Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:12]([NH:14][C@H:15]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@@H:23]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[C:44]([OH:50])([C:46]([F:49])([F:48])[F:47])=[O:45]>>[NH2:1][C@@H:2]([C:12]([NH:14][C@H:15]([C:20]([N:22]1[CH2:36][CH2:35][CH2:34][C@@H:23]1[C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:21])[C@H:16]([CH2:18][CH3:19])[CH3:17])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[F:47][C:46]([C:44]([OH:50])=[O:45])([F:49])[F:48]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](Cc1ccc(OC)cc1)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@H](NC(=O)[C@H](N)Cc1ccc(OC)cc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
Boc-D-Tyr(Me)-L-Ile-D-Pro-OBzl (1.19 g, 2.0 mmol) was dissolved in TFA (5 ml) and left with standing on ice for 30 minutes. On completion of the reaction, TFA was removed by evaporation, and the residue was vacuum-dried to obtain H-D-Tyr(Me)-L-Ile-D-Pro-OBzl.TFA. The compound was dissolved in DMF (4.0 ml), and Boc-L-Ab8-OH (676 mg, 2.0 mmol) was then added. HBTU (1.14 g, 3.0 mmol), HOBt.H2O (306 mg, 2.0 mmol), and triethylamine (1.4 ml, 10 mmol) were further added and stirred for 3 hours under ice-cooling. The reaction solution was concentrated, dissolved in ethyl acetate, and successively washed with an aqueous 10% citric acid solution, an aqueous 4% sodium bicarbonate solution, and saturated saline. The product was dried over MgSO4 and concentrated, and the resulting foam substance was purified by flash silica gel chromatography (4×30 cm, 2% methanol/chloroform) to obtain the foam title compound (1.44 g, 1.76 mmol, 88% yield). HPLC retention time: 10.9 min.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:33]([N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:2]1=[O:1])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCCCN(Cc2ccccc2)C1=O
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 85.6 %

Procedure:
To a stirring solution of (S)-tert-butyl 2-oxoazepan-3-ylcarbamate (250 mg, 1.10 mmol) in DMF (1 mL) was added a solution of 20 weight % LiHMDS in THF (870 mg, 1.04 mmol) at −70° C. under argon. The reaction mixture was stirred at −70° C. for 10 min followed by the addition of (bromomethyl)benzene (0.137 mL, 1.15 mmol) at the same temperature. Then the reaction was allowed to stir at rt for 30 min. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water, saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude product was purified using silica gel chromatography (ISCO system) eluting with a gradient of 0-80% EtOAc/Hex to give (S)-tert-butyl 1-benzyl-2-oxoazepan-3-ylcarbamate (300 mg, 0.942 mmol, 86% yield) as a colorless oil. Anal. Calcd. for C18H26N2O3 m/z 318.4. found: 319.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[O:16]1CCOCC1>O>[NH2:1][C:2]1[C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]([NH2:9])=[O:16]
Reactant: N#Cc1ccnc(-c2ccccc2)c1N
Reactant: C1COCCO1
Solvent: O
Product: NC(=O)c1ccnc(-c2ccccc2)c1N

Procedure:
1 g of 3-amino-2-phenyl-4-pyridinecarbonitrile was heated to reflux for 3.5 hours in 20 ml of water and 10 ml of dioxan in the presence of 4 g of Amberlite lRA-400-OH (basic form). The resin was removed by filtration and the filtrate was evaporated. The residue was chromatographed on silica gel using methanol/ethyl acetate (1:19) for the elution and the product was recrystallized from ethyl acetate/petroleum ether to yield 900 mg of 3-amino-2-phenyl-4-pyridinecarboxamide of melting point 163°-164° C.
Reaction SMILES: [C:1](=[O:23])(OC1C=CC=CC=1)[O:2][CH2:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.C([O-])(=O)C.[NH4+:28]>C(O)(=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:5]([C:4]2[NH:28][C:1](=[O:23])[O:2][CH:3]=2)=[CH:6][CH:7]=1
Reactant: O=C(OCC(=O)c1ccc(C(F)(F)F)cc1)Oc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)co1
Yield: 84.9 %

