Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:31])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[OH:22])[N:12]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[OH:30])[N:10]=1.[CH2:32]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:33]1[O:35][CH2:34]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1(C)C=C(C)C=C(C)C=1.C(OCC)(=O)C>[C:1]1([CH3:31])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:34][CH:33]([OH:35])[CH2:32][O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:25][C:24]=2[OH:30])[N:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:34][CH:33]([OH:35])[CH2:32][O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:17][C:16]=2[OH:22])[N:14]=1
Reactant: Cc1cc(C)c(-c2nc(-c3ccc(O)cc3O)nc(-c3ccc(O)cc3O)n2)c(C)c1
Reactant: CCCCOCC1CO1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: Cc1cc(C)cc(C)c1
Product: CCCCOCC(O)COc1ccc(-c2nc(-c3ccc(OCC(O)COCCCC)cc3O)nc(-c3c(C)cc(C)cc3C)n2)c(O)c1
Temperature: 140 °C
Reaction time: 21 h
Yield: 104.8 %

Procedure:
A mixture of 20.0 g (0.048 mol) of 2-mesityl-4,6-bis(2,4-dihydroxyphenyl)-1,3,5-triazine (compound 1b), 13.8 g (0.105 mol) of n-butyl glycidyl ether (purity 95%) and 1.8 g (4.8 mmol) of ethyltriphenylphosphonium bromide (purity 97%) in 100 ml of mesitylene (purity 99%) is stirred at 140° C. under nitrogen for 21 hours. Decantation and evaporation of the remaining solvent gives 41.2 g of crude product. This is dissolved in 100 ml of ethyl acetate and filtered through a 10.5 cm layer of silica gel 60 (230-400 mesh) of diameter 7.5 cm, with elution with 3 l of ethyl acetate/hexane (1:1 mixture). The 34.0 g of solid obtained after removal of the solvent are re-dissolved in 25 ml of ethyl acetate. 250 ml of hexane are added to the viscous solution. The mixture is stirred at 0° C. for 2 hours and filtered, and the solid is dried for 24 hours at 80° C. and a pressure of 60 mmHg (8000 Pa), giving 23.0 g of the title product (compound 2) of the formula ##STR105## of m.p. 125°-131° C.
Reaction SMILES: C([N:4]1[C:13]2[C:12]3=[N:14][C:15]([CH3:19])=[C:16]([CH2:17][OH:18])[N:11]3[CH:10]=[CH:9][C:8]=2[C@@H:7]([O:20][CH2:21][CH2:22][OH:23])[C@H:6]([O:24]C(=O)C(C)(C)C)[C@H:5]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>NC(O)C>[OH:18][CH2:17][C:16]1[N:11]2[CH:10]=[CH:9][C:8]3[C@@H:7]([O:20][CH2:21][CH2:22][OH:23])[C@H:6]([OH:24])[C@@H:5]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH:4][C:13]=3[C:12]2=[N:14][C:15]=1[CH3:19]
Reactant: CC(=O)N1c2c(ccn3c(CO)c(C)nc23)[C@@H](OCCO)[C@H](OC(=O)C(C)(C)C)[C@H]1c1ccccc1
Agent: CC(N)O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1nc2c3c(ccn2c1CO)[C@@H](OCCO)[C@H](O)[C@@H](c1ccccc1)N3
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A suspension of 0.17 g (0.30 mmol) (7R,8R,9R)-10-acetyl-3-hydroxymethyl-7-(2-hydroxyethoxy)-2-methyl-9-phenyl-8-pivaloyloxy-7.8.9.10-tetrahydroimidazo[1.2-h][1.7]naphthyridine and 0.30 g (2.10 mmol) potassium carbonate in aminoethanol is stirred at 90° C. for 2 h. The reaction is quenched by adding the mixture directly of silica gel for purification by column chromatography (dichloromethane/methanol: 13/1) to give 0.02 g (0.06 mmol/19%) of the title compound as a armorph solid. 1H-NMR (200 MHz, [D6] DMSO): δ=2.29 (s, 1H), 3.30–3.44 (m, 2H), 3.46–3.65 (m, 2H), 4.01 (q, 1H), 4.47 (t, 2 H), 4.70 (d, 2H), 6.79 (d, 1H), 7.20–7.43 (m, 5H), 7.63 (d, 1H).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O-:7])=[O:6])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.C(OCC)(=O)C>[CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([O:7][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:6])=[O:2]
Reactant: O=Cc1ccccc1C(=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccccc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
2-Formylbenzoate (500 mg, 3.33 mmol) was dissolved in N,N-dimethylformamide (3 mL), potassium carbonate (553 mg, 4.00 mmol) and benzyl bromide (0.396 mL, 3.33 mmol) were added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, and then the organic layer was washed with water (×3) and saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to give the title compound (795 mg; yield, 99%) as a colorless oily substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].CCN(C(C)C)C(C)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:20](=[O:22])[CH3:21])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(N)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(C)=O)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.3 %

