Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(S([CH2:9][C:10]2[CH:11]=[CH:12][N:13]3[C:18]=2[C:17]([NH:19][C:20]2[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=2)[N:25]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)[N:24]=[CH:23]4)=[N:16][CH:15]=[N:14]3)=O)C=CC=CC=1.[NH:37]1[CH2:43][CH:42]([OH:44])[CH2:41][NH:40][CH2:39][CH2:38]1>CS(C)=O.C(Cl)Cl>[F:36][C:32]1[CH:31]=[C:30]([CH:35]=[CH:34][CH:33]=1)[CH2:29][N:25]1[C:26]2[C:22](=[CH:21][C:20]([NH:19][C:17]3[C:18]4=[C:10]([CH2:9][N:37]5[CH2:43][CH:42]([OH:44])[CH2:41][NH:40][CH2:39][CH2:38]5)[CH:11]=[CH:12][N:13]4[N:14]=[CH:15][N:16]=3)=[CH:28][CH:27]=2)[CH:23]=[N:24]1
Reactant: OC1CNCCNC1
Reactant: O=S(Cc1ccn2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c12)c1ccccc1
Solvent: CS(C)=O
Solvent: ClCCl
Product: OC1CNCCN(Cc2ccn3ncnc(Nc4ccc5c(cnn5Cc5cccc(F)c5)c4)c23)C1
Temperature: 140 °C
Yield: 62.2 %

Procedure:
A mixture of (5-benzenesulfinylmethyl-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-[1-(3-fluoro-benzyl)-1H-indazol-5-yl]-amine (397 mg, 0.8 mmole) and [1,4]diazepan-6-ol (417 mg, 4.5 equiv, Saari et al., J. Org. Chem., 1971, 36, 1711) in dry DMSO (1.5 mL) in a sealed tube was heated at 140° C. for 11 hr. This was diluted with DCM (150 ml), washed with water and dried (Na2SO4). Removal of the solvent followed by radial chromatography (4 mm silica gel plate; gradient elution with DCM containing 0 to 3% of a 2N NH3 solution in MeOH) gave the title compound as a solid (242 mg, 62%), MS: 487 (M+H)+; HPLC Ret Time: 0.96 min (Xterra S7 3.0×50 mm S7 C18 column, 2 min gradient, 5 ml/min). The racemic material could be separated on a Chiralpak AD 4.6×250 mm column, eluting with 0.05% diethylamine in EtOH for 25 min with a flow rate of 0.7 mL/min) The S and R enantiomers had retention times of 16.20 and 18.90 min respectively. The R enantiomer was synthesized as outlined below.
Reaction SMILES: N([O-])=O.[Na+].O.[N+:6]([C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[CH:16]([CH3:18])[CH3:17])N)([O-:8])=[O:7].[ClH:19]>[Cu]Cl>[Cl:19][C:11]1[CH:13]=[CH:14][C:15]([CH:16]([CH3:18])[CH3:17])=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=1
Reactant: CC(C)c1ccc(N)cc1[N+](=O)[O-]
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)c1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 17 %

Procedure:
A solution of sodium nitrite in water (3.6 g, 52.2 mmol, 5 M, 10.4 mL) was added drop wise to a solution of 3-nitro-4-(propan-2-yl)aniline (9.4 g, 52.2 mmol) in conc. HCl (175 mL) at 0° C. and the reaction mixture was stirred at the same temperature for 1.5 h. Copper (I) chloride (8.3 g, 83.5 mmol) was then added and the solution was stirred at room temperature for 1 h and then at 80° C. for an additional hour. After cooling down the reaction mixture was extracted with DCM (3×100 mL) and the combined organic layers were dried over sodium sulfate. The crude was then purified by flash chromatography (hexane/EtOAc 95/5) to obtain the title compound as yellow oil (1.8 g, 17%).
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.[Li+].[F:10][C:11]([F:16])([F:15])[CH:12]1[CH2:14][O:13]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC#N>[CH2:17]([NH:24][CH2:14][CH:12]([OH:13])[C:11]([F:16])([F:15])[F:10])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: FC(F)(F)C1CO1
Reactant: NCc1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CC#N
Product: OC(CNCc1ccccc1)C(F)(F)F
Temperature: -10 °C