Procedure:
A mixture of 2-oxo-2-(4-trifluoromethylphenyl)ethyl phenyl carbonate (18.0 g), ammonium acetate (20 g) and acetic acid (100 ml) was stirred with heating under reflux for 1 hour. The reaction mixture was concentrated, and poured into ice water (200 ml). The solid precipitates were filtered, washed with water, and air-dried to give crystals of 4-(4-trifluoromethylphenyl)-2-oxazolone (10.8 g, 85%).
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5][CH:4]=1)=[O:2].[CH3:11][Si](C=[N+]=[N-])(C)C>CC(C)=O>[CH3:11][O:9][C:8]([C:6]1[O:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=1)=[O:10]
Reactant: O=Cc1ccc(C(=O)O)o1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(C=O)o1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-Formyl-2-furancarboxylic acid (5 g, 35.7 mmol) was dissolved in acetone (100 mL), and trimethylsilyl-diazomethane/2M hexane solution (23.2 mL, 46.4 mmol) was slowly added dropwise at room temperature. After stirring at room temperature for 10 minutes, the solvent was evaporated under reduced pressure to give 5-formyl-2-furancarboxylic acid methyl ester as a crude product.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[OH:31][C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1>C(#N)C>[CH3:15][N:13]([CH3:14])[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][N:34]2[CH2:35][CH2:36][C@@H:32]([OH:31])[CH2:33]2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(N(C)C)cc2)cc1
Reactant: O[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN(C)c1ccc(CCN2CC[C@@H](O)C2)cc1
Temperature: 90 °C

Procedure:
4-Dimethylaminophenethyl tosylate (1.91 g, 6.0 mmol), sodium carbonate (750 mg, 7.0 mmol) and sodium iodide (40 mg, 0.26 mmol) were added to a solution of (R)-3-hydroxypyrrolidine (522 mg, 6.0 mmol) in acetonitrile (40 ml), and they were heated under reflux at 90° C. for 4 hours. The solvent was evaporated under reduced pressure. The obtained residue was distributed in 2 M NaOH and chloroform. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography. The product was eluted with dichloromethane, then with dichloromethane and methanol (50:1) and finally with a mixture of the same solvents (20:1). The appropriate fractions were combined, and the solvent was evaporated under reduced pressure to obtain (R)-1-(4-dimethylaminophenethyl)-3-hydroxypyrrolidine in the form of a light yellow oil (1.00 g, 71%).
Reaction SMILES: [C:1]12([C:11]3[C:12]([O:21][CH3:22])=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=3)[C:16](O)=[O:17])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:23][C:24]1[CH:31]=[C:30]([OH:32])[CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[C:1]12([C:11]3[C:12]([O:21][CH3:22])=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=3)[C:16]([NH:27][CH2:26][C:25]3[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:24]=3[OH:23])=[O:17])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COc1cc(O)c(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: NCc1ccc(O)cc1O
Product: COc1cc(O)c(C(=O)NCc2ccc(O)cc2O)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
0.14 g of the target compound is obtained as solid of a light color in substantially the same manner as in (2) of Example 1, except for using 5-adamantan-1-yl-2-hydroxy-4-methoxybenzoic acid instead of 5-adamantan-1-yl-2,4-dihydroxybenzoic acid and using 2,4-dihydroxybenzylamine instead of dopamine.
Reaction SMILES: I.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10](SC)=[NH:11].N[C:15]1[C:20]([OH:21])=[CH:19][C:18]([O:22][CH3:23])=[CH:17][C:16]=1[OH:24]>C(O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]1[O:21][C:20]2[C:15](=[C:16]([OH:24])[CH:17]=[C:18]([O:22][CH3:23])[CH:19]=2)[N:11]=1
Reactant: CSC(=N)c1cc(F)ccc1F
Reactant: COc1cc(O)c(N)c(O)c1
Agent: I
Solvent: CCO
Product: COc1cc(O)c2nc(-c3cc(F)ccc3F)oc2c1
Temperature: 78 °C
Reaction time: 5 h
Yield: 34.4 %

