Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:23])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][OH:7].N1C=CC=CC=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1>C(Cl)Cl>[CH3:1][CH:2]([CH2:8][CH2:9][CH2:10][CH:11]([CH3:23])[CH2:12][CH2:13][CH2:14][CH:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][S:36]([C:33]1[CH:34]=[CH:35][C:30]([CH3:40])=[CH:31][CH:32]=1)(=[O:38])=[O:37]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCCCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCC(C)CCCC(C)CCCC(C)CCCC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
Under a nitrogen atmosphere, a solution of 30 g (0.09 mol) of 5,9,13,17-tetramethyl-1-octadecanol and 8.72 g (0.11 mol) of pyridine in 200 ml of dry methylene chloride was added dropwise to a solution of 19.3 g (0.10 mol) of p-toluenesulfonyl chloride in 100 ml of dry methylene chloride under ice cooling. After the dropwise addition, the mixture was agitated at room temperature overnight, the resulting reaction solution was successively washed with 200 ml of water, 200 ml of 2N hydrochloric acid, and 200 ml of a saturated sodium bicarbonate water, and it was dried over anhydrous magnesium sulfate. After the filtration, the resultant was concentrated under reduced pressure to obtain 42 g of (5,9,13,17-tetramethyloctadecyl)tosylate.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:51]=[CH:50][C:35]5[N:36]([CH3:49])[C:37]([S:39][CH2:40][C:41]6[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=6)=[N:38][C:34]=5[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:61])C=1.CSC.O>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:51]=[CH:50][C:35]5[N:36]([CH3:49])[C:37]([S:39]([CH2:40][C:41]6[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][CH:42]=6)=[O:61])=[N:38][C:34]=5[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:52]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc4c(c2)nc(SCc2cncn2CCC)n4C)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CSC
Solvent: O
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc4c(c2)nc(S(=O)Cc2cncn2CCC)n4C)CCN3CC(C)C)cc1
Temperature: -13 °C
Reaction time: 2.5 h
Yield: 28.7 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[1-methyl-2-(((1-propylimidazol-5-yl)methyl)sulfanyl)benzimidazol-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (160 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (82 mg) in dichloromethane (10 ml) at −78° C., and the mixture was stirred for 2.5 hours at −13° C. Dimethylsulfide (0.1 ml) was added to the mixture, and the mixture was allowed to be at room temperature and stirred for 30 minutes. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by basic silica gel column chromatography (hexane:ethyl acetate=1:4→ethyl acetate), and was recrystallized from hexane-ethyl acetate, to give 7-[4-(2-butoxyethoxy) phenyl]-1-isobutyl-N-[1-methyl-2-(((1-propylimidazol-5-yl)methyl)sulfinyl)benzimidazol-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (47 mg) (Compound 445) as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([NH:15][C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[N+:23]([O-])=O)[S:7][C:6]=2[CH:26]=1.Cl.[Sn](Cl)Cl>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:8]([NH:15][C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=3[NH2:23])[S:7][C:6]=2[CH:26]=1
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2cc(Br)ccc12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2cc(Br)ccc12
Yield: 40.8 %

Procedure:
In the same manner as in Starting Material Synthesis Example 21 and using ethyl 6-bromo-2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate (10 g), ethanol (80 ml), 18% hydrochloric acid (80 ml) and tin(II) chloride.dihydrate (20.6 g), ethyl 6-bromo-2-(2-amino-5-fluoroanilino)benzo[b]thiophene-3-carboxylate (3.8 g) was obtained.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:4]=[C:5](/[CH:42]=[CH:43]/[CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][CH2:49][C:48]3([CH2:56][CH2:55][N:54](C(OC(C)(C)C)=O)[CH2:53][CH2:52]3)[CH2:47]2)[CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[C:11]([O:18][C@@H:19]2[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[C@@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:20]2[O:21][C:22](=[O:24])[CH3:23])=[N:12][NH:13][C:14]=1[CH:15]([CH3:17])[CH3:16]>ClCCl>[ClH:1].[ClH:1].[C:22]([O:21][C@@H:20]1[C@@H:25]([O:26][C:27](=[O:29])[CH3:28])[C@H:30]([O:31][C:32](=[O:34])[CH3:33])[C@@H:35]([CH2:37][O:38][C:39](=[O:41])[CH3:40])[O:36][C@H:19]1[O:18][C:11]1[C:10]([CH2:9][C:8]2[CH:7]=[CH:6][C:5](/[CH:42]=[CH:43]/[CH2:44][CH2:45][N:46]3[CH2:51][CH2:50][CH2:49][C:48]4([CH2:52][CH2:53][NH:54][CH2:55][CH2:56]4)[CH2:47]3)=[CH:4][C:3]=2[CH3:2])=[C:14]([CH:15]([CH3:17])[CH3:16])[NH:13][N:12]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCN(C(=O)OC(C)(C)C)CC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(/C=C/CCN3CCCC4(CCNCC4)C3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 2 h
Yield: 98.3 %

