Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:64][CH2:65][C:66]1[CH:67]=[CH:68][C:69]2[C:73]([CH2:76][F:77])([CH2:74][F:75])[O:72][B:71]([OH:78])[C:70]=2[CH:79]=1>CN(C=O)C>[F:77][CH2:76][C:73]1([CH2:74][F:75])[O:72][B:71]([OH:78])[C:70]2[CH:79]=[C:66]([CH2:65][NH:64][C:23]([C:20]3[C:19]4[N:15]([CH:16]=[CH:17][CH:18]=4)[C:14]([C:11]4[CH2:10][C:9]([C:4]5[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=5)([C:26]([F:29])([F:27])[F:28])[O:13][N:12]=4)=[CH:22][CH:21]=3)=[O:25])[CH:67]=[CH:68][C:69]1=2
Reactant: NCc1ccc2c(c1)B(O)OC2(CF)CF
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1ccc2c(c1)B(O)OC2(CF)CF)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.24 mmol) and DIPEA (124 mg, 0.88 mmol) in DMF (5 mL) can be stirred at rt for 5 min and then HATU (183 mg, 0.48 mmol) can be added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-bis(fluoromethyl)benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (126 mg, 0.44 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified by prep-TLC to provide the final title product.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][O:20]C4CCCCO4)[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[S:29]([NH:32][CH:33]([CH3:35])[CH3:34])(=[O:31])=[O:30])=[CH:4][CH:3]=1>Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][CH2:18][CH2:19][OH:20])[C:12](=[O:27])[N:11]([CH3:28])[C:10]=3[N:9]=[C:8]2[S:29]([NH:32][CH:33]([CH3:34])[CH3:35])(=[O:30])=[O:31])=[CH:36][CH:37]=1
Reactant: CC(C)NS(=O)(=O)c1nc2c(c(=O)n(CCCOC3CCCCO3)c(=O)n2C)n1Cc1ccc(Cl)cc1
Agent: Cl
Product: CC(C)NS(=O)(=O)c1nc2c(c(=O)n(CCCO)c(=O)n2C)n1Cc1ccc(Cl)cc1
Yield: 34.6 %

Procedure:
A solution of 7-(4-chlorobenzyl)-N-isopropyl-3-methyl-2,6-dioxo-1-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide (61 mg, 0.11 mmol) in 1 mM ethanolic HCl (1 mL, 1 mmol/L) was stirred at room temperature for 30 min. The mixture was concentrated and purified by preparative HPLC to give 7-(4-chlorobenzyl)-1-(3-hydroxypropyl)-N-isopropyl-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purine-8-sulfonamide (17.9 mg, 34.6% yield) as white solid. 1H-NMR (CD3OD) δ 7.31-7.38(m, 4H), 5.89(s, 2H), 4.06-4.10 (t, 2H), 3.58-3.63 (m, 3H), 3.56 (s, 3H), 1.83-1.87 (m, 2H), 1.19-1.21 (d, 6H). LCMS retention time 2.315 min; LCMS MH+ 470.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)(=[O:13])=[O:12])[CH:3]=1.Cl.CN.[CH2:27]([N:29](CC)CC)C>CCO>[CH3:9][NH:8][C:6]1[N:5]=[C:4]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)(=[O:13])=[O:12])[CH:3]=[C:2]([NH:29][CH3:27])[N:7]=1
Reactant: CNc1nc(Cl)cc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)n1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: CCO
Product: CNc1cc(NS(=O)(=O)c2cccc(C(F)(F)F)c2)nc(NC)n1
Temperature: 145 °C
Reaction time: 17 h
Yield: 56.4 %

Procedure:
0.10 g (0.00027 mol) of N-(6-chloro-2-methylamino-pyrimidin-4-yl)-3-trifluoromethyl-benzenesulfonamide was dissolved in 5 ml of EtOH, treated with 0.27 g (0.004 mol) of methylamine hydrochloride and 1 ml (0.007 mol) of triethylamine and stirred in an autoclave at 145° C. for 17 hours. The entire reaction mixture was partitioned in ethyl acetate/water and extracted. The residue was recrystallized in MeOH. There was obtained 0.055 g (56%) of N-(2,6-bis-methylamino-pyrimidin-4-yl)-3-trifluoromethyl-benzenesulfonamide as white crystals; m.p. 234-235° C.
Reaction SMILES: [N+:1]([CH:4]([CH3:13])[CH:5]([CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[OH:6])([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][CH:4]([CH3:13])[CH:5]([CH:7]1[CH2:8][CH2:9][O:10][CH2:11][CH2:12]1)[OH:6]
Reactant: [H][H]
Reactant: CC(C(O)C1CCOCC1)[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC(N)C(O)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
2-Nitro-1-(tetrahydro-pyran-4-yl)-propan-1-ol (1.3 g, 6.87 mmol) was dissolved in ethanol (55 mL) and treated with palladium on carbon (0.2 g) under 1 atm of hydrogen. After stirring at room temperature overnight, the palladium was filtered off and the solvent reduced under reduced pressure to provide 1.0 g (91%) of 2-amino-1-(tetrahydro-pyran-4-yl)-propan-1-ol.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[CH:10][S:9][C:8]=12)(=O)[NH2:2].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>ClCCl>[C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[CH:10][S:9][C:8]=12)#[N:2]
Reactant: NC(=O)c1ncn2ccsc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ncn2ccsc12
Yield: 97.9 %

