Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:18]([O:24][C:25](=[O:27])[CH3:26])[C@@H:17]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[O:16][C@@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=1)(=[O:3])[CH3:2].CC(C)=[O:35]>[N+]([O-])([O-])=O.[Ag+]>[C:1]([O:4][C@@H:5]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:18]([O:24][C:25](=[O:27])[CH3:26])[C@@H:17]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[O:16][C@@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:35])=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(=O)OC[C@H]1O[C@H](Oc2ccc(CBr)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: CC(=O)OC[C@H]1O[C@H](Oc2ccc(CO)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A solution of 1.89 g of the compound 2 in 80 ml of acetone is mixed with an equal volume of a 0.1N aqueous solution of silver nitrate. The mixture is stirred at 25° C. for 2 h, the acetone is then evaporated off under reduced pressure, the remaining aqueous phase is extracted with CH2Cl2 and the extract is washed with water and then dried over anhydrous sodium sulfate, filtered and evaporated to dryness under reduced pressure. The dry residue obtained (1.52 g) is then purified by flash chromatography on a column of silica (solvent: hexane/ethyl acetate: 60/40 v/v). The product 4 (0.94 g) is obtained with a yield of 56%.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:23])[CH3:22])[C:12]([CH:24]=[O:25])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].I[C:33]1[CH:34]=[CH:35][C:36]([C:41]([F:44])([F:43])[F:42])=[C:37]([CH:40]=1)[C:38]#[N:39].C([Mg]Cl)(C)C.[Cl-].[Li+].C([Mg]Cl)(C)C>O1CCCC1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][C:15]2[N:14]=[C:13]([CH:21]([CH3:22])[CH3:23])[C:12]([C@@H:24]([OH:25])[C:33]3[CH:34]=[CH:35][C:36]([C:41]([F:42])([F:43])[F:44])=[C:37]([CH:40]=3)[C:38]#[N:39])=[C:11]([C:26]3[CH2:27][CH2:28][O:29][CH2:30][CH:31]=3)[C:10]1=2)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)c1nc2c(c(C3=CCOCC3)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2
Reactant: N#Cc1cc(I)ccc1C(F)(F)F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1nc2c(c(C3=CCOCC3)c1[C@@H](O)c1ccc(C(F)(F)F)c(C#N)c1)[C@@H](O[Si](C)(C)C(C)(C)C)CC(C)(C)C2

Procedure:
Obtained by starting from (S)-5-(tert-butyldimethylsilyloxy)-4-(3,6-dihydro-2H-pyran-4-yl)-2-isopropyl-7,7-dimethyl-5,6,7,8-tetrahydroquinoline-3-carbaldehyde and 5-iodo-2-(trifluoromethyl)benzonitrile. A 1.3 M solution of isopropylmagnesium chloride-lithium chloride-complex in tetrahydrofurane is used instead of a 2 M solution of isopropylmagnesium chloride in tetrahydrofurane.
Reaction SMILES: Br[CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1.[Cl:20][C:21]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C([O-])([O-])=O.[K+].[K+]>CS(C)=O.C(Cl)Cl.O>[Cl:20][C:21]1[CH:28]=[C:27]([CH:26]=[CH:25][C:22]=1[C:23]#[N:24])[O:29][CH2:2][C:3]1[C:17]([F:18])=[CH:16][C:6]([C:7]([NH:9][S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[O:8])=[C:5]([F:19])[CH:4]=1
Reactant: N#Cc1ccc(O)cc1Cl
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(COc2ccc(C#N)c(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(bromomethyl)-N-[(dimethylamino)sulfonyl]-2,5-difluorobenzamide (Preparation 1, 33 mg, 0.092 mmol) in DMSO (1 mL) was added 2-chloro-4-hydroxybenzonitrile (114 mg, 0.092 mmol) and K2CO3 (25 mg, 0.18 mmol). The reaction was stirred at room temperature for 16 hours. The reaction was diluted with DCM (10 mL) and water (20 mL). The organic layer was separated and the aqueous layer extracted with DCM (2×10 mL). The combined organic layers were filtered through a phase separation cartridge and reduced to dryness to give a yellow oil which was purified by reverse phase preparative HPLC to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([OH:20])=O)=[CH:17][C:11]=3[O:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)[O:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[O:20])=[CH:17][C:11]=3[O:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2c(c1)OC(c1cc(Cl)cc(Cl)c1)(c1cc(Cl)cc(Cl)c1)O2