Procedure:
Add hydrogen chloride (4.0 M solution in 1,4-dioxane, 1.5 mL, 5.8 mmol) to a solution of tert-butyl 2-{(3E)-4-[3-methyl-4-({5-(propan-2-yl)-3-[(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyl)oxy]-1H-pyrazol-4-yl}methyl)phenyl]but-3-en-1-yl}-2,9-diazaspiro[5.5]undecane-9-carboxylate (500 mg, 0.58 mmol) in dichloromethane (20 mL). After 2 hours at room temperature, remove the solvent under reduced pressure to provide the title compound as solid (480 mg, 0.57 mmol). MS (m/z): 767.4 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:12].[OH-].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH2:15]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=c1[nH]ccc2c(O)cccc12
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]ccc2c(OCc3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 39.4 %

Procedure:
5-Hydroxyisoquinolin-1(2H)-one (0.65 g, 4.04 mmol) was added in portions to a solution of potassium hydroxide (0.23 g, 4.04 mmol) in methanol (15 mL). The mixture was stirred at ambient temperature for 10 minutes, then benzyl bromide (0.69 g, 0.48 mL, 4.04 mmol) was added. The mixture was stirred at ambient temperature for 30 minutes and then at 40° C. for 2 hours. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (100 mL) and washed with water (100 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from methanol (10 mL) to afford the title compound (0.40 g, 40%): mp 165-168° C.; MS (ES+) m/z 252.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:4][CH:3]=1.OC1C=CC(C2CC(C3C=CC(O)=CC=3)CCC=2)=CC=1.C(C(C)=O)C(C)C.CC(C1C=CC=CC=1)=C>C(OCC)(=O)C.[C].[Pd].C1CCCCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(C2=CC(c3ccc(O)cc3)CCC2)cc1
Agent: [Pd]
Agent: C=C(C)c1ccccc1
Agent: Oc1ccc(C2=CCCC(c3ccc(O)cc3)C2)cc1
Solvent: C1CCCCC1
Solvent: CC(=O)CC(C)C
Solvent: CCOC(C)=O
Product: Oc1ccc(-c2cccc(-c3ccc(O)cc3)c2)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 33 %

Procedure:
2.6 g of the 91% pure mixture of 1,3-bis(4-hydroxyphenyl)-1-cyclohexene and 1,5-bis(4-hydroxyphenyl)-1-cyclohexene obtained in Step (B), 15.6 g of methyl isobutyl ketone, 3.5 g of α-methyl styrene, and 0.2 g of 5% palladium carbon were introduced to an autoclave and agitated for 6 hours at 150° C. After the end of reaction, the reaction liquid was filtered to remove the 5% palladium carbon, and then the filtrate was condensed. The residue was dissolved in 3.2 g of ethyl acetate, after which 7.5 g of cyclohexane was added to the mixture and the separated crystal was filtered out and dried to obtain 1.9 g of 4,4″-dihydroxy-m-terphenyl of 99% purity (high-speed liquid chromatography).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:35])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[N:28]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[N:7]=1.[CH3:36][N:37]1CCOC[CH2:38]1.ClC(OCC(C)C)=O.CNC.CO>C1COCC1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:35])[C:5]2=[C:6]([CH2:8][C@H:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH3:34])[N:28]=3)[NH:10]/[C:11]/2=[N:12]\[O:13][CH2:14][CH2:15][CH2:16][C:17]([N:37]([CH3:38])[CH3:36])=[O:19])[N:7]=1
Reactant: CN1CCOCC1
Reactant: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCCCC(=O)O)N2)n1
Agent: CC(C)COC(=O)Cl
Agent: CNC
Solvent: CO
Solvent: C1CCOC1
Product: COc1cccc(-c2cc(F)ccc2[C@H]2Cc3nc(N)nc(C)c3/C(=N/OCCCC(=O)N(C)C)N2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23.3 %