Procedure:
Lithium triflate was suspended in CH3CN (15 mL) and the mixture is cooled to −10° C. 2-(Trifluoromethyl)oxirane is added and the suspension is allowed to warm to RT with stirring. Benzylamine (6.33 mL, 58 mmol, Aldrich) is added all-at-once and the resultant solution is stirred for 25 minutes. The reaction is quenched by pouring into CH2Cl2 (200 mL) and washing 3× with H2O (200 mL). The organic layer is dried over Na2SO4 and filtered. The product is purified on a Biotage Flash 75L using 20:70:10 CH2Cl2:pentane:triethylamine as eluent. The product containing fractions are pooled and the solvent is removed by rotary evaporation. The product is dried under vacuum at 100° C. yielding a white crystalline solid.
Reaction SMILES: C(O[C:6](=[O:25])[NH:7][C@@H:8]([CH2:21][CH:22]([CH3:24])[CH3:23])[C@@H:9]([OH:20])[CH2:10][C@H:11]([C:13](=[O:19])[NH:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH3:12])(C)(C)C.[Cl:26][C:27]1[CH:44]=[CH:43][C:30]2[C:31](C(O)=O)=[CH:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[O:35][C:29]=2[CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>Cl.O1CCOCC1.C(Cl)Cl>[CH2:15]([NH:14][C:13]([C@H:11]([CH3:12])[CH2:10][C@H:9]([OH:20])[C@@H:8]([NH:7][C:6]([C:31]1[C:30]2[CH:43]=[CH:44][C:27]([Cl:26])=[CH:28][C:29]=2[O:35][C:34]2[CH:36]=[CH:37][CH:38]=[CH:39][C:33]=2[CH:32]=1)=[O:25])[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)C1=Cc2ccccc2Oc2cc(Cl)ccc21
Reactant: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCCCNC(=O)[C@H](C)C[C@H](O)[C@H](CC(C)C)NC(=O)C1=Cc2ccccc2Oc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
((1S,2S,4R)-4-Butylcarbamoyl-2-hydroxy-1-isobutyl-pentyl)-carbamic acid tert-butyl ester (66 mg, 0.18 mmol) are dissolved in 4N HCl in dioxane (3 ml). After stirring for 1 h at rt the solvent is evaporated and the residue dried in vacuum. The residue is dissolved in DCM (3 ml) and 7-Chloro-dibenzo[b,f]oxepine-10-carboxylic acid (60 mg, 0.22 mmol, 1.2 eq), HOBT (30 mg, 0.22 mmol, 1.2 eq), EDCl (53 mg, 0.28 mmol, 1.5 eq) and triethylamine (0.077 ml, 0.55 mmol, 3 eq) are added. The mixture is stirred over night at rt. The reaction mixture is diluted with DCM and washed with water, bicarbonate and brine. The organic layer is dried over magnesium sulfate and the solvent is evaporated. Purification on silica (Flashmaster, DCM/methanol 100%→90%) and crystallization from DCM/hexane gives the products as white crystals (50 mg).
Reaction SMILES: [C:1]([N:4]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12](Cl)=[O:13])[C:7]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:6]1=2)(=[O:3])[CH3:2].[NH3:35]>CCOC(C)=O>[C:1]([N:4]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:22]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([NH2:35])=[O:13])[C:7]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:6]1=2)(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)Cl)c2cc(Cl)ccc21
Solvent: CCOC(C)=O
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(N)=O)c2cc(Cl)ccc21
Temperature: 70 °C

