Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([N:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[C:11]1=O)([CH3:9])[CH3:8].O>O1CCCC1>[CH:7]([N:10]1[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]1)([CH3:9])[CH3:8]
Reactant: CC(C)N1CC(C)(C)NC(C)(C)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CC(C)(C)NC(C)(C)C1

Procedure:
3.9 g (0.103 mol) of lithiumaluminium hydride are introduced into 100 ml of anhydrous tetrahydrofuran under a nitrogen atmosphere, while stirring and cooling. A solution of 19.8 g (0.1 mol) of 1-isopropyl-3,3,5,5-tetramethyl-2-piperazinone (obtainable, for example, in accordance with Synthesis 1981, page 40, or J. Organ. Chem., 45 (1980), 754-59) in 75 ml of anhydrous tetrahydrofuran is added dropwise at room temperature, whereupon the reaction temperature rises to 6020 C. The mixture is then stirred overnight at room temperature. After dropwise addition of about 10 ml of water, the mixture is subsequently stirred for 2 hours and the precipitate is then filtered off with suction. The filtrate is dried over potassium carbonate and concentrated in vacuo and the crude product which remains as a colourless oil is further processed without additional purification.
Reaction SMILES: [CH2:1]1[NH:6][CH2:5][CH2:4][N:3]2[CH2:7][C@@H:8]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)(=[O:13])=[O:12])[CH2:9][C@@H:2]12.C(N(CC)CC)C.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>ClCCl>[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([N:6]2[CH2:5][CH2:4][N:3]3[CH2:7][C@@H:8]([NH:10][S:11]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=4)(=[O:13])=[O:12])[CH2:9][C@H:2]3[CH2:1]2)=[O:37])=[CH:34][CH:33]=1
Reactant: O=S(=O)(N[C@H]1C[C@H]2CNCCN2C1)c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)N1CCN2C[C@@H](NS(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 42 (42 mg, 0.12 mmol) in dichloromethane (5 mL) was added triethylamine (17 mg, 0.168 mmol) followed by 4-fluorobenzoyl chloride (27 mg, 0.168 mmol) in dichloromethane (1 mL). The mixture was stirred at room temperature overnight and then concentrated. The residue was purified by chromatography on silica gel (ethyl acetate, then ethyl acetate/methanol=20:1) to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.20 (m, 1H), 1.80-2.10 (m, 3H), 2.20 (m, 1H), 2.70-2.95 (m, 3H), 3.12 (m, 1H), 3.40-3.70 (m, 2H), 4.45 (m, 1H), 7.22 (m, 2H), 7.42 (m, 2H), 7.82 (m, 1H), 8.05-8.20 (m, 4H); MS (ESI) m/z 472 (M+H)+.
Reaction SMILES: [F:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[CH2:4][C:5]#[N:6].C(C1C=C(N)[O:15][N:14]=1)(C)C>>[F:1][C:2]([C:3]1[CH:4]=[C:5]([NH2:6])[O:15][N:14]=1)([CH3:9])[CH3:8]
Reactant: CC(C)(F)C(=O)CC#N
Reactant: CC(C)c1cc(N)on1
Product: CC(C)(F)c1cc(N)on1
Yield: 71 %

Procedure:
Prepared from 4-fluoro-4-methyl-3-oxopentanenitrile (6 g, 47 mmol) according to the method described for 3-isopropylisoxazol-5-amine in Example 122A Step 2, to afford 3-(2-fluoropropan-2-yl)isoxazol-5-amine as a light yellow solid (4.83 g, 71%) which was used in the next step without further purification. 1H NMR (300 MHz, CDCl3) δ 5.19 (s, 1H), 4.48 (brs, 2H), 1.68 (d, J=21 Hz, 6H); LC-MS (ESI) m/z 145 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([N:17]1[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]1)=[O:9]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(I)c(Cl)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(I)c(Cl)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a stirred solution of 5-chloro-4-iodo-2-methoxybenzoic acid (1.55 g, 4.9 mmol) in DMF (30 mL) at RT, tert-butyl piperazine-1-carboxylate (1.02 g, 5.5 mmol), BOP (2.63 g, 25.9 mmol) and DIEA (1.92 g, 14.9 mmol) were added and the resulting mixture was stirred at RT for 1 h. The reaction mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (1.96 g, 76% yield).
Reaction SMILES: [H-].[Na+].[CH2:3]=[C:4]([CH2:7][OH:8])[CH2:5][OH:6].[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].O>C1COCC1>[Si:9]([O:6][CH2:5][C:4](=[CH2:3])[CH2:7][OH:8])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: C=C(CO)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(CO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.9 %

