Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][C:21]3[N:26]=[CH:25][C:24]([C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)=[CH:23][CH:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([OH:38])=[O:37].C[O-].[Na+:41].CO>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:35])[NH:20][C:21]3[N:26]=[CH:25][C:24]([C:27]4[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)=[CH:23][CH:22]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:36]([O-:38])=[O:37].[Na+:41]
Reactant: COc1ccc(-c2ccc(NC(=O)c3ccc(Oc4cc5c(cc4Cl)C(C(=O)O)CCO5)cc3)nc2)cn1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccc(NC(=O)c3ccc(Oc4cc5c(cc4Cl)C(C(=O)[O-])CCO5)cc3)nc2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
To a solution of 6-chloro-7-(4-(6′-methoxy-3,3′-bipyridin-6-ylcarbamoyl)phenoxy)chroman-4-carboxylic acid (0.040 g, 0.0752 mmol) in 1:1 THF/MeOH (2 ml) was added a 0.5M solution of sodium methoxide in methanol (0.150 ml, 0.0752 mmol), and the reaction was stirred for 2 hours at ambient temperature. The reaction was concentrated to yield the desired compound (0.040 g, 0.0722 mmol, 96.0% yield). MS (apci) m/z=532.2 (M-Na+2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:10])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[F:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18](Cl)(=[O:20])=[O:19]>>[CH3:1][O:2][C:3]1[C:4]([NH:10][S:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[F:11])(=[O:20])=[O:19])=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1
Reactant: O=S(=O)(Cl)c1ccccc1F
Reactant: COc1nc(C)cnc1N
Product: COc1nc(C)cnc1NS(=O)(=O)c1ccccc1F

Procedure:
Prepared by the method of Example 1 using 3-methoxy-5-methyl-2-pyrazinamine and 2-fluorobenzenesulphonyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:7][N:8]2[CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:4][CH:3]=1.C[O:24][C:25](=[O:36])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34]Cl>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:34][CH2:33][O:32][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:25]([OH:36])=[O:24])[CH2:19][CH2:18]3)=[CH:7][N:8]2[CH2:11][C:12]2[CH:16]=[CH:15][S:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1OCCCl
Reactant: Fc1ccc2c(C3CCNCC3)cn(Cc3ccsc3)c2c1
Product: O=C(O)c1ccccc1OCCN1CCC(c2cn(Cc3ccsc3)c3cc(F)ccc23)CC1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 0.98 g (0.31 mmol) of 6-fluoro-3-piperidin-4-yl-1-thiophen-3-ylmethyl-1H-indole (example 108, part B) and 0.09 g (0.40 mmol) 2-(2-chloro-ethoxy)-benzoic acid methyl ester. The crude mixture was purified by HPLC-MS using a C-18 column.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][OH:10].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([Si:20]([O:10][CH2:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])([CH3:23])[CH3:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: OCCc1ccccc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccccc1F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of 2-(2-fluorophenyl)ethanol (5.5 g) and imidazole (8.0 g) in DMF (50 mL) was cooled in ice-water, treated with tert-butyldimethylchlorosilane (6.52 g), then removed from the cooling bath and stirred at room temperature for 3.5 hours. The solution was poured into water and extracted three times with diethyl ether. The combined organic extracts were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and concentrated under reduced pressure to afford the subtitled compound as a colourless oil. Yield 9.9 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[O:9]1[CH2:13][CH2:12]OC1=O>N1C=CN=C1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][OH:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C1OCCO1
Agent: c1c[nH]cn1
Product: OCCOc1ccc(Br)cc1
Temperature: 140 °C
Yield: 103.3 %

Procedure:
4-Bromophenol (100 g, 0.58 mol) was dissolved in in xylenes (220 mL). [1,3]Dioxolan-2-one (53.7 g, 0.61 mol) and imidazole (592 mg, 8.70 mmol) were added. The mixture was heated to 140° C. for 3 days. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. Drying the residue under high vacuum yielded the title compound (130 g, quantitative). LC-MS: tR=0.81 min.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH3:10]>CO.[Pd]>[CH2:9]([C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1])[CH3:10]
Reactant: CC(=O)c1ccc(C)cc1O
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(C)cc1O
Reaction time: 24 h

