Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[F:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[CH:4][C:5]([CH3:12])=[C:6]([NH:8][C:9](=[O:11])[CH3:10])[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1cc(F)ccc1C
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc(F)c([N+](=O)[O-])cc1C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 57.9 %

Procedure:
To a solution of 5.01 g of N-(5-fluoro-2-methyl-phenyl)-acetamide in 30 mL of concentrated sulfuric acid was added dropwise 2.74 g of 70% nitric acid (d=1.42) while keeping the inner temperature at 3° C. After stirring for 40 minutes at this temperature, the reaction solution was poured dropwise into ice water under stirring. After collecting the precipitated powder by filtration, the powder was dissolved in 100 mL of ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate (twice) and saturated brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated. The residue was crystallized from ethanol, to afford 3.68 g of the title compound as yellow needle crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([NH:21][CH2:22][CH2:23][OH:24])[CH:13]=[C:14](Br)[CH:15]=3)[C:10](=[O:25])[C:9]=2[CH:8]=[C:7](Br)[CH:6]=1.CN(C)C=O.[C:32]1([S-:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[Na+]>CO>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[C:12]([NH:21][CH2:22][CH2:23][OH:24])[CH:13]=[C:14]([S:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:15]=3)[C:10](=[O:25])[C:9]=2[CH:8]=[C:7]([S:38][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=1
Reactant: [S-]c1ccccc1
Reactant: O=C1c2cc(Br)cc(NCCO)c2C(=O)c2cc(Br)cc(NCCO)c21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1c2cc(Sc3ccccc3)cc(NCCO)c2C(=O)c2cc(Sc3ccccc3)cc(NCCO)c21
Temperature: 120 °C

Procedure:
24 g of 1,5-bis(2-hydroxyethylamino)-3,7-dibromoanthraquinone are introduced at RT into 100 ml of dimethylformamide (DMF). After the addition of 16.3 g of sodium thiophenolate, the mixture is heated to 120° C. and maintained at that temperature for one hour. After cooling the mixture to RT, 100 ml of methanol are added thereto. The precipitate is filtered off, washed with a methanol/water mixture (1:1) and dried in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]([CH2:15][C@H:16]1[O:21][C@@H:20]([CH2:22]I)[CH2:19][CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:5])[CH3:2].[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K].C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:3][C:4]([N:6]([CH2:15][C@H:16]1[O:21][C@@H:20]([CH2:22][N:28]2[C:27](=[O:29])[C:26]3=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]3[C:24]2=[O:34])[CH2:19][CH2:18][CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N(Cc1ccc(F)cc1)C[C@@H]1CCC[C@H](CI)O1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N(Cc1ccc(F)cc1)C[C@@H]1CCC[C@H](CN2C(=O)c3ccccc3C2=O)O1
Temperature: 100 °C
Reaction time: 10 h
Yield: 202.3 %

