Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH2:11])[N:3]=1.FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.S(O)(C(F)(F)F)(=O)=O.C(O[C@@H:39]1[O:61][C@H:60]([CH2:62][O:63][C:64](=[O:71])[C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)[C@@H:50]([O:51][C:52](=[O:59])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@H:40]1[O:41][C:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=O)C>CC(OC)(C)C.CC#N>[C:42]([O:41][C@@H:40]1[C@H:50]([O:51][C:52](=[O:59])[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C@@H:60]([CH2:62][O:63][C:64](=[O:71])[C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[O:61][C@H:39]1[N:8]1[C:9]2[N:10]=[C:2]([Cl:1])[N:3]=[C:4]([NH2:11])[C:5]=2[N:6]=[CH:7]1)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CC#N
Solvent: COC(C)(C)C
Product: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 27.5 °C

Procedure:
Under an atmosphere of N2(g), 2-chloroadenine (A (9), 50 g, 294.9 mmol), MeCN (600 mL), and BSTFA (227.5 g, 883.8 mmol) were stirred and heated under reflux until the mixture turned mostly clear (about 1 h). TfOH (8.77 g, 58.5 mmol) and 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (C, 142.5 g, 282.5 mmol) were sequentially added into the mixture and were stirred at reflux for about 1 h. The mixture was cooled to 20-35° C. and diluted with MTBE (500 mL), and washed over a 0.5 to 1 h period with saturated NaHCO3 (750 mL). The organic phase was evaporated in vacuo at 40 to 50° C. to give 2′,3′,5′-tri-O-benzoyl-2-chloroadenosine (D): 1H NMR (300 MHz, CDCl3) δ 7.9-8.1 (m, 6H), 7.94 (s, 1H), 7.3-7.6 (m, 9H), 6.45 (d, J=2.7 Hz 1H), 6.15 (m, 2H), 5.30 (s, 2H), 4.90 (dd, J4′,5a=3.2 Hz, J5′a,5′b=12.0 Hz, 1H), 4.82 (m, 1H), 4.72 (dd, J4′,5a=4.1 Hz, J5′a,5′b=12.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 166.3, 165.5, 165.4, 156.4, 154.7, 151.1, 139.1, 134.1, 134.1, 133.8, 130.2, 130.1, 129.9, 129.4, 129.0, 128.8, 128.5, 119.1, 86.5, 81.3, 74.6, 71.7, 64.0.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Br:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.C1C(=O)N([Br:21])C(=O)C1>>[Br:1][CH:2]([Br:21])[C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([Br:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: BrCc1cc(Br)c2ncccc2c1
Reactant: O=C1CCC(=O)N1Br
Product: Brc1cc(C(Br)Br)cc2cccnc12

Procedure:
A mixture of 6-bromomethyl 8-bromoquinoline (2) and 6-dibromomethyl 8-bromoquinoline (4) (2:4=3:1 mole ratio, with about 30 wt % succinimide) was obtained by bromination of the compound 1 in the presence of NBS and was carried through the sulfonation reaction. The presence of succinimide did not affect the sulfone formation and did simplify the isolation of the bromination product. To a slurry of the above mixture (15.0 g) in 48 mL of 20% water-DMAC was added sodium methane sulfinate (6.6 g, 64.8 mmol) in one portion at room temperature. The resulting solution was aged at room temperature until 2 was consumed (about 2h, by HPLC). Then, the reaction solution was allowed to warm up to 90° C. After 4h aging, the 6-dibromomethyl 8-bromoquinoline (4) was completely converted to product 3 (by HPLC). Then, the reaction solution was allowed to cool to room temperature and ½ saturated NaHCO3/H2O solution (160 mL) was added over 1 h. The slurry was cooled to 0° C. and aged for 1 h before filtration. The wet cake was washed with a solution of 5:1 DMAC:H2O (2×20 mL) and then H2O (2×20 mL). After drying, 3 was obtained.
