Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CN1CC[C:7]2([CH2:18][C:17]3[C:12](=[N:13][CH:14]=[C:15](/[CH:19]=[CH:20]/[C:21]([O:23]CC)=[O:22])[CH:16]=3)[NH:11][C:10]2=[O:26])CC1.[Cl:27]CCl>C(O)C>[ClH:27].[O:26]=[C:10]1[NH:11][C:12]2[N:13]=[CH:14][C:15](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])=[CH:16][C:17]=2[CH2:18][CH2:7]1
Reactant: CCOC(=O)/C=C/c1cnc2c(c1)CC1(CCN(C)CC1)C(=O)N2
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cl
Product: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Temperature: 45 °C
Reaction time: 8 h

Procedure:
An aqueous solution of sodium hydroxide (1N, 7.83 mL) was added to a solution of (E)-ethyl 3-(1′-methyl-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-6-yl)acrylate (860 mg, 2.61 mmol) in a mixture of dichloromethane (10 mL) and ethanol (10 mL) at room temperature. The reaction mixture was stirred at 45° C. overnight then concentrated to dryness. The residue was acidified by addition of an aqueous solution of hydrochloric acid (1N, 30 mL) until pH 1. The resulting solid was filtered and washed with water and diethyl ether. The title product was obtained as a white solid (586 mg, 66%).
Reaction SMILES: [CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]([NH2:21])=[N:18][CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:6][CH2:7][CH2:8]1)[CH2:4][CH2:3][CH2:2]2.C([O:26][C:27](=O)[C:28]#[C:29][CH2:30][CH:31]([CH3:33])[CH3:32])C>C(O)C>[CH:1]12[CH:9]([C:10]3[CH:23]=[CH:22][C:13]([O:14][CH2:15][C@H:16]4[O:20][C:19]5=[N:21][C:27](=[O:26])[CH:28]=[C:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[N:18]5[CH2:17]4)=[CH:12][CH:11]=3)[CH:5]([CH2:4][CH2:3][CH2:2]1)[CH2:6][CH2:7][CH2:8]2
Reactant: CCOC(=O)C#CCC(C)C
Reactant: NC1=NC[C@@H](COc2ccc(C3C4CCCC3CCC4)cc2)O1
Solvent: CCO
Product: CC(C)Cc1cc(=O)nc2n1C[C@@H](COc1ccc(C3C4CCCC3CCC4)cc1)O2
Temperature: 160 °C
Yield: 35.1 %

Procedure:
To a solution of (S)-5-(4-bicyclo[3.3.1]non-9-yl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.600 g, 1.91 mmol) in ethanol (5 mL) was added 0.294 g (2.86 mmol) of 5-methyl-hex-2-ynoic acid ethyl ester. The reaction mixture was heated in a microwave oven at 160° C. for 20 minutes. The reaction mixture was concentrated and purified by chromatography on silica gel eluting with MeOH/CH2Cl2 to afford 0.283 g of the title compound. [α]D25 −11.17 (c 0.537, CHCl3).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([NH2:11])[CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[S:13]>ClCCl.CCCCCC.C(OCC)(=O)C>[CH2:7]([CH:8]1[CH2:9][NH:10][C:12](=[S:13])[NH:11]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NCC(N)Cc1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: S=C1NCC(Cc2ccccc2)N1
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A solution of 3 (9.75 g, 0.65 mol) in dichloromethane (75 mL) under argon was treated with a solution of 1,1′-thiocarbonyldiimidazole in dichloromethane (12.16 g, 0.068 mol) added over 45 min. The reaction was stirred for 15 min after the addition was complete and HPLC analysis indicated complete reaction. The reaction mixture was diluted with dichloromethane (200 mL) and washed with water (3×100 mL) and brine (100 mL). The organic solution was filtered through 1PS filter paper and evaporated under reduced pressure to give a yellow solid. The solid was suspended in 100 mL of 10% hexane-ethyl acetate and filtered. The filter cake was washed with 50 mL of 10% hexane-ethyl acetate and air dried to give 11.2 g (90% yield) of 4. HPLC analysis indicated 99% purity. NMR (CDCl3:d6-DMSO) δ 7.8 (S br, 2H), 7.4 (S, 5H), 4.0–4.7 (m, 1H), 3.3–3.9 (m, 2H), 2.7–3.2 (m, 2H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH:6]([CH3:11])[CH2:5]1)(=[O:3])[CH3:2].[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C@H:7]1[CH2:8][CH2:9][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][C@H:6]1[CH3:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)N1CCC(=O)C(C)C1
Product: CC(=O)N1CC[C@H](NCc2ccccc2)[C@H](C)C1