Procedure:
To a solution of cis-6-[N-ethoxycarbonyl-N-(p-fluorobenzyl)aminomethyl]-2-iodomethyltetrahydropyrane (2.71 g, 5.10 mmol) in dimethylformamide (30 ml) was added potassium phthalimide (1.04 g, 5.61 mmol) and the mixture was stirred at 100° C. for 10 hours. To the reaction mixture was added ethyl acetate (200 ml), washed successively with purified water (50 ml) and saturated aqueous sodium chloride (50 ml), dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to give crude cis-6-[N-ethoxycarbonyl-N-(p-fluorobenzyl)aminomethyl]-2-phthalimidomethyltetrahydropyrane (4.69 g). This compound was used for the subsequent reaction without purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[CH:27]=[C:26](O)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[Cl-].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:45]>CC#N>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[CH:27]=[C:26]([Cl:45])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cccc2cc(Cc3cc(O)ncn3)ccc12
Agent: [Cl-]
Solvent: CN(C)c1ccccc1
Solvent: CC#N
Product: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cccc2cc(Cc3cc(Cl)ncn3)ccc12
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of 200 mg (0.453 mMol) 6-(6-hydroxy-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide in 15 ml CH3CN, 165.7 mg (1.0 mMol) tetrmethylammonium chloride, 127 μl (1.0 mMol) N,N-dimethylaniline and 0.55 ml (6.0 mMol) POCl3 are added. The mixture is heated up to 75° C. for 1 h, cooled to rt and poured into 30 g ice. After 1 h of vigorous stirring, the title compound can be filtered off and washed with 6 ml CH3CN/H2O 1:2: MS: [M+1]+=460/462; HPLC: tRet=16.5.
Reaction SMILES: C(O)(=O)C.[CH2:5]([N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][O:17][C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:24]2=[O:48])=[CH:20][CH:19]=1)[CH3:6].C(=O)([O-])O.[Na+]>O>[CH2:5]([N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][O:17][C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:48])=[CH:20][CH:19]=1)[CH3:6]
Reactant: CCn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cccnc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
12 ml of a 3:1 by volume mixture of acetic acid and water were added to 300 mg of 5-{4-(3-ethyl-3H-imidazo[4,5-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 29), and the resulting mixture was stirred at 60° C. for 2 hours. At the end of this time, the reaction mixture was neutralized by the addition of sodium hydrogencarbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 85 mg of the title compound, melting at 210-212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.CN(C)CCN(C)C.C([Li])CCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>CCOCC.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([B:24]([OH:29])[OH:25])=[CH:7][C:6]=2[CH:10]=1
Reactant: Clc1ccc2occc2c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1cc2cc(Cl)ccc2o1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8.8 g (57.7 mmol) 5-chlorobenzofuran in 250 ml dry ether were added 7.32 g (63.0 mmol) tetramethylethylenediamine (TMEDA). The solution was kept below −60° C. under argon, while 37.5 ml of a 1.6M solution of butyllithium in hexane was added dropwise. It was warmed to −10° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −60° C. followed by dropwise addition of 35.7 g (190 mmol) triisopropyl borate. After warming to room temperature the mixture was quenched with 70 ml 2N hydrochloric acid and stirred for 1 h. The organic layer was washed three times with 30 ml 2N hydrochloric acid, twice with water, and extracted with 2N sodium hydroxide solution, successively. The alkaline aqueous layer was brought to pH5 and extracted with tert.-butylmethylether. All organic layers were combined, dried over sodium sulfate, and concentrated in vacuo to give the pale yellow crystalline boronic acid which was used for the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[CH:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:4](=[O:25])[NH:3]1.[CH:26](=O)[CH3:27].[BH4-].[Na+]>FC(F)(F)C(O)=O.CN(C)C=O>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[CH:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][CH2:26][CH3:27])(=[O:22])=[O:23])=[CH:17][CH:16]=2)[C:4](=[O:25])[NH:3]1
Reactant: NS(=O)(=O)c1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCNS(=O)(=O)c1ccc(CNC=C2C(=O)NC(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 4-{[(1,3-Dioxo-2,3-dihydro-1H-isoquinolin-4-ylidenemethyl)-amino]-methyl}-benzenesulfonamide (35.7 mg, 0.1 mmol) in Trifluoroacetic acid (250 μL) is added acetaldehyde (16.3 μL, 0.3 mmol) and sodium borohydride (11.4 mg, 0.3 mmol). The reaction mixture is shaken at ambient temperature for 18 hours. The reaction mixture is diluted to 2 mL with N,N-dimethylformamide and purified by C18 reverse phase HPLC.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:9][C:10]1[CH:11]=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=1>CN(C)C=O>[Br:9][C:10]1[CH:11]=[N:12][C:13]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[N:14][CH:15]=1
Reactant: CS(=O)(=O)c1ncc(Br)cn1
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCOc1ncc(Br)cn1
Temperature: 50 °C
Yield: 48.4 %