Product: O=C(c1ccc2c(c1)OC(c1cc(Cl)cc(Cl)c1)(c1cc(Cl)cc(Cl)c1)O2)N1CCOCC1

Procedure:
This compound was prepared from 2,2-bis-(3,5-dichloro-phenyl)-benzo[1,3]dioxole-5-carboxylic acid and morpholine according to Example 269f; waxy solid,
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]([O:12]C)=[O:11])[CH3:2].Br[CH2:22][C:23]1[C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[C:27]([O:36]C(OC(C)(C)C)=O)[C:26]([C:44]([F:47])([F:46])[F:45])=[CH:25][CH:24]=1>>[C:32]([O:31][C:29]([C:28]1[C:27]([OH:36])=[C:26]([C:44]([F:46])([F:47])[F:45])[CH:25]=[CH:24][C:23]=1[CH2:22][O:20][C:17]1[CH:16]=[CH:15][C:14]([C:5]2[CH:6]=[CH:7][C:8]([CH2:9][C:10]([OH:12])=[O:11])=[C:3]([CH2:1][CH3:2])[CH:4]=2)=[CH:19][CH:18]=1)=[O:30])([CH3:33])([CH3:35])[CH3:34]
Reactant: CCc1cc(-c2ccc(O)cc2)ccc1CC(=O)OC
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Product: CCc1cc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)ccc1CC(=O)O
Yield: 46 %

Procedure:
According to a method similar to Example (40-2), Example (33-5) and Example (17-4), from methyl (3-ethyl-4′-hydroxy-1,1′-biphenyl-4-yl)acetate (122 mg, 0.45 mmol) synthesized in Example (85-4) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (226 mg, 0.50 mmol) obtained in Example (28-5), the title compound was obtained (107 mg, three-step total yield: 46%).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][C:9]([NH:10][C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:16]([OH:18])=O)=[C:4]2[CH:3]=[CH:2]1.C(N(C(C)C)CC)(C)C.[C:28]([N:35]1[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.C(OCC)(=O)C>[C:31]([O:30][C:28]([N:35]1[CH2:39][CH2:38][CH:37]([NH:40][C:16]([C:12]2[S:13][CH:14]=[CH:15][C:11]=2[NH:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[NH:1][CH:2]=[CH:3][C:4]=23)=[O:18])[CH2:36]1)=[O:29])([CH3:34])([CH3:32])[CH3:33]
Reactant: O=C(O)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
To a solution of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (100 mg, 0.39 mmol), diisopropylethylamine (0.1 mL, 0.54 mmol), 1-BOC-3-aminopyrrolidine (143 mg, 0.77 mmol) in dimethylformamide (2 mL) was added HATU (176 mg, 0.463 mmol). The solution stirred at room temperature for 18 h then diluted with ethyl acetate and washed with aqueous 1% lithium chloride. The organic layer was dried, concentrated in vacuo and purified by ISCO Companion to provide 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (161 mg, 95%). LCMS (ESI) 428 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (1H, br. s.) 10.24 (1H, s) 8.20 (1H, d, J=6.83 Hz) 8.02 (1H, d, J=5.47 Hz) 7.81 (1H, d, J=5.47 Hz) 7.47 (1H, d, J=5.47 Hz) 7.31 (1H, dd, J=3.32, 2.54 Hz) 6.80 (1H, d, J=5.47 Hz) 6.44 (1H, dd, J=3.42, 1.85 Hz) 4.35-4.58 (1H, m) 3.47-3.65 (1H, m) 3.33-3.44 (1H, m) 3.26 (1H, t, J=9.08 Hz) 3.09-3.21 (1H, m) 1.99-2.14 (1H, m) 1.81-1.95 (1H, m) 1.39 (9H, s).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[C:19]2[NH:20][CH:21]=[CH:22][C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11]1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:15]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:9])[C:19]3[NH:20][CH:21]=[CH:22][C:18]=3[C:17]=2[CH:16]=1.[CH2:23]([C:25]([O-:27])=[O:26])[CH3:24]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=c1[nH]c2ccccc2c2cc[nH]c12
Agent: CCC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]c2ccc(Br)cc2c2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