Procedure:
2.8 g (9.02 mmol; 1 equivalent) of methyl 2,5-difluorobenzene carbimidothioate hydroiodide in solution in 20 ml of ethanol is added to a solution of 1.4 g (9.02 mmol) of 2-amino-5-methoxybenzene-1,3-diol in 80 ml of ethanol. The reaction mixture is maintained under stirring at 78° C. for 5 hours then the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a silica column (eluent: dichloromethane/methanol mixture 98:2) and 860 mg (34% yield) of 2-(2,5-difluorophenyl)-6-methoxy-1,3-benzoxazol-4-ol is obtained.
Reaction SMILES: C(/[CH:4]=[CH:5]/[C:6]1[C:7](=[O:21])[NH:8][C:9](=[O:20])[N:10]([CH:19]=1)[C@@H:11]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]1)(O)=O.C([O-])([O-])=O.[K+].[K+].[Br:28]N1C(=O)CCC1=O>CN(C)C=O>[Br:28]/[CH:4]=[CH:5]/[C:6]1[C:7](=[O:21])[NH:8][C:9](=[O:20])[N:10]([CH:19]=1)[C@@H:11]1[O:18][C@H:15]([CH2:16][OH:17])[C@@H:13]([OH:14])[CH2:12]1
Reactant: O=C(O)/C=C/c1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](CO)O2)cc1/C=C/Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89681.6 %

Procedure:
To a solution of (E)-5-(2-carboxyvinyl)-2′-deoxyuridine (5.777 g, 19.37 mmol) in dimethylforamide (29 mL) was added K2CO3 (5.890 g, 42.61 mmol) and the suspension stirred at room temperature for 15 mins. A solution of N-bromosuccinimide (3.655 g, 20.53 mmol) was added dropwise over 30 mins at 20° C. The resulting suspension was filtered and the solid washed with DMF. The combined filtrate and washings were evaporated to dryness in vacuo and the residue dissolved in MeOH. To this silica gel was added and the suspension evaporated to dryness and the solid applied to the top of chromatographic column. The column was eluted with chloroform/methanol 92/8 to give a white solid (5787 g, 71.9%). Crystallisation from water gave a white powder.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:10][N:9]([C:11](=[O:21])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH:8]([CH3:22])[C:7](=[O:23])[N:6]1[CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:36][CH2:35][C:32]2([CH2:34][CH2:33]2)[C@H:31]([OH:37])[CH2:30]1)=[O:28])=[O:4].O.[OH-].[Li+]>CO>[Cl:20][C:15]1[CH:14]=[C:13]([NH:12][C:11]([N:9]2[C@@H:8]([CH3:22])[C:7](=[O:23])[N:6]([CH2:24][CH2:25][CH2:26][C:27]([N:29]3[CH2:36][CH2:35][C:32]4([CH2:33][CH2:34]4)[C@H:31]([OH:37])[CH2:30]3)=[O:28])[CH:5]([C:3]([OH:4])=[O:2])[CH2:10]2)=[O:21])[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: COC(=O)[C@@H]1CN(C(=O)Nc2ccc(Cl)c(Cl)c2)C(C)C(=O)N1CCCC(=O)N1CCC2(CC2)[C@H](O)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C(C(=O)O)CN1C(=O)Nc1ccc(Cl)c(Cl)c1
Reaction time: 16 h
Yield: 73 %

Procedure:
To 0.15 g (0.26 mmol) of (S)-4-(3,4-dichloro-phenylcarbamoyl)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-5-methyl-6-oxo-piperazine-2-carboxylic acid methyl ester in 2 ml of MeOH was added 0.01 g (0.26 mmol) of lithium hydroxide monohydrate. The reaction was stirred for 16 h after which time Amberlite IR120 resin was added until the pH was 5 and the reaction filtered and concentrated to afford the titled compound in 73% yield, a 6:4 mixture of diasteriomers as a colorless gum. MS: 541.3 (MH+, 2Cl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]([CH2:15][CH2:16][N:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][NH2:22])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:26]([NH:28][C:29](=[N:37][CH2:38][CH2:39][S:40][CH2:41][C:42]1[N:43]=[C:44]([NH:47][C:48]([NH2:50])=[NH:49])[S:45][CH:46]=1)OC1C=CC=CC=1)#[N:27]>>[C:26]([NH:28][C:29]([NH:37][CH2:38][CH2:39][S:40][CH2:41][C:42]1[N:43]=[C:44]([NH:47][C:48]([NH2:50])=[NH:49])[S:45][CH:46]=1)=[N:22][CH2:21][CH2:20][CH2:19][CH2:18][N:17]([CH2:16][CH2:15][N:8]([CH2:7][C:6]1[CH:24]=[CH:25][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:23])#[N:27]
Reactant: N#CNC(=NCCSCc1csc(NC(=N)N)n1)Oc1ccccc1
Reactant: COc1ccc(CN(CCN(C)CCCCN)c2ccccn2)cc1
Product: COc1ccc(CN(CCN(C)CCCCN=C(NC#N)NCCSCc2csc(NC(=N)N)n2)c2ccccn2)cc1