Procedure:
Racemic cis 1-(4-benzylamino-3-methyl-piperidin-1-yl)-ethanone was prepared in the same manner from racemic 1-acetyl-3-methyl-piperidin-4-one. In this instance, benzylamine was used instead of (R)-1-phenylethylamine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[F:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([O:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][O:27][CH2:26]2)[CH:18]=1>>[CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:21][C:20]3[CH:22]=[CH:23][C:17]([F:16])=[CH:18][C:19]=3[O:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][O:27][CH2:26]3)[C:7]=2[C:6]=1[CH3:15])=[O:4]
Reactant: Nc1ccc(F)cc1O[C@@H]1CCCOC1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3O[C@@H]3CCCOC3)c2c1C

Procedure:
Prepared analogously to example 87.1 from 4-chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester and (R)-4-fluoro-2-(tetrahydro-2H-pyran-3-yloxy)aniline (Intermediate XIV).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([C:23]1[C:24](C)=[C:25](C)[C:26]2[C:30]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)=[C:29](O[SiH3])[O:28][C:27]=2[CH:39]=1)(C)(C)C.C1C[O:45]CC1>>[N:33]1[CH:34]=[CH:35][CH:36]=[C:31]([C:30]2[C:26]3[CH:25]=[CH:24][C:23]([OH:45])=[CH:39][C:27]=3[O:28][CH:29]=2)[CH:32]=1
Reactant: C1CCOC1
Reactant: Cc1c(C(C)(C)C)cc2oc(O[SiH3])c(-c3cccnc3)c2c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Oc1ccc2c(-c3cccnc3)coc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
1M tetrabutylammonium fluoride solution in THF (16 ml, 16.00 mmol) was added to a THF (150 ml) solution of 3-(6-t-butyldimethyl silyloxybenzo[b]furan-3-yl)pyridine (5.2 g, 15.88 mmol) obtained above, and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting concentrate was charged to short path silica gel column chromatography (chloroform:ethyl acetate=1:1-1:2). A white powder of 3-(3- pyridyl)benzo[b]furan-6-ol (2.7g, 79%) was then obtained by crystallization using ether-hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=2)=[CH:6][C:4]=1[NH2:5].[C:17]([O:21][C:22]([NH:24][C:25]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=S)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(C(C)C)CC)(C)C.[I-].C[N+]1C=CC=CC=1Cl>ClCCl.C(OCC)(=O)C>[C:31]([O:30][C:28]([NH:27][C:25]([NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])=[N:5][C:4]1[CH:6]=[C:7]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]=2)[CH:8]=[CH:9][C:3]=1[O:2][CH3:1])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)NC(=S)NC(=O)OC(C)(C)C
Reactant: COc1ccc(-c2cc(C)ccn2)cc1N
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(C)ccn2)cc1N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
To a suspension of 2-methoxy-5-(4-methylpyridin-2-yl)aniline (294 mg), N,N′-bis(tert-butoxycarbonyl)thiourea (455 mg) and diisopropylethylamine (0.55 ml) in dichloromethane (15 ml) was added 1-methyl-2-chloropyridinium iodide (455 mg), and the mixture was stirred for 16 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 70 g, n-hexane:ethyl acetate=3:1) to give N,N′-bis(tert-butoxycarbonyl)-N″-(2-methoxy-5-(4-methylpyridin-2-yl)phenyl)guanidine (334 mg).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:31][C:32]1(C)[O:37]C(=O)[CH2:35][C:34](=O)[O:33]1.N1C=CC=CC=1>C(Cl)Cl>[CH2:34]([O:33][C:32](=[O:37])[CH2:31][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=1)[CH3:35]
Reactant: O=C(O)Cc1ccncc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Cc1ccncc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 19.8 %