Procedure:
To a dry flask containing sodium hydride (2.270 g, 56.75 mmol) in THF (150 mL) under N2 at 0° C. was added slowly 2-methylenepropane-1,3-diol (5 g, 56.75 mmol). The reaction was warmed to room temperature and stirred 45 min. TBS-Cl (8.55 g, 56.75 mmol) was added in one batch and stirring was continued for another 45 min, until complete by TLC. To the reaction was added water and the mixture was extracted three times with EtOAc and washed with brine. The organics were dried over magnesium sulfate, filtered and concentrated at −10-15° C. Silica gel chromatography (20%-50% EtOAc/Hex) afforded the title compound (11.36 g, 99%) as a clear oil.
Reaction SMILES: [CH2:1]([N:7]1[C:15]2[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=2)[C:9]([CH2:17][C:18]([NH2:20])=[O:19])=[C:8]1[CH3:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>CN(C=O)C.O>[CH2:31]([O:30][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][O:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8]([CH3:21])=[C:9]2[CH2:17][C:18]([NH2:20])=[O:19])[CH3:32]
Reactant: CCOC(=O)CCCBr
Reactant: CCCCCCn1c(C)c(CC(N)=O)c2cc(O)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCn1c(C)c(CC(N)=O)c2cc(OCCCC(=O)OCC)ccc21
Reaction time: 1 h
Yield: 53 %

Procedure:
1-Hexyl-5-hydroxy-2-methyl-1H-indole-3-acetamide (230 mg, 0.8 mmol) was dissolved in 10 mL of DMF and 26 mg (0.8 mmol) of 60% NaH/mineral oil added. The mixture was stirred for 1 hour, 0.115 mL (0.8 mmol) of ethyl 4-bromobutyrate added and stirring continued for 96 hours. The mixture was diluted with water, extracted with ethyl acetate, the ethyl acetate washed with water and dried (Na2SO4). The solution was concentrated at reduced pressure and the residue chromatographed on silica gel (eluted with 3% MeOH/methylene chloride) to give 170 mg (53% yield of [4-[[3-(2-amino-2-oxoethyl)-1-hexyl-2-methyl-1-H-indol-5-yl]oxy]butanoic acid ethyl ester, mp, 69-71° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.Cl.[CH3:17][N:18]([CH3:26])[C@H:19]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:25][C@H:22]1[CH2:23][CH2:24][C@H:19]([N:18]([CH3:26])[CH3:17])[CH2:20][CH2:21]1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CN(C)[C@H]1CC[C@H](N)CC1
Agent: Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (250 mg, 0.880 mmol) was reacted with trans-N1,N1-dimethylcyclohexane-1,4-diamine hydrochloride (280 mg, 1.32 mmol) to afford the desired product (63 mg, 18%): ESI MS m/z 390 [C19H24BrN3O+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:29](=[O:31])[NH2:30]
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 22 h
Yield: 90.3 %