Procedure:
A mixture of 1-(2-hydroxy-4-methyl-phenyl)-ethanone (5 g, 33.3 mmol) and 10 wt % Pd/C (2 g, Degussa type) in MeOH (50 mL) was stirred under a balloon of H2 for 24 hours. The reaction mixture was filtered through a pad of celite washing with EtOAc. The filtrate was concentrated to a clear oil (4.5 g, 99%). 1H NMR (400 MHz, CDCl3): δ 1.23 (t, J=7.6 Hz, 3 H), 2.27 (s, 3 H), 2.59 (q, J=7.6 Hz, 2 H), 4.68 (s, 1 H), 6.59 (s, 1 H), 6.71 (d, J=7.7 Hz, 1 H), 7.01 (d, J=7.7 Hz, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[S:29])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:38][C:39](=O)[CH3:40]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[S:29][CH:38]=[C:39]([CH3:40])[N:30]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1csc(NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a stirred mixture of 4.3 parts of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]thiourea, 2.1 parts of potassium carbonate and 45 parts of tetrahydrofuran was added dropwise a solution of 0.9 parts of 1-chloro-2-propanone in a small amount of tetrahydrofuran. Upon completion, stirring at room temperature was continued overnight. The reaction mixture was filtered over Hyflo and the filtrate was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 3.8 parts (81%) of 1-[(4-fluorophenyl)methyl]-N-[1-[2-[(4-methyl-2-thiazolyl)amino]ethyl]-4-piperidinyl]-1H-benzimidazol-2-amine; mp. 184° C. (compound 85).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[N:8]=[C:7]2[CH2:9][N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:11][C:6]2=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>>[F:32][C:2]([F:1])([F:31])[C:3]1[N:8]=[C:7]2[CH2:9][NH:10][CH2:11][C:6]2=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc2c(n1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1ccc2c(n1)CNC2

Procedure:
Prepared in analogy to Example A2 (c) from 2-Trifluoromethyl-6-trityl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine and trifluoroacetic acid. Light yellow solid. MS (m/e): 189.3 ([M+H+, 100%).
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].O=[C:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1>C1COCC1>[CH2:2]=[C:29]1[CH2:34][CH2:33][CH2:32][N:31]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:30]1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 65 %

Procedure:
A suspension of methyltriphenylphosphonium iodide (15.22 g, 37.6 mmol, Sigma-Aldrich) in THF (75 mL) was stirred at RT before addition of potassium t-butoxide (4.22 g, 37.6 mmol, Sigma-Aldrich) in one portion. The resulting bright yellow solution was stirred at RT for 30 minuets before adding tert-butyl 3-oxopiperidine-1-carboxylate (3 g, 15.06 mmol) and stirring for 3 h. It was poured into ice water, and the mixture was extracted with DCM (4×50 mL) before drying the combined organics over Na2SO4, filtering, and concentrating under reduced pressure. The crude material was purified by column chromatography (eluant: 0 to 10% EtOAc/hexanes), affording the product as a clear oil (1.93 g, 65%). 1H NMR (DMSO-d6) δ: 4.70-4.81 (m, 2H), 3.80 (s, 2H), 3.30-3.40 (m, 2H), 2.18-2.26 (m, 2H), 1.47-1.56 (m, 2H), 1.38 (s, 9H)
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]1.[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]1[CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[Cl:15]
Reactant: Clc1ccccc1CBr
Reactant: CC1(C)NN(C2CC3CCC2C3)C1=O
Product: CC1(C)C(=O)N(C2CC3CCC2C3)N1Cc1ccccc1Cl

Procedure:
2-(Bicyclo[2.2.1]heptan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-chlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1([CH:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)(=O)[C:19]([Cl:21])=[O:20].[Cl-].[Ca+2].[Cl-]>C(Cl)Cl.O>[O:17]=[C:14]1[CH2:15][CH2:16][CH:11]([C:5]2[CH:10]=[CH:9][C:8]([C:19]([Cl:21])=[O:20])=[CH:7][CH:6]=2)[CH2:12][CH2:13]1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C1CCC(c2ccc(C(=O)Cl)cc2)CC1
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
A suspension of 133.3 g of aluminium chloride in 250 ml of methylene chloride was treated dropwise at 20° C. while cooling and gassing with nitrogen with a solution of 174.2 g of 4-phenylcyclohexanone in 250 ml of methylene chloride. The reaction mixture was stirred for a further 30 minutes until a clear solution was obtained. In the meanwhile, a suspension of 133.3 g of aluminium chloride in 500 ml of methylene chloride was treated with 172 ml of oxalyl chloride while gassing with nitrogen. This mixture was subsequently treated dropwise at 20°-25° C. within 1 hour with the above solution of the 4-phenylcyclohexanone-aluminium chloride complex. The reaction mixture was stirred for a further 30 minutes, then cooled to 2° C. and added dropwise within 20 minutes while stirring to a solution of 300 g of calcium chloride in 1 l of water. The mixture was stirred at room temperature for a further 1.5 hours and then poured on to 500 ml of ice/water. The organic phase was separated and washed with 500 ml of semi-saturated sodium chloride solution. The aqueous phases were back-extracted twice with 500 ml of methylene chloride each time. The combined organic phase was dried over sodium sulfate, filtered and concentrated. The oily 4-(4-oxocyclohexyl)benzoyl chloride obtained was dissolved in 400 ml of toluene and this solution was added dropwise to a mixture of 150 ml of methanol, 200 ml of pyridine and 1 l of toluene. The reaction mixture was left to stand overnight and then washed in succession with water, 3N hydrochloric acid, semi-saturated sodium hydrogen carbonate solution and again with water, dried over sodium sulfate, filtered and concentrated. Recrystallization of the residue from toluene at -25° C. gave 128 g of pure methyl 4-(4-oxocyclohexyl)-benzoate with m.p. 91°-92° C.
Reaction SMILES: [CH:1]1(Br)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[OH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[N+:24]([O-:26])=[O:25])[C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O>[CH:1]1([O:13][C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=2[N+:24]([O-:26])=[O:25])[C:17]([O:19][CH3:20])=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(O)c1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Reaction time: 4 h
Yield: 102.2 %