Procedure:
A solution of pyridin-4-yl-acetic acid hydrochloride salt (1.73 g 10 mmol) in CH2Cl2 (50 mL) was treated with triethylamine (2.09 mL, 15 mmol), followed by 1,1′-carbonyldiimidazole (2.43 g, 15 mol). After 4 h, the solution was added dropwise to a 0° C. solution of 2,2-dimethyl-[1,3]dioxane-4,6-dione (Meldrum's acid; 1.73 g, 12 mmol) and pyridine (1.63 mL, 20 mmol) in CH2Cl2 (50 mL). The reaction mixture was allowed to warm slowly to rt and was stirred for 18 h. The mixture was washed with H2O (2×), and the organic layer was dried and concentrated. The crude residue was dissolved in EtOH (100 mL) and heated at reflux for 4 h. The mixture was allowed to cool to rt and was concentrated. The residue was purified by chromatography (EtOAc/hexanes) to give the title compound (411 mg, 15%) as a pale yellow oil. MS (ESI): mass calcd. for C11H13NO3, 207.1; m/z found, 208.1 [M+H]+. 1H NMR (CDCl3): 8.57 (dd, J=4.4, 1.6, 2H), 7.16 (dd, J=4.4, 1.6, 2H), 4.20 (q, J=7.2, 2H), 3.88 (s, 2H), 3.51 (s, 2H), 1.28 (t, J=7.2, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.CS(O[CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:18]2[CH2:19][CH2:14][CH2:15][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(OS(C)(=O)=O)C1
Reactant: Sc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC(Sc2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 18.2 %

Procedure:
A mixture of 4-bromobenzenethiol (4.697 g, 24.84 mmol), tert-butyl 3-methylsulfonyloxypiperidine-1-carboxylate (6.939 g, 24.84 mmol) and K2CO3 (6.866 g, 49.68 mmol) in DMF (40 mL) were stirred at ambient temperature for 16 hours. The reaction mixture was cooled to 0° C. and diluted with water. The reaction mixture was extracted with ethylacetate (×2) and the combined organic extracts washed with saturated aqueous sodium thiosulphate solution (×2), water (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion, 330 g eluting with 0 to 50% Et2O/Petroleum Ether, loaded in DCM) to give tert-butyl 3-((4-bromophenyl)thio)piperidine-1-carboxylate as a colourless oil (1.68 g, 18% Yield). H NMR (400.0 MHz, CDCl3) δ 0.97-0.86 (m, 2H), 1.44 (s, 9H), 1.80-1.76 (m, 1H), 2.12-2.08 (m, 1H), 2.92-2.86 (m, 1H), 3.14-3.08 (m, 2H), 3.89 (br d, 1H), 4.05 (br s, 1H), 7.30 (d, 2H) and 7.45-7.43 (m, 2H) ppm;
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:49]=[CH:50][C:51]=1[F:52])[O:31][C:32]1[CH:46]=[CH:45][C:35]2[N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[S:38][C:34]=2[C:33]=1[C:47]#[N:48]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([C:11]2([C:14]#[N:15])[CH2:13][CH2:12]2)=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:27][C:28]1[CH:29]=[C:30]([O:31][C:32]2[CH:46]=[CH:45][C:35]3[N:36]=[C:37]([NH:39][C:40]([CH:42]4[CH2:44][CH2:43]4)=[O:41])[S:38][C:34]=3[C:33]=2[C:47]#[N:48])[CH:49]=[CH:50][C:51]=1[F:52])=[O:6]
Reactant: N#Cc1c(Oc2ccc(F)c(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Reactant: N#CC1(c2cccc(C(=O)O)c2Cl)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1c(Oc2ccc(F)c(NC(=O)c3cccc(C4(C#N)CC4)c3Cl)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a solution of 2-chloro-3-(1-cyanocyclopropyl)benzoic acid (60 mg, 0.272 mmol) in tetrahydrofuran (1.5 mL) were added oxalyl chloride (29 μL, 0.340 mmol) and N,N-dimethylformamide (15 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Amino-4-fluorophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (84 mg, 0.227 mmol) was added to the solution, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (50 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (25 mL) and saturated brine (25 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→480/20), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (92 mg, 59%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[Mg].Cl[P:14]([C:23]1[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=1)[C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=1.[OH:31]O>C1COCC1.II.O>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([P:14](=[O:31])([C:23]2[CH:28]=[C:27]([CH3:29])[CH:26]=[C:25]([CH3:30])[CH:24]=2)[C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: OO
Reactant: Cc1cc(C)cc(P(Cl)c2cc(C)cc(C)c2)c1
Reactant: COc1cc(Br)cc(OC)c1
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(P(=O)(c2cc(C)cc(C)c2)c2cc(C)cc(C)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
1-Bromo-3,5-dimethoxybenzene (20.2 g, 93 mmol) in THF (80 ml) was added to a flask (500 ml) with magnesium (2.4 g, 99 mmol) and I2 (20 mg) in THF (100 ml) at 60° C. The mixture was refluxed for 2 h after the addition was completed. It was cooled to RT. The resulting light brown solution was transferred to another flask (250 ml). It was cooled to −78° C. Chlorobis(3,5-dimethylphenyl)phosphine (27.4 g, 99 mmol) in THF (100 ml) was added dropwise at −78° C. within 1 h. The resulting mixture was stirred at −78° C. for 0.5 h, then was slowly warmed up to RT and stirred at RT for 30 min. To the resulting reactions, H2O (100 ml) was added, then H2O2 (25 ml, 30%) was added dropwise at 0° C. The mixture was stirred for 0.5 h at RT. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 ml×2). The combined organic layer was washed with brine (200 ml×2), NaHSO3 (Saturated, 200 ml×3) and dried over MgSO4. It was filtered and the solvent was removed. The viscous residues were stirred with CH2Cl2/Hexane (20 ml/800 ml) for 1 h. The solid was collected by filtration to give the product as a colorless solid (32.3 g, 88% yield). 1H NMR (300 MHz, CD2Cl2) δ: 7.29 (br, 2H), 7.24 (br, 2H), 7.20 (br, 2H), 6.79-6.77 (m, 1H), 6.75-6.73 (m, 1H), 6.63-6.60 (m, 1H), 3.78 (s, 6H), 2.34 (s, 12H). 31P NMR (121.5 MHz, CD2Cl2) δ: 29.4.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:12]1(Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrC1CCCCCC1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\OC1CCCCCC1)C(C)=O
Yield: 80 %