Procedure:
To a solution of 3-fluoro-4-methoxyaniline (1.15 g, 8.15 mmol) in dry CH2Cl2 (81 mL) in a 250 mL round-bottomed flask equipped with a magnetic stirrer were added DIEA (5.4 mL, 32.7 mmol), DMAP (221 mg, 1.81 mmol) and acetic anhydride (4.4 mL, 46.5 mmol) and the mixture was stirred overnight at RT. The solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 50:50) gave N-(3-fluoro-4-methoxyphenyl)acetamide SMA 44032 as a brown solid (1.08 g, 72% yield).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[NH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:24]2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=[C:20]([NH2:27])[C:19]=2[N:18]=[C:17]1[CH2:28][O:29][CH2:30][CH3:31]>>[NH2:27][C:20]1[C:19]2[N:18]=[C:17]([CH2:28][O:29][CH2:30][CH3:31])[N:16]([CH2:15][CH2:14][CH2:13][NH:12][C:3](=[O:4])[N:2]([CH3:1])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:24]=2[C:23]([CH3:25])=[C:22]([CH3:26])[N:21]=1
Reactant: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCN
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CCOCc1nc2c(N)nc(C)c(C)c2n1CCCNC(=O)N(C)c1ccccc1

Procedure:
Using the method of Examples 94-105, N-methyl-N-phenylcarbamoyl chloride was reacted with 1-(3-aminopropyl)-2-(ethoxymethyl)-6,7-dimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 411.2513.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CS(C)=O.Br[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=1>C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]([CH2:41][C:42]3[CH:43]=[CH:44][C:45]([C:48]([F:49])([F:50])[F:51])=[CH:46][CH:47]=3)[C:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: CC(C)c1ccc(S(=O)(=O)NC(=O)Cc2ccc3c(c2)OCO3)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CC(C)c1ccc(S(=O)(=O)NC(=O)C(Cc2ccc(C(F)(F)F)cc2)c2ccc3c(c2)OCO3)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 28.5 %

Procedure:
To a suspension of 0.992 g (0.27 mmol) of the product of Example 1 in 0.5 mL of anhydrous THF was added 825 μL (0.82 mmol) of a 1.0M solution of lithium bis(trimethylsilyl)amide in THF at -78° C. under a nitrogen atmosphere. After stirring at -78° C. for 10 minutes, the starting material had not fully dissolved. The reaction mixture was then warmed to 0° C. (ice-water bath) and 300 μL of DMSO was added which resulted in a clear yellow solution, then 0.131 g (0.55 mmol) of α'-bromo-α,α,α-trifluoro-p-xylene was added as a solid. Stirring was maintained for 1 hour, then the reaction mixture was partitioned between EtOAc and water and extracted. The organic layer was washed with saturated brine, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 2.5% MeOH--CHCl3. Evaporation of the product fractions and drying in vacuo afforded 0.040 g (28%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9][C:10]1[N:11]=[C:12]([NH:21][C@H:22]([CH3:25])[CH2:23][OH:24])[C:13]2[S:18][C:17]([O:19]C)=[N:16][C:14]=2[N:15]=1.O.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][S:9][C:10]1[N:11]=[C:12]([NH:21][C@H:22]([CH3:25])[CH2:23][OH:24])[C:13]2[S:18][C:17](=[O:19])[NH:16][C:14]=2[N:15]=1
Reactant: COc1nc2nc(SCc3ccccc3F)nc(N[C@H](C)CO)c2s1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](CO)Nc1nc(SCc2ccccc2F)nc2[nH]c(=O)sc12

Procedure:
The product of example 32 step e) was dissolved in 1,4-dioxane (50 ml), H2O (1 ml) and concentrated HCl solution (0.5 ml) and stirred for 20 h at 40° C. The volatiles were removed under reduced pressure and the crude product purified by preparative HPLC to afford the subtitle compound as a white solid (21 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.O[CH2:11][C:12]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([O:8][CH2:11][C:12]2([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C1(CO)CCC1
Reactant: Cc1cc(O)ncc1Br
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(COc2cc(C)c(Br)cn2)CCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 57.2 %