Procedure:
To a suspension of 997 mg of 7-carbamoylimidazo[5,1-b]-thiazole in 80 ml of dichloromethane were add under ice-cooling 7.28 ml of N,N-diisopopylethylamine and 2.23 ml of phosphorus oxychloride. After the reaction mixture was stirred at the same temperature, it was poured onto ice-water, adjusted pH to 7.5 with aqueous sodium hydrogen carbonate, and extracted three times with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography on silica gel (dichloromethane:methanol=15:1) to give 871 mg of 7-cyanoimidazo[5,1-b]thiazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.Br[CH2:29][CH2:30][O:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][O:33]1>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]([CH2:29][CH2:30][O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: BrCCOC1CCCCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(NS(C)(=O)=O)cc3)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N(CCOC4CCCCO4)S(C)(=O)=O)cc3)CC2)c(C)c1

Procedure:
Using N-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}methanesulfonamide (271 mg) described in Example 461 and 2-(2-bromoethoxy)tetrahydropyran (1.21 mL) and by the reaction and treatment in the same manner as in Example 36, N-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-N-[2-(tetrahydropyran-2-yloxy)ethyl]methanesulfonamide was obtained. The obtained N-{4-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]phenyl}-N-[2-(tetrahydropyran-2-yloxy)ethyl]methanesulfonamide was dissolved in methanol (5 mL), p-toluenesulfonic acid 1 hydrate (121 mg) was added, and the mixture was stirred at room temperature. To the reaction mixture was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (chloroform:methanol) to give the title compound (185 mg).
Reaction SMILES: [CH3:1][C:2]([C:6]([OH:8])=[O:7])([CH2:4][OH:5])[NH2:3].O=S(Cl)Cl.[CH3:13]O>>[CH3:13][O:7][C:6](=[O:8])[C:2]([NH2:3])([CH3:1])[CH2:4][OH:5]
Reactant: CO
Reactant: CC(N)(CO)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(C)(N)CO
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A stirring solution of α-methyl-DL-Serine (1 g, 8.39 mmol) in MeOH (40 mL) in a flame dried round bottom flask under an inert atmosphere was cooled to 0° C. and SOCl2 (1.84 mL, 25.19 mmol) was slowly added. After addition of the SOCl2 was complete, the reaction mixture was stirred 12 hours at room temperature and then concentrated in vacuo to a white solid that was used directly in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:10](=[O:11])[O:9][CH:8]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H][H]>C(O)C.[Pd]>[CH2:8]([C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:12]=1[C:10]([OH:11])=[O:9])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1cccc2c1C(=O)OC2c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cccc(Cc2ccccc2)c1C(=O)O

Procedure:
The phthalide (30 g.) is dissolved in ethanol (500 ml.) by warming, 5% palladium-on-charcoal (3 g.) is added and the solution is hydrogenated until hydrogen uptake ceases. After removal of the catalyst by filtration, the ethanol is evaporated, and the residue is crystallised from chloroform-petroleum ether (b.p. 60°-80°C.) to give 2-benzyl-6-methoxy-benzoic acid m.p. 159°-161°C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[CH:9]=[C:10]([N:14]2[CH2:18][CH2:17][CH:16]([C:19]([OH:21])=O)[CH2:15]2)[CH:11]=[CH:12][CH:13]=1.[CH3:22][N:23](C)[CH:24]=O.N(C)C>ClCCCl.C1COCC1.C1(C)C=CC=CC=1>[Br:7][C:8]1[CH:9]=[C:10]([N:14]2[CH2:18][CH2:17][CH:16]([C:19]([N:23]([CH3:24])[CH3:22])=[O:21])[CH2:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)C1CCN(c2cccc(Br)c2)C1
Reactant: CN(C)C=O
Agent: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: ClCCCl
Product: CN(C)C(=O)C1CCN(c2cccc(Br)c2)C1
Temperature: 65 °C
Reaction time: 16 h
Yield: 523.4 %

