Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20](Br)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([OH:31])=[O:30].C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC.O>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([C:37]3[CH:38]=[CH:39][C:34]([CH2:33][CH2:32][C:29]([OH:31])=[O:30])=[CH:35][CH:36]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cccc2c(-c3cccc(Br)c3)c(Cc3ccccc3)cnc12
Reactant: O=C(O)CCc1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(O)CCc1ccc(-c2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1
Yield: 67 %

Procedure:
To a solution of 3-benzyl-4-(3-bromophenyl)-8-(trifluoromethyl)quinoline (0.30 g, 0.7 mmol), 4-(2-carboxyethyl) benzene boronic acid (0.15 g, 0.75 mmol) in 15 ml DME under a nitrogen atmosphere is added terakistriphenyl phosphine palladium (0.08 g, 0.07 mmol) followed by sodium carbonate (0.22 g, 2.04 mmol) dissolved in 5 ml water. The reaction mixture was heated to reflux for 12 hr. The reaction was cooled, poured into 1N HCl and extracted with EtOAc. The organic layer was dried and concentrated to provide the title compound as a tan solid (0.24 g, 70%): MS (ES) m/z 509.9; HRMS: calcd for C32H24F3NO2+H+, 512.18319; found (ESI, [M+H]+), 512.1842;
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]([NH2:21])=[O:20])=[CH:16][C:3]1=2.C1C2CCC3C=CC=CC=3C(=O)C=2C=CC=1C1C(=O)N[C:40](=[O:44])[C:39]=1[OH:45]>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][C:18]3[C:19](=[O:20])[NH:21][C:40](=[O:44])[C:39]=3[OH:45])=[CH:16][C:3]1=2
Reactant: NC(=O)COc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: O=C1NC(=O)C(c2ccc3c(c2)CCc2ccccc2C3=O)=C1O
Product: O=C1NC(=O)C(Oc2ccc3c(c2)C(=O)c2ccccc2CO3)=C1O

Procedure:
When [(6,11-dihydro-11-oxodibenzo[b,e]-oxepin-2-yl)oxy]acetamide is employed as the starting amide there is obtained 4-[(6,11-dihydro-11-oxodibenzo[b,e]oxepin-2-yl)oxy]-3-hydroxy-3-pyrroline-2,5-dione.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:6][C:5]2=[O:18].C([O:26][C:27]1[C:28](=[O:43])[O:29][CH:30]([CH2:40][CH2:41]O)[C:31]=1[O:32]CC1C=CC=CC=1)C1C=CC=CC=1>>[OH:26][C:27]1[C:28](=[O:43])[O:29][CH:30]([CH2:40][CH2:41][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[O:8][C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][C:5]3=[O:18])[C:31]=1[OH:32]
Reactant: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Product: O=C1OC(CCOc2ccc3oc(-c4ccccc4)cc(=O)c3c2)C(O)=C1O

Procedure:
Mitsunoble coupling of 0.33 g (1.4 mmol) of 6-hydroxyflavone with 0.40 g (1.17 mmol) of 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone and subsequent benzyl group deprotection by hydrogenation were performed in a similar manner as described in the synthesis of 3,4-dihydroxy-5-[2-(4-phenoxy)phenoxyethyl]-2(5H)-furanone to provide 3,4-dihydroxy-5-[2-(flavone-6-oxy)ethyl]-2(5H)-furanone as a tan solid: mp 200-220° C. dec. (acetone/hexanes), 1H NMR (DMSO-d6) δ 8.13-7.36 (m, 8H), 7.01 (s, 1H), 4.92 (dd, 1H), 4.17 (t, 2H), 2.47-2.27 (m, 1H), 1.98-1.85 (m, 1H). 13C NMR (DMSO-d6) δ 177.23, 170.22, 162.71, 156.02, 155.36, 150.80, 132.06, 131.51, 129.42, 126.59, 124.31, 123.85, 120.49, 117.44, 106.43, 105.85, 72.24, 64.20, 31.71. Anal Calcd for C21H16O7 +0.25 H2O: C, 65.55; H, 4.44. Found: C, 65.59; H, 4.49.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[NH:18][CH:19]=[N:20]2>>[Cl:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[C@@H:12]([C@@:9]1([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH2:11][O:10]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: Clc1ncnc2nc[nH]c12
Product: C[C@@H](n1cnc2c(Cl)ncnc21)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 47.9 %

