Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][N:7]2[C:12](=[O:25])[CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24].[C:26]([Zn]C#N)#[N:27]>CN(C=O)C.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].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]>[CH3:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[O:16][CH2:15][CH2:14][CH2:13][C:12]([N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([C:26]#[N:27])[C:3]=2[CH2:4][CH2:5][CH2:6]1)=[O:25]
Reactant: N#C[Zn]C#N
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(Br)cccc32)c1C
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(C#N)cccc32)c1C
Temperature: 120 °C
Yield: 86.1 %

Procedure:
To a degassed solution of 1-(5-bromo-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one (0.330 g, 0.820 mmol) and dicyanozinc (0.116 g, 0.984 mmol) in DMF (1.50 mL) was added 1,1′-bis(diphenylphosphino)ferrocene (0.023 g, 0.041 mmol) and Pd2(dba)3 (0.038 g, 0.041 mmol). The vial was purged with argon, sealed, and heated at 120° C. for 16 h. The mixture was partitioned between EtOAc and water. The organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (0.246 g, 82% yield) as an off-white solid. LCMS, [M+H]+=349.1. 1H NMR (400 MHz, CDCl3) δ 7.41 (d, J=7.7 Hz, 1H), 7.28-7.17 (m, 2H), 7.01 (t, J=7.9 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.64 (d, J=8.2 Hz, 1H), 3.96 (t, J=5.6 Hz, 2H), 3.82-3.71 (m, 2H), 2.85 (s, 2H), 2.73 (t, J=7.1 Hz, 2H), 2.24 (s, 3H), 2.18 (dt, J=12.9, 6.4 Hz, 2H), 2.05-1.88 (m, 5H).
Reaction SMILES: C([O:8][C:9]1[C:10]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[O:18])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1>[C].[Pd].C(O)C>[OH:8][C:9]1[C:10]([C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)=[O:18])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccnc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1O
Yield: 81.3 %

Procedure:
3-Benzyloxy-4-methoxy-4′-phenoxypicolinanilide (0.64 g, 1.5 mmol) was mixed with ethanol (4 ml) to prepare a suspension. To this suspension was added 64 mg of 10% palladium-carbon. The mixture was subjected to catalytic reduction under atmospheric conditions overnight. The reaction solution was filtered, and the filtrate was concentrated under the reduced pressure. The residue was dissolved in a water-methanol mixed solution, and was recrystallized to give 0.41 g (yield 81%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]([N:9]([CH3:22])[C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16]OS(C)(=O)=O)[CH2:12][CH2:11]2)=[O:8])=[CH:4][CH:3]=1.[C:25]([O-:28])(=[S:27])[CH3:26].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([N:9]([CH3:22])[C@H:10]2[CH2:11][CH2:12][C@H:13]([CH2:16][S:27][C:25](=[O:28])[CH3:26])[CH2:14][CH2:15]2)=[O:8])=[CH:23][CH:24]=1
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1
Temperature: 100 °C

Procedure:
To 1.72 g (4.58 mmol) trans-Methanesulfonic acid 4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexylmethyl ester in 17 ml DMF, 0.78 g (6.86 mmol, 1.5 eq) potassium thioacetate were added and the mixture was heated to 100° C. for 10 min. The mixture was concentrated under vacuum and the residue was dissolved in saturated NaHCO3/Et2O(3×). The organic phases were washed with brine, dried over Na2SO4 and evaporated to yield 1.69 g (quantitative) of trans-Thioacetic acid S-{4-[(4-chloro-phenoxycarbonyl)-methyl-amino]-cyclohexylmethyl} ester, MS: 356 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([CH:25]=[O:26])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[P:34](Cl)([O:39][CH2:40][CH3:41])([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][P:34]([O:39][CH2:40][CH3:41])([O:36][CH2:37][CH3:38])=[O:35])=[C:20]([CH:25]=[O:26])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)c(C=O)c1)NC(=O)OCc1ccccc1
Reactant: CCOP(=O)(Cl)OCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)Oc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC)cc1C=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 1.03 g 3C in 20 mL anhydrous dichloromethane in an ice-water bath were added 0.60 ml triethylamine and 0.48 mL diethyl chlorophosphate. The mixture was kept in the ice-water bath for 1 hour and then kept at room temperature overnight. After wash with water, with brine and drying with anhydrous sodium sulfate, the mixture was concentrated to an oily liquid and then purified by flash column chromatography (0.1% Et3N/20% EtOAc/CH2Cl2). The desired orthoformylated phosphotyrosine (3D) was obtained as colorless oil (1.21 g, 85%). 1H NMR (CDCl3, 200 MHz): δ 10.37 (s, 1H), 7.64 (s, 1H), 7.43-7.31 (m, 7H), 5.28 (d, J=7.7 Hz, 1H), 5.11 (s, 2H), 4.66 (m, 1H), 4.33-4.18 (m, 4H), 3.75 (s, 3H), 3.21 (dd, J1=14.1 Hz, J2=5.6 Hz, 1H), 3.09 (dd, J1=14.1 Hz, J2=6.1 Hz, 1H), 1.37 (m, 6H). 13C NMR (CDCl3, 50 MHz): δ 188.3, 171.4, 155.5, 152.0 (d), 136.5, 136.1, 133.4, 129.3, 128.6, 128.3, 128.1, 127.2 (d), 121.3, 67.1, 65.2 (d), 54.7, 52.6, 37.4, 16.1 (d). 31P NMR (CDCl3, 81 MHz): δ −6.4.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:15][C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[CH2:8][C:7](=[O:16])[C:6]=2[CH:17]=1.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:16]=[C:7]1[C:6]2[CH:17]=[C:2]([O:1][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:3]=[CH:4][C:5]=2[O:15][C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8]1
Reactant: CCOC(=O)CBr
Reactant: O=C1CC2(CCCCC2)Oc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(c1)C(=O)CC1(CCCCC1)O2
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.2 %