Procedure:
A mixture of 5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-8-chloro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carbonyl chloride (0.1 mmol, 50.0 mg) and ammonia (1.0 mmol, 1.0 mL, 1M in MeOH) was refluxed at 70° C. for 6 h with vigorous stirring. The solvent was removed in vacuo and the crude product was purified by crystallization using EtOAc. The product was obtained as a white solid; Rf 0.1 (EtOAc); MS (ES+): 508 (M+H+).
Reaction SMILES: B.C1COCC1.[OH:7][CH2:8][CH:9]([C:14]([N+:21]([O-:23])=[O:22])([N+:18]([O-:20])=[O:19])[N+:15]([O-:17])=[O:16])[CH2:10][C:11](O)=[O:12]>O>[N+:15]([C:14]([N+:18]([O-:20])=[O:19])([N+:21]([O-:23])=[O:22])[CH:9]([CH2:10][CH2:11][OH:12])[CH2:8][OH:7])([O-:17])=[O:16]
Reactant: O=C(O)CC(CO)C([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])C(C(CO)CCO)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A 1M solution of borane-THF (10 ML, 10 mmole) was stirred under a nitrogen atmosphere in a cold water bath (15° C.) while 2.1 g (8.94 mmole) of 4-hydroxy-3-(trinitromethyl)butyric acid, gamma-lactone was added. The solution was stirred at 25° C. for 1 hr. and then at 35°-37° C. for 3 days before it was cooled to room temperature and 1 ml of water was slowly added dropwise. Most of the THF was removed and the residue was stirred with ether. The insoluble material (boric acid) was removed by filtration and the ether filtrate was extracted twice with water to remove remaining boric acid. The ether was removed to give 2.10 g (98%) of an oil which was essentially pure by TLC. An analytical sample was obtained by chromatography on silica gel 60 with methylene chloride-acetone (80/20) as eluent: 1H NMR (CD2Cl2) 1.90-2.12 (m, 2H), 2.44 (broad OH), 3.60 (broad m, 1H), 3.93 (t, 2H), 4.23 (d, 2H); IR (film) 3700-3050 (OH), 1600 (NO2) cm-1.
Reaction SMILES: CS(Cl)(=O)=O.[N:6]([CH2:9][C@H:10]1[C:15]2[C:16]([CH3:22])=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:14]=2[CH2:13][C@@H:12]([CH2:23]O)[O:11]1)=[N+:7]=[N-:8].C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Li+]>C(Cl)Cl.C(OCC)C.O>[N:6]([CH2:9][C@H:10]1[C:15]2[C:16]([CH3:22])=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:14]=2[CH2:13][C@@H:12]([CH2:23][N:32]=[N+:33]=[N-:34])[O:11]1)=[N+:7]=[N-:8]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C)c2c1C[C@@H](CO)O[C@H]2CN=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C)c2c1C[C@@H](CN=[N+]=[N-])O[C@H]2CN=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.128 mL, 1.65 mmol) is added dropwise to a solution of [1R,3S] 1-azidomethyl-3,4-dihydro-3-hydroxymethyl-5-methoxy-8-methyl-1H-2-benzopyran (395 mg, 1.5 mmol), from Step 4, and 0.314 mL (2.25 mmol) of triethylamine (TEA) in 15 mL of methylene chloride at 0° C. After stirring for 30 min at 0° C., the reaction mixture is transferred to a separatory funnel and diluted with diethyl ether. The layers are separated and the organic layer is washed with 2×20 mL of water, 2×15 mL of 1 N aqueous hydrochloric acid solution and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue is dissolved in 20 mL of DMF and 440 mg (9 mmol) of lithium azide is added. The reaction mixture is heated to 80° C. and stirred at 80° C. for 4 h then cooled and poured into 50 mL of water. The aqueous solution is extracted with 3×30 mL of diethyl ether and the combined ether extracts are washed with 30 mL of water and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified on silica gel to give the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH:24]=O>>[CH2:1]([N:8]([CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[F:21])[C:9]1[C:10]([CH3:20])=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1F
Reactant: Cc1c(NCc2ccccc2)cccc1NS(C)(=O)=O
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccccc1F

