Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[CH:3]=1.[CH2:18]([O:20][C:21](=[O:28])[CH2:22][C:23](=O)[CH:24]([CH3:26])[CH3:25])[CH3:19]>CCO.C(OCC)(=O)C>[CH2:18]([O:20][C:21]([C:22]1[C:23]([CH:24]([CH3:26])[CH3:25])=[N:8][C:5]2[C:4]([C:9]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:28])[CH3:19]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: Nc1ccc(Cl)cc1C#Cc1ccccc1Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1c(C(C)C)nc2ccc(Cl)cc2c1Cc1ccccc1Cl
Yield: 22.9 %

Procedure:
To a solution of 4-chloro-2-(2-chloro-phenylethynyl)-phenylamine (prepared as described in example 10 step A, 100 mg, 0.38 mmol) and 4-methyl-3-oxo-pentanoic acid ethyl ester (0.092 ml, 0.57 mmol) in anhydrous EtOH (10 ml), was added p-TsOH—H2O (72.56 mg, 0.38 mmol) and the mixture was refluxed for 72 h. After cooling, the reaction mixture was diluted with ethyl acetate and the organic layer was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, concentrated in vacuo. The crude residue was purified by flash column chromatography (elution with 3% EtOAc in hexane) to give 6-chloro-4-(2-chloro-benzyl)-2-isopropyl-quinoline-3-carboxylic acid ethyl ester (35 mg, 23% yield) as a yellow sticky solid. LC-MS: 402 (M+H)+.
Reaction SMILES: CCO.C([O:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([C:22]2[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:25]=[N:24][N:23]=2)[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16])C1C=CC=CC=1.[H][H]>[C].[Pd].C1COCC1>[OH:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([C:22]2[N:26]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[N:25]=[N:24][N:23]=2)[CH:21]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: [H][H]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(-c2nnnn2COCC[Si](C)(C)C)c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COC(=O)c1cc(O)cc(-c2nnnn2COCC[Si](C)(C)C)c1

Procedure:
In a nitrogen atmosphere, 10% palladium-carbon (2.4 g) was added to an EtOH (35 mL)-THF (35 mL) mixed solution of methyl 3-benzyloxy-5-[({[2-(trimethylsilyl)ethyl]oxy}methyl)-tetrazol-5-yl]benzoate (4.02 g), and in a hydrogen atmosphere this was stirred at room temperature for 2 hours. The reaction liquid was filtered through Celite, concentrated under reduced pressure, and dried to obtain the title compound as a white powder. Not purified, this was used in the next step.
Reaction SMILES: [N:1]([C:4]1[S:8][C:7]2[CH2:9][CH:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]=1[C:14]([O:16]C)=O)=[C:2]=[S:3].[CH3:18][C:19]1[N:23]([CH2:24][CH2:25][CH2:26][NH2:27])[CH:22]=[N:21][CH:20]=1>>[CH3:13][CH:10]1[CH2:11][CH2:12][C:6]2[C:5]3[C:14](=[O:16])[N:27]([CH2:26][CH2:25][CH2:24][N:23]4[C:19]([CH3:18])=[CH:20][N:21]=[CH:22]4)[C:2](=[S:3])[NH:1][C:4]=3[S:8][C:7]=2[CH2:9]1
Reactant: COC(=O)c1c(N=C=S)sc2c1CCC(C)C2
Reactant: Cc1cncn1CCCN
Product: Cc1cncn1CCCn1c(=S)[nH]c2sc3c(c2c1=O)CCC(C)C3

