Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[N:5]=[C:6]([O:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])(=[O:13])=[O:12])=[N:8][CH:9]=1.[CH2:30]([O:34][C:35](Cl)=[O:36])[CH:31]([CH3:33])[CH3:32]>COCCOC>[Br:3][C:4]1[N:5]=[C:6]([O:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[C:7]([N:10]([S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=2[Cl:21])(=[O:12])=[O:13])[C:35](=[O:36])[O:34][CH2:30][CH:31]([CH3:33])[CH3:32])=[N:8][CH:9]=1
Reactant: O=S(=O)(Nc1ncc(Br)nc1OCc1cccnc1)c1cccc(Cl)c1Cl
Reactant: CC(C)COC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)COC(=O)N(c1ncc(Br)nc1OCc1cccnc1)S(=O)(=O)c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
Sodium hydride (0.045 g of a 60% dispersion in oil) was added to N-[5-bromo-3-(3-pyridinylmethoxy)-2-pyrazinyl]-2,3-dichlorobenzenesulphonamide (Example 34) (0.5 g) in 1,2-dimethoxyethane (3 mL). Iso-butylchloroformate (0.15 mL) was added. After 2 h, the mixture was partitioned between water and ethyl acetate. The organic layer was dried (Na2SO4) and evaproated to yield the product (0.65 g). Used directly.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[O:3][C:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[CH3:11])[CH2:6][CH:5]=1.O.[CH3:16]COCC>>[CH3:1][Si:2]([CH3:14])([CH3:13])[O:3][C:4]1[CH2:9][CH2:8][CH:7]([C:10]([CH3:16])=[CH2:11])[CH2:6][CH:5]=1
Reactant: CC(=O)C1CC=C(O[Si](C)(C)C)CC1
Reactant: CCOCC
Solvent: O
Product: C=C(C)C1CC=C(O[Si](C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
From 23.5 g (0.066 mol) of methyltriphenylphosphonium bromide and 6.9 g (0.061 mol) of potassium tert-butylate, in 80 ml of ether at room temperature, the ylide was formed. To this solution were added dropwise at from 20° to 30° C. 10.0 g (0.047 mol) of 1-trimethylsilyloxy-4-acetyl-1-cyclohexene (Org. Synth. Coll. Vol. VI, 445) dissolved in 20 ml of ether. The mixture was stirred at room temperature for 3 hours. Water was then added, and extraction was carried out with ether. A spatula tip of hydroquinone was added to the combined ether phases, which were then dried and concentrated. The residue was extracted by stirring with heptane and the combined heptane phases were concentrated. 8.0 g (81% of theory) were obtained of a colorless oil which was reacted further without purification.
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH:5]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])[N:7]=1)[CH3:2].[ClH:39]>O1CCOCC1>[ClH:39].[CH2:1]([C:3]1[O:4][CH:5]=[C:6]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])[N:7]=1)[CH3:2]
Reactant: CCc1nc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)co1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1nc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)co1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Tert-butyl 4-{1-[(2-ethyl-1,3-oxazol-4-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (650 mg; compound B17) is dissolved in a solution of hydrogen chloride in 1,4-dioxane (10 ml, 6.8 M). The solution is stirred for 0.5 h at RT. The resulting precipitate is filtered off, washed with diethyl ether and dried in vacuo to give the title compound as a solid.
Reaction SMILES: C(OC([NH:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:16]2[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:15]=2[N:14]([CH2:30][C:31]2[N:32]=[CH:33][N:34](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:35]=2)[C:13]1=[O:55])=O)C1C=CC=CC=1.Br.C(OCC)(=O)C>C(O)(=O)C>[NH2:11][CH:12]1[N:18]=[C:17]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:16]2[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:15]=2[N:14]([CH2:30][C:31]2[N:32]=[CH:33][NH:34][CH:35]=2)[C:13]1=[O:55]
Reactant: Cc1cccc2c1N(Cc1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn1)C(=O)C(NC(=O)OCc1ccccc1)N=C2C1CCCCC1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cccc2c1N(Cc1c[nH]cn1)C(=O)C(N)N=C2C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
A mixture of (3RS)-3-benzyloxycarbonylamino-5-cyclohexyl-2,3-dihydro-9-methyl-1-(1-triphenylmethylimidazol-4-yl)methyl-1H-1,4-benzodiazepin-2-one (0.5 g) and 30% hydrobromic acid in acetic acid (2.0 ml) was stirred at room temperature overnight. The reaction mixture was poured into a mixture of an ice and ethyl acetate under stirring. The separated water layer was washed with ethyl acetate once, and neutralized with a saturated aqueous solution of sodium bicarbonate. The resultant aqueous mixture was extracted with ethyl acetate and the extract was dried over sodium sulfate. Removal of the solvent in vacuo afforded (3RS)-3-amino-5-cyclohexyl-2,3-dihydro-1-(imidazol-4-yl)methyl-9-methyl-1H-1,4-benzodiazepin-2-one (174 mg, 72.1%) as a crystalline powder.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1>>[CH3:17][N:4]1[C:3]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:2]([C:35]2[CH:36]=[N:31][CH:32]=[N:33][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1
Reactant: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cncnc1
Product: Cn1c(-c2ccc(C(F)(F)F)cc2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(4-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 104) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as colorless amorphous solid. MS: 485.3 (MH+).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].C(Cl)(=O)C([Cl:20])=O.C(Cl)(Cl)Cl>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:20])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C(=O)Cl)cc1[N+](=O)[O-]

