Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:24])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30]>>[CH3:25][N:26]([CH2:27][CH2:28][CH2:29][NH:30][C:1](=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:31]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CN(C)CCCN
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)NCCCN(C)C

Procedure:
Behenic acid (LUNAC BA, manufactured by Kao Corporation) and dimethyl aminopropylamine were subjected as starting materials to amidation reaction to give behenic acid dimethylaminopropylamide. The purity was 98%, and other components include unreacted behenic acid, unreacted amine, water, etc. The composition of the fatty acid residue (R4CO) was C17H35CO/C19H39CO/C21H43CO/C23H47CO=1%/9%/88%/2%.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Mg].[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=[O:12].Cl>C(OCC)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]([OH:12])([CH3:13])[C:10]([OH:15])=[O:14])=[CH:3][CH:4]=1
Reactant: CC(=O)C(=O)O
Reactant: Fc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(O)(C(=O)O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 17 h

Procedure:
A Grignard reagent was prepared from a solution of 1-bromo-4-fluorobenzene (50 g.) in diethyl ether (100 ml.) and a stirred suspension of magnesium (6.8 g.) in diethyl ether (20 ml.), and was heated under reflux for 1 hour and then cooled to 0° C. A solution of pyruvic acid (10.8 g.) in diethyl ether (50 ml.) was added dropwise and the mixture was stirred at laboratory temperature for 17 hours, cooled to 0° C., acidified with dilute aqueous hydrochloric acid and extracted three times with diethyl ether. The combined ethereal extracts were washed with water and extracted with saturated aqueous sodium bicarbonate solution, and the bicarbonate extract was acidified with concentrated aqueous hydrochloric acid and then extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed with water and then with saturated aqueous sodium chloride solution, dried over magnesium sulphate and evaporated to dryness under reduced pressure. There was thus obtained as residue 2-p-fluorophenyl-2-hydroxypropionic acid which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11](Cl)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:14]1(C(OC(C)(C)C)=O)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)Cc1cccc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Cc1cccc([N+](=O)[O-])c1)N1CCNCC1
Reaction time: 1 h

Procedure:
2-(3-nitrophenyl)acetyl chloride (0.20 ml, 1.0 mmol.) was added to a vigorously stirred mixture of tert-butyl piperazine-1-carboxylate (0.19 g, 1.0 mmol.) in CH2Cl2 (2 ml) and sat. aq. NaHCO3 (1 ml). The reaction was stirred for 1 hour; then the organic layer was separated, filtered through a plug of MgSO4, and concentrated under vacuum. The residue was treated with TFA in CH2Cl2 to remove the Boc group to give 2-(3-nitrophenyl)-1-(piperazin-1-yl)ethanone, which was carried on crude.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([C:19](O)([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[N-:23]=[N+:24]=[N-:25].[Na+].FC(F)(F)C(O)=O.N>ClCCl.O>[N:23]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:7]2[NH:8][C:9](=[O:12])[C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)=[CH:14][CH:15]=1)([CH3:21])[CH3:20])=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(O)c1ccc(-c2cc3ccc(F)cc3c(=O)[nH]2)cc1
Agent: N
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(N=[N+]=[N-])c1ccc(-c2cc3ccc(F)cc3c(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 7-fluoro-3-[4-(1-hydroxy-1-methyl-ethyl)-phenyl]-2H-isoquinolin-1-one (149 mg, 0.50 mmol) and sodium azide (71.5 mg, 1.10 mmol) in dichloromethane (1 ml) is added a solution of trifluoroacetic acid (316 μl, 4.1 mmol) in dichloromethane (0.5 ml) dropwise under external cooling with ice. The reaction mixture is stirred for 2 hours at room temperature. Water and 25% aqueous ammonia (0.5 ml) are added. The organic phase is separated and the aqueous phase is extracted with dichloromethane. The combined organic phases are dried over sodium sulfate and evaporated to afford 3-[4-(1-azido-1-methyl-ethyl)-phenyl]-7-fluoro-2H-isoquinolin-1-one as white powder; HPLC/MS 2.07 min (A), [M+H] 323.
Reaction SMILES: C(O[C:9]([NH:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=O)C1C=CC=CC=1.[Na].[CH:24](=O)[CH:25]=[CH:26][CH2:27]C.C(O)(=O)C>C(O)C.[Pd]>[CH2:25]([CH:26]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:11][CH:9]=[CH:27]1)[CH3:24]
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Reactant: CCC=CC=O
Agent: [Pd]
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)NC=CC1CC
Reaction time: 1 h
Yield: 63 %