Procedure:
The compound was synthesized starting from methyl 4,5,6,7-tetrahydro-2-isothiocyanato-6-methylbenzo[b]thiophene-3-carboxylate (0.10 g, 0.37 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.052 g, 0.37 mmol) as described above.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([C:9]([CH3:27])([N:12]1[C:16](=[O:17])[C:15]2[CH:18]=[CH:19][C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][C:24]=3[C:14]=2[C:13]1=[O:26])[C:10]#[N:11])([CH3:8])[CH3:7].[OH-].[Na+].CC[O:32]CC>C(Cl)Cl.C(OCC)(=O)C>[CH:6]([C:9]([CH3:27])([N:12]1[C:16](=[O:17])[C:15]2[CH:18]=[CH:19][C:20]3[N:21]([CH3:25])[CH:22]=[CH:23][C:24]=3[C:14]=2[C:13]1=[O:26])[C:10]([NH2:11])=[O:32])([CH3:8])[CH3:7]
Reactant: CC(C)C(C)(C#N)N1C(=O)c2ccc3c(ccn3C)c2C1=O
Reactant: CCOCC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C(C)(C(N)=O)N1C(=O)c2ccc3c(ccn3C)c2C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.7 %

Procedure:
Concentrated sulfuric acid (5.50 mL) is added slowly to a solution of 3,6-dihydro-α-isopropyl-α,6-dimethyl-1,3-dioxobenzo[1,2-b:3,4-c']dipyrrole-2(1H)-acetonitrile (5.50 g, 19.0 mmol) in methylene chloride at 10° C. Crushed ice is added. The mixture is stirred for 24 hours at ambient temperature and poured onto crushed ice, treated with 6N sodium hydroxide to pH 2, and extracted with methylene chloride. The organic layer is separated, dried (MgSO4) and concentrated in vacuo to give an orange foamy residue. Flash chromatography (silica gel, ether then ethyl acetate eluents) affords the title product as a yellow foam (1.53 g, 25.7%), mp 159°-168° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[O:30]1[CH2:33][CH:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:31]1.COC(OC)OC.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:37]4[CH2:38][CH2:39][CH:34]([CH:32]5[CH2:33][O:30][CH2:31]5)[CH2:35][CH2:36]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: C1CC(C2COC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: COC(OC)OC
Solvent: CC(=O)O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C4COC4)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 34.4 %

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (0.105 g, 0.27 mmol), 4-oxetan-3-ylpiperidine (0.045 g, 0.32 mmol) in DCE (2 mL), trimethoxymethane (0.314 mL, 2.9 mmol) and acetic acid (0.017 mL, 0.29 mmol) was stirred for 18 h at room temperature. Sodium triacetoxyborohydride (0.101 g, 0.48 mmol) was added and the reaction mixture was stirred for 5 h at room temperature. After adding sodium triacetoxyborohydride (0.101 g, 0.48 mmol) the reaction mixture was stirred for a further 2 h and the suspension was partitioned between DCM and water. The organic layer was separated, washed with brine, dried over sodium sulphate and concentrated. The residue was purified by flash chromatography (Si—PPC, MEOH:DCM gradient 0:100 to 5:95) then (Si—PPC, acetone:EtOAc, 0:100 to 70:30) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 20 mM triethylamine in water on a gradient of acetonitrile 95:5 to 2:98) to give 314 as an off-white solid (0.048 g, 35%). LCMS (Method G): RT=5.92 min, [M+H]+ 517.3. 1H NMR (CDCl3, 400 MHz) δ 8.03-7.99 (m, 1 H); 7.78-7.74 (m, 1H); 7.29-7.25 (m, 2 H); 4.76 (dd, J=7.9, 6.2 Hz, 2 H); 4.46 (t, J=6.2 Hz, 2 H); 4.44-4.35 (m, 4 H); 3.90-3.84 (m, 7 H); 3.78-3.73 (m, 2 H); 3.36 (q, J=7.5 Hz, 2 H); 2.95-2.91 (m, 2H); 2.79-2.71 (m, 1 H); 2.21-2.17 (m, 2 H); 1.81-1.50 (m, 4 H); 1.49-1.41 (t, J=7.5 Hz, 3H); 1.21-1.15 (m, 1 H)
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[CH2:11][C:12](O)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.[N:41]1([O:50]C(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.NO>CN(C)C=O>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:15]2[O:16][CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[CH2:11][C:12]([NH:41][OH:50])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 14.6 %