Procedure:
A mixture of 6-hydroxy-spiro[2H-1-benzopyran-2,1'-cyclohexan]-4(3H)-one (prepared in Preparation 14) (0.878 g, 3.78 mmol), ethyl bromoacetate (0.69 g, 4.13 mmol), anhydrous potassium carbonate (0.78 g, 5.65 mmol) and dry N,N-dimethylformamide (DMF) (7.5 ml) is stirred at room temperature for 4 hours under nitrogen gas. DMF is removed by distillation under reduced pressure and the residue is extracted with diethyl ether. The ether layer is separated and washed successively with water, dilute sodium hydroxide and saturated brine, dried and distilled to remove ether. The residue is recrystallized from cyclohexane to obtain the title compound as a crystalline solid (1.11 g, yield 92.5%, m.p=72°-73° C.). ##STR10##
Reaction SMILES: [C:1]([C:5]1[CH:43]=[CH:42][C:8]([C:9]([N:11]([CH2:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38]C)=[O:37])=[CH:34][CH:33]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C1(CCC(Cl)=O)CCCC1>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]([CH2:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([OH:38])=[O:37])=[CH:34][CH:33]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)=[O:10])=[CH:42][CH:43]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(C(=O)OC)cc3)C(=O)c3ccc(C(C)(C)C)cc3)cc2)cc1
Agent: O=C(Cl)CCC1CCCC1
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1ccc(C#Cc2ccc(CN(Cc3ccc(C(=O)O)cc3)C(=O)c3ccc(C(C)(C)C)cc3)cc2)cc1

Procedure:
The titled compound was prepared following the procedure F using methyl 4-[((4-tert-butylbenzoyl){4-[(4-butylphenyl)ethynyl]benzyl}amino)methyl]benzoate and NaOH 5M in the presence of MeOH/THF 1/1, as a brown solid (95%). 1H NMR (CDCl3, 300 MDz) δ 8.09 (d, 2H, J=7.9 Hz), 7.54-7.32 (m, 6H), 7.22-7.09 (m, 4H), 4.79-4.42 (m, 4H), 2.62 (t, 2H, J=7.7 Hz), 1.70-1.05 (m, 14H), 0.97-0.75 (m, 6H). M− (ESI): 556.3; M+ (ESI): 558.4. HPLC, Rt: 6.03 min (Purity: 98.8%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][C@H:17]([CH3:19])[O:16][C@H:15]([CH3:20])[CH2:14]3)=[N:10][C:9]=2[C:21]2[C:22]([F:39])=[C:23]([NH:27][S:28]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:40].[OH-]>O1CCOCC1>[NH2:40][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][C@H:17]([CH3:19])[O:16][C@H:15]([CH3:20])[CH2:14]3)=[N:10][C:9]=2[C:21]2[C:22]([F:39])=[C:23]([NH:27][S:28]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C[C@@H]1CN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(Cl)n3)s2)C[C@H](C)O1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C[C@@H]1CN(c2nc(-c3cccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c(-c3ccnc(N)n3)s2)C[C@H](C)O1
Temperature: 100 °C
Yield: 75 %