Procedure:
The product from Example 8A and 2-fluorobenzaldehyde were processed as described in Example 1C to provide the title compound. 1H NMR (300 MHz, CDCl3) δ7.22 (m, 8H), 7.10 (t, J=8.0 Hz, 1H), 6.98 (m, 3H), 6.11 (s, 1H), 4.13 (s, 2H), 4.10 (s, 2H), 2.91 (s, 3H), 2.31 (s, 3H); MS (ESI+) m/z 399 (M+H)+; Analysis calculated for C22H23FN2O2S 0.20 TFA: C, 63.96; H, 5.55; N, 6.65. Found: C, 64.11; H, 5.69; N, 6.61.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18].C(=O)([O-])[O-].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].CN(C)C=O>O>[Cl:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[C:9]([F:16])[CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:18][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: CCOC(=O)CBr
Reactant: O=c1c2ccc(O)c(Cl)c2oc2cccc(F)c12
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc2c(=O)c3c(F)cccc3oc2c1Cl

Procedure:
A mixture of 2.6 g of 4-chloro-8-fluoro-3-hydroxy-9-oxo-9H-xanthene, 2.8 g of postassium carbonate, 3.3. g of ethyl bromoacetate and 40 ml of N,N-dimethylformamide (DMF) was stirred at 60°-70° C. for 4 hours. After cooling the mixture, water was added thereto and the resulting crystal was recovered by filtration, washed with water and dried. Recrystallization from ethanol gave 3.4 g of ethyl 4-chloro-8-fluoro-9-oxo-9H-xanthene-3-yloxyacetate. A mixture of this ester (3.3 g), sodium hydroxide (1.9 g) and water (100 ml) was refluxed for 30 minutes. After cooling, the mixture was rendered acidic with concentrated hydrochloric acid and the resulting crystal was recovered by filtration and dried. Recrystallization from DMF gave 2.5 g of 4-chloro-8-fluoro-9-oxo-9H-xanthene-3-yloxyacetic acid. m.p. 300° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[C:11]([NH:14][C:15]1[CH:16]=[CH:17][C:18](Br)=[C:19]([CH:25]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1.C(O)C>C(OCC)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]([NH:14][C:15]1[CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]
Reactant: CCOC(=O)c1cc(NC(C)=O)ccc1Br
Reactant: OB(O)c1ccccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(NC(C)=O)ccc1-c1ccccc1Br
Temperature: 90 °C
Yield: 49 %

Procedure:
A mixture of 2-bromophenylboronic acid (1.61 g, 8.0 mmol), ethyl 5-(acetylamino)-2-bromobenzoate (2.15 g, 7.5 mmol), potassium carbonate (5.52 g, 40 mmol) and tetrakis(triphenylphosphine)palladium(0) (869 mg, 0.75 mmol) in 1:1 toluene/ethanol (40 ml) was stirred and heated at 90° C. under nitrogen for 2 hours. After cooling the mixture was diluted with diethyl ether and water and the organic phase dried (MgSO4) and evaporated to dryness. The residue was chromatographed with ethyl acetate/iso-hexane (2:3) to yield 1.33 g of the title compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([CH:20]=[CH:21][CH:22]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:16]=O)[CH:14]=2)[N:9]=[CH:8][N:7]=1.[N:24]1([CH2:29][CH2:30][NH2:31])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([NH:5][C:6]2[C:15]3[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH2:16][NH:31][CH2:30][CH2:29][N:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:14]=3)[N:9]=[CH:8][N:7]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1C=O
Reactant: NCCN1CCCC1
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CNCCN1CCCC1