434 mg (2.44 mmol) of N-bromosuccinimide is added to 500 mg (1.95 mmol) of 4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate (synthesis 1) dissolved in 10 ml of anhydrous dimethylformamide and the reaction mixture is stirred for 1 h at room temperature. The mixture is then diluted in 10 mL of ethyl acetate, the solid is filtered, rinsed with diethyl ether then recrystallized from acetic acid to give 360 mg (55%) of 8-bromo-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate cocrystallized with one equivalent of acetic acid in the form of a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[N:6]=[C:5]2[C:19](O)=[O:20].Cl.[CH3:23][O:24][C:25]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:26]=1[CH2:27][CH2:28][NH:29][CH2:30]2>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=1)[N:6]=[C:5]2[C:19]([N:29]1[CH2:28][CH2:27][C:26]2[C:31](=[CH:32][CH:33]=[CH:34][C:25]=2[O:24][CH3:23])[CH2:30]1)=[O:20]
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccc(F)cc12
Reactant: COc1cccc2c1CCNC2
Agent: Cl
Product: COc1cccc2c1CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccc(F)cc13)C2
Yield: 13.4 %

Procedure:
Reaction of 6-fluoro-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 98 (13.4% yield). 1H NMR (400 MHz, CDCl3) δ 2.83 and 3.05 (2t, 2H), 3.61 and 4.20 (2t, 2H), 3.85 and 3.89 (2s, 3H), 4.57 and 5.12 (2s, 2H), 6.44-6.93 (m, 2H), 7.10-7.27 (m, 2H), 7.50-7.53 (m, 1H), 7.69-7.76 (m, 2H), 8.18-8.21 (m, 1H), 8.33-8.36 (m, 1H), 8.40-8.45 (m, 1H); MS (ESI) m/z 432 ([M+H]+).
Reaction SMILES: [N+]([O-])(O)=O.OS(O)(=O)=O.F[C:11]1C=CC=C(C)C=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21](C)[C:20]=1[N+:29]([O-:31])=[O:30]>>[F:18][C:19]1[CH:24]=[C:23]([CH3:11])[C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30]
Reactant: Cc1cccc(F)c1
Reactant: Cc1c([N+](=O)[O-])ccc(F)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: Cc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of HNO3 (60 mL) and H2SO4 (80 mL), cooled in an ice bath, was added 1-fluoro-3-methyl-benzene (27.5 g, 25 mmol) at such a rate that the temperature did not rise over 35° C. The mixture was allowed to stir for 30 min at room temperature and poured into ice water (500 mL). The resulting precipitate (a mixture of the desired product and 1-fluoro-3-methyl-2,4-dinitro-benzene, approx. 7:3) was collected via filtration and purified by recrystallization from 50 mL isopropyl ether to give 1-fluoro-5-methyl-2,4-dinitro-benzene as a white solid (18 g, 36
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][C:14]([CH3:17])=[N:15][N:16]=1)[C:8]([C@@H:18]([NH2:20])[CH3:19])=[CH:7]2.CCN(C(C)C)C(C)C.Cl[C:31]1[N:39]=[CH:38][N:37]=[C:36]2[C:32]=1[NH:33][CH:34]=[N:35]2>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][C:14]([CH3:17])=[N:15][N:16]=1)[C:8]([C@@H:18]([NH:20][C:31]1[N:39]=[CH:38][N:37]=[C:36]3[C:32]=1[N:33]=[CH:34][NH:35]3)[CH3:19])=[CH:7]2
Reactant: Clc1ncnc2nc[nH]c12
Reactant: Cc1nnc(-c2nc3c(Cl)cccc3cc2[C@H](C)N)s1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc(-c2nc3c(Cl)cccc3cc2[C@H](C)Nc2ncnc3[nH]cnc23)s1
Temperature: 130 °C

Procedure:
To a stirred solution of (1S)-1-(8-chloro-2-(5-methyl-1,3,4-thiadiazol-2-yl)-quinolin-3-yl)ethanamine (9 mg, 30 μmol) in 1-butanol (1.5 mL) was added huenig's base (6 μl, 35 mol) and 6-chloropurine (5 mg, 30 μmol). The reaction was heated to 130° C. for 16 hours and then cooled to room temperature. The crude reaction mixture was purified by reverse phase HPLC (gradient: 20% water in acetonitrile to 85% water in acetonitrile) to give N—((S)-1-(8-chloro-2-(5-methyl-1,3,4-thiadiazol-2-yl)quinolin-3-yl)ethyl)-9H-purin-6-amine. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.62 (1H, s), 8.05 (1H, s), 7.83-7.89 (2H, m), 7.53-7.57 (1H, m), 2.89 (3H, s), 1.83 (3H, d, J=6.6 Hz). Mass Spectrum (ESI) m/e=423.1 (M+1).