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (607 mg) and 6-chloropurine (422 mg), (2S)-2-[(1R)-1-[6-chloro-9(9H)-purinyl]ethyl]-2-(2,4-difluorophenyl)oxirane (440 mg) was obtained as a white powder by the same way as in Reference Example 2.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].NC1C2C(=CC(CN3CC[C@@H](NC([NH:28][C:29]4S[C:31]([Cl:34])=[CH:32][CH:33]=4)=O)C3=O)=CC=2)N=CN=1.FC(F)(F)C(O)=O.[NH2:43][C:44]1[C:53]2[C:48](=[CH:49][C:50]([CH2:54][N:55]3[CH2:59][CH2:58][C@@H:57]([NH:60][C:61]([C:63]4S[C:65](Cl)=[CH:66][CH:67]=4)=O)[C:56]3=[O:69])=[CH:51][CH:52]=2)[N:47]=[CH:46][N:45]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:43][C:44]1[C:53]2[C:48](=[CH:49][C:50]([CH2:54][N:55]3[CH2:59][CH2:58][C@@H:57]([NH:60][CH2:61][C:63]4[NH:28][C:29]5[C:66]([CH:67]=4)=[CH:65][C:31]([Cl:34])=[CH:32][CH:33]=5)[C:56]3=[O:69])=[CH:51][CH:52]=2)[N:47]=[CH:46][N:45]=1
Reactant: Nc1ncnc2cc(CN3CC[C@@H](NC(=O)Nc4ccc(Cl)s4)C3=O)ccc12
Reactant: Nc1ncnc2cc(CN3CC[C@@H](NC(=O)c4ccc(Cl)s4)C3=O)ccc12
Solvent: O=C(O)C(F)(F)F
Product: Nc1ncnc2cc(CN3CC[C@@H](NCc4cc5cc(Cl)ccc5[nH]4)C3=O)ccc12

Procedure:
1-[1-(4-Aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]-3-(5-chlorothiophen-2-yl)urea trifluoroacetate and 5-Chlorothiophene-2-carboxylic acid [1-(4-aminoquinazolin-7-ylmethyl)-2-oxopyrrolidin-3-(R)-yl]amide trifluoroacetate;
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=3)[N:19]=[CH:18][N:17]=2)[CH2:9]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH:1]1([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:27])([F:29])[F:28])[CH:24]=4)[N:19]=[CH:18][N:17]=3)[CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCCCC2)C1

Procedure:
Reaction of cyclohexanone with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].[H-].[Na+]>CN(C=O)C.C1COCC1>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]2[O:12][CH:2]([CH3:7])[C:3](=[O:12])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1Oc2cc([N+](=O)[O-])c(Cl)cc2NC1=O
Reaction time: 4 h
Yield: 72 %