Procedure:
A solution of (3R)-6-cyclohexyl-3-[4-(ethoxycarbonyl)-1,3-oxazol-2-yl]hexanoic acid (Preparation 63) (130 mg, 0.39 mmol) and N,N-diisopropylethylamine (67 μl, 0.39 mmol) in N,N-dimethylformamide (6 ml) was treated with O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (220 mg, 0.58 mmol) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 45 minutes. Further N,N-diisopropylethylamine (270 μl, 1.54 mmol) was then added, followed by hydroxylamine hydrochloride (80 mg, 1.16 mmol) and the mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and pH 7 aqueous buffer. The organic layer was separated, washed sequentially with water and brine, dried over anhydrous magnesium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (99:1) gradually changing to dichloromethane:methanol (98:2) to afford the title compound (20 mg).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13](=O)/[CH:14]=[CH:15]/[C:16]1[CH:17]=[N:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:20][CH:21]=1>C(Cl)Cl>[C:22]1([C:19]2[N:20]=[CH:21][C:16](/[CH:15]=[CH:14]/[CH2:13][OH:12])=[CH:17][N:18]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COC(=O)/C=C/c1cnc(-c2ccccc2)nc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: OC/C=C/c1cnc(-c2ccccc2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95.6 %

Procedure:
Diisobutylaluminum hydride (1.0 M solution in THF, 2.1 mL, 2.10 mmol) was added dropwise to a 0° C. solution of the product from step A (165 mg, 0.69 mmol) in methylene chloride (5 mL). The resulting solution was stirred for 15 min at 0° C., quenched with methanol (0.5 mL) followed by 15% aq. Rochelle salt (15 mL) and dichloromethane (5 mL), and allowed to stir at room temperature for 18 h. The layers were separated and the aqueous layer was extracted with methylene chloride (5 mL). The combined organic layers were dried (MgSO4) and concentrated to provide 140 mg (96%) of the title compound as a colorless solid. MS 213 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14](Br)=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:25]1[CH2:29][CH2:28][NH:27][C:26]1=[N:30][C:31]#[N:32])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1(N)CCCCC1N.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([N:27]2[CH2:28][CH2:29][N:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:26]2=[N:30][C:31]#[N:32])=[N:13][C:12]=1[CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(Br)sc1C(=O)NCc1ccccc1
Reactant: N#CN=C1NCCN1Cc1ccccc1
Agent: [Cu]I
Agent: NC1CCCCC1N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=NC#N)sc1C(=O)NCc1ccccc1
Yield: 8 %

Procedure:
A mixture of N-benzyl-2-bromo-4-methylthiazole-5-carboxamide (0.25 g, 0.80 mmol). N-(1-benzylimidazolidin-2-ylidene)cyanamide (0.18 g, 0.88 mmol), copper(I) iodide (0.030 g, 0.16 mmol), cyclohexane-1,2-diamine (0.018 g, 0.16 mmol) and potassium carbonate (0.17 g, 1.20 mmol) in anhydrous N,N-dimethylformamide (15 mL) was heated at 100° C. under nitrogen atmosphere for 16 hours. The solvent was removed in vacuo diluted with ethyl acetate (250 mL), washed with saturated sodium bicarbonate solution (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was recrystallized from ethyl acetate and hexane. The solid was collected by filtration and washed with methanol and hexane to afford the title compound as a colourless solid in 8% yield (0.030 g): mp 226-228° C. (ethyl acetate/hexanes): 1H NMR (300 MHz, DMSO-d6) δ 8.59 (t, J=5.9 Hz, 1H), 7.49-7.17 (m, 10H), 4.99 (s, 2H), 4.35 (d, J=5.9 Hz, 2H), 4.14-4.08 (m, 2H), 3.66-3.60 (m, 2H), 2.44 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.9, 156.1, 153.3, 151.5, 140.0, 135.4, 129.3, 128.7, 128.4, 128.1, 127.7, 127.1, 119.8, 113.9, 49.0, 46.6, 44.72, 43.1, 17.5; MS (ES+) m/z 431.3 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=2[F:27])=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.CCC(O)(C)C.N#N.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.Cl.[CH3:59][C:60]1([CH3:66])[O:65][CH2:64][CH2:63][NH:62][CH2:61]1.[OH-].[K+]>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CCOC(C)=O>[F:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[O:17][C:3]1[C:2]([N:62]2[CH2:63][CH2:64][O:65][C:60]([CH3:66])([CH3:59])[CH2:61]2)=[CH:10][C:9]2[C:5](=[CH:6][N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:8]=2)[CH:4]=1
Reactant: CC1(C)CNCCO1
Reactant: O=[N+]([O-])c1ccc(Oc2cc3cn(C4CCCCO4)nc3cc2Br)c(F)c1
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: Cl
Solvent: CCC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)CN(c2cc3nn(C4CCCCO4)cc3cc2Oc2ccc([N+](=O)[O-])cc2F)CCO1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 25.6 %