Reaction SMILES: B(F)(F)F.CC[O:7]CC.N[C:11]1[CH:24]=[CH:23][C:22]2[CH:21]3[CH2:25][C:14]([C:27]([O:29][CH3:30])=[O:28])([C:15]4[C:20]3=[CH:19][CH:18]=[C:17]([Cl:26])[CH:16]=4)[C:13]=2[CH:12]=1.N(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].C1C2C(=CC=CC=2)C=CC=1O>C(Cl)Cl.FC(F)(F)C(O)=O.Cl.O>[Cl:26][C:17]1[CH:18]=[CH:19][C:20]2[CH:21]3[CH2:25][C:14]([C:27]([O:29][CH3:30])=[O:28])([C:13]4[C:22]3=[CH:23][CH:24]=[C:11]([OH:7])[CH:12]=4)[C:15]=2[CH:16]=1
Reactant: COC(=O)C12CC(c3ccc(N)cc31)c1ccc(Cl)cc12
Reactant: CCOCC
Agent: CC(C)(C)ON=O
Agent: Cl
Agent: FB(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: COC(=O)C12CC(c3ccc(O)cc31)c1ccc(Cl)cc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.2 %

Procedure:
To boron trifluoride etherate (0.413 mL, 3.36 mmol, 1.5 eq) cooled to -15° C. under nitrogen was added a solution of methyl 2-amino-7-chloro-9,10-dihydro-9,10-methano-9-anthracenecarboxylate (described in example 35c) (670 mg, 2.24 mmol) in methylene chloride (5 mL). This was followed by t-butyl nitrite (0.320 mL, 2.69 mmol, 1.2 eq) resulting in a precipitate and a dark blue-green solution color. After 10 min at -15° C., the reaction was warmed to 0° C. and stirred for additional 20 min The diazonium salt was precipitated by pentane dilution (100 mL). The precipitate was filtered and rinsed with cold diethyl ether to recover 650 mg of the crude salt. The diazonium salt was added to a solution of potassium carbonate (155 mg, 0.5 eq) in trifluoroacetic acid (5 mL) at 0° C. The reaction was brought to reflux for 20 h at which time the alkaline beta-naphthol test for diazonium salt was negative. Water (5 mL) was added to quench the reaction and the trifluoroacetic acid was removed in vacuo. The crude reaction mixture was diluted with 3N HCl (30 mL) and extracted with ethyl acetate (3×25 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (35 mL, eluent; 10% ethyl acetate in hexane) to yield 540 mg (80%) of the title compound as a white solid. TLC analysis (Rf 0.21, 10% ethyl acetate in hexane). MS (CI, CH4) m/z 301 (M+1,100), 303 (42), 329 (M+29,10), 269 (31), 241 (56) b. 2-Chloro-7-hydroxy-9,10-dihydro-9,10-methano-9-anthracene-carboxylic acid
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[N:13]=[C:12]([S:14][CH2:15][S:16]([NH:19][CH:20]2[CH2:22][CH2:21]2)(=[O:18])=[O:17])[C:11]([CH:23]=O)=[C:10]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[CH3:32])[N:9]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.N>ClCCl>[CH:20]1([NH:19][S:16]([C:15]2[S:14][C:12]3[N:13]=[C:8]([NH2:7])[N:9]=[C:10]([C:25]4[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=4[CH3:32])[C:11]=3[CH:23]=2)(=[O:18])=[O:17])[CH2:22][CH2:21]1
Reactant: Cc1ccc(-c2nc(N)nc(SCS(=O)(=O)NC3CC3)c2C=O)c(C)c1
Agent: N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-c2nc(N)nc3sc(S(=O)(=O)NC4CC4)cc23)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Pyridine was added to a suspension of C-[2-Amino-6-(2,4-dimethylphenyl)-5-formyl-pyrimidin-4-ylsulphanyl]-N-cyclopropyl-methane sulphonamide in dichloromethane and the mixture cooled, ice/water. Trifluoroacetic anhydride was added and the mixture stirred for ˜2 hrs and heated under reflux for ˜24 hrs. The resulting dark red solution was allowed to cool and aqueous ammonia (0.880) added and the mixture stirred for ˜30 mins. Dichloromethane was added and the mixture washed with dilute hydrochloric acid, water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a red/orange solid. The crude solid was purified by preparative HPLC.