Procedure:
7.52 g of 2-amino-4-chloro-5-nitrophenol is added to a mixture of 1.6 g of sodium hydride in 60 ml of DMF and mixed with 1.1 equivalents of D,L-2-bromopropionic acid ethyl ester in 20 ml of THF at 5° C. It is stirred for 4 hours. The mixture is poured onto water, extracted with ethyl acetate, the organic phase is dried with magnesium sulfate and concentrated by evaporation. 1.7 g of crude product, which is recrystallized from isopropyl ether, results. The yield is 72%.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([F:35])=[CH:31][C:32]([F:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[C:30]([F:35])=[CH:31][C:32]([F:34])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(F)cc(F)c2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cc(F)cc(F)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5,7-difluoro-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:44][C@H:45]1[CH2:47][O:46]1.CCN(C(C)C)C(C)C>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[CH:24][C:25]([N:28]5[CH2:29][CH2:30][N:31]([CH2:44][C@@H:45]([OH:46])[CH3:47])[CH2:32][CH2:33]5)=[CH:26][CH:27]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:35])=[O:36])[CH:14]=2)[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Reactant: C[C@H]1CO1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 62.1 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-benzyl-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (175 mg. 0.249 mmol) was alkylated using (S)-2-methyloxirane (27 mg, 0.498 mmol), DIPEA (129 mg, 0.996 mmol) and ethanol (5 mL) to get 100 mg (62.1% yield) of the titled compound. MS: m/z=647.2 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39]O>C(Cl)Cl.O>[I:25][CH2:39][CH:35]1[CH2:36][CH2:37][CH2:38][CH:34]1[O:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][O:27]1
Reactant: OCC1CCCC1OC1CCCCO1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: ICC1CCCC1OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
A solution of triphenylphosphine (1.70 g, 6.49 mmol) and imidazole (884 mg, 12.98 mmol) in methylene chloride (8.32 mL) cooled to 0° C. was treated with iodine (1.64 g, 6.49 mmol). After the iodine was completely dissolved, a solution of [2-(tetrahydro-pyran-2-yloxy)-cyclopentyl]-methanol (1.0 g, 4.99 mmol) was added to the reaction mixture. The reaction was stirred at 0° C. for 1 h and at 25° C. for 2 h. At this time, the reaction was poured into water (100 mL) and extracted with methylene chloride (1×30 mL). The organics were washed with a saturated aqueous sodium thiosulfate solution (1×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo at 25° C. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 2-(2-iodomethyl-cyclopentyloxy)-tetrahydropyran (1.17 g, 75.8%) as a clear liquid: EI-HRMS m/e calcd for C11H19IO2 (M+) 309.0352. found 309.0348.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[CH3:13]>C1(C)C=CC=CC=1>[CH2:12]([O:14][C:15](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:10])=[O:9])[CH:17]=1)[CH3:13]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2cccc(Cl)c2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
A solution of 3-chloro-benzenesulfonyl chloride (2.68 g, 13.0 mmol) in toluene (10.0 ml) was warmed to 100° C. and treated with a solution of 3-amino-benzoic acid ethyl ester (2.00 g, 12.0 mmol) in toluene (10.0 ml). The mixture was stirred at 100° C. for 1 h, then cooled to 0° C. for 1 h. The precipitated solid was filtered, washing with toluene. Drying of the solid under high vacuum yielded 3-(3-chloro-benzenesulfonylamino)-benzoic acid ethyl ester (4.03 g, 98%) as an off-white solid, which was used crude in the following reaction.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[NH2:12][C:13]1[CH:14]=[C:15]([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:19][C:18]1[CH:17]=[CH:16][C:15]([NH:20][C:21](=[O:34])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[CH:23]=2)=[CH:14][C:13]=1[NH:12][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([CH2:2][Cl:1])[CH:4]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1N
Reactant: O=C(Cl)c1cccc(CCl)c1
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(CCl)c1
Yield: 98 %

Procedure:
Using an analogous procedure to that described in Example 63, 3-chloromethylbenzoyl chloride was reacted with N-(3-amino-4-methylphenyl)-3-morpholinobenzamide. There was thus obtained the title compound in 98% yield; NMR Spectrum: (DMSOd6) 2.19 (s, 3H), 3.17 (m, 4H), 3.75 (m, 4H), 4.85 (s, 2H), 7.13 (d, 1H), 7.22 (d, 1H), 7.34 (m, 2H), 7.44 (s, 1H), 7.54 (m, 2H), 7.65 (d, 1H), 7.79 (s, 1H), 7.95 (d, 1H). 8.03 (s, 1H), 9.96 (s, 1H), 10.12 (s, 1H); Mass Spectrum: M+H+ 464.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([CH2:25][C:26]2[CH:27]=[C:28]([CH:35]=[CH:36][C:37]=2[Cl:38])[O:29][C@@H:30]([CH3:34])[C:31](O)=[O:32])[C:20]([CH3:39])=[C:19]3[CH3:40])=[O:15])[CH3:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].C[N:44](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH2:44][C:31](=[O:32])[C@@H:30]([O:29][C:28]1[CH:35]=[CH:36][C:37]([Cl:38])=[C:26]([CH:27]=1)[CH2:25][N:21]1[C:22]2[C:18](=[CH:17][C:16]([C:14]([NH:13][C@H:11]([C:8]3[CH:9]=[CH:10][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][CH:7]=3)[CH3:12])=[O:15])=[CH:24][CH:23]=2)[C:19]([CH3:40])=[C:20]1[CH3:39])[CH3:34]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1c(C)n(Cc2cc(O[C@@H](C)C(=O)O)ccc2Cl)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C)n(Cc2cc(O[C@@H](C)C(N)=O)ccc2Cl)c2ccc(C(=O)N[C@@H](C)c3ccc(C(C)(C)C)cc3)cc12
Yield: 89.3 %