Reaction SMILES: N[C:2]1[C:3]([CH3:14])=[C:4]2[N:11]=[C:10]([CH2:12][CH3:13])[NH:9][C:5]2=[N:6][C:7]=1[CH3:8].N([O-])=O.[Na+].[ClH:19]>O>[ClH:19].[Cl:19][C:2]1[C:3]([CH3:14])=[C:4]2[N:11]=[C:10]([CH2:12][CH3:13])[NH:9][C:5]2=[N:6][C:7]=1[CH3:8]
Reactant: CCc1nc2c(C)c(N)c(C)nc2[nH]1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1nc2c(C)c(Cl)c(C)nc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
6-Amino-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]-pyridine (0.85 g; preparable as in Example 10(b)) was dissolved with stirring in a mixture of concentrated hydrochloric acid (1.15 ml) and water (1.15 ml) and the resulting solution was cooled to 0° C. A solution of sodium nitrite (0.34 g) in water (1 ml) was added, dropwise, keeping the internal temperature below 5° C. The resulting solution was stirred at this temperature for 10 minutes and then added to a stirred solution of cuprous chloride (0.48 g) in concentrated hydrochloric acid (t.7 ml) keeping the temperature below 10° C. The mixture obtained was stirred at 70° C. for 2 hours and then cooled to ambient temperature. A precipitate was collected and washed with water (5 ml). Recrystallisation of this precipitate from methanol (7.5 ml) gave the intermediate compound 6-chloro-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine hydrochloride (0.21 g; m.p. 284°-287° C. with decomposition). When left for 18 hours the reaction mixture yielded a further quantity of precipitate, which was collected by filtration and recrystallised from methanol to give a second crop (70 mg) of the intermediate compound identified above.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:41]=[CH:40][C:39]([N:42]=[C:43]=[O:44])=[CH:38][CH:37]=1>ClCCl>[CH3:33][O:34][C:35](=[O:45])[C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:43]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:44])=[CH:40][CH:41]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: COC(=O)c1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (0.25 g, 0.67 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (0.168 g, 1.67 mmol) (Aldrich), followed by the addition of 4-isocyanato-benzoic acid methyl ester (0.142 g, 0.80 mmol) (Aldrich). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated. The residue was purified by chromatography to give rac-4-({3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carbonyl}-amino)-benzoic acid methyl ester as a white solid. (Yield 0.3 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:25](#N)C.[H-].[Na+]>IC>[Cl:1][C:2]1[N:24]=[C:5]2[C:6]([N:10]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH3:25])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: CC#N
Reactant: CN(c1ccccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(Cc1ccccc1N(C)S(C)(=O)=O)c1cccn2nc(Cl)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N-{2-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-phenyl}-N-methyl-methanesulfonamide (250.0 mg, 0.6834 mmol) in acetonitrile (1 mL, 20 mmol) at room temperature was added sodium hydride, 60% disp. in mineral oil (33.0 mg, 0.825 mmol) followed by iodomethane (46.80 uL, 0.7517 mmol). The mixture was stirred at room temperature for 2 hours then additional iodomethane (10 uL) was added and the mixture was stirred at room temperature overnight. The mixture was quenched with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to a tan resin. The recovered material was purified via chromatography using an ISCO automated purification apparatus (silica gel column 24 g 20%→80% ethyl acetate:hexane solvent gradient). N-(2-{[(2-Chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-methyl-amino}-methyl]-phenyl)-N-methyl-methanesulfonamide was isolated as tan foam (0.207 g, 80%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.96 (d, J=6.6 Hz, 1H), 7.35-7.27 (m, 4H), 6.89-6.84 (m, 1H), 6.54 (d, J=8.0 Hz, 1H), 5.54-5.40 (br m, 1H), 5.06-4.90 (br m, 1H), 3.32 (s, 3H), 3.24 (s, 3H), 3.01 (s, 3H). MS=380, 382 (MH)+.