Procedure:
A solution of (R,Z)-4-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)butanoic acid (110a, 26 mg, 0.054 mmol) in anhydrous THF was chilled in an ice bath and N-methylmorpholine (9 μL, 0.081 mmol) and isobutyl chloroformate (7.7 μL, 0.060 mmol) were added sequentially. The mixture was stirred under an N2 atmosphere for 20 min. A 33 wt % solution of dimethylamine in methanol (54 μL, 0.11 mmol) was added to the reaction which was subsequently allowed to warm to room temperature with stirring overnight. The THF was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with H2O×2 and dried over anhydrous Na2SO4. The ethyl acetate was removed in vacuo and the residue was purified via preparative HPLC to yield (R,Z)-4-(2-amino-7-(4-fluoro-2-(6-methoxypyridin-2-yl)phenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylideneaminooxy)-N,N-dimethylbutanamide (98, 6.4 mg, 0.0126 mmol).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[S:36](Cl)([CH3:39])(=[O:38])=[O:37]>ClCCl.O>[CH3:39][S:36]([O:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:10]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH2:22][C:23]4=[O:28])=[CH:11][CH:12]=[C:13]([O:17][CH3:18])[C:14]=2[O:15][CH3:16])[CH2:4][O:5][CH2:6]1)(=[O:38])=[O:37]
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CO)COC2)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(COS(C)(=O)=O)COC2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 4-(2-((3-(hydroxymethyl)oxetan-3-yl)methoxy)-3,4-dimethoxyphenyl)-indan-1-one (4 g, 10.41 mmol) in dichloromethane (70 mL) at 0° C., were added triethylamine (3.15 g, 31.25 mmol) and mesyl chloride (1.78 g, 15.614 mmol), the resultant reaction mixture was warmed to RT and stirred for 30 min. The reaction mixture was diluted with water and extracted with dichloromethane (3×). The combined dichloromethane layer was washed with brine and dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford (3-((2,3-dimethoxy-6-(1-oxo-2,3-dihydro-1H-inden-4-yl)phenoxy)methyl)oxetan-3-yl)methyl methanesulfonate as a solid.
Reaction SMILES: [CH3:1][S:2][C:3]([C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=[CH:4]N(C)C.C(O)(=O)C.[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[NH:30])=[CH:27][CH:26]=1.C[O-].[Na+]>CO>[Cl:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]2[N:31]=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:17])([F:16])[F:18])[CH:10]=3)[C:3]([S:2][CH3:1])=[CH:4][N:30]=2)=[CH:27][CH:26]=1
Reactant: N=C(N)c1ccc(Cl)cc1
Reactant: CSC(=CN(C)C)C(=O)c1cccc(C(F)(F)F)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CSc1cnc(-c2ccc(Cl)cc2)nc1-c1cccc(C(F)(F)F)c1
Yield: 67.8 %

Procedure:
2.8 g of 1-methylmercapto-1-(3-trifluoromethylbenzoyl)-2-(N,N-dimethylamino)ethene, 2.3 g of 4-chlorobenzamidine acetate and 650 mg of sodium methoxide were added to 200 ml of methanol and the resulting mixture was allowed to react under reflux for 5 hours. After completion of the reaction, the solvent was distilled away under reduced pressure. After adding water, the residue was extracted with ethyl acetate and subjected to column chromatography. Thus 2.5 g of 2-(4-chlorophenyl)-4-(3-trifluoromethylphenyl)-5-methylmercaptopyrimidine was obtained (Compound 150).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([N:19](CC)CC)[CH3:18].ClC(OCC(C)C)=O.C(N)C>O1CCCC1.CN(C)C=O>[CH2:17]([NH:19][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:18]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: CCN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)[C@H](C)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 60.5 %