Procedure:
4-(3-Chloro-2-fluoroanilino)-7-methoxyquinazoline-6-carbaldehyde was coupled with (2-pyrrolidin-1-ylethyl)amine using an analogous method to that described for the equivalent step in Example 1 to give N-(3-chloro-2-fluorophenyl)-7-methoxy-6-{[(2-pyrrolidin-1-ylethyl)amino]methyl}quinazolin-4-amine; 1H NMR Spectrum: (DMSO-d6) 1.66 (m, 4H); 2.40 (m, 4H); 2.55 (t, 2H); 2.67 (t, 2H); 3.85 (s, 2H); 3.96 (s, 3H); 7.21 (s, 1H); 7.28 (t, 1H); 7.51 (m, 2H); 8.32 (s, 1H); 8.44 (s, 1H); 9.78 (s, 1H); Mass Spectrum: (M+H)+ 430.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([S:7][CH2:8][C:9]2[N+:18]([O-:19])=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N+:11]([O-:20])[C:10]=2[C:21]([O:23][CH3:24])=[O:22])=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([S:7]([CH2:8][C:9]2[N+:18]([O-:19])=[C:17]3[C:12]([CH:13]=[CH:14][CH:15]=[CH:16]3)=[N+:11]([O-:20])[C:10]=2[C:21]([O:23][CH3:24])=[O:22])=[O:33])=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1c(CSc2ccncc2)[n+]([O-])c2ccccc2[n+]1[O-]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(CS(=O)c2ccncc2)[n+]([O-])c2ccccc2[n+]1[O-]

Procedure:
Methyl 3-[(4-pyridyl)-thiomethyl]-2-quinoxalinecarboxylate-1,4-dioxide (0.03 moles) in 120 ml of chloroform was treated dropwise with m-chloroperbenzoic acid (0.03 moles) in 80 ml of chloroform at 0°-5° C. The solution after 2 hours was washed with 5% NaHCO3 solution (3 × 200 ml), water (1 × 60 ml) and then dried over sodium sulfate. The chloroform solution was concentrated to a small volume and added with stirring to 300 ml of ether to precipitate the desired product. Yield, 10.1 grams (94%); m.p. 137°-39° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:29])=[C:16]([N:19]3[CH2:23][CH2:22][CH:21]([N:24]4[CH:28]=[CH:27][N:26]=[N:25]4)[CH2:20]3)[N:17]=2)[C:12](=[O:30])[C:11]([C:31]([O:33]CC)=[O:32])=[CH:10]1.C1COCC1.[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:29])=[C:16]([N:19]3[CH2:23][CH2:22][CH:21]([N:24]4[CH:28]=[CH:27][N:26]=[N:25]4)[CH2:20]3)[N:17]=2)[C:12](=[O:30])[C:11]([C:31]([OH:33])=[O:32])=[CH:10]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ccc(F)cc2F)c2nc(N3CCC(n4ccnn4)C3)c(F)cc2c1=O

Procedure:
A mixture of crude ethyl 1-(2,4-difluorophenyl) -6-fluoro-7-[3-(1,2,3-triazol-1-yl)pyrrolidin-1-yl]-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (150 mg, 0.31 mmol), THF (15 ml), NaOH (20 mg, 1.5 mmol) and water (15 ml) was heated under reflux for 3 h, cooled and the THF was evaporated. The residue was diluted with water, aqueous solution was acidified and the precipitated yellow solid was filtered, washed with water, dried in vac-oven at 50° C. This solid was washed with ether to get the pure compound. Yield: 50 mg (35.7%), m.p. 253° C. (dec). 1H NMR (TFA) δ: 2.85 (m, 2H), 3.70-4.50 (m, 4H), 5.80 (m, 1H), 7.20 (m, 2H), 7.60 (m, 1H), 8.25 (s, 1H), 8.57 (s, 1H), 8.62 (s, 1H), 9.20 (s, 1H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]2[C:10](=[C:11]([O:16][CH3:17])[N:12]=[CH:13][CH:14]=2)[N:9]([C:18]2[CH:23]=[CH:22][C:21]([S:24](=[O:27])(=[O:26])[NH2:25])=[CH:20][CH:19]=2)[N:8]=1)(=O)=O.[C:30]1(B2OC(C)(C)C(C)(C)O2)[CH2:34][CH2:33][CH2:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:30]1([C:7]2[C:15]3[C:10](=[C:11]([O:16][CH3:17])[N:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:23]=[CH:22][C:21]([S:24]([NH2:25])(=[O:27])=[O:26])=[CH:20][CH:19]=3)[N:8]=2)[CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: CC1(C)OB(C2=CCCC2)OC1(C)C
Reactant: COc1nccc2c(OS(=O)(=O)C(F)(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c(C3=CCCC3)nn(-c3ccc(S(N)(=O)=O)cc3)c12
Yield: 45.6 %