Procedure:
6-Bromo-5-(2-fluoro-4-nitrophenoxy)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (1.5 g, 3.4 mmol) is added to a 50 mL Genevac Carousel® tube and is suspended into the amylene hydrate (10 mL, 91.4 mmol) and N2 is bubbled in suspension. To the mixture is added 2-(di-tert-butylphosphino)-2′-methylbiphenyl (97.7 mg, 309 μmol), Pd2(dba)3 (94.5 mg, 103 μmol) and DI water (0.3 mL), and N2 bubbling is continued for 10 min. To this mixture is added 2,2-dimethylmorpholine hydrochloride (1.04 g, 6.9 mmol) and a solution of KOH (617 mg, 11.0 mmol) dissolved in 0.3 mL of distilled water. The reaction mixture is heated at 80° C. for 2 hours and then cooled to RT. The mixture is then poured into EtOAc (300 mL), washed with distilled water (1×100 mL) and then saturated aqueous sodium chloride (100 mL). The combined aqueous layers are extracted with EtOAc (100 mL). The combined organic solution is dried with Na2SO4, filtered, and concentrated to dryness to give a gold solid. The solid is purified on a silica gel column eluting with hexanes (A) and EtOAc (B), gradient from 95%(A):5%(B) to 75%(A):25%(B) over 70 min to give a light yellow solid as the desired product (410 mg, 25% yield). MS (m/z): 470.8 (M+H).
Reaction SMILES: [C:1]([CH2:3][C:4]1([C:8]([O:10]CC)=[O:9])[CH2:7][CH2:6][CH2:5]1)#[N:2].[OH-].[Na+]>C(O)C.C1COCC1.O>[C:1]([CH2:3][C:4]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5]1)#[N:2]
Reactant: CCOC(=O)C1(CC#N)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: N#CCC1(C(=O)O)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 65.5 %

Procedure:
To a stirred solution of Intermediate 220B (0.110 g, 0.658 mmol) in ethanol (3.5 mL), THF (3.5 mL) and water (3 mL) was added NaOH (0.079 g, 1.974 mmol) and the reaction mixture was stirred at RT for 16 h. The reaction mixture was concentrated and the residue was diluted with water (3 mL) and extracted with EtOAc (3×20 mL) The pH of the aqueous layer was adjusted to 3 using a 1.5N aqueous solution of HCl and extracted with EtOAc (3×10 mL). The combined organic layer was washed with water, dried over Na2SO4, filtered and the filtrate concentrated. The residual mass was then azeotroped with toluene to obtain the Intermediate 220C as a brown oil (0.06 g, 66% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.65 (br. s., 1H), 3.04-2.79 (m, 2H), 2.42-2.17 (m, 2H), 2.09-1.67 (m, 4H).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[C:31]([CH3:32])=[CH:30][C:29]([CH3:33])=[CH:28][N:27]=3)[CH2:22][CH2:21]2)=[O:19])=[C:14]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:13]=1>>[CH3:32][C:31]1[C:26]([N:23]2[CH2:24][CH2:25][N:20]([C:18]([C:15]3[CH:16]=[CH:17][C:12]([N:5]4[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]4(=[O:10])=[O:9])=[CH:13][C:14]=3[S:34]([CH3:37])(=[O:36])=[O:35])=[O:19])[CH2:21][CH2:22]2)=[N:27][CH:28]=[C:29]([CH3:33])[CH:30]=1
Reactant: CC(C)[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4[C@H](C(C)C)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 26.6 %