Procedure:
33.48 g (0.15 mol) of N-benzyloxycarbonyl-L-alanine were dissolved in 225 ml of dry tetrahydrofuran and the solution was cooled to -10° C. 22.95 ml (0.15 mol) of triethylamine and 19.8 ml (0.15 mol) of isobutyl chloroformate were then added and the solution was stirred at -10° C. for 20 minutes. To this mixture was then added a solution of 7.53 g (0.15 mol) of monoethylamine in 215 ml of dimethylformamide. The solution was stirred at -10° C. for 5 minutes and then left to stand for 16 hours at room temperature. The solvents were removed by evaporation and the residue was triturated with 450 ml of ethyl acetate and washed successively with 200 ml of 1-N hydrochloric acid, 200 ml of water and 200 ml of 5% sodium bicarbonate solution. After drying over sodium sulphate and filtration, the solvent was removed by evaporation. The resulting oil crystallised on the addition of petrol to yield 22.70 g (60.5%) of N-benzyloxycarbonyl-L-alanine ethylamide of melting point 127°-128° C.; [α]D20 =+11.2° (c=0.83% in dimethylformamide).
Reaction SMILES: [Li+].[CH3:2][C:3]1[S:7][CH:6]=[C:5]([S:8]([O-:11])(=O)=[O:9])[CH:4]=1.C([O-])(=O)C.[Na+].[NH2:17]OS(O)(=O)=O>O>[CH3:2][C:3]1[S:7][CH:6]=[C:5]([S:8]([NH2:17])(=[O:11])=[O:9])[CH:4]=1
Reactant: Cc1cc(S(=O)(=O)[O-])cs1
Reactant: NOS(=O)(=O)O
Agent: CC(=O)[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Product: Cc1cc(S(N)(=O)=O)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.7 %