Procedure:
A solution of 7-methoxy-1-(4-sulfamoylphenyl)-1H-pyrazolo[3,4-c]pyridin-3-yl trifluoromethanesulfonate (59 mg), 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25.3 mg), tetrakis(triphenylphosphine)palladium(0) (7.5 mg) and 2M aqueous sodium carbonate solution (0.33 mL) in DME (5 mL) was stirred under argon atmosphere at 100° C. for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (22 mg).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[C:32]([OH:40])[C:31]=1[O:41][CH3:42]>C(Cl)Cl>[Br:18][CH2:19][C:20]1[CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=[CH:22][C:21]=1[C:30]1[CH:35]=[C:34]([CH:36]([CH3:38])[CH3:37])[C:33]([F:39])=[C:32]([O:40][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:31]=1[O:41][CH3:42]
Reactant: COc1c(-c2ccc(C(F)(F)F)cc2CBr)cc(C(C)C)c(F)c1O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: COc1c(-c2ccc(C(F)(F)F)cc2CBr)cc(C(C)C)c(F)c1OC1CCCCO1
Reaction time: 8 h

Procedure:
3,4-Dihydro-2H-pyran (51.9 mg, 56 μL, 0.617 mmol) was added to a stirred solution of p-toluenesulfonic acid (2.3 mg, 0.0123 mmol) and 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-ol (52.0 mg, 0.123 mmol) in dry CH2Cl2 (6.1 mL) at room temperature under N2 and the reaction was stirred overnight. The reaction mixture was diluted with CH2Cl2 (45 mL) and washed with saturated NaHCO3 (5 mL) and 30% saturated Na2SO3 (5 mL), dried (Na2SO4) and concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-40% EtOAc in hexanes gradient) to afford 2-{[2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl-3-yl]oxy}tetrahydro-2H-pyran. Rf=0.59 (20% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3) 7.82 (s, 1H), 7.60 (d, J=7.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 1H), 6.67 (d, J=7.8 Hz, 1H), 5.77 (s, 1H), 4.97 (dd, J=4.9, 2.9 Hz, 1H), 4.49 (d, J=9.8 Hz, 1H), 4.37 (d, J=9.8 Hz, 1H), 3.89-3.87 (m, 1H), 3.61-3.49 (m, 1H), 3.46 (s, 3H), 3.27-3.21 (m, 1H), 1.89-1.83 (m, 1H), 1.78-1.70 (m, 1H) 1.64-1.48 (m, 3H), 1.26 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH2:1]1[NH:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2]1.[C:19]([O:27][CH2:28][CH2:29]Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:19]([O:27][CH2:28][CH2:29][N:18]1[CH2:1][CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(OCCCl)c1ccccc1
Reactant: C1COCCOCCOCCOCCOCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCCN1CCOCCOCCOCCOCCOCC1)c1ccccc1
Temperature: 80 °C
Reaction time: 10 h
Yield: 778.6 %

Procedure:
A mixture of 26.3 g of 1-aza-18-crown-6, 19.9 g of 2-chloroethyl benzoate, 21.0 g of potassium carbonate, and 60 g of N,N-dimethylformamide was stirred for 10 hours at 80° C. The reaction mixture was subjected to conventional aqueous work-up and purification by column chromatography. There was obtained 320 g of 2-(1,4,7,10,13-pentaoxa-16-azacyclo-octadecan-16-yl)ethyl benzoate (yield 75%).