Procedure:
4-Acetamido-3-nitrobenzoic acid 1 (Alfa Aesar, 5.6 g, 25 mmol), oxalyl chloride (4.76 g, 38 mmol), chloroform (50 ml), DMF (few drops) were stirred at 40° C. for 3 hours. The solvent was removed in vacuo to give a yellow solid that was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:40][NH:41][O:42][CH3:43]>CN(C=O)C>[CH3:43][O:42][N:41]([CH3:40])[C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Commercially available 4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.95 g, 8.43 mmol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (1.94 g, 10.1 mmol) and 1-hydroxybenztriazole monohydrate (1.25 g, 9.28 mmol) were combined in DMF (10 mL) and stirred at rt for 15 min. before adding N,O-dimethylhydroxylamine (0.987 g, 10.1 mmol), The reaction was stirred at rt overnight. The reaction was then concentrated and partitioned between saturated NaHCO3 and 20% isopropanol in CHCl3. The organic layer was dried (MgSO4) and concentrated. The crude residue was pulled through a layer of silica using CH2Cl2 and the eluting solvent. A colorless oil was isolated (0.7 g, 30%). 1H-NMR (DMSO-d6) δ 4.31-4.18 (bs, 1 H), 3.94-3.78 (m, 2 H), 3.76-3.61 (m, 4 H), 3.48 (dt, J1=11 Hz, J2=2.7 Hz, 1 H), 3.19-2.80 (m, 5 H), 1.39 (s, 9 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1(O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.S(=O)(=O)(O)O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:10]2([CH3:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:3]=1
Reactant: CC1(O)CCCCC1
Reactant: Oc1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC1(c2cc(F)ccc2O)CCCCC1
Temperature: 25 °C
Reaction time: 50 h

Procedure:
4-Fluorophenol (41.8 g, 373 mmol) and 1-methylcyclohexanol (63.8 g, 560 mmol) dissolved in 600 mL of dried CH2Cl2, were treated with concentrated sulfuric acid (98%, 22.3 mL, 418 mmol). The mixture was stirred at room temperature for 50 hours. The reaction mixture was then extracted by CH2C2 (250 mL×3). The organic layer was washed with saturated a.q. NaHCO3, dried over MgSO4, and evaporated under vacuum. The residue was purified by column chromatography on silica gel to give 4-fluoro-2-(1-methylcyclohexyl)phenol as a dark green oil—47.6 g. 1H NMR (400 MHz, CDCl3) δ 7.00 (dd, J=3.2, 11.2 Hz, 1H), 6.76-6.71 (m, 1H), 6.62-6.59 (m, 1H), 5.27 (brs, 1H), 2.13-2.07 (m, 2H), 1.70-1.37 (m, 8H), 1.32 (s, 3H).
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:16](=[O:17])[C:15]3[CH:19]=[CH:20][CH:21]=[C:13]([Cl:12])[CH:14]=3)[CH2:2]1)[CH2:8]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cccc(Cl)c1
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc(Cl)c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 3-chlorobenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.84-2.05 (m, 5H), 2.11 (s, 1H), 2.29 (s, 1H), 2.32 (s, 1H), 2.39 (s, 2H), 3.47-3.53 (m, 2H), 3.62-3.74 (m, 1H), 3.77-3.88 (m, 1H), 4.38 (s, 1H), 7.43-7.52 (m, 1H), 7.54-7.61 (m, 1H), 7.73-7.80 (m, 1H), 7.78-7.88 (m, 1H); MS (APCI/NH3) m/z 291 (M+H)+.
Reaction SMILES: B.O1CCCC1.[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([CH3:42])([CH3:41])[C:16]([N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[N:39]([CH3:40])[N:38]=[N:37][N:36]=4)[CH:30]=3)=[O:27])[CH2:19]2)=O)=[CH:10][CH:9]=1.Cl>CO>[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([CH3:42])([CH3:41])[CH2:16][N:18]2[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][NH:25][C:26]([NH:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]4[N:39]([CH3:40])[N:38]=[N:37][N:36]=4)[CH:30]=3)=[O:27])[CH2:19]2)=[CH:10][CH:9]=1
Reactant: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCN(C(=O)C(C)(C)Cc3ccc(F)cc3)C2)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cn1nnnc1-c1cccc(NC(=O)NCC2CCCN(CC(C)(C)Cc3ccc(F)cc3)C2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.3 %