Procedure:
Using (S)-3-isopropylisothiazolidine 1,1-dioxide (240 mg) described in Preparation Example 6 and (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (452 mg) described in Preparation Example 112 and by the reaction and treatment in the same manner as in Example 4, the title compound (142 mg) was obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]([CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[C:13]4[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=4[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:14]([CH2:15][C:16]([OH:18])=[O:17])[C:13]4[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=4[N:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Cn1c(-c2ccc3c(c2)OCO3)nc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cn1c(-c2ccc3c(c2)OCO3)nc2ccccc21
Temperature: 25 °C

Procedure:
A solution of 0.5 g (1.42 mmol) of 1,1-dimethylethyl 2-(1,3-benzodioxol-5-yl)-1H-benzimidazole-1-acetate (the title compound of EXAMPLE 2) in 10 mL of chloroform was treated with 10 mL of trifluoro-acetic acid (TFA), and the reaction was stirred at rt until completion. Volatiles were evaporated in vacuo, and the residue was recrystallized from ether to give 2-(1,3-benzodioxol-5-yl)-1H-benzimidazole-1-acetic acid as a white solid: 1H NMR (DMSO, d6) δ 5.25 (s, 2H), 6.18 (s, 2H), 7.19 (d, J=8.1 Hz, 1H), 7.23-7.35 (m, 2H), 7.37-7.53 (m, 2H), 7.70-7.87 (m, 2H); HRMS (EI) Calc'd for M+ : 297.0875, found: 297.0885. Anal. Calc'd for [C16H12N2O4 +0.67 CF3CO2H]: C, 55.91; H, 3.43; N, 7.52. Found: C, 55.91; H, 3.52; N, 7.51.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[O:12][C@H:13]([C:15](=[O:37])[NH:16][C@@H:17]2[C:23](=[O:24])[N:22]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[C:19]3[CH:33]=[CH:34][CH:35]=[CH:36][C:18]2=3)[CH3:14])=CC=1)([O-])=O.[F:39][C:40]([F:47])([C:43]([F:46])([F:45])[F:44])[CH2:41][NH2:42]>ClCCl.C(OC(=O)C)C>[CH:26]1([CH2:25][N:22]2[C:23](=[O:24])[C@@H:17]([NH:16][C:15]([C@@H:13]([O:12][C:11](=[O:10])[NH:42][CH2:41][C:40]([F:47])([F:39])[C:43]([F:46])([F:45])[F:44])[CH3:14])=[O:37])[C:18]3[CH:36]=[CH:35][CH:34]=[CH:33][C:19]=3[C:20]3[CH:32]=[CH:31][CH:30]=[CH:29][C:21]2=3)[CH2:28][CH2:27]1
Reactant: C[C@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Reactant: NCC(F)(F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C[C@H](OC(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Yield: 98 %

Procedure:
0.61 g (1.18 mmol) carbonic acid (S)-1-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-ethyl ester 4-nitro-phenyl ester and 2.5 ml 2,2,3,3,3. pentafluoropropylamine were stirred at room temperature over night. Chromatography on silicagel with dichloromethane/ethylacetate (100-70/0-30) yielded 0.61 g (98%) (2,2,3,3,3-pentafluoro-propyl)-carbamic acid (S)-1-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-ylcarbamoyl)-ethyl ester as white solid; MS: m/e: 526.0 (M+H+), [α] 589=−940° (1.1% in MeOH).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=2)OCC[O:3]1>Cl>[C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1)(=[O:3])[CH3:1]
Reactant: CC(C)(C)C(=O)c1ccc(C2(C)OCCO2)cc1
Agent: Cl
Product: CC(=O)c1ccc(C(=O)C(C)(C)C)cc1

