylbenzothiazole-5-carbonitrile 271 mg (97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([F:18])=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH:26]1([N:32]=[C:33]=[O:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CCN(CC)CC>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]([C:9]2[N:10]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=3)[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][C:14]([F:18])=[CH:13]3)[C:33]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[O:34])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: Fc1ccc2c(Nc3cccc(Cl)c3)n(-c3ccc(Cl)cc3)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(NC1CCCCC1)N(c1cccc(Cl)c1)c1c2ccc(F)cc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, (3-chloro-phenyl)-[2-(4-chloro-phenyl)-6-fluoro-2H-indazol-3-yl]-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in 1,2-dichloroethane in the presence of Et3N (3 eq.) for 4 days under reflux conditions to give the title compound as yellow foam. MS: m/e=497.1 [M+H+].
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:29][CH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>>[ClH:29].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][C:31]4[C:40]5[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=5)[CH:34]=[CH:33][CH:32]=4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Reactant: ClCc1cccc2ccccc12
Agent: Cl
Product: O=C1N(Cc2cccc3ccccc23)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 210° C. and MS: m/e=510.4 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 1-chloromethylnaphthaline.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C:24]([NH2:26])=[O:25].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[NH2:26][C:24](=[O:25])[CH2:23][O:22][NH:21][C:18]([C@@H:13]1[CH2:12][CH2:11][C@@H:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20]
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: NOCC(N)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: NC(=O)CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.200 g, 0.723 mmol, US 2005/20572 A1) in DCM (6.0 mL) were added 2-(aminooxy) acetamide 53 (0.098 g, 1.086 mmol), 1-hydroxybenzotriazole (0.147 g, 1.086 mmol) and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.208 g, 1.086 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 54 (0.203 g, 81%) as a white solid.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]#[N:18])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([CH2:4][NH2:1])=[CH:10][CH:9]=1)#[N:18]
Reactant: N#Cc1ccccc1-c1ccc(CN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccccc1-c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5.85 g (25 mmole) of 4-azidomethyl-2'-cyanobiphenyl (from Step A) in 50 ml of dry tetrahydrofuran was treated portionwise with 6.55 g (25 mmole) of triphenylphospine over 3-4 minutes. The solution was stirred at ambient temperature under N2, and gas evolution proceeded at a moderate rate. A mild exotherm occurred, and the solution was cooled in a water bath as necessary. After 2 hours, by which time gas evolution had ceased, 675 μl (37.5 mmole) of H2O was added, and stirring was continued at room temperature under N2. After 22 hours, the solution was concentrated in vacuo, and the residual oil was chromatographed on a column of silica gel (gradient elution with 2-10% methanol in CH2Cl2). The residue from evaporation of the pooled product fractions was partitioned between ether-CH2Cl2 and saturated Na2CO3 (aqueous). The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to yield the title compound as air-sensitive, nearly white crystals, mp 54°-55° C., homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 209(M+1)+.
Reaction SMILES: [NH2:1][CH:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:3]([OH:20])[CH:4]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[N+](C1C=CC([O:37][C:38](=O)[C@H:39]([C@H:51]([CH2:53][CH3:54])[CH3:52])[NH:40][C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])=CC=1)([O-])=O.C(N(CC)CC)C>C1COCC1.[OH-].[Na+].C(Cl)(Cl)Cl.CO>[C:16]([O:15][C:13]([NH:12][CH:4]([CH:3]([OH:20])[CH:2]([NH:1][C:38](=[O:37])[C@H:39]([C@H:51]([CH2:53][CH3:54])[CH3:52])[NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)NC(Cc1ccccc1)C(O)C(N)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)NC(Cc1ccccc1)C(O)C(Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