Reaction SMILES: O[CH2:2][CH:3]1[N:8]([C:9](=[S:17])[NH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:7][C:6]2[S:18][CH:19]=[CH:20][C:5]=2[CH2:4]1.C>Cl>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:10]=[C:9]2[N:8]3[CH2:7][C:6]4[S:18][CH:19]=[CH:20][C:5]=4[CH2:4][CH:3]3[CH2:2][S:17]2)[CH:12]=1
Reactant: OCC1Cc2ccsc2CN1C(=S)Nc1cccnc1
Agent: Cl
Product: c1cncc(N=C2SCC3Cc4ccsc4CN23)c1
Yield: 55.4 %

Procedure:
A suspension of (RS)-5-hydroxymethyl-6-[(pyrid-3-yl)thiocarbamoyl]-4,5,6,7-tetrahydrothieno[2,3-c]pyridine (2.3 g) in 6 N hydrochloric acid (34 cc) is heated under reflux for 2 hours. The resulting brown solution is decolorised with animal charcoal and filtered. The filtrate is rendered alkaline to pH 11 with a 15% aqueous solution of potassium carbonate and extracted with methylene chloride (150 cc and then 3×100 cc). The organic extracts are combined and dried over sodium sulphate. After filtering and concentrating the filtrate to dryness under reduced pressure (25 mm Hg; 3.3 kPa) at 40° C., an oil is obtained which crystallises slowly. This oil is dissolved in a mixture, heated under reflux, of isopropanol and diisopropyl ether (4:1 by volume; 100 cc). The solution is cooled at +5° C. for 20 hours. The solid is filtered off, washed with diisopropyl ether (50 cc) and dried at 60° C. under reduced pressure (0.1 mm Hg; 0.013 kPa). (RS)-7-[(Pyrid-3-yl)imino]-4,4a,5,9-tetrahydrothiazolo[ 3,4-a]thieno[3,2-d]pyridine (1.2 g) is obtained in the form of white crystals melting at 136° C.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].S(Cl)([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[N:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: [N-]=[N+]=NCc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=NCc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of p-azidomethylbenzoic acid (1.063 g, 6.00 mmol) in CH2Cl2 (60 ml) at room temperature were added dropwise thionyl chloride (1 ml, excess) and DMF (5drops). The mixture was stirred at room temperature for 2.5 h and evaporated, yielding 1.13 g of title compound as a light yellow oil: 1Hmr (CDCl3) δ: 4.48 (2H, s, --CH2N3), 7.38-7.52-8.07-8.22 ppm (4H, A2 'B2 ', aromatic Hs); ir (neat) νmax : 2090(--N3) and 1750 cm-1 (br. --COCl). This material was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:31]#[N:32])=[CH:4][N:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1B(O)O>>[C:31]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:13])=[O:14])[CH:7]=2)[C:2]([C:36]2[CH:37]=[CH:38][C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:35]=2[O:34][CH3:33])=[N:3][CH:4]=1)#[N:32]
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)ncc(C#N)c3c2)cc1
Product: COc1cc(C(F)(F)F)ccc1-c1ncc(C#N)c2cc(S(=O)(=O)Nc3ccncn3)ccc12

Procedure:
The title compound was prepared in an analogous manner to that of Example 228, except that 1-chloro-4-cyano-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide and (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (12 g silica gel column, gradient elution 50 to 100% EtOAc:Heptane) to afford 4-cyano-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=9.30 (s, 1H), 8.68-8.51 (m, 2H), 8.14 (d, J=9.6 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.67-7.60 (m, 1H), 7.59-7.49 (m, 2H), 3.76 (s, 3H). m/z (ESI) 486.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[N:19]([CH3:20])[N:18]=[C:17]([O:21][CH2:22][CH2:23][OH:24])[C:16]=2[C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:34][C:35]1[CH:36]=[N:37][C:38](Cl)=[N:39][CH:40]=1.CC(N(C)C)=O>O1CCCC1.O>[Br:34][C:35]1[CH:36]=[N:37][C:38]([O:24][CH2:23][CH2:22][O:21][C:17]2[C:16]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=3)=[C:15]([NH:14][S:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=3)(=[O:12])=[O:13])[N:19]([CH3:20])[N:18]=2)=[N:39][CH:40]=1
Reactant: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(-c2c(OCCOc3ncc(Br)cn3)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 0.08 h
Yield: 35.5 %

Procedure:
To 4-(tert-butyl)-N-[3-(2-hydroxyethoxy)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-5-yl]benzenesulfonamide (Example 2) (25 mg) in tetrahydrofuran (2 ml) at room temperature under an atmosphere of nitrogen was added sodium hydride (60% dispersion in oil, 4.5 mg) and the mixture was stirred for 5 minutes. To the mixture was added 5-bromo-2-chloropyrimidine (Liquid Crystals, 1993, 14(3), 741) (12 mg) and the reaction was stirred for 30 minutes after which dimethyl acetamide (0.5 ml) was added to give a homogenous mixture. After further stirring for 3 hrs the reaction was diluted with water (20 ml) and extracted with ethyl acetate (20 ml). The organic fraction was dried over magnesium sulfate, filtered concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with dichloromethane:ether (1:1) to yield the title compound as a white solid (12 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:11]=2[N:10]=[C:9]1[Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1N(CC2C=CC(Cl)=CC=2)C2C(=O)N([CH2:47][CH2:48][CH2:49][O:50][CH:51]3[CH2:56][CH2:55][CH2:54][CH2:53][O:52]3)C(=O)N(C)C=2N=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.O>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:47][CH2:48][CH2:49][O:50][CH:51]3[CH2:56][CH2:55][CH2:54][CH2:53][O:52]3)[C:13](=[O:18])[N:12]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:26])[CH3:25])[C:11]=2[N:10]=[C:9]1[Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c1nc(Cl)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Cl)n2Cc1ccccc1
Temperature: 65 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
To a solution of 7-benzyl-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (5 g, 12.32 mmol) in DMF (30 mL) was added 2-(3-bromopropoxy)tetrahydro-2H-pyran (3.60 g, 16.22 mmol, intermediate 14 step 1), followed by potassium carbonate (3.4 g, 24.64 mmol). The mixture was stirred at 65° C. overnight. The mixture was diluted with ethyl acetate and water, and the phases were separated. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give 7-benzyl-8-chloro-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (6.3 g, 93.3% yield) as yellow oil. LCMS retention time 3.574 min; LCMS MNa+ 571.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[NH2:17])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>CN(C)C=O.N1C=CC=CC=1>[Cl:19][CH2:20][CH2:21][C:22]([NH:1][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[NH:17][C:22](=[O:23])[CH2:21][CH2:20][Cl:19])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1)=[O:23]
Reactant: O=C(Cl)CCCl
Reactant: Nc1cccc2c1C(=O)c1c(N)cccc1C2=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(CCCl)Nc1cccc2c1C(=O)c1c(NC(=O)CCCl)cccc1C2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
Dissolve 1,8-diaminoanthraquinone (0.476 g, 2 mmol) in N,N-dimethylformamide (20 ml). Add pyridine (0.5 ml) as catalyst in an ice bath and then add 3-chloropropioyl chloride (0.6 ml, 6 mmol). Remove the ice bath, introduce nitrogen, protect from light, and stir the solution at room temperature for one day. The reacted mixture is poured into ice water and filtered to get precipitate. The precipitate is recrystallized from ethanol to obtain orange compound 4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([CH3:14])[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[Li]CCCC.CN([CH:23]=[O:24])C>C1COCC1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2([CH3:14])[O:13][CH2:12][CH2:11][O:10]2)=[CH:3][C:2]=1[CH:23]=[O:24]
Reactant: CC1(c2ccc(F)c(Br)c2)OCCO1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(c2ccc(F)c(C=O)c2)OCCO1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.3 %

Procedure:
Intermediate 416.1 (1 g, 3.83 mmol) in THF (20 mL) was cooled to −78° C. before adding 1.6 M n-BuLi (2.63 mL, 4.2 mmol) drop-wise. The reaction was stirred for 10 min before quenching with DMF (0.6 mL, 7.7 mmol) and allowing to warm to rt. The crude reaction mixture was quenched with NH4Cl (10 mL), extracted with EtOAc (3×10 mL), washed organic layer with H2O, brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 550 mg of Intermediate 416.2. 1H NMR (400 MHz, CDCl3) δ ppm 1.63 (s, 3H) 3.51-3.92 (m, 2H) 3.90-4.35 (m, 2H) 7.09-7.19 (m, 1H) 7.65-7.79 (m, 1H) 7.99 (dd, J=6.81, 2.42 Hz, 1H) 10.35 (s, 1H).