Procedure:
Preparation is effected analogously to Example 1, using 0.54 g (1.6 mol) of N-[2-[N-(4-methoxybenzyl)-N-(2-pyridyl)amino]ethyl]-N-methyl-1,4-butanediamine and the equimolar amount of N-cyano-N'-[2-[[(2-guanidino-4-thiazolyl)methyl]thio]ethyl]-O-phenyl-isourea as starting materials. Working up by chromatography analogously to Example 1 yields the purified title compound in the form of a dry foam. MS (+FAB method): m/z (rel. int. [%])=624 ([M+H]+, 1), 121 (100) IR (KBr): 2163 cm-1 (C≡N).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:24](=[O:26])[CH3:25])=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(C)=O)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-acetamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (300 mg, 0.97 mmol) and acetic anhydride. The title compound was obtained as light brown powder (93 mg).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[N:17][C:18]([O:24][CH3:25])=[CH:19][CH:20]=2)[N:15]=1.[CH:26]1([NH:32][C:33](=[O:36])[CH2:34]Cl)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.O>CN(C)C=O>[CH3:25][O:24][C:18]1[N:17]=[C:16]2[C:21]([CH:22]=[CH:23][C:14]([N:5]3[C:4](=[O:3])[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[CH:6]3[O:13][CH2:34][C:33]([NH:32][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:36])=[N:15]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Reactant: O=C(CCl)NC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)NC3CCCCC3)nc2n1
Temperature: 80 °C
Yield: 10.1 %