Procedure:
In a pressure vessel was placed N-(3-{5-(2-chloro-4-pyrimidinyl)-2-[(2R,6S)-2,6-dimethyl-4-morpholinyl]-1,3-thiazol-4-yl}-2-fluorophenyl)-2,5-difluorobenzenesulfonamide (0.30 g, 0.503 mmol) and NH4OH (3 mL, 77 mmol) and 1,4-dioxane (3 mL) were added. The vessel was sealed and heated at 100° C. for 18 h. The reaction was cooled, concentrated onto silica and the residue was column chromatographed to give the title compound was obtained (0.22 g, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.77 (br. s., 1H), 7.82 (d, J=5.3 Hz, 1H), 7.46-7.65 (m, 3H), 7.37-7.46 (m, 1H), 7.27 (t, J=6.7 Hz, 2H), 6.54 (br. s., 2H), 5.62 (d, J=5.3 Hz, 1H), 3.77 (d, J=12.2 Hz, 2H), 3.60-3.73 (m, 2H), 2.73 (t, J=11.6 Hz, 2H), 1.14 (d, J=6.0 Hz, 6H). m/z (ES+): 577 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([C:15]1[NH:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH3:14])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][N:2]([C:15]1[N:16]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([F:24])=[CH:26][CH:27]=2)[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH3:14])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: Fc1ccc(CCl)cc1
Reactant: CN(CCCN(C)c1nc2ccccc2[nH]1)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCCN(C)c1nc2ccccc2n1Cc1ccc(F)cc1)C(=O)OC(C)(C)C

Procedure:
A solution comprising 1.0 g of N-methyl-N-(benzimidazol-2-yl)-N'-methyl-N'-t-butoxycarbonyl-1,3-propylenediamine, 540 mg of 4-fluorobenzyl chloride, 3 g of potassium carbonate and 20 ml of dimethylformamide, was reacted at room temperature overnight under a stirring condition. Further, it was reacted at a temperature of from 50 to 60° C. for 10 hours. Then, 50 ml of water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate (30 ml×3), and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: ethyl acetate) to obtain 1.4 g of the above identified compound as a colorless oily substance.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27](=[O:32])[NH:28][C:29](=[NH:31])[NH2:30])[C:20]=3[F:33])[CH2:15][CH2:14]2)=[CH:9][N:8]=1)=[O:6].C1COCC1.Cl>CO>[C:29]([NH:28][C:27]([O:26][CH2:25][C:21]1[C:20]([F:33])=[C:19]([N:16]2[CH2:17][CH2:18][N:13]([C:10]3[CH:11]=[CH:12][C:7]([C:5]([OH:6])=[O:4])=[N:8][CH:9]=3)[CH2:14][CH2:15]2)[CH:24]=[CH:23][CH:22]=1)=[O:32])(=[NH:30])[NH2:31]
Reactant: COC(=O)c1ccc(N2CCN(c3cccc(COC(=O)NC(=N)N)c3F)CC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N=C(N)NC(=O)OCc1cccc(N2CCN(c3ccc(C(=O)O)nc3)CC2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A 1M aqueous NaOH solution (1.14 ml) was added to a mixture of 5-[4-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)piperazin-1-yl]pyridine-2-carboxylate methyl ester (326 mg), THF (9 ml), and MeOH (3 ml), followed by stirring at room temperature overnight. 1M hydrochloric acid (1.14 ml) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The generated solid was collected by filtration, washed with water, and then dried at 50° C. under reduced pressure to obtain 5-[4-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)piperazin-1-yl]pyridine-2-carboxylic acid (293 mg).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23]([OH:25])=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[C:26](N1C=CN=C1)([N:28]1C=CN=[CH:29]1)=O.CNC.O>CN(C)C=O>[CH3:26][N:28]([CH3:29])[C:23](=[O:25])[CH2:22][CH2:21][C:20]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][C:12]=1[CH:11]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Agent: CNC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
3-[2-(2-Oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (10 g) was dissolved in 100 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. Dimethylamine (2.7 g) and 30 mL of dimethylformamide were added and the stirring continued overnight at room temperature. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed in 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 8.9 g (83% yield) of N,N-dimethyl-3-[2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionamide.
Reaction SMILES: FC1C=CC([N+]([O-])=O)=C(C(F)(F)F)C=1.N1CCCC1.[N:20]1([C:25]2[CH:26]=[CH:27][C:28]([N+:35]([O-])=O)=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([C:25]2[CH:26]=[CH:27][C:28]([NH2:35])=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(N2CCCC2)cc1C(F)(F)F
Agent: O=[N+]([O-])c1ccc(F)cc1C(F)(F)F
Solvent: C1CCNC1
Product: Nc1ccc(N2CCCC2)cc1C(F)(F)F
Yield: 79.4 %