Procedure:
To a solution of the above prepared 5-methyl-thiophene-3-sulfonic acid lithium salt (1.100 g, 6.03 mmol) in 5.0 ml of water was added 0.792 g of sodium acetate (1.6 eq.) and 1.024 g of hydroxylamine-O-sulfonic acid (1.5 eq.), and this mixture was stirred for 2 h at room temperature. HPLC showed complete conversion to the product. The reaction mixture was then partitioned between ethyl acetate and water, the layers were separated, the organic phase was washed with citric acid (10% in water), water and brine, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica column chromatography (SiO2, hexane/ethyl acetate), to yield finally 0.745 g of the title compound as light yellow solid of mp. 105-106.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:19])=[C:9]([C:11]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=O)[O:10][C:5]2=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>C(Cl)Cl.O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(N(CC)CC)C>[Cl:1][C:2]1[N:7]=[C:6]2[C:8]([CH3:19])=[C:9]([CH:11]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=3)[CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: Cc1c(C(=O)C2CCCCC2)oc2ccc(Cl)nc12
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(c2oc3ccc(Cl)nc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a mixture of (5-chloro-3-methylfuro[3,2-b]pyridin-2-yl)(cyclohexyl)methanone (1.00 g) synthesized above, methyl 4-aminobenzoate (599 mg), triethylamine (4.01 mL) and methylene chloride (10 mL) was added a 1.0M solution (4.32 mL) of titanium (IV) chloride in methylene chloride at 0° C., and the mixture was stirred under argon atmosphere overnight at room temperature. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown oil. To a solution (15 mL) of the obtained oil in tetrahydrofuran were added acetic acid (1.03 mL) and sodium cyanoborohydride (452 mg), and the mixture was stirred at room temperature for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-40% ethyl acetate/hexane) to give the title object compound (1.31 g, 81%) as an orange solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:26][CH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[C:30](=[O:47])[N:31]([CH:39]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][C:40]1=[O:46])[C:32]([CH3:38])=[N:33]2>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:26][CH2:27][C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[C:30](=[O:47])[N:31]([CH:39]2[CH2:44][CH2:43][C:42](=[O:45])[NH:41][C:40]2=[O:46])[C:32]([CH3:38])=[N:33]3)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(CNC(=O)Cc3ccc(Cl)c(Cl)c3)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a stirred solution of (3,4-dichloro-phenyl)-acetic acid (0.30 g, 1.5 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1.1′ carbonyldiimidazole (0.26 g, 1.6 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 2-(3,4-dichloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-acetamide as a yellow solid (540 mg, 74% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.41 min (98.4%); mp, 262-264° C.; 1HNMR (DMSO-d6) 2.14-2.19 (m, 1H, CHH), 2.57-2.89 (m, 6H, CHCH2, CH3), 3.57 (s, 2H, ArCH2), 4.69-4.85 (m, 2H, CH2NH), 5.24 (dd, J=6, 11 Hz, 1H, CH), 7.26-7.73 (m, 6H, Ar), 8.42 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.73, 23.28, 30.60, 40.98, 41.76, 56.49, 117.70, 124.84, 125.65, 129.06, 129.55, 130.27, 130.63, 131.11, 133.82, 137.43, 140.52, 148.46, 154.81, 160.90, 169.42, 169.49, 172.59. LCMS MH=487, 489; Anal Calcd For C23H20N4O4Cl2: C, 56.69; H, 4.14; N, 11.50; Cl, 14.55. Found: C, 56.50; H, 3.95; N, 11.25; Cl, 14.29.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:15].C(N(CC)CC)C.[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32](O)=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[F:23][C:24]1[CH:25]=[C:26]([CH2:31][C:32]([NH:1][N:2]2[N:11]=[C:10]([CH:12]([CH3:13])[CH3:14])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:15])=[O:33])[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: CC(C)c1nn(N)c(=O)c2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1nn(NC(=O)Cc2cc(F)cc(F)c2)c(=O)c2ccccc12
Reaction time: 8 h
Yield: 32.4 %

Procedure:
A mixture of the product of Example 1B (44.5 mg, 0.219 mmol), triethylamine (0.050 mL, 0.36 mmol), 2-(3,5-difluorophenyl)acetic acid (41.0 mg, 0.238 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (77.5 mg, 0.241 mmol) in DMF (0.75 mL) was stirred overnight, diluted with EtOAc, washed with 1 N NaOH and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (8% EtOAc/CH2Cl2) to give the title compound as a white solid (25.4 mg, 0.071 mmol). 1H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.33 (dd, 1H), 8.16-8.09 (m, 1H), 8.00 (td, 1H), 7.89 (ddd, 1H), 7.19-7.07 (m, 3H), 3.75 (s, 2H), 3.61 (quin, 1H), 1.27 (d, 6H); MS (ESI+) M/Z 357.9 (M+H)+.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][C:9]2([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[O:12]2)[CH2:8][CH2:7]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[N:21]([CH:6]1[CH2:11][CH2:10][C:9]2([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[O:12]2)[CH2:8][CH2:7]1)=[N+:22]=[N-:23]
Reactant: CS(=O)(=O)OC1CCC2(CC1)OC(=O)c1ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC1CCC2(CC1)OC(=O)c1ccccc12
Temperature: 80 °C
Yield: 92.5 %

Procedure:
A mixture of 3-oxo-3H-spiro[2-benzofuran-1,1′-cyclohexan]-4′-yl methanesulfonate (120 mg, 0.40 mmol), sodium azide (263 mg, 4.05 mmol) in DMF (2.0 mL) was maintained at 80° C. overnight. After cooling, it was quenched with sat'd NH4Cl solution, then extracted with ethyl acetate. The extract was washed with water twice, brine once, and dried over anhydrous sodium sulfate. After filtration the filtrate was concentrated to yield 90 mg of 4′-azido-3H-spiro[2-benzofuran-1,1′-cyclohexan]-3-one (yield: 91%).