Procedure:
Cyclopentyl bromide (38.7 g, 0.26 mol) is added slowly (over 1 hour) to a stirred suspension of potassium carbonate (41.4 g, 0.3 mol) in N,N-dimethylformamide (200 mL) containing methyl 3-hydroxy-4-nitrobenzoate (39.4 g, 0.2 tool) at 65° C. and then the stirring is continued for 4 hours. The mixture is allowed to cool and then filtered. The flitrate is diluted with water (700 mL) containing sodium chloride (50 g) and then extracted with toluene (3×200 mL). The combined organic extract is washed with 1N sodium hydroxide solution (1×200 mL) and then water (2×200 mL) and then evaporated under reduced pressure to give methyl 3-cyclopentyloxy-4-nitrobenzoate (54.2 g, 100%) as a pale green solid which is used without further purification.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.Cl[C@@H:18]1[C@@H](CO)O[C@@H](N2C=CC(=O)NC2=O)[CH2:19]1.[N-]=[N+]=[N-].[Li+]>CN(P(N(C)C)(N(C)C)=O)C>[CH2:18]([C:15]1[C:13](=[O:14])[NH:12][C:10](=[O:11])[N:9]([CH:16]=1)[C@@H:1]1[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1)[CH3:19]
Reactant: O=c1ccn([C@H]2C[C@H](Cl)[C@@H](CO)O2)c(=O)[nH]1
Reactant: O=c1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Agent: [Li+]
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O

Procedure:
5-Chloromercuri-2'-deoxyuridine was prepared from 2'-deoxyuridine (10 g, 0.044 moles) by the procedure of Bergstron and Ruth (J. Carb. Nucl, and Nucl., 4,257, (1977)). 2'-Deoxy-5-ethyluridine was prepared by the method of Berstrom et al., (J. Am. Chem. Soc., 100, 8106, (1978)). The 5'-hydroxyl group was protected by the method of Example 62. The 3'-hydroxyl group was chlorinated and the 5'-hydroxyl was deprotected by the method of Example 64. The 3'-chloro of threo 3'-chloro-2',3'-dideoxyuridine was displaced with inversion of configuration by heating in HMPA with lithium azide (5 eq.) at 55° C. for one hour. The title compound was purified by chromatography on silica gel eluted with ethyl acetate. Removal of solvent from the appropriate fractions gave the desired compound; mp=112.5°-115° C.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)=[CH:4][C:3]=1[F:24].[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[C:33]2=[O:41])=[CH:28][CH:27]=1>>[F:24][C:3]1[CH:4]=[C:5]([O:6][C:7]2[CH:16]=[CH:15][N:14]=[C:13]3[C:8]=2[C:9]2[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=2[C:11](=[O:17])[NH:12]3)[CH:22]=[CH:23][C:2]=1[NH:1][C:38]([C:34]1[C:33](=[O:41])[N:32]([C:29]2[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=2)[CH:37]=[CH:36][CH:35]=1)=[O:39]
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1F
Product: O=C(Nc1ccc(Oc2ccnc3[nH]c(=O)c4ccccc4c23)cc1F)c1cccn(-c2ccc(F)cc2)c1=O
Yield: 75.7 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 181 using Compound 185 (50 mg, 0.16 mmol) and 1-(4-fluoro-phenyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid (44 mg, 0.19 mmol) to provide 187 (65 mg, 78% yield) as a dark solid. LC-MS (M+H=537, obsd.=537).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1.[Cl:31][C:32]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:33]=1[CH:34]=[CH:35][C:36]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[N:37]2>>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27][N:45]3[CH2:46][CH2:47][N:42]([C:36]4[CH:35]=[CH:34][C:33]5[C:38](=[CH:39][CH:40]=[CH:41][C:32]=5[Cl:31])[N:37]=4)[CH2:43][CH2:44]3)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:5][CH:4]=1
Reactant: Clc1cccc2nc(N3CCNCC3)ccc12
Reactant: COc1ccc(CNC(=O)C2(CCCCBr)c3ccccc3-c3ccccc32)cc1
Product: COc1ccc(CNC(=O)C2(CCCCN3CCN(c4ccc5c(Cl)cccc5n4)CC3)c3ccccc3-c3ccccc32)cc1