Procedure:
Starting from 80 mg of 5-fluoro-2-nitrobenzotrifluoride and by reaction with pyrrolidine, 138 mg of 5-pyrrolidinyl-2-nitrobenzotrifluoride are prepared by general method A. The crude product is hydrogenated by general method B. 97 mg of 5-pyrrolidinyl-2-aminobenzo-trifluoride are obtained. Starting from this and by reaction with 3,5-dimethylisoxazole-4-sulfonyl chloride by general method C, 80 mg of 3,5-dimethylisoxazole-4-sulfonic acid 4-pyrrolidin-1-yl-2-trifluoromethyl-phenylamide are prepared.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>>[CH3:28][O:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[C:17]([CH2:16][N:7]1[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]1[C:4]([OH:3])=[O:5])=[CH:18][CH:19]=[CH:20]2
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: COc1ccc2c(CBr)cccc2c1
Product: COc1ccc2c(Cn3c(C(=O)O)cc4ccccc43)cccc2c1

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 1-bromomethyl-6-methoxy-naphthalene (Lit. 15) and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 330.1 ([M−H]−).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[N:9]([CH3:28])[CH:10]=[C:11]([C:13]([C:15]3[C:16]([C:21]4[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=4)=[N:17][O:18][C:19]=3[CH3:20])=[O:14])[CH:12]=2)=[O:7])[CH2:3][CH2:2]1.C1(NC(C2NC=C(C(C3C(C4C=CC=C([F:55])C=4)=NOC=3C)=O)C=2)=O)CCC1>>[CH:4]1([NH:5][C:6]([C:8]2[N:9]([CH3:28])[CH:10]=[C:11]([C:13]([C:15]3[C:16]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([F:55])[CH:22]=4)=[N:17][O:18][C:19]=3[CH3:20])=[O:14])[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH2:1]1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)c1c[nH]c(C(=O)NC2CCC2)c1
Reactant: Cc1onc(-c2ccc(F)cc2)c1C(=O)c1cc(C(=O)NCC2CC2)n(C)c1
Product: Cc1onc(-c2cccc(F)c2)c1C(=O)c1cc(C(=O)NC2CCC2)n(C)c1
Yield: 34.2 %

Procedure:
According to the procedure described for the synthesis of 4-(5-methyl-3-(4-fluorophenyl)-isoxazole-4-carbonyl)-1-methyl-pyrrole-2-carboxylic acid (cyclopropylmethyl)-amide (Example 229, step 3), the title compound was synthesized from 4-[5-methyl-3-(3-fluorophenyl)-isoxazole-4-carbonyl)-1H-pyrrole-2-carboxylic acid cyclobutylamide (example 174) in 34.2% yield as white solid. (m/e): 382.1 (M+1; 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][CH2:12][CH:13]([NH2:17])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:20](OCC)(=O)C.[OH-].[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9]([CH:11]([CH3:20])[CH2:12][CH:13]([NH2:17])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(C)=O
Reactant: NC(CCC(=O)OCc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CC(CC(N)C(=O)O)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In THF (500 ml) was dissolved 4-[(benzyloxy)carbonyl]-aminobutyric acid (25.0 g), and to the mixture was gradually added at −5° C. methyl iodide (37.4 g). Under nitrogen atmosphere, the mixture was stirred at 0° C. for 15 minutes and then at room temperature for 24 hours. To the mixture was added ethyl acetate (300 ml) and then water (800 ml). The mixture was made pH 11 with sodium hydroxide and washed with ether (400 ml×2). The aqueous layer was made pH 2 with concentrated hydrochloric acid and extracted with ethyl acetate(1000 ml and 500 ml×3). The organic layer was washed with 1M sodium thiosulfate solution (300 ml) and dried with magnesium sulfate. The solvent was evaporated under reduced pressure to give 4-[(benzyloxy)carbonyl]-4-methyl-aminobutyric acid (26.3 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:29])[CH2:11][N:12]1[CH2:17][CH2:16][N:15](CC2C=CC=CC=2)[CH2:14][CH:13]1[CH2:25][C:26]([NH2:28])=[O:27].[H][H]>[Pd].CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:29])[CH2:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[CH2:25][C:26]([NH2:28])=[O:27]
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(Cc2ccccc2)CC1CC(N)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(C)c1NC(=O)CN1CCNCC1CC(N)=O
Yield: 97.5 %