Procedure:
Ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (5.Og) was treated with cycloheptyl bromide as described in Example 13a to give the title compound as a colourless liquid (6.36 g, 80%). (Found: M+ +H, 256.1547, C13H21NO4 requires M+H 256.1550), νmax (film) 2940, 1750, 1690 cm-1 ; δH (CDCl3): 1.31 (3H, t) 1.4-2.0 (12H, m), 2.35 (3H, s) 4.32 (3H, q+m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]1[O:27][CH2:26]1)[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:39]([NH2:42])([CH3:41])[CH3:40]>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:28]=[CH:29][C:30]=1[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:24][CH:25]([OH:27])[CH2:26][NH:42][CH:39]([CH3:41])[CH3:40])[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2cc(OCC3CO3)ccc12
Solvent: CO
Product: CC(C)NCC(O)COc1ccc2c(=O)cc(-c3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)oc2c1

Procedure:
3′,4′-Dibenzyloxy-7-(2,3-epoxy-propoxy)-flavone, 29 (2.5 g, 4.9 mmol) and iso-propyl amine (1.8 mL, 14.7 mmol) in dry methanol (160 mL) were reacted in a similar manner to that described under 34 to afford 38. Yield 2.4 g (87%); mp 177-179° C.; MS (FAB) 566 (M++1); IR (KBr) 3423, 1635; 1H NMR (200 MHz, CDCl3) δ 8.02 (d, J=8.5 Hz, 1H), 7.70-7.32 (m, 12H), 7.11-6.98 (m, 3H), 6.64 (s, 1H), 5.24 (s, 2H), 5.23 (s, 2H), 4.14-4.09 (m, 3H), 3.05 (s, 2H), 2.92-2.68 (m, 3H), 1.09 (d, J=6.2 Hz, 6H). Analysis Calcd for C35H35NO6: C, 74.32; H, 6.24; N, 2.48. Found: C, 74.46; H, 6.19; N, 2.36.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7]2)([O-:3])=[O:2].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:18]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)[CH:7]=[C:8]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2n1C(=O)c1ccccc1
Reaction time: 16 h
Yield: 85.3 %