Procedure:
A solution of N,N-dimethylethanolamine (0.23 ml, 2.3 mmol) in dry dimethylformamide (5 ml) was treated with sodium hydride (60% suspension in mineral oil, 0.092 g, 2.3 mmol) and heated at 50° C. for 30 minutes. The product from Step 2 (0.50 g, 2.1 mmol) was added and the reaction heated at 50° C. overnight. After cooling to room temperature the reaction mixture was applied to a SCX column and washed with methanol then a mixture of 0.880 ammonia/methanol (1:9). The basic fractions were combined and chromatographed on silica gel eluting with 0.880 ammonia/methanol/dichloromethane solution (0.1:1.9:98 and 0.5:4.5:95) to afford the title compound (0.25 g, 48%); 1H NMR (CDCl3) 8.52 (2H, s), 4.45 (2H, t, J 8 Hz), 2.74 (2H, t, J 8 Hz), 2.33 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][O:19][C:8]4[CH:9]=[CH:10][CH:11]=[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][C:17]#[N:18])[C:7]3=4.CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:21]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:20][O:19][C:8]4[CH:9]=[CH:10][CH:11]=[C:12]([C:13]=2[C:14]=1[O:15][CH2:16][CH2:17][NH2:18])[C:7]3=4
Reactant: N#CCOc1c(Cl)ccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Solvent: C1CCOC1
Solvent: CO
Product: NCCOc1c(Cl)ccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Temperature: 82 °C
Yield: 27.9 %

Procedure:
To a mixture of 2-[(8chloro-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile (0.2838 g, 0.757 mmol) in dry THF (10 mL) is added borane-methylsulfide complex (0.22 mL, 2.27 mmol). The mixture is refluxed under an argon atmosphere at 82° C. for 18 h. The mixture is then cooled, to rt and methanol is slowly added until gas evolution ceased. The solvents are removed under vacuum and methanol (5 mL) is added and again removed. The residue is dissolved in methanol (10 mL), CH2Cl2 (5 mL), and conc. HCl (3 mL) and heated at 60° C. for 1 h. The mixture is neutralized with aqueous potassium carbonate and partitioned between water and CH2Cl2. The organic layer is washed with water, dried over magnesium sulfate and concentrated. Column chromatography (50 g silica gel) using CH3OH/CH2Cl2 (4/96) as eluent gave 0.080g (28%) of 2-[(8-chloro-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]-1-ethanamine; mp 127-128° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[C:7]([O:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[C:5]=2[CH:6]=1.C1C(=O)N([Br:34])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:34][CH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:8]=[C:7]([O:16][C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=3)[C:5]=2[CH:6]=1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C)oc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(CBr)oc2c1
Yield: 73 %

Procedure:
To a solution of ethyl 2-methyl-4-(4-(methylsulfonyl)phenoxy)benzofuran-6-carboxylate (252d) (226 mg, 0.604 mmol) and NBS (183 mg, 1.03 mmol) in CHCl3 (10 mL) was added benzoyl peroxide (14.6 mg, 0.0604 mmol). After stirring the mixture at refluxed for 4 hr, the solvent was evaporated. The product was purified by gradient silica gel chromatography with hexanes/EtOAc (100/0 to 70/30) to give the title compound (200 mg, 73%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.39 (t, J=7.16 Hz, 3 H) 3.07 (s, 3 H) 4.39 (q, J=7.16 Hz, 2 H) 4.53 (s, 2 H) 6.62 (s, 1 H) 7.05-7.18 (m, 2 H) 7.62 (d, J=0.75 Hz, 1 H) 7.86-7.98 (m, 2 H) 8.07 (d, J=0.75 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH:7]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C1C=CC=CC=1>[CH2:23]([O:22][C:20]([NH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][N:9]([CH3:12])[CH2:8][CH:7]2[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)Cl
Reactant: CN1Cc2c(N)cccc2C(c2ccccc2)C1
Solvent: c1ccccc1
Product: CCOC(=O)Nc1cccc2c1CN(C)CC2c1ccccc1
Reaction time: 3 h
Yield: 42 %