Procedure:
A mixture of 12.8 parts of N1 -(2,6-dimethylphenyl)-4-(phenylmethyl)-1,2-piperazinediacetamide and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The oily residue was crystallized from acetonitrile, yielding 7.7 parts (97.5%) of N1 -(2,6-dimethylphenyl)-1,2-piperazinediacetamide; mp. 171.9° C. (intermediate 72).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]([CH3:14])([CH3:13])[CH2:9][C:10](=O)[CH3:11])([CH3:4])([CH3:3])[CH3:2].[C:16]([O:19][CH2:20][CH3:21])(=[O:18])[CH3:17].Cl>O1CCCC1>[CH2:20]([O:19][C:16](=[O:18])/[CH:17]=[C:10](\[CH3:11])/[CH2:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])([CH3:13])[CH3:14])[CH3:21]
Reactant: CC(=O)CC(C)(C)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)CC(C)(C)NC(=O)OC(C)(C)C

Procedure:
(1,1-dimethyl-3-oxobutyl)carbamic acid tert-butylester (2.5 g; 11.6 mmol) was dissolved in tetrahydrofuran (15 mL) and added dropwise to the reaction mixture which was heated to reflux for 12 h. Ethyl acetate (100 mL) and hydrochloric acid (1 N; 100 mL) were added and the phases were separated. The aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with an aqueous solution of sodium hydrogen carbonate (saturated; 100 mL), dried (magnesium sulfate) and evaporated in vacuo. The residue was chromatographed on silica (3×40 cm) using ethyl acetate/heptane (1:2) as eluent to afford 2.0 g of (E)-5-tert-Butoxycarbonylamino-3,5-dimethylhex-2-enoic acid ethylester.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:12][CH2:11]2)=[O:9])[N:6]=1.[O:24]1[C:28]2[CH:29]=[CH:30][C:31]([C:33](O)=[O:34])=[CH:32][C:27]=2[CH2:26][CH2:25]1>>[O:9]=[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17](=[O:23])[N:18]2[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][CH2:11]1)[CH2:7][C:5]1[N:6]=[C:2]([NH:1][C:33]([C:31]2[CH:30]=[CH:29][C:28]3[O:24][CH2:25][CH2:26][C:27]=3[CH:32]=2)=[O:34])[S:3][CH:4]=1
Reactant: Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1
Reactant: O=C(O)c1ccc2c(c1)CCO2
Product: O=C(Nc1nc(CC(=O)N2CCN(CC(=O)N3CCCC3)CC2)cs1)c1ccc2c(c1)CCO2

Procedure:
In analogy to example 37.5, 2-(2-amino-thiazol-4-yl)-1-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethanone (example 37.4) was coupled with 2,3-dihydrobenzofurane-5-carboxylic acid, using general method D, to give 2,3-dihydro-benzofuran-5-carboxylic acid (4-{2-oxo-2-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-ethyl}-thiazol-2-yl)-amide. White solid. MS 506.5 ([M+Na]+)
Reaction SMILES: O1CCCC1.CC[O:8][C:9]([C@H:11]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[N:12]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O.O>C(OCC)(=O)C>[C:26]([O:25][C:23]([N:12]1[C@@H:11]([CH2:9][OH:8])[CH2:15][CH2:14][C@H:13]1[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(F)cc2)N1C(=O)OC(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@@H](CO)CC[C@H]1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
Ice-cold lithium borohydride (256 mg) was added to a tetrahydrofuran (30 mL) solution of (2R,5S)-5-(4-fluorophenyl)pyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-ethyl ester (2.64 g) obtained in Example 4. Stirring was continued for 30 minutes at the same temperature and for 14 hours at room temperature. Water and ethyl acetate were added, and the organic layer was partitioned. The organic layer was washed with brine, and the resultant was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the title compound (2.31 g) was obtained. The physical property values are as follows.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:18])([CH3:17])[CH2:9]1.C(N(CC)CC)C>C1COCC1>[CH3:17][C:10]1([CH3:18])[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH2:9]1
Reactant: CCS(=O)(=O)Cl
Reactant: CC1(C)CC(N)c2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCS(=O)(=O)NC1CC(C)(C)c2ccccc21
Reaction time: 2 h
Yield: 79.9 %

Procedure:
With ice-cooling, 4.44 g (34.7 mmol) of ethanesulfonyl chloride were added dropwise to a solution of 5.1 g (31.6 mmol) of 1-amino-3,3-dimethylindan (Example 1a) and 12.8 g (126 mmol) of triethylamine in 100 ml of THF. After 2 h at RT, the reaction mixture was concentrated under reduced pressure and the residue was taken up in water and EA. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure, giving 6.4 g of 3,3-dimethyl-1-ethylsulfonylaminoindan.