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:11][C:12]([F:42])([F:41])[C:13]([NH:15][C:16]1[N:17]=[C:18]2[CH:23]=[CH:22][C:21]([C:24](=O)[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=3[F:32])=[CH:20][N:19]2[C:34]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:14]>C1COCC1>[F:42][C:12]([F:11])([F:41])[C:13]([NH:15][C:16]1[N:17]=[C:18]2[CH:23]=[CH:22][C:21](/[C:24](/[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=3[F:32])=[CH:12]\[C:13](=[O:14])[NH:15][CH3:16])=[CH:20][N:19]2[C:34]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:14]
Reactant: O=C(c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccccc3)n2c1)c1cccc(F)c1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)/C=C(\c1ccc2nc(NC(=O)C(F)(F)F)c(-c3ccccc3)n2c1)c1cccc(F)c1F
Temperature: -78 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
The diethyl-(N-methylcarbamoylmethyl)phosphonate (217 mg, 1.04 mmol) in 250 mL of dry THF was placed in a flame dried flask under an argon atmosphere. The solution was cooled to −78° C. before the dropwise addition of potasium hexamethyldisilazide (5.13 mL, 2.56 mmol; 0.5 M in toluene). The mixture was stirred for 2 hours at −78° C. A solution of the 2-trifluoroacetamido-3-phenyl-6-(2,3-difluorobenzoyl)-imidazo[1,2-a]pyridine (300 mg, 0.693 mmol) in 100 mL of dry THF was added dropwise. The reaction mixture was stirred at −78° C. for 2 hours and then allowed to warm to RT. The resulting brown solution was stirred at RT for 48 hours (as it is noted a high amount of sovent was required in order to avoid dealing with heterogenous medium once the reagents were mixed). The THF was removed in vacuo and the mixture was diluted in 400 mL of EtOAc and washed with saturated NH4Cl (2×100 mL) and once with brine. After drying over MgSO4, the solvents were removed in vacuo to give a brown solid. The residue was purified by column chromatography (CH3CN:CH2Cl2, 2:1) to give 57.6 mg of product. (22%). 1H NMR, 13C NMR.
Reaction SMILES: [NH2:1][C:2]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3]1.[OH-].[Na+].Cl[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12]>>[CH:14]([O:13][C:11]([NH:1][C:2]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3]1)=[O:12])([CH3:16])[CH3:15]
Reactant: NC1(C(=O)O)CC1
Reactant: CC(C)OC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)OC(=O)NC1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 54 %

Procedure:
0.2 g (1.98 mmol) of 1-aminocyclopropane-1-carboxylic acid were initially charged in 10 ml of 12% strength aqueous sodium hydroxide solution. After addition of 0.24 g (1.98 mmol) of isopropyl chloroformate, the pH was adjusted to 9 by dropwise addition of 12% strength aqueous sodium hydroxide solution. The mixture was stirred at room temperature for 14 hours and then, for work-up, extracted twice with methyl tert-butyl ether. The pH was subsequently adjusted to 1-2 using phosphoric acid. The mixture was extracted three times using dichloromethane, the extracts were dried with magnesium sulfate and the solvent was removed, after which the title compound was isolated as a white solid (0.2 g; 54% yield).