Procedure:
To a solution of 5.5 g 0.023 mole of 8-amino-4-phenyl-2-methyl-1,2,3,4-tetrahydro-isoquinoline and 50 ml of anhydrous benzene a solution of 3.4 g (0.031 mole) of ethyl chloroformate and 30 ml of anhydrous benzene is added. The reaction mixture is heated to boiling for 3 hours, the benzene is distilled off in vacuo. The residue is dissolved in 5 ml of water, made alkaline with a 30% aqueous sodium hydroxide solution and extracted three times with 50 ml of chloroform each. The chloroform extracts are united, dried over sodium sulfate and evaporated. The residue is washed with some cold ethanol and recrystallized from ethanol. Thus 3.0 g of the title compound are obtained in the form of white crystals. Yield 37.5%. Mp.: 178° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]23[CH2:15][CH:10]4[CH2:11][CH:12]([CH2:14][CH:8]([N:9]4C(OC(C)(C)C)=O)[CH2:7]2)[CH2:13]3)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:1]1([CH2:4][O:5][C:6]23[CH2:15][CH:10]4[CH2:11][CH:12]([CH2:14][CH:8]([NH:9]4)[CH2:7]2)[CH2:13]3)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1C2CC3CC1CC(OCC1CC1)(C3)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C1CC1COC12CC3CC(C1)NC(C3)C2
Temperature: 0 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged tert-butyl 5-(cyclopropylmethoxy)-2-azatricyclo[3.3.1.13,7]decane-2-carboxylate, Intermediate-19 (50 mg, 0.016 mmol) in DCM (5 mL). Then reaction mixture was cooled to 0° C. and trifluoroacetic acid (0.099 g, 0.084 mmol) was added and stirred for 4 hours. After completion of the reaction (reaction was monitored by LCMS) the reaction mixture was concentrated followed by trituration with mixture of hexane:ether (1:1) to give Intermediate-20 (50 mg, yield=95%) as an oily mass.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](Cl)=[O:11].[NH2:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][CH2:16]1>C(OCC)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([NH:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][CH2:16]1)=[O:11]
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Reactant: CCc1cn([C@H]2CC[C@@H](CN)O2)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCc1cn([C@H]2CC[C@@H](CNC(=O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h

Procedure:
A solution of (2,6-dichlorophenyl)acetyl chloride (prepared from 146 mg of the acid) in 1 ml of diethyl ether was added to a solution of 170 mg of 5'-amino-2',3',5'-trideoxy-5-ethyluridine in 2.72 ml of 0.26M sodium hydroxide solution and the mixture was shaken for 10 minutes. The mixture was filtered and the solid was recrystallized from 20 ml of ethanol to give 150 mg of 2',3',5'-trideoxy-5'-[2-(2,6-dichlorophenyl)acetamido]-5-ethyluridine in the form of a white solid of melting point 237°-238° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]2=[O:19])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C=O)C>[CH2:23]([O:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]2=[O:19])=[CH:6][CH:7]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCI
Reactant: O=C1O[C@H](c2ccccc2)CN1c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(N2C[C@@H](c3ccccc3)OC2=O)cc1
Temperature: 0 °C
Yield: 30.1 %