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-4-methoxy-benzylamide and 5-chloro-2-piperazin-1-yl-quinoline.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]3[CH2:17][CH2:16][C:15](=O)[CH:14]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1.Cl.[NH2:22][OH:23]>>[F:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:8]=[C:9]([C:13]3[CH2:17][CH2:16][C:15](=[N:22][OH:23])[CH:14]=3)[CH:10]=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C1C=C(c2cccc(Oc3ccc(F)cc3)c2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1C=C(c2cccc(Oc3ccc(F)cc3)c2)CC1
Reaction time: 4 h
Yield: 113.6 %

Procedure:
To a stirred solution of 3-[3-(4-fluorophenoxy)phenyl]-2-cyclopentenone (10 g; 0.0373M) in ethanol-pyridine (75 ml-21 ml) was added hydroxylamine hydrochloride (3.37 g; 0.0485M) at room temperature. After stirring for 4 hrs, solvent was removed. To the residue was added dilute aqueous HCl (100 ml), and the whole was extracted with ethyl acetate (200 ml×1, 100 ml×1). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over MgSO4, and concentrated in vacuo to give 12 g of crude subtitle compound [E] as a brown oil, which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[O:11][CH:10]=[N:9][CH:8]=1.[CH2:12]([O:19][C:20]1[CH:21]=[C:22]([CH2:26][CH2:27][C:28](O)=[O:29])[CH:23]=[CH:24][CH:25]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[O:29]=[C:28]([C:10]1[O:11][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][N:9]=1)[CH2:27][CH2:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:21]=1
Reactant: c1ccc(-c2cnco2)nc1
Reactant: O=C(O)CCc1cccc(OCc2ccccc2)c1
Product: O=C(CCc1cccc(OCc2ccccc2)c1)c1ncc(-c2ccccn2)o1
Yield: 18 %

Procedure:
The title compound was prepared from 5-(2-pyridyl)oxazole and 3-(3-(benzyloxy)phenyl)propanoic acid (Bänteli, R.; Brun, I.; et al. Tetrahedron Lett. 1999, 40, 2109-2112) using General Procedure B. Column chromatography (SiO2, 2.5×6 cm, 10-20% EtOAc-hexanes gradient) followed by PTLC (SiO2, 50% EtOAc-hexanes) afforded 11c (46 mg, 0.12 mmol, 18%) as a yellow solid: 1H NMR (CDCl3, 400 MHz) 8.67 (m, 1H), 7.88 (s, 1H), 7.87-7.85 (m, 1H), 7.81 (td, 1H, J=7.8, 1.8 Hz), 7.45 (d, 2H, J=8.5 Hz), 7.38 (t, 2H, J=7.3 Hz), 7.32 (t, 2H, J=6.8 Hz), 7.22 (t, 2H, J=7.9 Hz), 6.92 (d, 2H, J=2.1 Hz), 6.88 (d, 2H, J=7.6 Hz), 6.83 (dd, 2H, J=7.9, 2.4 Hz), 5.06 (s, 2H), 3.47 (t, 2H, J=7.4 Hz), 3.10 (t, 2H, J=7.4 Hz); 13C NMR (CDCl3, 100 MHz) 187.2, 158.9, 157.2, 153.4, 150.1, 146.2, 142.0, 137.1, 137.0, 129.5, 128.5, 127.9, 127.5, 127.0, 124.2, 121.0, 120.4, 115.1, 112.5, 69.9, 40.5, 29.7; IR (film) νmax 3073, 3032, 2929, 1697, 1601, 1582, 1499, 1468, 1452, 1425, 1380, 1256, 1154, 1027, 784, 737, 695 cm−1; ESI-TOF m/z 385.1549 (C24H20N2O3+H+ requires 385.1547).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[CH:6][CH:7]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([C:26](O)=[O:27])[CH:21]=1.Cl.CN(C)CCCN=C=NCC>ClCCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:29][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[C:26]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[CH:6][CH:7]=1)=[O:27]
Reactant: Cc1cccc(C(=O)O)c1
Reactant: NC(=O)n1c(-c2cccc(N)c2)cc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Cc1cccc(C(=O)Nc2cccc(-c3cc4ccccc4n3C(N)=O)c2)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To the solution of 2-(3-aminophenyl)-1H-indole-1-carboxamide (50.2 mg, 0.2 mmol, 1 eq) and m-toluic acid (27.5 mg, 1 eq) in anhydrous DCE (2 mL) was added 4-(dimethylamino)pyridine (4.9 mg, 0.2 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46.1 mg, 1.2 eq). After the reaction was stirred at 60° C. for 1 hour, it was diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the oily residue was subject to a gradient column chromatography (EtOAc-Hex 1:10 to 1:1) to give 2-{3-[(3-methylbenzoyl)amino]phenyl}-1H-indole-1-carboxamide as a clear oil which turned into a white foam in vacuo in amount of 34 mg.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH:6](=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[C:7]1([CH:6]([OH:13])[C@@H:2]([C:3]([OH:5])=[O:4])[NH2:1])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCC(=O)O
Reactant: O=Cc1ccccc1
Product: N[C@H](C(=O)O)C(O)c1ccccc1