Procedure:
In tetrahydrofuran (11 mL) were dissolved 5-bromo-4-methylpyridin-2-ol (639 mg), ethyl 1-(hydroxymethyl)cyclobutanecarboxylate (538 mg) and triphenylphosphine (1.07 g), 40% diethyl azodicarboxylate-toluene solution (1.86 mL) was added dropwise to the solution at room temperature, and then, the resulting mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the precipitated solid was removed by filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=100:0 to 90:10) to obtain ethyl 1-{[(5-bromo-4-methylpyridin-2-yl)oxy]methyl}cyclobutanecarboxylate (638 mg).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:8]=1)#[N:2].FC1C=C(F)C=CC=1N.[Cl:28][C:29]([Cl:33])([Cl:32])[S:30]Cl>>[C:1]([C:3]1[C:4](=[O:18])[N:5]([S:30][C:29]([Cl:33])([Cl:32])[Cl:28])[C:6](=[O:17])[N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:8]=1)#[N:2]
Reactant: N#Cc1cn(-c2ccc(F)cc2F)c(=O)[nH]c1=O
Reactant: ClSC(Cl)(Cl)Cl
Agent: Nc1ccc(F)cc1F
Product: N#Cc1cn(-c2ccc(F)cc2F)c(=O)n(SC(Cl)(Cl)Cl)c1=O

Procedure:
In like manner, 5-cyano-1-(2,4-difluorophenyl)uracil is prepared, starting with 2,4-difluoroaniline, and is then reacted with trichloromethanesulphenyl chloride, giving 5-cyano-1-(2,4-difluorophenyl)-3-trichloromethanesulphenyluracil, m.p. 196°-198°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:17]3[CH:18]=[CH:19][C:20]([C:22](O)=[O:23])=[CH:21][C:16]=3[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]2=[O:25])=[CH:5][CH:4]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:17]3[CH:18]=[CH:19][C:20]([C:22]([NH:51][CH2:52][CH2:53][N:54]4[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]4)=[O:23])=[CH:21][C:16]=3[C:15]3[N:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:9]2=[O:25])=[CH:5][CH:4]=1
Reactant: NCCN1CCCCC1
Reactant: COc1ccc(Cn2c(=O)c3cccnc3c3cc(C(=O)O)ccc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)c3cccnc3c3cc(C(=O)NCCN4CCCCC4)ccc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 193.6 %

Procedure:
The compound (30 mg, 0.09 mmol) prepared in Step 1, 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC, 48 mg, 0.25 mmol), and 1-hydroxy-benzotriazole hydrate (HOBt, 34 mg, 0.25 mmol) were dissolved in N,N-dimethylformamide (5 ml) and added with 1-(2-aminoethyl)piperidine (0.033 ml, 0.23 mmol) at room temperature. The resulting mixture was stirred for 18 hours and poured into ice water. After extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then purified by flash column chromatography (chloroform:methanol=7:1) to obtain the title compound (82 mg, yield: 92%, white solid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[CH:10]=[C:4]2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[CH:26]=[O:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[C:10]([CH:26]=[O:27])=[C:4]2[CH:3]=1
Reactant: COc1ccc(-c2cc3cc(Cl)ccn3n2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nn3ccc(Cl)cc3c2C=O)cc1

Procedure:
5-Chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine (1.0 g, 3.86 mmol) was treated with N,N-dimethylformamide (20 mL) and phosphorous oxychloride (0.54 mL, 7.8 mmol) as described in Example 12 to give 5-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde as a white crystalline solid, (0.9 g, 81%). 1H NMR (CDCl3): δ 10.12 (s, 1H), 8.52 (d, 1H), 8.47 (d, 1H), 7.76 (d, 2H), 7.11-7.06 (m, 3H), 3.93 (s, 3H); MS m/z 287 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C@H:4]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH2:13][OH:14])=[CH:7][CH:6]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:23])[C@H:4]([NH:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][CH2:13][O:14][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:9][CH:10]=1
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.6 %