Procedure:
An oily suspension (50% by weight; 2.1 g) of sodium hydride is added at a temperature in the region of 0° C. to a solution, maintained under a nitrogen atmosphere, of 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (12.3 g) in anhydrous dimethylformamide (150 cc). The suspension obtained is stirred for 45 minutes at a temperature in the region of 0° C., N-(cyclohexyl)chloroacetamide (7.7 g) is then added and the mixture is heated to 80° C. for 18 hours. After being cooled, the reaction mixture is poured into water (700 cc) and the precipitate obtained is separated by filtration, washed with water and dried in the air. The solid obtained is purified by chromatography on silica (0.063-0.2 mm; 220 g) contained in a column 4 cm in diameter (eluant: methylene chloride), collecting 50-cc fractions. Fractions 41 to 60 are combined and concentrated to dryness under reduced pressure (2.7 kPa). By recrystallization of the residue obtained in acetonitrile, [2-(7-methoxy-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyloxy]-N-cyclohexylacetamide (1.8 g), m.p. 175° C., is obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([CH2:17][CH3:18])[CH:5]=2)[CH2:3][CH2:2]1.Cl.[F:20][C:21]1([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:31]([C:30]1[CH:29]=[CH:28][C:27]([C:21]2([F:20])[CH2:26][CH2:25][N:24]([C:8]([C:7]3[C:6]([CH2:17][CH3:18])=[CH:5][C:4]([CH:1]4[CH2:2][CH2:3]4)=[C:12]([CH:11]=3)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[CH2:23][CH2:22]2)=[CH:34][CH:33]=1)#[N:32]
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Reactant: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C2CC2)c(C(=O)OC)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a solution of 4-cyclopropyl-2-ethyl-5-(methoxycarbonyl)benzoic acid (compound 226.6, 150 mg, 0.600 mmol, 1.00 equiv) in N,N-dimethylformamide (15 mL) were added 4-(4-fluoropiperidin-4-yl)benzonitrile hydrochloride (compound 11.2, 150 mg, 0.620 mmol, 1.00 equiv), DIPEA (450 mg, 3.49 mmol, 6.00 equiv), and HBTU (300 mg, 0.790 mmol, 1.30 equiv). The resulting solution was stirred for 4 h at 20° C., then quenched by the addition of 20 mL of brine. The resulting mixture was extracted with 4×30 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified via silica gel column with ethyl acetate/petroleum ether (1:3) as eluent. This resulted in 0.200 g (76%) of methyl 5-(4-(4-cyanophenyl)-4-fluoropiperidine-1-carbonyl)-2-cyclopropyl-4-ethylbenzoate as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=O)[C:11]3([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[S:31])[C:11]3([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCC1(CC)C(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Solvent: Cc1ccccc1
Product: CCC1(CC)C(=S)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
The title compound was prepared from 5-(3-chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one compound (100 mg) and Lawesson's reagent (100 mg) in toluene (10 ml) at reflux, according to General Procedure A, to afford the product (0.023 g) as a yellow solid: 1H NMR (DMSO-d6) δ 12.73 (br s, 1H), 7.77 (t, 1H, J=1.8 Hz), 7.75 (d, 1H, J=1.6 Hz), 7.68-7.62 (m, 2H), 7.48 (t, 1H, J =7.9 Hz), 7.40 (d, 1H, J=8.3 Hz), 7.09 (d, 1H, J=8.1 Hz), 2.07-2.00 (m, 2H), 1.86-1.79 (m, 2H) and 0.37 (t, 6H, J=7.3 Hz): MS ((−)-APCI) m/z 314/316 [M−H]−.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[NH:11][CH:12]1[CH2:14][CH2:13]1)=[O:5])C.[Li+:15].[OH-]>C1COCC1.CO>[CH:12]1([NH:11][C:10]2[S:9][CH:8]=[N:7][C:6]=2[C:4]([O-:5])=[O:3])[CH2:13][CH2:14]1.[Li+:15]
Reactant: CCOC(=O)c1ncsc1NC1CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C([O-])c1ncsc1NC1CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
198 mg of 5-cyclopropylamino-thiazole-4-carboxylic acid ethyl ester (0.93 mmol) were dissolved in a 3:1 mixture of THF/methanol (2 ml) and 1.4 ml of a 1N LiOH-solution were added. The reaction mixture was stirred at RT for 3 days, then concentrated in vacuo and the remaining residue was dried. This gave 191 mg of a yellow solid containing the crude title compound (contaminated with excess of lithium hydroxide) that was used in the following step without further purification. MS (ISP) 182.9 (M−H)−.
Reaction SMILES: [C:1]1([C:7](=[CH:11][CH2:12][CH3:13])[CH:8]=[N:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27]Br)[CH2:21]1)=[O:19])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][O:10][N:9]=[CH:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:11][CH2:12][CH3:13])[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCC=C(C=NO)c1ccccc1
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCC=C(C=NOCCN1CCC[C@@H](C(=O)OCC)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 96 h
Yield: 52.7 %

Procedure:
A mixture of the above oxime (2.0 g, 11 mmol), (R)-1-(2-bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (3.94 g, 11 mmol), potassium carbonate (4.73 g, 34 mmol) and acetone (25 ml) was stirred at room temperature for 4 days. The mixture was filtered and the solvent was evaporated from the filtrate in vacuo. The residue was purified by column chromatography on silica gel (75 g, cyclohexane/ethyl acetate 3/1) to give 2.08 g of (R)-1-(2-(((2-phenyl-2-penten-1-ylidene)amino)oxy)ethyl)-3-piperidinecarboxylic acid ethyl ester.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[C:29]1([C:39](Cl)=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@H:2]([NH:1][C:39]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)=[O:40])[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:21])[CH3:20]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3cccc4ccccc34)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-naphthoyl chloride: ESMS m/e: 533.7 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:18]([CH2:22][CH3:23])[C:19]([NH2:21])=O)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:18]([CH2:22][CH3:23])[CH2:19][NH2:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCC(C(N)=O)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(CN)C(c1ccccc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
To a stirred solution of the crude 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-ethyl-3-phenylpropanamide in anhydrous THF (10 mL) was added 1.0M lithium aluminum hydride in diethyl ether (2.0 mL, 2.0 mmol) portionwise at RT under nitrogen. After stirring at RT for 24 hr, the mixture was carefully quenched with MeOH, poured into brine (100 mL), extracted with ethyl acetate (2×100 mL), dried (Na2SO4) and concentrated to give 50 mg (88% yield, 3 steps) of 2-((1-(4-fluorophenyl)-1H-indazol-5-yl)(phenyl)methyl)butan-1-amine.