Procedure:
Diethyl benzyloxycarbonylaminomalonate (11.5 g, 38 mM) was dissolved in dry ethanol (50 ml) and added to a solution of sodium (150 mg) in dry ethanol (10 ml). Pent-2-enal (3.2 g 38 mM) in ethanol (10 ml) was added dropwise to the stirred mixture and the solution stirred for 1 hr. A solution of acetic acid (0.29 ml) in ethanol (1 ml) was then added and the solution hydrogenated for 2 hrs at atmospheric pressure using palladium on carbon (5%) as catalyst. The catalyst was removed by filtration and the filtrate evaporated. The residue was dissolved in chloroform and the solution washed with brine containing a little sodium bicarbonate, dried (Na2SO4) and evaporated. Distillation of the residue at 15 mm Hg gave 4-ethyl-5,5-dicarboethoxy-2-pyrroline (5.65 g) as a colourless oil b.p. 115°-120° (15 mm Hg) I.R. 1715, 1610 cm-1.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][CH:15]([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][CH:15]([F:18])[CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCC(F)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC1CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.6 %

Procedure:
A 25 mL round-bottomed flask was charged with a solution of 3-(4-fluoro-piperidin-1-yl)-azetidine-1-carboxylic acid tert-butyl ester (0.59 g, 2.26 mmol) in DCM/TFA (4 mL/4 mL). The reaction mixture was stirred for 6 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-fluoropiperidine as a pale yellow oil (0.263 g, 74%). 1H NMR (CDCl3, 400 MHz) δ 4.60 (m, 1 H); 3.64-3.52 (m, 4 H); 3.26-3.18 (m, 1 H); 2.45-2.38 (m, 2 H); 2.28-2.17 (m, 2 H); 1.96-1.81 (m, 4 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][C@H:20]3[CH2:24][N:23]([C:25](=[O:43])[C@@H:26]([NH:34][C:35]([O:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[C@H:22]([C:44]([O:46]C)=[O:45])[CH2:21]3)=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[CH:48]=[CH2:49].[Li+].[OH-].Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][C@H:20]3[CH2:24][N:23]([C:25](=[O:43])[C@@H:26]([NH:34][C:35]([O:37][CH2:38][CH2:39][CH2:40][CH:41]=[CH2:42])=[O:36])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]=[CH2:33])[C@H:22]([C:44]([OH:46])=[O:45])[CH2:21]3)=[CH:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[CH:48]=[CH2:49]
Reactant: C=CCCCCC[C@H](NC(=O)OCCCC=C)C(=O)N1C[C@H](Oc2cc(-c3ccccc3)nc3cc(OC)c(C=C)cc23)C[C@H]1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCCCCC[C@H](NC(=O)OCCCC=C)C(=O)N1C[C@H](Oc2cc(-c3ccccc3)nc3cc(OC)c(C=C)cc23)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
A mixture of the product from Step 1 (0.68 g, 1.02 mmol) in THF (7 mL), MeOH (1 mL) and 1 M aqueous LiOH (7.15 mL, 7.15 mmol) was stirred at RT for 2 hours. The reaction mixture was acidified to pH 5 with 1 M aqueous HCl and extracted with EtOAc (3×70 mL). The combined organic phases were washed with water (50 mL), brine (30 mL), dried over Na2SO4, filtered and concentrated to give the title compound (0.56 g). LRMS (ESI) m/z 656.5 [(M+H)+; calcd for C38H46N3O7: 656.3].
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[CH3:28][O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH2:33]>CCO>[CH3:28][O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][NH:33][C:6]([C:8]1[N:9]=[C:10]([C:26]#[N:27])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7]
Reactant: CCCCOC(=O)c1nc(C#N)c2ccc(Oc3ccccc3)cc2c1O
Reactant: COC(=O)C(C)(C)CN
Solvent: CCO
Product: COC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2ccc(Oc3ccccc3)cc2c1O
Yield: 64.7 %

Procedure:
A mixture of 1-cyano-4-hydroxy-6-phenoxy-isoquinoline-3-carboxylic acid butyl ester (50 mg, 0.14 mmol) (prepared according to U.S. Pat. No. 7,928,120) and 3-amino-2,2-dimethyl-propionic acid methyl ester (90 mg, 0.70 mmol) in EtOH (2 mL) was heated at 150° C. in a microwave reactor for 3 h. The solvent was evaporated, and the residue was purified by column chromatography (0-30% EtOAc/hexanes) to give 38 mg of the title compound. 1H NMR (CDCl3, 200 MHz): δ ppm=13.9 (s, 1H), 8.20-8.40 (m, 2H), 7.10-7.70 (m, 7H), 3.79 (s, 3H), 3.62 (d, 2H, J=7.0 Hz), 1.30 (s, 6H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[CH:23])[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.I[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:25]4[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C#CC1(c2ccc(OC)c(OC3CCCC3)c2)CCCC(=O)C1
Reactant: N#Cc1cccc(I)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C2(C#Cc3cccc(C#N)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 80 °C
Yield: 72.5 %