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[O:31]C)=[C:13]([F:33])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Al+3].[Cl-].[Cl-].[Cl-].CCS>C(Cl)Cl>[F:1][C:2]1[C:14]([NH:15][CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:20]=[C:19]([CH3:30])[C:18]=2[OH:31])=[C:13]([F:33])[CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2OC)c1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2O)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.8 %

Procedure:
To a stirred solution of ethyl 2-[2,4-difluoro-3-[[5-(3-fluorophenyl)-2-methoxy-3-methyl-phenyl]methylamino]phenoxy]acetate (see example 20) (190 mg, 0.414 mmol, 1.0 eq) in DCM (5 mL) at 0° C. under N2 was added AlCl3 (330.8 mg, 2.48 mmol, 6.0 eq) and EtSH (154.2 mg, 2.48 mmol, 6.0 eq). The resulting mixture was stirred for 1.5 h at room temperature then the reaction was quenched by dropwise addition of water. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried (Na2SO4) filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc 1:0 to 10:1 v/v) to give the title compound as an oil (90 mg, 49%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:8][C:9]([N:11]([CH2:13][CH2:14][OH:15])[CH3:12])=[O:10])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:15][CH2:14][CH2:13][N:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH3:12])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)N(C)CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N(C)CCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
1.65 g of methanesulfonyl chloride was added dropwise, with stirring, to a solution of 1.66 g of 2-(N-ethoxycarbonyl-N-methylamino)ethanol and 1.65 g of triethylamine in 20 ml of methylene chloride, whilst ice-cooling, and the solution was then stirred at the same temperature for 30 minutes. At the end of this time, the mixture was poured into ice-water and extracted with methylene chloride. The extracts were combined and washed with water, after which they were dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gave a residue which was purified by column chromatography through silica gel, using a 2:1 by volume mixture of ethyl acetate and hexane as the eluent, to give 2.62 g (yield 81%) of the title compound as an oil.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[CH2:5][C:6](OC)=O.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[C:20](CBr)[CH:19]=1>O1CCCC1>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([F:24])=[C:22]([CH2:6][CH2:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])=[O:3])[CH:23]=1
Reactant: Fc1ccc(Br)cc1CBr
Reactant: COC(=O)CC(=O)c1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccccc1C(=O)CCc1cc(Br)ccc1F
Yield: 67.1 %

Procedure:
Sodium hydride (60% in oil, 2.1 g, 52 mmol) and methyl 3-oxo-3-o-tolylpropanoate (10 g, 52 mmol) were suspended in tetrahydrofuran and 4-bromo-2-(bromomethyl)-1-fluoro-benzene (15.3 g, 57 mmol) was added. After complete conversion, the mixture was quenched with ice and a saturated solution of ammonium chloride and extracted with n-heptane. The combined organic layers were washed once with a saturated solution of ammonium chloride, water and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness. The obtained yellow oil was dissolved in 25 ml of acetic acid, 25 ml of concentrated hydrochloric acid and 20 ml of 1,4-dioxane and heated under reflux for 4 h until LC/MS showed consumption of the starting material. 50 ml of water and 100 ml of tert-butyl methyl ether were added and the product was extracted. The combined organic layers were washed once with saturated solution of ammonium chloride, water and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness. The residue was purified by column chromatography (silica gel, heptane/ethyl acetate gradient) to give 11.2 g of 3-(5-bromo-2-fluoro-phenyl)-1-o-tolyl-propan-1-one as a colorless oil.