The resultant compound of Example 11 (125 mg, 0.34 mmol), N-benzyloxycarbonyl-isoleucine p-nitrophenyl ester (196 mg, 0.51 mmol) and triethylamine (94 μL, 0.67 mmol) were combined with 1.0 mL of dry THF and stirred together at ambient temperature overnight. The reaction mixture was then heated at reflux temperature for 3 h. The cooled reaction mixture was then diluted with 5 mL of THF and 5 mL of 3M aqueous sodium hydroxide solution was added. The mixture was stirred at ambient temperature for approximately 0.5 h. and was then diluted with chloroform. The chloroform solution was washed with 3×25 mL of 0.5M aqueous sodium hydroxide solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue (227 mg) was taken up in approximately 5 mL of chloroform and applied to a 1.0×45 cm column of 40 mesh silica gel. The column was eluted @ 5-10 p.s.i. sequentially with 100 mL of chloroform, 100 mL of 0.5% methanol in chloroform and 100 mL of 1% methanol in chloroform to give 169 mg (81% yield) of the title compound; FAB MS M/Z: 618 (M+H)+. The 300 MHz 1H NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16]C)=[CH:13][CH:14]=3)[N:9]([CH3:18])[C:8]=2[CH3:19])=[O:6])[CH2:3][CH2:2]1.B(Br)(Br)Br>>[CH:1]1([NH:4][C:5]([C:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[N:9]([CH3:18])[C:8]=2[CH3:19])=[O:6])[CH2:2][CH2:3]1
Reactant: COc1ccc2c(C(=O)NC3CC3)c(C)n(C)c2c1
Agent: BrB(Br)Br
Product: Cc1c(C(=O)NC2CC2)c2ccc(O)cc2n1C
Yield: 21.3 %

Procedure:
This material was prepared from 6-methoxy-1,2-dimethyl-1H-indole-3-carboxylic acid cyclopropylamide 20a (655 mg, 2.5 mmole) by treatment with BBr3 in a manner as previously described for example 1d to give 130 mg (21%) of a white solid. 1H NMR (DMSO-d6) δ 9.06 (1H, s), 7.51 (1H, d, J=4.0 Hz), 7.41 (1H, d, J=8.5 Hz), 6.73 (1H, d, J=1.8 Hz), 6.60 (1H, dd, J=1.8, 8.5 Hz), 3.56 (3H, s), 2.82 (1H, m), 2.50 (3H, s), 0.62 (2H, m), 0.52 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([CH3:23])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:22])[NH:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:9]=1)[CH3:6])[CH3:2].[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH:31]=O)[CH3:26].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:24])[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:22])[NH:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:31][C:30]3[CH:33]=[CH:34][C:35]([O:36][CH3:37])=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=3)[CH2:20][CH2:21]2)[CH:9]=1)([CH3:23])[CH3:6])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OC
Reactant: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCNCC2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cccc(C(=O)NC2CCN(Cc3ccc(OC)c(OCC)c3)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 2-methyl-2-[3-(piperidin-4-ylcarbamoyl)-phenoxy]-propionic acid ethyl ester (example 50i) was reacted with 3-ethoxy-4-methoxybenzaldehyde, sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless foam. MS: 499.2 (MH+).
Reaction SMILES: O[CH2:2][CH2:3][C@H:4]1[C:9]2[CH:10]=[CH:11][C:12]([CH2:14][N:15]3[CH2:19][CH2:18][O:17][C:16]3=[O:20])=[CH:13][C:8]=2[CH2:7][CH2:6][O:5]1.CS(Cl)(=O)=O.CS(OCC[C@H]1C2C=CC(C(N)=O)=CC=2CCO1)(=O)=O.S([O-])(=O)(=O)C.[C:51]([C:53]1[CH:54]=[C:55]2[C:60](=[CH:61][CH:62]=1)[C:59]([N:63]1[CH2:68][CH2:67][NH:66][C@H:65]([CH3:69])[CH2:64]1)=[CH:58][CH:57]=[CH:56]2)#[N:52]>>[CH3:69][C@H:65]1[N:66]([CH2:2][CH2:3][C@H:4]2[C:9]3[CH:10]=[CH:11][C:12]([CH2:14][N:15]4[CH2:19][CH2:18][O:17][C:16]4=[O:20])=[CH:13][C:8]=3[CH2:7][CH2:6][O:5]2)[CH2:67][CH2:68][N:63]([C:59]2[CH:58]=[CH:57][CH:56]=[C:55]3[C:60]=2[CH:61]=[CH:62][C:53]([C:51]#[N:52])=[CH:54]3)[CH2:64]1
Reactant: C[C@@H]1CN(c2cccc3cc(C#N)ccc23)CCN1
Reactant: O=C1OCCN1Cc1ccc2c(c1)CCO[C@H]2CCO
Agent: CS(=O)(=O)Cl
Agent: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Agent: CS(=O)(=O)[O-]
Product: C[C@@H]1CN(c2cccc3cc(C#N)ccc23)CCN1CC[C@@H]1OCCc2cc(CN3CCOC3=O)ccc21

Procedure:
3-{[(1S)-1-(2-Hydroxyethyl)-3,4-dihydro-1H-2-benzopyran-6-yl]methyl}-1,3-oxazolidin-2-one was reacted with methanesulfonyl chloride, as described for the preparation of 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate. The resultant crude mesylate was then condensed with (3R)-1-(6-cyano-1-naphthyl)-3-methylpiperazine, as described for Example 1b), to yield the title compound. M+H=511.