Procedure:
To a stirred solution of (R)-tert-butoxycarbonylamino-[4-(2-hydroxy-ethoxy)-phenyl]-acetic acid methyl ester (80 mg, 0.25 mmol) in pyridine (1.5 mL) was added methanesulfonyl chloride (0.023 mL, 0.30 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. The solvent was evaporated and the crude product was purified by chromatography over silica gel eluted with 3:1 v/v hexanes/ethyl acetate to give (R)-tert-butoxycarbonylamino-[4-(2-methanesulfonyloxy-ethoxy)-phenyl]-acetic acid methyl ester (50 mg, 50% yield) as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([CH:16]=1)[C@@H:8]1[O:14][C@H:11]([CH2:12][OH:13])[C@@H:10]([F:15])[CH2:9]1)#[CH:2].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[C:19]([O:13][CH2:12][C@H:11]1[O:14][C@@H:8]([N:7]2[CH:16]=[C:3]([C:1]#[CH:2])[C:4](=[O:18])[NH:5][C:6]2=[O:17])[CH2:9][C@@H:10]1[F:15])(=[O:21])[CH3:20]
Reactant: C#Cc1cn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: C#Cc1cn([C@H]2C[C@H](F)[C@@H](COC(C)=O)O2)c(=O)[nH]c1=O
Temperature: 0 °C

Procedure:
To a stirred solution of 2',3'-dideoxy-5-ethynyl-3'-fluorouridine (0.106 g 0.4 mmol) in dry pyridine (5 ml) at 0° C. was added acetic anhydride (0.05 ml, 0.48 mmol) and stirring maintained at 0° C. for 1.5 hours. After stirring at room temperature for 24 hours, a further aliquot of acetic anhydride (0.02 ml, 0.2 mmol) was added and the mixture stirred at room temperature for 3 hours. After quenching with methanol (1 ml) the solvent was removed by evaporation under reduced pressure and co-evaporated with portions of ethanol (2×30 ml). The residue was recrystallised from ethanol to give a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1>O1CCCC1.[Ni].O>[F:11][C:4]1[CH:5]=[C:6]([CH:7]=[C:2]([F:1])[C:3]=1[N:12]1[CH2:17][CH2:16][S:15][CH2:14][CH2:13]1)[NH2:8]
Reactant: O=[N+]([O-])c1cc(F)c(N2CCSCC2)c(F)c1
Agent: [Ni]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(F)c(N2CCSCC2)c(F)c1
Reaction time: 24 h

Procedure:
A solution of 4-(2,6-difluoro-4-nitrophenyl)thiomorpholine (3.00 g, 11.5 mmol) in tetrahydrofuran (60 mL) is added to a Parr bottle containing a mixture of Raney nickel (1 g) in water (15 mL) under N2, and the reaction mixture is shaken on a Parr apparatus under a hydrogen atmosphere at 40 psi for 24 hrs. The catalyst is removed by filtration through Celite, rinsing with tetrahydrofuran and water, the filtrate is diluted with water (50 mL) and EtOAc (50 mL), and the layers are separated. The organic phase is washed with saline (25 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting oil is chromatogtaphed on a Flash 40M 90 g silica gel cartridge eluting with EtOAc/heptane (15/85). Pooling and concentration of those fractions with an Rf=0.19 by TLC (EtOAc/hexanes, 25/75) gives the title compound, mp 85-86° C.; MS (ESI+) for C10H12N2F2S m/z 231 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[N+:7]([O-])[CH:8]=1)[CH3:2].C(N(CC)CC)C.C(Cl)[Cl:19]>CCOC(C)=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:10][Cl:19])=[N:7][CH:8]=1)[CH3:2]
Reactant: ClCCl
Reactant: CCc1ccc(C)[n+]([O-])c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCc1ccc(CCl)nc1
Temperature: 20 °C