Procedure:
A suspension of the {9-[(2,6-dichlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (45.7 mg, 0.1 mM) and 0.11 mL (0.11 mM) of 1 N NaOH in 5 mL of ethanol was stirred for 22 hours at 25° C. A small volume of diethyl ether/hexanes was added, then cooled in the refrigerator. The resultant white precipitate was collected by filtration, washed with a small amount of EtOH/diethyl ether/hexanes, then dried in vacuo to afford 40 mg (86%) of the {9-[(2,6-dichlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ 7.6-7.4 (m, 6H), 7.3 (t, 1H, J=8 Hz), 7.2 (t, 1H, J=8 Hz), 7.0 (d, 1H, J=8 Hz), 6.9 (t, 1H, J=8 Hz), 6.5 (d, 1H, J=8 Hz), 5.8 (s, 2H), and 4.25 (s, 2H). MS (ES) m/e 441, 443, 445.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH:3]=[CH:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[F:18][C:19]1[C:27]([CH3:28])=[C:26]([F:29])[C:25]([F:30])=[C:24]([N+:31]([O-:33])=[O:32])[C:20]=1[C:21](Cl)=[O:22]>C(OCC)(=O)C>[CH3:1][N:2]([CH3:10])[CH:3]=[C:4]([C:21](=[O:22])[C:20]1[C:24]([N+:31]([O-:33])=[O:32])=[C:25]([F:30])[C:26]([F:29])=[C:27]([CH3:28])[C:19]=1[F:18])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)Cl)c1F
Reactant: CCOC(=O)C=CN(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=CN(C)C)C(=O)c1c(F)c(C)c(F)c(F)c1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1 h

Procedure:
1.4 g (0.01 mol) of ethyl 3-dimethylaminoacrylate, 15 ml of ethyl acetate and 1.4 ml (0.01 mol) of triethylamine were loaded and cooled to 5° C., and a liquid mixture of 3.5 g (0.011 mol) of 2,4,5-trifluoro-3-methyl-6-nitrobenzoyl chloride and 5 ml of ethyl acetate was added dropwise while the temperature was maintained at 0 to 5° C. The resulting mixture was stirred at 5° C. for 1 hour and then stirred at room temperature (25° C.) for 2 hours. The precipitated triethylamine hydrochloride was filtered off, and the filtrate was concentrated under reduced pressure to give ethyl 3-dimethylamino-2-(2,4,5-trifluoro-3-methyl-6-nitrobenzoyl)acrylate with a 43.6% purity as the residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:10])[C:5]([OH:9])=[CH:6][C:7]=1[F:8].[C:11]1([C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(Cl)Cl)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[O:9][C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:10][C:4]=2[CH:3]=1
Reactant: ClC(Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1cc(F)c(Br)cc1O
Solvent: CO
Product: Fc1cc2c(cc1Br)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-5-fluoro-benzene-1,2-diol (12 g, 58.0 mmol) and diphenyldichloromethane (1.2 eq., 16.50 g) was stirred at room temperature until gaseous evolution ceased. The mixture was heated with stirring at 180° C. for 20 min. The reaction mixture was allowed to cool to room temperature, diluted with methanol (50 ml) and vigorously stirred. The precipitated product was collected by filtration and dissolved in toluene (50 ml). Methanol (100 ml) was added and the mixture stirred 30 min at room temperature. The precipitated product was collected by filtration (yield 10.3 g, 48%), a further batch (6.4 g, 30%) was recovered from the mother liquors.
Reaction SMILES: Br.[Br:2][CH2:3][C:4]([C:6]([C:8]1[N:9]=[CH:10][NH:11][CH:12]=1)=[O:7])=O.[C:13]([NH:16][C:17]([NH2:19])=[S:18])(=[NH:15])[NH2:14]>CC(C)=O>[BrH:2].[NH:16]([C:17]1[S:18][CH:3]=[C:4]([C:6]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[O:7])[N:19]=1)[C:13]([NH2:15])=[NH:14]
Reactant: O=C(CBr)C(=O)c1c[nH]cn1
Reactant: N=C(N)NC(N)=S
Agent: Br
Solvent: CC(C)=O
Product: N=C(N)Nc1nc(C(=O)c2c[nH]cn2)cs1
Yield: 54.1 %