Procedure:
A mixture of 70.3 g. (0.284 mole) 4'-(2-methyl-2-dioxolanyl) pivalophenone and 700 ml of 2N hydrochloric acid is refluxed for 18 hours. The resulting solution is cooled, extracted with ether, the ether washed with salt water, dried, evaporated and the resulting residue is distilled at 88°-86° C mm Hg to give 4'-acetylpivalophenone.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[S:14](Cl)(=[O:17])(=[O:16])[NH2:15]>>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:2]=1[NH:1][S:14]([NH2:15])(=[O:17])=[O:16])#[N:5]
Reactant: NS(=O)(=O)Cl
Reactant: N#Cc1ccc(C(F)(F)F)cc1N
Product: N#Cc1ccc(C(F)(F)F)cc1NS(N)(=O)=O

Procedure:
Prepared as in Example 77a from 2-amino-4-trifluoromethylbenzonitrile and sulfamoyl chloride. 1H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 1H), 7.74-7.76 (d, J=8.4 Hz, 1H), 8.01-8.03 (dd, J=8.4 Hz, 1.6 Hz, 1H), 8.23 (s, 1H), 10.16 (b, 1H).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[C:22]([NH:24][O:25][CH3:26])=[O:23])[CH2:17][CH2:16]1.O.NN>CCO.CCOCC>[NH2:3][CH2:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([N:21]([CH2:27][C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[C:22]([NH:24][O:25][CH3:26])=[O:23])[CH2:17][CH2:16]1
Reactant: CONC(=O)N(Cc1ccsc1)C1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CONC(=O)N(Cc1ccsc1)C1CCN(CCCN)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of 1-{1-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-piperidin-4-yl}-3-methoxy-1-thiophen-3-ylmethyl-urea (0.69 g, 1.56 mmol) in EtOH (15 ml) was added hydrazine hydrate (0.49 ml, 15.6 mmol) and the reaction was stirred at rt for 16 h. The reaction mixture was diluted with Et2O (40 ml) to give a white precipitate. The solid was removed via suction filtration and the filtrate was concentrated in vacuo to give a white foam. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 83:15:2, v/v/v) gave 1-[1-(3-amino-propyl)-piperidin-4-yl]-3-methoxy-1-thiophen-3-ylmethyl-urea as a white foam (0.280 g, 57%). 1H NMR (CDCl3) δ 1.60-1.72 (m, 6H), 2.00 (t, 2H, J=9.0 Hz), 2.07 (br s, 3H), 2.39 (t, 2H, J=6.0 Hz), 2.75 (t, 2H, J=6.0 Hz), 2.98 (d, 2H, J=12.0 Hz), 3.65 (s, 3H), 4.25 (m, 1H), 4.29 (s, 2H), 6.95 (d, 1H, J=3.0 Hz), 7.10 (s, 2H), 7.34 (m, 1H).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:10][C:11](=O)[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15]([NH2:17])=[O:16].C(O)(=O)C(C(C(O)=O)O)O.N>C(OC(C)C)(=O)C.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].COC(C)(C)C>[CH2:1]([O:8][C:11](=[O:10])[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15]([NH2:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C[C@@H](O)CC(N)=O
Reactant: OCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: N
Solvent: CC(=O)OC(C)C
Solvent: COC(C)(C)C
Product: NC(=O)C[C@H](O)CC(=O)OCc1ccccc1
Temperature: 55 °C
Reaction time: 5 h

Procedure:
Mixture of Benzyl alcohol (131.0 g), (S)-methyl-3-hydroxyglutaramate (100 g) and Tetraisopropyl orthotitanate (17.5 g) are mixed in a flask. The mixture was stirred under vacuum at 50-60° C. for about 5 hrs. The reaction mixture was cooled and diluted with isopropyl acetate (500 ml). The reaction mixture was added to a stirred solution of Tartaric acid (37 g in 370 ml DM water) and 500 ml isopropyl acetate mixture. The reaction mixture was stirred and pH was adjusted to 7.0-8.0 by Aq ammonia solution. Layers were separated. The organic phase was removed and the aqueous phase was extracted with isopropyl acetate. Combined organic layer was washed with Aq ammonia and tartaric acid solution followed by brine wash. The organic phase was dried over anhydrous sodium sulphate and evaporated under reduced pressure to yield oil. To this oil tert-butyl methyl ether (800 ml) was added, stirred, cooled, filtered and dried to give (S)-Benzyl-3-hydroxyglutaramate.