Procedure:
To a solution of the compound from Example 3 (E1) (0.125 g, 0.4 mmol) and 3-iodobenzonitrile (Transworld, 0.09 g, 0.4 mmol) in triethylamine (3 mL) under an argon atmosphere was added trace tetrakis(triphenylphosphine)palladium(0), copper(I) iodide and triphenylphosphine. The mixture was heated at 80° C. for 0.2 h, was cooled to room temperature and was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, was dried (MgSO4) and was evaporated. The residue was purified by flash chromatography, eluting with 2:1 hexanes/ethyl acetate, to provide the title compound as a clear yellow glass (0.12 g, 73%). MS(EI) m/e 414 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1>CN(C=O)C.O>[Br:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[NH:59][CH:60]1[CH2:65][CH2:64][N:63]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:62][CH2:61]1
Reactant: Brc1ccccc1NC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2Br)CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.038 g, 0.00013 mol) in DMF (2 mL), was added DIPEA (0.0872 g, 0.00067 mol), HOBt (0.023 g, 0.00017 mol) and EDCI.HCl (0.0325 g, 0.0001686 mol) at ambient temperature. After 2 minutes (2-bromo-phenyl)-piperidin-4-yl-amine dihydrochloride (0.0393 g, 0.00013 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and dried to afford 0.0375 g (58%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-bromo-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 482.11 (M+1)+, 91.09%, 1H NMR (DMSO-d6): δ 13.7 (s, 1H), 8.0 (s, 1H), 7.8 (d, 2H), 7.38 (m, 4H), 7.16 (t, 1H), 7.06 (s, 1H), 6.84 (d, 1H), 6.5 (t, 1H), 4.6 (d, 1H), 4.3 (d, 1H), 4.1 (d, 2H), 3.9 (m, 1H), 3.6 (m, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 1.9 (m, 2H), 1.4 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][O:22][CH2:23][CH2:24][NH:25][C:26]([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:26]([N:25]([CH2:24][CH2:23][O:22][CH3:21])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:29])([CH3:28])[CH3:27]
Reactant: COCCNC(C)(C)C
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)C(C)(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with N-(2-methoxyethyl)-2-methylpropan-2-amine (CAN 22687-22-5) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=398.4 [MH+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1)([O-])=O>CO.CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1
Reactant: O=[N+]([O-])c1cnn(-c2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cnn(-c2ccccc2)c1
Reaction time: 8 h
Yield: 73.3 %

Procedure:
10% Pd/C (25 mg) was added to a stirred solution of 4-nitro-1-phenyl-1H-pyrazole (240 mg, 1.2 mmol) in a mixture of MeOH (2.5 mL) and EtOAc (2.5 mL) and stirred under H2 atmosphere overnight. The reaction mixture was filtered through celite and the filtrate so obtained was concentrated under reduced pressure to afford 140 mg (69365% Yield) of 4-amino-1-phenyl-1H-pyrazole.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:27]([N:34]1[CH2:39][CH2:38][O:37][CH:36]([CH2:40]Cl)[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([N:34]1[CH2:39][CH2:38][O:37][CH:36]([CH2:40][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=3)[C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7]2)[CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(c1cn(CC2CN(Cc3ccccc3)CCO2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with commercially available 4-benzyl-2-(chloromethyl)morpholine gave the title compound. ES-MS m/e (%): 556.3 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[S:9][CH:10]=1)=[O:5])C.[Li+].[OH-]>O>[CH:11]1([C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CCOC(=O)c1csc(C2CCCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1csc(C2CCCCC2)n1
Yield: 83 %

Procedure:
To a solution of 2-cyclohexylthiazole-4-carboxylic acid ethyl ester (116, 6.8 g, 28.5 mmol) in water was added 1M LiOH (50 mL). The solution was kept at room temperature and monitored by LC-MS. When the hydrolysis was completed the reaction mixture was neutralized with myriatic acid and extracted with ethyl acetate and diethyl ether. The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure to give 5.0 g (83%) of the title compound 117: m/z=212 (M+H)+.
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:12][C:13]1[C:17]([C:18]2[CH:19]=[C:20]([C@@H:24]([NH2:26])[CH3:25])[CH:21]=[CH:22][CH:23]=2)=[C:16]([CH3:27])[O:15][N:14]=1>>[CH3:12][C:13]1[C:17]([C:18]2[CH:19]=[C:20]([C@@H:24]([NH:26][C:1](=[O:11])[CH:2]=[CH:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH3:25])[CH:21]=[CH:22][CH:23]=2)=[C:16]([CH3:27])[O:15][N:14]=1
Reactant: Cc1noc(C)c1-c1cccc([C@H](C)N)c1
Reactant: O=C(O)C=Cc1ccccc1
Product: Cc1noc(C)c1-c1cccc([C@H](C)NC(=O)C=Cc2ccccc2)c1