Procedure:
A mixture of 0.38 g (1.4 mmol) of 2-bromo-1-(4-imidazoyl)ethanone hydrobromide in 10 ml of acetone was warmed until homogeneous, then 0.17 g (1.4 mmol) of amidinothiourea was added and the mixture was heated at reflux for 0.5 hour. The mixture was cooled and the white precipitate was collected, washed with ether, and dried, thereby affording 0.24 g (60%) of 2-guanidino-4-(4-imidazoyl)thiazole hydrobromide, mp 225° (dec). nmr (DMSO-d6) (δ): 8.20 (s, 1H); 8.0 (b, 4H); 7.77 (s, 1H); 7.36 (s, 1H); high resolution mass spectrum: calcd. C7H8N6S: for 208.0531; found: 208.517; calcd. for C7H8N6S.HBr.H2O: C, 27.37; H, 3.60; N, 27.36; found: C, 27.23; H, 3.57; N, 27.64.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]2[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][C:3]=1[F:22].[C:23]([O:27][C:28]([NH:30][CH:31]1[CH2:34][NH:33][CH2:32]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>ClCCl>[C:23]([O:27][C:28]([NH:30][CH:31]1[CH2:32][N:33]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:21])[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][N:9]3[CH2:12][CH2:13][C:14]#[N:15])=[CH:4][C:3]=2[F:22])[CH2:34]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(Cl)c(F)cc2c1=O
Solvent: ClCCl
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CC(NC(=O)OC(C)(C)C)C3)c(F)cc2c1=O

Procedure:
A solution of Example 7C (0.3 g) and 3-(tert-butoxycarbonylamino)azetidine (0.46 g) in dichloromethane (60 mL) was stirred for 2 hours, diluted with dichloromethane, washed with water, 10% citric acid, and brine, and dried (MgSO4), filtered, and concentrated.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2/[C:5]/1=[CH:14]/[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:3])[CH3:2]>CO>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C@@H:5]1[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(/C=C2/C3=C(CCCC3)CCN2C(C)=O)cc1
Solvent: CO
Product: COc1ccc(C[C@H]2C3=C(CCCC3)CCN2C(C)=O)cc1
Reaction time: 22 h
Yield: 13.1 %

Procedure:
A 500 ml autoclave was loaded in a glove box with 15.0 g (50.4 mmol) of (Z)-2-acetyl-1-(p-methoxybenzylidene)-1,2,3,4,5,6,7,8-octahydroisoquinoline, 170 ml of methanol and 3.9 mg (0.0050 mmol) of Ru(CH3COO)2 [(R)-HOBIPHEP] as the catalyst. The hydrogenation was carried out at 100° and 35 bar for 22 hours. The conversion was 98.5%. A 2 g product-containing aliquot of the hydrogenation solution was evaporated and the residue was dissolved in diethyl ether. The ether solution was filtered through a silica gel pad in order to separate the catalyst. Evaporation of the filtrate gave 1.97 g of (S)-2-acetyl-1-(p-methoxybenzyl)-1,2,3.4,5,6,7,8-octahydroisoquinoline as yellowish crystals of 95.9% e.e.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:15][C:14]=3[C:25](O)=[O:26])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C[O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=1>>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])=[N:15][C:14]=3[C:25]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([C:30]([OH:29])=[O:38])=[CH:32][CH:33]=3)=[O:26])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: O=C(O)c1nc(-c2ccccc2F)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1ccc(N)cc1
Product: O=C(O)c1ccc(NC(=O)c2nc(-c3ccccc3F)[nH]c2CCC23CC4CC(CC(C4)C2)C3)cc1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-(2-fluoro-phenyl)-1H-imidazole-4-carboxylic acid (Example 50) was reacted with 4-amino-benzoic acid methyl ester according to the procedure of Example 20, step d. Deprotection was carried out using essentially the same procedure as in Example 36, step d to afford the title compound as a white solid.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[CH3:8][C:9]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[NH:11][CH:10]=1>C(O)=O>[CH:5]([N:11]1[C:12]2[N:13]([N:14]=[CH:15][CH:16]=2)[C:9]([CH3:8])=[CH:10]1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c[nH]c2ccnn12
Solvent: O=CO
Product: Cc1cn(C=O)c2ccnn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of acetic anhydride (4.83 ml) and formic acid (3.86 ml) was stirred at room temperature for 1 hour. The solution was cooled at ice-bath and 3-methyl-1H-imidazo[1,2-b]pyrazole (3.1 g) was added thereto. The mixture was stirred at the same condition for 1 hour. The reaction mixture was evaporated and the residue was subjected to column chromatography on silica gel using ethyl acetate as an eluent. Fractions containing the object compound were combined and the solvent was evaporated to give 1-formyl-3-methyl-1H-imidazo[1,2-b]pyrazole (2.99 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.O.[NH2:14][NH2:15]>>[NH2:7][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[CH2:5][C:6]([NH:14][NH2:15])=[O:11]
Reactant: O=C1Nc2ccc(F)cc2C1=O
Reactant: NN
Solvent: O
Product: NNC(=O)Cc1cc(F)ccc1N
Temperature: 110 °C