Procedure:
A solution of (S)-2-(3-((5-(((S)-1-(4-(tert-butyl)phenyl)ethyl)carbamoyl)-2,3-dimethyl-1H-indol-1-yl)methyl)-4-chlorophenoxy)propanoic acid (20 mg, 0.036 mmol), NH4Cl (19 mg, 0.36 mmol), HATU (14 mg, 0.036 mmol) and DIEA (25 μl, 0.144 mmol) in DCM (0.5 ml) was stirred at rt for 1 h. After concentration, the obtained oil was purified by reverse phase prep-HPLC (MeOH/Acetonitrile/water) to afford a white powder (18 mg). ESI-MS (m/z): 560/561/562 [MH]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:18])[CH2:14][O:15][CH2:16][CH3:17])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1F.CCO>CN(C=O)C.Cl>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[O:18][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][O:15][CH2:16][CH3:17]
Reactant: CCOC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC[C@H](Oc1ccc(Cl)cc1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-2-Ethoxy-1-hydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (25.0 mg, 96.4 μmol) was dissolved in DMF (200 μL). NaH (2776 μg, 115.7 mmol) was added and the mixture was stirred at room temperature for 15 minutes. 2,4-Dichloro-1-fluorobenzene (22.6 μL, 192.8 μmol) was added and the mixture was stirred at 70° C. for 3 hours. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) and stirred overnight. The product was concentrated and purified by preparative HPLC (10-40%, 60 min, BDS) to yield the title compound as a mono-TFA salt oil (24.4 mg, 100% purity). MS m/z: [M+H]+ calcd for C14H19Cl2NO2, 304.08. found 304.0.
Reaction SMILES: FC(F)(F)C(O)=O.CC(C)(O[N:12]1[CH2:17][CH2:16][CH:15]([N:18]([CH3:28])[C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:14][C:13]1=C=O)C.[OH-].[Na+]>C(Cl)Cl>[CH3:28][N:18]([CH:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]1)[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: CN(c1ncccc1[N+](=O)[O-])C1CCN(OC(C)(C)C)C(=C=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(c1ncccc1[N+](=O)[O-])C1CCNCC1
Reaction time: 17 h

Procedure:
Trifluoroacetic acid (13.0 ml) is added to a solution of 1-((1,1-dimethylethoxy)-carbonyl-4-(N-methyl-N-(3-nitro-2-pyridinyl)amino)piperidine (PREPARATION 49) in methylene chloride (100 ml) with cooling to -78°. The mixture is warmed to 20°-25° , stirred 17 hrs, cooled to 0° and basified to pH 12 with 5% sodium hydroxide. The phases are separated and the aqueous phase is extracted with methylene chloride (2×50 ml). The combined organic phases are dried over sodium sulfate and concentrated to give the title compound, mp 115.5°-117°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH3:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=2)[C:13]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:12]([C:27]#[N:28])[C:11]1=[O:29]>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:24]1[CH2:25][CH2:26][N:21]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[N:10]([CH3:9])[C:11](=[O:29])[C:12]=2[C:27]#[N:28])[CH2:22][CH2:23]1)=[O:7]
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2C
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3ccco3)CC1)c(C#N)c(=O)n2C
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
2-Furoyl chloride (148 μL, 1.5 mmol) was added to a stirred solution of Compound 28 (282 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 221 mg (59%) of white solids. M.P. 231° C. 1H NMR (DMSO-d6): δ 2.41 (s, 3H), 3.56 (s, 3H), 3.63 (m, 4H), 3.95 (m, 4H), 6.66 (dd, J=1.5, 3.6 Hz, 1H), 7.08 (d, J=3.4 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.59 (dd, J=1.2, 8.8 Hz, 1H), 7.69 (s, 1H), 7.88 (s, 1H). EIMS m/z 399 (M+23). Anal. (C21H20N4O3) C, H, N.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH2:18]([C:22]1([N:29]([CH3:31])[CH3:30])[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21].FC(F)(F)S(O)(=O)=O>ClCCl>[CH2:18]([C:22]1([N:29]([CH3:31])[CH3:30])[CH2:27][CH2:26][C:25]([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)([C:10]2[NH:11][C:12]3[C:17]([C:9]=2[CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: c1ccc2c(CCc3ccncc3)c[nH]c2c1
Reactant: CCCCC1(N(C)C)CCC(=O)CC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCC1(N(C)C)CCC(c2[nH]c3ccccc3c2CCc2ccncc2)(c2[nH]c3ccccc3c2CCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 67 h