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH2:22][N:20]2[CH2:21][C@@H:5]([CH2:6][C@:7]([C:56]([O:58][CH3:59])=[O:57])([C:23]3[CH:24]=[C:25]4[C@:33]56[C@@H:37]7[C@:38]([CH2:53][CH3:54])([C@@H:42]([O:49][C:50]([CH3:52])=[O:51])[C@:43]([OH:48])([C:44]([O:46][CH3:47])=[O:45])[C@@H:32]5[N:31]([CH3:55])[C:26]4=[CH:27][C:28]=3[O:29][CH3:30])[CH:39]=[CH:40][CH2:41][N:36]7[CH2:35][CH2:34]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][C:12]([I:17])=[CH:11][C:10]=4[C:9]=3[CH2:18][CH2:19]2)[CH:4]=1.Cl.C(C[OH:66])(F)(F)F.[BH4-].[Na+]>O.O.O.O.O.O.O.C([O-])(=O)C([O-])=O.[Fe+3].C([O-])(=O)C([O-])=O.C([O-])(=O)C([O-])=O.[Fe+3].CCOC(C)=O.CO.CCN(CC)CC>[CH3:1][CH2:2][C@@:3]1([OH:66])[CH2:22][N:20]2[CH2:21][C@@H:5]([CH2:6][C@:7]([C:56]([O:58][CH3:59])=[O:57])([C:23]3[CH:24]=[C:25]4[C@:33]56[C@@H:37]7[C@:38]([CH2:53][CH3:54])([C@@H:42]([O:49][C:50]([CH3:52])=[O:51])[C@:43]([OH:48])([C:44]([O:46][CH3:47])=[O:45])[C@@H:32]5[N:31]([CH3:55])[C:26]4=[CH:27][C:28]=3[O:29][CH3:30])[CH:39]=[CH:40][CH2:41][N:36]7[CH2:35][CH2:34]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][C:12]([I:17])=[CH:11][C:10]=4[C:9]=3[CH2:18][CH2:19]2)[CH2:4]1
Reactant: CCC1=C[C@H]2CN(CCc3c([nH]c4ccc(I)cc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Reactant: OCC(F)(F)F
Agent: [Fe+3]
Agent: Cl
Agent: O=C([O-])C(=O)[O-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4ccc(I)cc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
A mixture of iron(III) oxalate hexahydrate (112.4 mg, 0.23 mmol, 10 equiv) in H2O (93 mL) was stirred for 2 hours, cooled to 0° C. and air was bubbled through the mixture for 10 minutes. A solution of 10′-iodoanhydrovinblastine (16a, 21.3 mg, 0.023 mmol, 1 equiv) in H2O (0.5 mL), aqueous 0.1 N HCl (0.5 mL), and CF3CH2OH (0.1 mL) was transferred by pipette to the mixture and NaBH4 (17.6 mg, 0.464 mmol, 20 equiv) in H2O (1 mL) was added to the mixture at 0° C. The resulting mixture was stirred for 30 minutes before being quenched by addition of 28-30% aqueous NH4OH (10 mL). The mixture was extracted with 10% MeOH in CH2Cl2 and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. PTLC (SiO2, Et3N:MeOH:EtOAc=3:3:97) provided 10′-iodovinblastine (16b, 5.8 mg, 0.062 mmol, 27%) as a white solid and 10′-iodoleurosidine (2.3 mg, 0.0025 mmol, 11%). For 16b.
Reaction SMILES: OO.C(OCC)(=O)C.[Br:9][C:10]1[CH2:14][CH:13]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[C:25](=[O:32])[NH:26][CH:27]([CH:29]2[CH2:31][CH2:30]2)[CH3:28])=[O:16])[N:12]([C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][N:34]=2)[N:11]=1>O>[Br:9][C:10]1[CH:14]=[C:13]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[C:25](=[O:32])[NH:26][CH:27]([CH:29]2[CH2:31][CH2:30]2)[CH3:28])=[O:16])[N:12]([C:33]2[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][N:34]=2)[N:11]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1NC(=O)C1CC(Br)=NN1c1ncccc1Cl)C1CC1
Agent: OO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Yield: 60.6 %

Procedure:
1.13 g of a 30% hydrogen peroxide solution was added to an ethyl acetate 12 ml solution comprising 0.53 g of 3-bromo-N-(4-chloro-2-(1-cyclopropylethylcarbamoyl)phenyl)-1-(3-chloropyridin-2-yl)-4,5-dihydro-1H-pyrazole-5-carboxamide, followed by reflux with heating. 30 hours later, the reaction liquid was stood to cool and poured to water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1) to obtain 0.32 g of the desired product.