Procedure:
A solution of borane in tetrahydrofuran (1.0 M, 5.3 mL, 5.3 mmol) was added to 1-{1-[3-(4-fluorophenyl)-2,2-dimethylpropionyl]-piperidin-3-ylmethyl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea (66 mg, 134 μmol) and the resulting solution was stirred at room temperature for 18 hours. A mixture of 1.0 N hydrochloric acid (5 mL) and methanol (5 mL) was added very slowly until the resulting vigorous reaction subsided, then the remainder was added quickly and the resulting solution was stirred at room temperature for 5 hours. The solution was concentrated under vacuum. The residue was dissolved in 1.0 N aqueous sodium hydroxide and dichloromethane, and the phases were separated. The aqueous phase was extracted twice with dichloromethane, and the combined organic phases were dried over sodium sulfate and concentrated under vacuum. The residue was purified twice by flash chromatography, eluting with 4% methanol in dichloromethane containing 0.4% aqueous ammonium hydroxide, to provide a white amorphous solid (24 mg, 38%). 1H NMR (300 MHz, CDCl3) δ7.81 (s, 1H), 7.68 (d, J=8 Hz, 1H), 7.34 (t, J=8 Hz, 1H), 7.18 (m, 1H), 7.01 (m, 2H), 6.84 (t, J=9 Hz, 2H), 4.09 (s, 3H), 3.09 (m, 2H), 2.95 (m, 1H), 2.55 (s, 2H), 2.40 (m, 3H), 2.10 (m, 1H), 1.9-1.5 (m, 5H), 1.0 (m, 1H), 0.85 (s, 6H). Mass spec (ES+) m/z 480.5 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:14]2[O:15][CH:16]=[CH:17][CH:18]=2)=[N:3]1.C(N(CC)C(C)C)(C)C.[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:28][C:29]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:30]=1[C:31]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)[CH:5]=2)=[CH:12][CH:11]=1)=[O:32]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: Cn1nc(-c2ccco2)cc1-c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1nc(-c2ccco2)cc1-c1ccc(NC(=O)c2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
To a solution of 71 (11 mg, 0.05 mmol) in CH2Cl2 (10 ml) was added N,N-diisopropylethylamine (DIEA, 26 mg, 36 μL, 0.2 mmol), 4-dimethylaminopyridine (DMAP, 0.6 mg, 0.05 mmol). The 2,6-difluorobenzoyl chloride (15 mg, 0.08 mmol) was dropped into above solution. The mixture was stirred for 2 h at room temperature. The reaction was quenched with saturated NaHCO3 (20 ml) and extracted with EtOAc. The dicarboxamide was hydrolyzed with 1M NaOH in THF and MeOH (1:1). The product was purified by HPLC and afforded 72 (5 mg, 28%) as yellow solid. LC-MS: calcd. for C21H15F2N3O2: 380 (M+1).
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:10])[CH2:8]Br)[N:6]=1.[OH:11][CH2:12][CH2:13][NH:14][CH:15]([CH3:29])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25](OC)=[O:26])=[CH:19][CH:18]=1.[BH4-].[Na+]>CO>[OH:26][CH2:25][CH2:24][O:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH:15]([N:14]([CH2:13][CH2:12][OH:11])[CH2:8][CH:7]([OH:10])[C:5]2[N:6]=[C:2]([Cl:1])[S:3][CH:4]=2)[CH3:29])=[CH:18][CH:19]=1
Reactant: O=C(CBr)c1csc(Cl)n1
Reactant: COC(=O)COc1ccc(CC(C)NCCO)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(Cc1ccc(OCCO)cc1)N(CCO)CC(O)c1csc(Cl)n1