Procedure:
3-(2-pyridin-4-ylethyl)-1H-indole (667 mg, 3 mmol, synthesis cf. WO2008009415, indole unit Ind-14) together with 4-butyl-4-(dimethylamino)cyclohexanone (592 mg, 3 mmol, synthesis cf. WO2008009415, ketone unit Ket-4) was dissolved in dichloromethane (45 ml) and mixed with trifluoromethane sulphonic acid (0.553 ml, 6.3 mmol). The batch was stirred for 67 h at RT, and a brown oil separated out. For work up the reaction solution was mixed with 1N NaOH (10 ml) and THF (10 ml). The mixture was stirred a further 60 min. After separation of the phases the aqueous phase was extracted with dichloromethane (3×10 ml). The combined organic extracts were dried over Na2SO4 and then concentrated to low volume. The raw product obtained (1.24 g) was purified by column chromatography [silica gel 60 (100 g); ethyl acetate/methanol (10:1, 1200 ml), ethyl acetate/methanol (5:1, 600 ml) ethyl acetate/methanol (2:1, 700 ml), ethyl acetate/methanol (1:2, 750 ml), methanol (800 ml)].
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27]O)=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:24]4[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=4)=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1
Reactant: OCc1ccc(F)cc1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c2cc(-n3ccc(OCc4ccc(F)cc4)cc3=O)ccc2nn1C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (500 mg), (4-fluorophenyl)methanol (494 mg) and triphenylphosphine (1.54 g) in tetrahydrofuran (40 ml) was added bis(2-methoxyethyl)azodicarboxylate (1.38 g) at room temperature, and the mixture was stirred at the same temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/methanol) to give the title compound (712 mg).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]1[C:14]2[NH:13][C:12](=[O:15])[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[CH2:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:18][CH2:19][CH3:20]>>[CH2:17]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][CH:34]([NH:1][CH2:2][C@H:3]([OH:16])[CH2:4][O:5][C:6]3[C:14]4[NH:13][C:12](=[O:15])[NH:11][C:10]=4[CH:9]=[CH:8][CH:7]=3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:23])=[O:24])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCNS(=O)(=O)c1ccc(N2CCC(=O)CC2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: CCCCNS(=O)(=O)c1ccc(N2CCC(NC[C@H](O)COc3cccc4[nH]c(=O)[nH]c34)CC2)cc1

Procedure:
The title compound was prepared from 4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one and Reference Example 11, N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to the procedure of Example 1 as an off-white solid; mp 69-75° C.; 1H NMR (300 MHz, DMSO-d6) δ 0.79 (t, 3H), 1.10-1.40 (m, 6H), 1.75-1.90 (m, 2H), 2.67 (t, 2H), 2.10-3.00 (m, 5H), 3.70-4.10 (m, 5H), 6.55 (d, 3H), 6.62 (d, 1H), 6.83 (t, 1H), 7.00 (d, 2H), 7.52 (d, 2H), 10.45-10.80 (m, 2H); MS (ES) m/z: 518.1 (MH+); HRMS Calcd. for C25H36N5O5S (MH+): 518.2437. Found: 518.2446.
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[NH2:19][C:20]1[CH:32]=[CH:31][C:23]2[O:24][C:25]([CH3:30])([CH3:29])[O:26][C:27](=[O:28])[C:22]=2[CH:21]=1>>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:19][C:20]2[CH:32]=[CH:31][C:23]3[O:24][C:25]([CH3:29])([CH3:30])[O:26][C:27](=[O:28])[C:22]=3[CH:21]=2)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Reactant: CC1(C)OC(=O)c2cc(N)ccc2O1
Product: CCCCCCCCC#Cc1ccc(CNc2ccc3c(c2)C(=O)OC(C)(C)O3)cc1

Procedure:
The title compound was prepared following the procedure A using 4-dec-1-ynylbenzaldehyde and 6-amino-2,2-dimethyl-4H-1,3-benzodioxin-4-one (purification by flash chromatography on SiO2, EtOAc/c-Hex 10/90 up to 40/60 in 45 min.) as a colorless oil (55%). HPLC, Rt: 5.9 min (purity: 99.4%). 1H NMR (CDCl3) δ 7.29 (d, J=8.3 Hz, 2H), 7.19 (d, J=8.3 Hz, 2H), 7.09 (d, J=2.6 Hz, 1H), 6.79-6.67 (m, 2H), 4.21 (s, 2H), 4.18 (brs, 1H), 2.31 (t, J=7.2 Hz, 2H), 1.62 (s, 6H), 1.57-1.45 (m, 2H), 1.43-1.31 (m, 3H), 1.30-1.12 (m, 7H), 0.80 (t, J=7.2 Hz, 3H)