Procedure:
The title compound was prepared from cinnamic acid and (S)-1-[3-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethylamine following the general procedures as described for Example 1.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[O:4][C@@H:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[F:24][C:25]1[CH:26]=[C:27]([CH2:32][C:33]([NH:35][C@H:36]([C:38](O)=[O:39])[CH3:37])=[O:34])[CH:28]=[C:29]([F:31])[CH:30]=1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[CH:11]1([CH2:10][N:7]2[C:6]3[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=3[O:4][C@H:3]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@H:2]([NH:1][C:38](=[O:39])[C@H:36]([CH3:37])[NH:35][C:33](=[O:34])[CH2:32][C:27]3[CH:28]=[C:29]([F:31])[CH:30]=[C:25]([F:24])[CH:26]=3)[C:8]2=[O:9])[CH2:13][CH2:12]1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2O[C@@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2O[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
To a stirred solution of (2R,3S)-3-amino-5-(cyclopropylmethyl)-2-phenyl-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (72b) (150 mg, 0.486 mmol) in dichloromethane (4 mL) was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (1e) (130 mg, 0.534 mmol), HOBt (75 mg, 0.555 mmol), NMM (60 mg, 0.594 mmol) and EDAC-HCl (103 mg, 0.537 mmol). After stirring at ambient temperature under nitrogen overnight the solvent was evaporated and the residue partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic solution was separated, washed with 1N aqueous HCl then dried, filtered and evaporated. The residue was purified by flash chromatography on silica gel eluting with 5:1 (v/v) dichloromethane: ethyl acetate to afford the title compound (230 mg, 88%) as a white solid. TLC Rf=0.22 (5:1 dichloromethane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ0.20 (m, 1H), 0.36-0.64 (m, 3 h), 1.14 (m, 1H), 1.21 (d, 3H, J=7.0 Hz), 3.47 (s, 2H), 3.52 (m, 1H), 4.10-4.29 (m, 2H), 5.05 (t, 1-H, J=7.0 Hz), 5.68 (d, 1H, J=7.4 Hz), 5.90 (d, 1H), 6.24 (d, 1H), 6.68-6.85 (m, 3H), 7.28 (s, 4H), 7.36, s, 5H). MS APCI, m/z=534 (M+1). LC/MS: 2.78 min.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][O:15][C:16]1[CH:30]=[CH:29][CH:28]=[CH:27][C:17]=1[O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:23]([CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][C:17]3[CH:27]=[CH:28][CH:29]=[CH:30][C:16]=3[O:15][CH3:14])[CH:20]=1)[CH2:11]2
Reactant: COc1ccccc1Oc1cccc(CN)c1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1cccc(CN2Cc3cccc(I)c3C2=O)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 23.8 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.178 g, 0.5 mmol), 3-(2-methoxy-phenoxy)-benzylamine (0.160 g, 0.6 mmol), and K2CO3 (0.138 g, 1.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-[3-(2-methoxy-phenoxy)-benzyl]-2,3-dihydro-isoindol-1-one (0.056 g, 24%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.82 (s, 3H), 4.16 (s, 2H), 4.74 (s, 2H), 6.84-7.40 (m, 10H), 7.92 (d, 1H). GC-MS: m/z 471 (M)+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([N:9]2[CH2:12][CH:11](OS(C)(=O)=O)[CH2:10]2)[O:7][CH:8]=1)(=[O:3])[NH2:2].[C:18]([O-:21])(=[S:20])[CH3:19].[K+]>CN(C)C=O>[C:18]([S:20][CH:11]1[CH2:10][N:9]([C:6]2[O:7][CH:8]=[C:4]([C:1](=[O:3])[NH2:2])[N:5]=2)[CH2:12]1)(=[O:21])[CH3:19]
Reactant: CS(=O)(=O)OC1CN(c2nc(C(N)=O)co2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(N)=O)co2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 63.3 %

Procedure:
To a solution of 1-(4-carbamoyl-1,3-oxazol-2-yl)-3-methanesulfonyloxyazetidine (469 mg, 1.80 mmol) (obtained as described in Reference Example 22(3)) in dimethylformamide (23 ml) was added potassium thioacetate (1.23 g, 10.80 mmol) at room temperature, and the mixture was stirred in an oil bath (80° C.) for 8 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate: methanol (10:1) as the eluant to afford 3-acetylthio-1-(4-carbamoyl-1,3-oxazol-2-yl)azetidine (275 mg, yield 63%) as a white solid.