Procedure:
Prepared by analogy to Example 30 by reaction of 2-chloro-4-bromoacetyl-thiazole with N-(2-hydroxyethyl)-2-(4-carbomethoxymethoxyphenyl)-1-methylethylamine followed by reduction in methanol with sodium borohydride at room temperature. The crude product is purified on a silica gel column using chloroform/ ethyl acetate/ methanol=10:9:1 as eluant.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CO
Product: COC(=O)Cc1ccc(F)cc1

Procedure:
4-Fluorophenyl acetic acid (25 g) was dissolved in anhydrous methanol, stirred under nitrogen and cooled in an ice/methanol bath. Dry HCl gas was bubbled through the reaction for 1 hr. The methanol was removed by rotary evaporator and the residue was dispersed between aqueous sodium hydrogen carbonate and dichloromethane. The organic layer was washed with brine, dried (MgSO4) and concentrated to afford the title compound as a clear oil (24.4 g). 1H NMR (360 MHz, CDCl3) δ 3.61 (2H, s), 3.70 (3H, s), 6.97-7.06 (2H, m), 7.20-7.27 (2H, m). MS Cl+ 169 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]([OH:115])[C@@H:3]1[NH:51][C:49](=[O:50])[C@H:48]([CH2:52][CH2:53][CH2:54][CH2:55][NH2:56])[NH:47][C:45](=[O:46])[C@H:44]([CH2:57][C:58]2[C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=3[NH:60][CH:59]=2)[NH:43]C(=O)[C@H](CC2C=CC=CC=2)NC(=O)[C@H](CC2C=CC=CC=2)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(CNC([C@@H](N)C)=O)=O)CSSC[C@@H](C(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@H](O)C)[NH:10][C:8](=[O:9])[C@H:7]([CH2:108][C:109]2C=CC=C[CH:114]=2)[NH:6][C:4]1=[O:5].[CH:116]1[CH:121]=[C:120]2[C:122]([C:124](O)(O)[C:125](=O)[C:119]2=[CH:118][CH:117]=1)=[O:123].C1(OC)C=CC=CC=1>>[N:6]12[CH2:114][CH2:109][CH2:108][C@H:7]1[C:8]([NH:10][C@H:124]([C:122]([NH:43][C@@H:44]([C:45]([NH:47][C@H:48]([C:49]([NH:51][C@H:3]([C:4]2=[O:5])[C@@H:2]([CH3:1])[OH:115])=[O:50])[CH2:52][CH2:53][CH2:54][CH2:55][NH2:56])=[O:46])[CH2:57][C:58]1[C:62]2[C:61](=[CH:66][CH:65]=[CH:64][CH:63]=2)[NH:60][CH:59]=1)=[O:123])[CH2:125][C:119]1[CH:118]=[CH:117][CH:116]=[CH:121][CH:120]=1)=[O:9]
Reactant: C[C@H](N)C(=O)NCC(=O)N[C@H]1CSSC[C@@H](C(=O)O)NC(=O)[C@H](CO)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC1=O
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Solvent: COc1ccccc1
Product: C[C@@H](O)[C@@H]1NC(=O)[C@H](CCCCN)NC(=O)[C@@H](Cc2c[nH]c3ccccc23)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@@H]2CCCN2C1=O

Procedure:
After conventional solid-phase assembly beginning with 1 mmole of Boc-Phe-Merrifield resin (1% cross-linked), the protected peptide hydrazide, H-D-Trp-Lys(Cl-Z)-Thr(Bzl)-Pro-Phe-NHNH2, is cleaved from the support by treatment with hydrazine in methanol and isolated by a procedure described by D. F. Veber et al., Proceedings of the National Academy of Science, U.S.A., 75: 2636-2640, (1978). Without further purification, the hydrazide is converted to the azide, neutralized with triethylamine, and cyclized in DMF solution to yield the protected ninhydrin negative material, cyclo[Pro-Phe-D-Trp-Lys-(Cl-Z)-Thr(Bzl)]. When this protected ninhydrin negative material is hydrogenated at atmospheric pressure and room temperature over 10% Pd on charcoal, the compound, cyclo[Pro-Phe-D-Trp-Lys-Thr(Bzl)], is formed and found to be a very effective somatostatin antagonist. When, however, the protected crude ninhydrin negative material is deprotected by treatment with HF-anisole under standard conditions, as described by G. T. Engberg et al., Nature, 293: 222-223, (1981), and purified by preparative HPLC eluting with 10-55% gradient of CH3CN in 20% AcOH, the reaction yields the pure peptide, cyclo(Pro-Phe-D-Trp-Lys-Thr), which has somatostatin antagonist activity.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=2[F:20])=[C:6]([CH:10]=1)[C:7]([NH:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1COc1cccc(F)c1F
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2cccc(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(2,3-difluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]1([S:14]([C:17]2[C:18]([S:35][CH3:36])=[N:19][N:20]3[C:25](Cl)=[CH:24][C:23]([CH2:27][N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CN(C=O)C>[C:8]1([S:14]([C:17]2[C:18]([S:35][CH3:36])=[N:19][N:20]3[C:25]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:24][C:23]([CH2:27][N:28]4[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]4)=[N:22][C:21]=23)(=[O:16])=[O:15])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CN1CCNCC1
Reactant: CSc1nn2c(Cl)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3CCN(C)CC3)cc(CN3CCN(C)CC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.2 %