Procedure:
To a solution of 5-ethyl-2-methyl-pyridine-1-oxide (427 mg, 3.11 mmol, example 45c) in CH2Cl2 (2 mL) is added a solution (0.2 mL) of phosphorous (v) trichloride oxide (327 μL) in CH2Cl2 (2 mL). Added simultaneously the remaining phosphorous (v) trichloride oxide solution and a solution of triethylamine (488 μL) in CH2Cl2 (2 mL) at such a rate as to maintain a reflux. After the addition is complete, let reaction mixture cool to 20° C. and diluted with EtOAc. The organic layer is washed with sat. NaHCO3 soln., brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 10% ethyl acetate in dichloromethane) to provide the title compound. MS (ESI) 156 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[CH2:7][C:8]1[C:13]([Cl:14])=[CH:12][N+:11]([O-:15])=[CH:10][C:9]=1[Cl:16])=[O:4].BrCC(O[C@H](C1C=CC(OC(F)F)=C(OCC2CC2)C=1)CC1C(Cl)=CN=CC=1Cl)=O.C([O-])([O-])=O.[K+].[K+].[CH3:68][S:69]([NH:72][C:73]1[CH:82]=[CH:81][CH:80]=[CH:79][C:74]=1[C:75]([O:77][CH3:78])=[O:76])(=[O:71])=[O:70]>CN(C=O)C.O>[Cl:16][C:9]1[CH:10]=[N+:11]([O-:15])[CH:12]=[C:13]([Cl:14])[C:8]=1[CH2:7][C@@H:6]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[C:19]([O:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)[CH:18]=1)[O:5][C:3](=[O:4])[CH2:2][N:72]([C:73]1[CH:82]=[CH:81][CH:80]=[CH:79][C:74]=1[C:75]([O:77][CH3:78])=[O:76])[S:69]([CH3:68])(=[O:71])=[O:70]
Reactant: O=C(CBr)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COC(=O)c1ccccc1NS(C)(=O)=O
Agent: O=C(CBr)O[C@@H](Cc1c(Cl)cncc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccccc1N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
The mixture obtained in step 2, containing (S)-4-(2-(2-bromoacetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine (100 mg) was dissolved in DMF (2 ml), and K2CO3 (30 mg, 0.22 mmol) and methyl 2-(methylsulfonamido)benzoate (82 mg, 0.36 mmol) were added. The mixture was stirred at RT for 5 hours. The reaction was diluted with water, and the product was extracted with EtOAc. The organic layer was washed with water, dried over Na2SO4 and evaporated under vacuum. The crude product was purified by preparative reverse-phase HPLC to give 105 mg of the desired product (Yield: 85%, MS/ESI+ 689.5 [MH]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([C:25]([F:28])([F:27])[F:26])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([F:29])[CH:3]=1.[S:30]1(=[O:36])(=[O:35])[CH2:34][CH2:33][CH2:32][NH:31]1>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:31]5[CH2:32][CH2:33][CH2:34][S:30]5(=[O:36])=[O:35])=[CH:3][C:4]=4[F:29])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:24][CH2:23]1
Reactant: O=S1(=O)CCCN1
Reactant: O=C(c1ccc(Br)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Product: O=C(c1ccc(N2CCCS2(=O)=O)cc1F)N1CCN(c2ncc(C(F)(F)F)cc2C2CC2)CC1
Yield: 51.5 %

Procedure:
Using (4-bromo-2-fluorophenyl)[4-(3-cyclopropyl-5-trifluoromethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 123 and isothiazolidine 1,1-dioxide (96 mg) and by the reaction and treatment in the same manner as in Example 4, the title compound (209 mg) was obtained.
Reaction SMILES: [N+:1]([C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[CH:7]=[CH:6][C:5]=1[C:20]([OH:22])=[O:21])([O-])=O.Cl.[NH2:24]O.[OH-].[Na+].Cl>O.C(O)C>[NH2:1][C:4]1[C:17]2[C:16](=[O:18])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:19])[C:8]=2[C:7]([NH2:24])=[CH:6][C:5]=1[C:20]([OH:22])=[O:21]
Reactant: NO
Reactant: O=C1c2ccccc2C(=O)c2c1ccc(C(=O)O)c2[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(C(=O)O)c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C

Procedure:
10 parts of 1-nitroanthraquinone-2-carboxylic acid and 10 parts of hydroxylamine hydrochloride are suspended at room temperature in 60 parts of ethanol and 100 parts of 4 N sodium hydroxide. The mixture is refluxed for 3 hours, then cooled to room temperature, diluted with water and acidified with hydrochloric acid. The mixture is filtered and the filter cake is washed neutral with water and dried, affording 7.5 parts of 1,4-diaminoanthraquinone-2-carboxylic acid. Recrystallisation from alcohol yields an analytically pure sample with a melting point of about 352° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12](Cl)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2].[NH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=1>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([O:27][CH3:28])[CH:21]=3)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccnc(Cl)n2)cc1
Reactant: COc1cc(CCN)ccc1O
Product: CCOc1ccc(-c2ccnc(NCCc3ccc(O)c(OC)c3)n2)cc1

Procedure:
Intermediate 47 was coupled with 4-(2-Amino-ethyl)-2-methoxy-phenol following procedure F. LC-MS showed the product had the expected M+H+ of 366. 1H NMR (Varian 300 MHz, DMSO-d6, shifts relative to the solvent peak at 2.49 ppm) δ 8.0 (d, 1H), 7.1-7.0 (m, 4H) 6.8 (s, 1H), δ 6.7-6.6 (m, 3H), δ 4.0 (q, 2H), δ 3.7 (s, 3H), 3.5 (t, 2H), δ 2.7 (t, 2H), 1.3 (t, 3H).