Procedure:
Hydrazine hydrate (55%, 3000 mL) and 5-fluoroisatin (300 g) were heated to 100° C. An additional 5-fluoro-isatin (500 g) was added in portions (100 g) over 120 minutes with stirring. The mixture was heated to 110° C. and stirred for 4 hours. The mixture was cooled to room temperature and the solids collected by vacuum filtration to give crude (2-amino-5-fluoro-phenyl)-acetic acid hydrazide (748 g). The hydrazide was suspended in water (700 mL) and the pH of the mixture adjusted to <pH 3 with 12 N hydrochloric acid. The mixture was stirred for 12 hours at room temperature. The solids were collected by vacuum filtration and washed twice with water. The product was dried under vacuum to give 5-fluoro-1,3-dihydro-indol-2-one (600 g, 73% yield) as as a brown powder. 1H-NMR (dimethylsulfoxide-d6) δ 3.46 (s, 2H, CH2), 6.75, 6.95, 7.05 (3×m, 3H, aromatic), 10.35 (s, 1H, NH). MS m/z 152 [M+1].
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:17]12[O:23][CH:18]1[CH2:19][CH2:20][CH2:21][CH2:22]2>O1CCCC1>[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C@H:18]1[OH:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C1CCC2OC2C1
Reactant: Brc1ccccc1OCc1ccccc1
Agent: [Mg]
Solvent: C1CCOC1
Product: O[C@@H]1CCCC[C@H]1c1ccccc1OCc1ccccc1
Temperature: -30 °C
Yield: 69629.6 %

Procedure:
A mixture of 3.24 g (0.1 35 mol) of magnesium and 20 ml of tetrahydrofuran was charged into a three-necked flask of 300 ml and stirred. Then, a solution of 35.6 g of o-benzyloxyphenylbromide in 80 ml of tetrahydrofuran was added dropwise at a temperature of 60° C. or less. After the dropping was stopped, the mixture was cooled to -30° C., 0.65 g of cuprous chloride was added, and the mixture was stirred for 10 minutes. To the mixture, a solution of 13.3 g (0.135 mol ) of cyclohexene oxide in 15 ml tetrahydrofuran was added dropwise at -30° C. After the dropping was stopped. The temperature was raised to 0° C., and the mixture was stirred for three hours at 0° C. After the temperature was raised to room temperature, the mixture was charged into a separatory funnel and extracted with 600 ml of methylene chloride, and the organic layer was washed with 600 ml of saturated ammonium sulfate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled away under reduced pressure. The concentrate was distilled under reduced pressure to obtain 26.5 g (0,094 mol) of (±)-trans-2-(2-benzyloxyphenyl)-1-cyclohexanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C@@H:18]3[CH2:24][C@@H:23]4[C@H:19]3[CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22]4)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[O:34][CH:35]=[CH:36][CH:37]=1)CCC>O1CCCC1>[CH2:25]([N:21]1[CH2:20][C@@H:19]2[C@@H:23]([CH2:24][C@H:18]2[C:15]2[CH:16]=[CH:17][C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:33]4[O:34][CH:35]=[CH:36][CH:37]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])=[CH:13][CH:14]=2)[CH2:22]1)[CH2:26][CH3:27]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: CCCN1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(Br)cc4)cc3)[C@@H]2C1
Solvent: C1CCOC1
Product: CCCN1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(-c5ccco5)cc4)cc3)[C@@H]2C1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 8.7 %