Procedure:
0.4 g (4 mmol) of 1-methyl-piperazine was added to a solution of 0.8 g (1.77 mmol) of 3-benzenesulphonyl-7-chloro-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 20 ml of DMF and stirred at RT for 6 hrs. The reaction solution was evaporated and the residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH/NH4OH 80:10:1) and crystallization from EtOH yielded 0.75 g (82%) of 3-benzenesulphonyl-7-(4-methyl-piperazin-1-yl)-5-(4-methyl-piperazin-1-ylmethyl)-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 193-195°.
Reaction SMILES: C(OC(=O)C)(=O)C.C(Cl)(=O)C.[F:12][C:13]([F:21])([CH2:17][C:18]([OH:20])=[O:19])[C:14](O)=[O:15]>>[F:12][C:13]1([F:21])[CH2:17][C:18](=[O:20])[O:19][C:14]1=[O:15]
Reactant: O=C(O)CC(F)(F)C(=O)O
Solvent: CC(=O)Cl
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(F)(F)C(=O)O1
Temperature: 50 °C

Procedure:
To a solution of 10.8 mL of acetic anhydride and 10.8 mL of acetyl chloride at 0° C. was added 10.80 g (0.070 mol) of 2,2-difluorosuccinic acid in several portions. The mixture was heated for 1 hr at 50° C. and cooled. The reaction was concentrated under reduced pressure to yield 2,2-difluorosuccinic anhydride. NMR (CDCl3) δ3.56 ppm (triplet, 2, J=15 Hz).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[C:15]([F:16])=[CH:14][C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)=[CH:12][C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:16][C:15]1[CH:14]=[C:13]([O:17][C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[C:23]2[N:27]([CH3:28])[N:26]=[CH:25][CH:24]=2)[CH:12]=[C:11]([F:29])[C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2c(F)cc(O[C@H]3CCC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)c(F)c1
Yield: 73.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,6-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (192 mg, 0.33 mmol) prepared in Example 27b, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (106 mg, 74%) as a colorless solid.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][O:19]1>>[O:16]=[C:12]1[C:11](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:18](=[O:17])[O:19][CH2:20][CH2:21][C:22]=23)[C:10]2[C:14](=[CH:15][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)[NH:13]1
Reactant: O=Cc1[nH]cc2c1CCOC2=O
Reactant: O=C1Cc2ccc(-c3ccccc3)cc2N1
Product: O=C1Nc2cc(-c3ccccc3)ccc2C1=Cc1[nH]cc2c1CCOC2=O

Procedure:
6-Phenyl-1,3-dihydro-indol-2-one was condensed with 4-oxo-2,4,6,7 tetrahydro-pyrano[3,4-c]pyrrole-1-carbaldehyde to give the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][C:15]([F:19])([F:18])[CH2:14][CH2:13]2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][C:15]([F:18])([F:19])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCC(F)(F)CC2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC1(F)CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-(4,4-difluoropiperidin-1-yl)azetidine-1-carboxylic acid tert-butyl ester (0.684 g, 2.47 mmol) in DCM/TFA (4 mL/4 mL). The reaction mixture was stirred for 3 h at room temperature. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 1-Azetidin-3-yl-4,4-difluoropiperidine as a pale yellow oil (0.279 g, 64%). 1H NMR (CDCl3, 400 MHz) δ 3.64-3.54 (m, 4 H); 3.30-3.25 (m, 1 H); 2.43-2.37 (m, 4 H); 2.06-1.93 (m, 5 H).