Procedure:
β-Phenylserine was synthesized from glycine and benzaldehyde in the same way as in Example 1 except that the organic solvent was changed as shown in Table 1. The results are shown in Table 1.
Reaction SMILES: [NH2:1][CH:2]1[CH2:20][C:6]2[C:7]3[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=3[CH:13]=[C:14]([N+:15]([O-:17])=[O:16])[C:5]=2[CH2:4][CH2:3]1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>CN(C)C=O>[N+:15]([C:14]1[C:5]2[CH2:4][CH2:3][CH:2]([NH:1][C:21](=[O:23])[CH3:22])[CH2:20][C:6]=2[C:7]2[NH:8][C:9](=[O:19])[C:10](=[O:18])[NH:11][C:12]=2[CH:13]=1)([O-:17])=[O:16]
Reactant: NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCc2c([N+](=O)[O-])cc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of 9-amino-6-nitro-1,4,7,8,9,10-hexahydro-benzo[f]quinoxaline-2,3-dione (0.15 g, 0.5 mmol), acetic anhydride (0.1 g, 1 mmol) and triethylamine (0.2 g, 2 mmol) in dimethylformamide (5 mL) was stirred at room temperature for 3 h. The solvent was removed by rotoevaporation, and the residue suspended in water and 2N HCl. The solid which formed was collected by filtration, washed with diethyl ether and dried to give the acetamide (0.14 g) in 88% yield. Anal. calc'd for C14H14N4O5.H2O: C, 50.00; H, 4.80; N, 16.66; found-C, 49.92; H, 4.77; N, 16.04.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C@@H:7]([C:22](O)=[O:23])[CH2:6]1)=[O:4].Cl.[CH2:26]([O:33][NH2:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(OCC)(=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][N:8]([S:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)(=[O:12])=[O:13])[C@@H:7]([C:22](=[O:23])[NH:34][O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CCN(S(=O)(=O)c2ccc(OC)cc2)[C@@H](C(=O)O)C1
Reactant: NOCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCN(S(=O)(=O)c2ccc(OC)cc2)[C@@H](C(=O)NOCc2ccccc2)C1
Reaction time: 24 h

Procedure:
To a stirred solution of (2R,4R)-1-(4-methoxy-benzenesulfonyl)-piperidine-2,4-dicarboxylic acid 4-methyl ester (4.4 g, 12.3 mmol), O-benzylhydroxylamine hydrochloride (2.15 g, 13.5 mmol), and triethylamine (5.15 mL, 36.9 mmol) was added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (6.0 g, 12.3 mmol) at ambient temperature. The resulting mixture was stirred for 24 hours. The mixture was diluted with ethyl acetate and washed with 1 M aqueous hydrogen chloride, aqueous sodium bicarbonate, and brine. The organic mixture was dried over magnesium sulfate, filtered, and the filtrate was concentrated. The crude residue was purified by silica gel chromatography (elution with 5% methanol in methylene chloride) to provide (2R,4R)-2-benzyloxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-piperidine-4-carboxylic acid methyl ester as a colorless solid.