Procedure:
4-Bromo-N-[4-((1R,5S,6R)-3-propyl-3-aza-bicyclo[3.2.0]hept-6-yl)-phenyl]-benzenesulfonamide (50 mg, 0.11 mmol), 2-(tributylstannyl)-furan (199 mg, 0.56 mmol) and tetrakistriphenylphosphinpalladium(0) (26 mg, 0.02 mmol) were dissolved in 5 ml of tetrahydrofuran and stirred for 40 minutes at 150° C. in the microwave (CEM). The reaction mixture was filtered over celite, washed with methanol, and the filtrate evaporated to dryness under reduced pressure. The residue was purified via silica gel chromatography with ethyl acetate, and ethyl acetate/methanol (15%). Fractions containing the product were combined, the solvent evaporated to yield 4.2 mg of the title product (yield 9%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:5]=[C:6]([O:10]COCCOC)[CH:7]=[CH:8][CH:9]=1.Cl[C:18]1[O:19][C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1>>[O:19]1[C:20]2[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=[C:18]1[N:2]([CH2:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:1]
Reactant: CNCc1cccc(OCOCCOC)c1
Reactant: Clc1nc2ccccc2o1
Product: CN(Cc1cccc(O)c1)c1nc2ccccc2o1
Temperature: 140 °C

Procedure:
MS (ESI) 255 (M+H)+. Prepared from 3-[(methylamino)-methyl]-(2-methoxyethoxy-methoxy)benzene (example 28) and 2-chloro-benzoxazole. Also, omit heating to 140° C. Reaction stirred at room temperature.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:9]=[CH:10][CH:11]=1.[OH-].[K+:25]>C(O)C>[K+:25].[CH3:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:2]([CH3:1])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:18])[CH2:13][CH2:14][C:15]([O-:17])=[O:16])[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cccc(C)c1COc1cccc(C(=O)CCC(=O)O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1COc1cccc(C(=O)CCC(=O)[O-])c1
Reaction time: 1 h

Procedure:
The 4-(3-(2,6-Dimethylbenzyloxy)phenyl)-4-oxobutyric acid (Step D, 6.0 g, 19.4 mmol) was dissolved in abs ethanol (20 ml) by warming gently followed by addition of KOH (1.21 g) at 0° C. temperature. The reaction mixture was stirred for one hour, concentrated in vaccuo and lyophilized to give the title compound as white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9]C)=[O:8].C[NH:12][CH2:13][C:14]([OH:16])=[O:15].[H-].[Na+]>>[C:14]([CH2:13][NH:12][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])([OH:16])=[O:15]
Reactant: COC(=O)CCCCCBr
Reactant: CNCC(=O)O
Agent: [H-]
Agent: [Na+]
Product: O=C(O)CCCCCNCC(=O)O

Procedure:
In this reaction scheme, methyl 6-bromohexanoate is alkylated with methyl glycine in the presence of sodium hydride to afford the 6-[(carboxymethyl)amino]hexanoic acid. Treatment of 6-[(carboxymethyl)amino]hexanoic acid with sodium hydroxide affords the corresponding 6-[(carboxymethyl)amino]hexanoic acid disodium salt.