Procedure:
Ethyl 5-nitroindole-2-carboxylate (3.1) (1.5 g, 6.41 mmol) in CH2Cl2 (30 ml) was treated with benzoyl chloride (1.19 ml, 10.26 mmol), Et3N (891 μl, 6.41 mmol) and DMAP (783 mg, 6.41 mmol). The mixture was stirred for 16 h. 10% NaHCO3 (10 ml) and CH2Cl2 (10 ml) were added and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (3×5 mL). The combined organic layers were washed with H2O (10 ml), 5% HCl (10 ml) and H2O (10 ml). The solution was dried (MgSO4) and concentrated. The 10 residue was crystalised from EtOAc/Hex 1:9 to afford 1.85 g (87%) of 3.2 as a yellow powder: 1H NMR (250 MHz, CDCl3) δ ppm 8.66 (d, 1H), 8.25 (d, 1H), 7.80 (d,1H), 7.6-7.72 (m, 3H), 7.48 (m, 3H), 4.00 (q, 2H), 1.10 (t, 3H). FABMS (NBA/NaI) m/z 339 (M+H+ expected 339)
Reaction SMILES: Cl.[CH3:2][NH2:3].[C:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1)(=[O:6])[CH3:5]>N1C=CC=CC=1.C(Cl)Cl>[CH3:2][NH:3][S:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:4](=[O:6])[CH3:5])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(NC(C)=O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of methylamine hydrochloride (1.4 g) in pyridine (5 ml) was added 4-acetamidobenzenesulfonyl chloride (2.3 g), and the mixture was stirred at 50° C. for 2 hours. The residue obtained by an evaporation of pyridine under a reduced pressure was dissolved in methylene chloride (50 ml), washed with water, 1 N hydrochloric acid, and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Evaporation of the solvent under a reduced pressure gave N-methyl-4-(acetamido)benzenesulfonamide (1.6 g).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=1.[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH:12]1([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([O:4][CH3:3])[CH:6]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCCCC1
Reactant: COc1cccc(N)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cccc(NC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Under ice cooling, 45 ml of acetic acid was added dropwise over 1 hour to 300 ml of a dichloroethane suspension of 8 g of sodium borohydride. To said mixture were added slowly a solution of 17.48 g of m-anisidine and 16 ml of cyclohexanone in 50 ml of dichloroethane, and the mixture was stirred at room temperature for 40 minutes. The reaction mixture was poured into an aqueous saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed, dried and then purified by silica gel column chromatography [ethyl acetate-hexane (1:5)] to afford 29.37 g of cyclohexyl-(3-methoxyphenyl)-amine as an oil. IR (Neat) (cm-1): 3400, 2920, 2850, 1615, 1510, 1500, 1450, MS (m/z): 205 (M+), 162.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C@H:3]([N:29]1[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30]1)[C:4]1[CH:5]=[N:6][C:7]([NH:10]/[N:11]=[CH:12]/[C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([CH3:28])[C:17]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][CH:19]=3)[N:14]=2)=[CH:8][CH:9]=1.C(O)(=O)C.C(O)(=O)C.I(C1C=CC=CC=1)=O>C(Cl)Cl>[F:43][C:2]([F:42])([F:1])[C@H:3]([N:29]1[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:38])[CH3:39])[CH2:30]1)[C:4]1[CH:9]=[CH:8][C:7]2[N:6]([C:12]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[C:16]([CH3:28])[C:17]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:18][CH:19]=4)[N:14]=3)=[N:11][N:10]=2)[CH:5]=1
Reactant: COCCOc1ccc2ccc(/C=N/Nc3ccc([C@@H](N4CC[C@H](NC(=O)OC(C)(C)C)C4)C(F)(F)F)cn3)nc2c1C
Agent: O=Ic1ccccc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCCOc1ccc2ccc(-c3nnc4ccc([C@@H](N5CC[C@H](NC(=O)OC(C)(C)C)C5)C(F)(F)F)cn34)nc2c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
To tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(6-((E)-2-((7-(2-methoxyethoxy)-8-methylquinolin-2-yl)methylene)hydrazinyl)pyridin-3-yl)ethyl)pyrrolidin-3-ylcarbamate (157 mg, 0.261 mmol) in DCM (5 mL) was added iodosobenzene diacetate (101 mg, 0.313 mmol) and the reaction was stirred at ambient temperature for 2 hours. After concentration, the residue was purified by reverse phase chromatography (SP4, 12M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield tert-butyl (S)-1-((R)-2,2,2-trifluoro-1-(3-(7-(2-methoxyethoxy)-8-methylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)ethyl)pyrrolidin-3-ylcarbamate (93 mg, 59.4% yield) as a beige solid
Reaction SMILES: [F:1][C:2]([F:16])([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][NH2:27])[CH:22]=[CH:23][CH:24]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:25][CH2:26][NH:27][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:2]([F:1])([F:16])[C:3]([F:4])([F:5])[F:6])=[CH:15][CH:14]=2)[CH:22]=[CH:23][CH:24]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=C(O)c1ccc(C(F)(F)C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1cccc(CCNC(=O)c2ccc(C(F)(F)C(F)(F)F)cc2)c1
Yield: 96.1 %

Procedure:
A solution of 4-pentafluoroethyl-benzoic acid (500 mg, 2.08 mmol), 2-(3-methoxyphenyl)-ethylamine (361 mg, 2.29 mmol), 4-methylmorpholine (632 mg, 6.24 mmol), and HBTU (1.19 g, 3.12 mmol) in DMF (38 mL) was stirred at RT for 16 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (746 mg, 96%). Light yellow solid, MS (ISP) 374.2 (M+H)+.