Procedure:
Then, 0.30 g (1.18 mM) of (5R)-3-(4-hydroxyphenyl)-5-phenyl-2-oxazolidinone and 4.6 ml of DMF were placed in 30 ml-round bottomed flask, followed by stirring to form a solution. To the solution, 0.053 g (1.33 mM) of 60%-oily sodium hydride was added under stirring at room temperature. After the settlement of foaming, 0.25 ml (1.38 mM) of 1-iodooctane was added to the mixture, followed by stirring for 30 minutes on an oil bath kept at about 70° C. After the reaction, the reaction mixture was poured into ice water to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by purification by silica gel column chromatography (eluent: toluene/ethyl acetate =100/1) and recrystallization from a toluene-methanol mixture solvent to obtain 0.13 g of (5R)-3-(4-octyloxyphenyl)-5-phenyl-2-oxazolidinone (Yield: 30.1%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([OH:15])(=[O:14])[C:7]1[C:8](=[CH:10][CH:11]=[CH:12][CH:13]=1)[OH:9]>>[Cl:1][S:2]([C:12]1[CH:11]=[CH:10][C:8]([OH:9])=[C:7]([CH:13]=1)[C:6]([OH:15])=[O:14])(=[O:5])=[O:3]
Reactant: O=C(O)c1ccccc1O
Reactant: O=S(=O)(O)Cl
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3.26 mol chlorosulfonic acid at 0° C. was added 652 mmol salicylic acid in small portions, and the mixture was then allowed to stir at RT for 1 h, then at 50° C. for 1 h, and finally at 70° C. for 1 h. The mixture was then added dropwise to 1000 ml ice-water with stirring and stirring continued for an additional 30 min. The ensuing white crystals were collected by filtration, washed three times with water, and then dried in vacuo at 45° C. for 16 h to yield the title compound. MS (m/e): 236.8 ([{37Cl}M−H]−, 33%), 235.0 ([{37Cl}M−H]−, 100%)
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13]([NH2:15])=[O:14])[C:8]=2[Cl:16])=[C:4]([F:19])[CH:3]=1.[CH3:20][N:21]1[C:25]([CH3:26])=[C:24]([C:27](O)=[O:28])[C:23](=[O:30])[N:22]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN=C=NCCCN(C)C.C1C=NC2N(O)N=NC=2C=1>C(Cl)Cl>[Cl:16][C:8]1[C:9]([C:13]([NH2:15])=[O:14])=[N:10][CH:11]=[CH:12][C:7]=1[O:6][C:5]1[CH:17]=[CH:18][C:2]([NH:1][C:27]([C:24]2[C:23](=[O:30])[N:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:21]([CH3:20])[C:25]=2[CH3:26])=[O:28])=[CH:3][C:4]=1[F:19]
Reactant: NC(=O)c1nccc(Oc2ccc(N)cc2F)c1Cl
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3Cl)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 45 °C
Reaction time: 14.5 h
Yield: 93.2 %

Procedure:
To a suspension of 4-(4-amino-2-fluorophenoxy)-3-chloropicolinamide (306 mg, 1.40 mmol) and 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (390 mg, 1.68 mmol) in DCM (6 mL) was added EDCI (322 mg, 1.68 mmol) and HOAT (38 mg, 0.28 mmol). The mixture was stirred at 45° C. for 14.5 hours, then cooled to rt and quenched with 5 mL of water. The mixture was extracted with EtOAc (10 mL×3) and the combined organic phases were washed with brine (10 mL×3), dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=1/4) to give the title compound as a pale yellow solid (647 mg, 93.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([O:22][CH3:23])=[C:16]([CH3:24])[C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([OH:15])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12].[C:25](OC(=O)C)(=[O:27])[CH3:26]>O>[CH3:1][O:2][C:3]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:17]([O:22][CH3:23])=[C:16]([CH3:24])[C:4]=1[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:15][C:25](=[O:27])[CH3:26])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12]
Reactant: COc1c(C)c(C)c(OC)c(Cc2ccc(O)c(C(=O)O)c2)c1C
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: COc1c(C)c(C)c(OC)c(Cc2ccc(OC(C)=O)c(C(=O)O)c2)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
5-(2,5-Dimethoxy-3,4,6-trimethylbenzyl)-2-hydroxybenzoic acid (0.150 g, 0.455 mmol) was dissolved in acetic anhydride (3 ml) and the resulting solution was stirred at 80° C. for 1 hour. The reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (0.170 g, 0.454 mmol, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][NH2:39])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([CH2:38][NH:39][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Yield: 66.8 %

Procedure:
4-({[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (155 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (150 mg), 4-aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (100 mg), HBTU (200 mg), and DIEA (1.2 mL) in DMF (2 mL).