Procedure:
Oxalyl chloride (104 μL, 1.19 mmol) was added to a mixture of 1-(3-bromophenyl)pyrrolidine-3-carboxylic acid (293 mg, 1.08 mmol) and N,N-dimethylformamide (8.4 μL, 0.108 mmol) in DCE (5 mL). After heating the mixture at 65° C. for 2 hours, the mixture was coevaporated with toluene. The residue was diluted with THF (5 mL) and Me2NH (2M/THF, 2.71 mL, 5.42 mmol) was added to the mixture at 0° C. After stirring the mixture for 16 hours at room temperature, the mixture was concentrated and the residue was diluted with water and extracted with EtOAc (3×). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=9:1→4:1→2:1) to afford desired product (168 mg, 48.0%) as orange oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[N:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:19])=[CH2:18])=[CH:13][CH:12]=2)[C:9]=1[CH3:10])=[O:4].Cl>O1CCOCC1.[C].[Pd]>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([N:8]2[C:9]([CH3:10])=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[N:7]2)=[CH:16][CH:15]=1)([CH3:19])[CH3:18]
Reactant: C=C(C)c1ccc(-n2ncc(C(=O)OC)c2C)cc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(C(=O)O)cnn1-c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 90.6 %

Procedure:
10% palladium carbon (containing ca. 50% water; 1.00 g) was added to a solution of 1-(4-isopropenylphenyl)-5-methyl-1H-pyrazole-4-carboxylic acid methyl ester (2.05 g) in 1,4-dioxane (40 ml) and the mixture was stirred under hydrogen atmosphere at room temperature for seven hours. The reaction solution was filtered through Celite and the filtrate was concentrated. Ethanol (40 ml), water (20 ml) and 4N aqueous solution of sodium hydroxide (20 ml) were added to the resultant residue and the mixture was stirred at 80° C. for two hours. After completion of the reaction, the reaction solution was cooled to 0° C. and 1N hydrochloric acid aqueous solution was added therein, the precipitated solid was collected by filtration to give the titled compound (1.77 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:16])[CH2:9][CH2:10][CH:11]([O:14][CH3:15])[O:12][CH3:13])[C:5]([F:17])=[CH:4][N:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8](=[O:16])[CH2:9][CH2:10][CH:11]([O:12][CH3:13])[O:14][CH3:15])[C:5]([F:17])=[CH:4][N:3]=1
Reactant: COC(CCC(O)c1cc(Cl)ncc1F)OC
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(CCC(=O)c1cc(Cl)ncc1F)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
The suspension of 1-(2-chloro-5-fluoro-pyridin-4-yl)-4,4-dimethoxy-butan-1-ol (0.80 g, 3.03 mmol) and Dess-Martin reagent (1.54 g, 3.64 mmol) in DCM (20 mL) is stirred at room temperature for 3 hours. The precipitate is filtered. Water is added to the filtrate and extracted with DCM. The combined organic layers are washed with water, brine, dried over Na2SO4, filtered and concentrated down. The crude product is purified by chromatography (EtOAc/hexane: 5%˜20%) to give 1-(2-chloro-5-fluoro-pyridin-4-yl)-4,4-dimethoxy-butan-1-one (0.71 g, 89%). M/Z=262.10 [M+1]
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[N:3]=1.[F:23][C:24]1[CH:25]=[C:26](B2OC(C)(C)C(C)(C)O2)[C:27]([CH3:34])=[C:28]2[C:33]=1[O:32][CH2:31][CH2:30][CH2:29]2>>[F:23][C:24]1[CH:25]=[C:26]([C:2]2[C:7]([CH:8]([CH2:13][CH2:14][CH3:15])[C:9]([O:11][CH3:12])=[O:10])=[C:6]([CH3:16])[N:5]=[C:4]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[N:3]=2)[C:27]([CH3:34])=[C:28]2[C:33]=1[O:32][CH2:31][CH2:30][CH2:29]2
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1Cl
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cc(F)c2c1CCCO2
Product: CCCC(C(=O)OC)c1c(C)nc(N2CCCCC2)nc1-c1cc(F)c2c(c1C)CCCO2

Procedure:
This compound is prepared according to general method E starting from methyl 2-(4-chloro-6-methyl-2-(piperidin-1-yl)pyrimidin-5-yl)pentanoate and 2-(8-fluoro-5-methylchroman-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([NH:17][CH:18]3[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[F:29][C:30]([F:52])([F:51])[CH2:31][NH:32][C:33]([C:35]1([CH2:48][CH2:49]O)[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:34]>>[F:29][C:30]([F:51])([F:52])[CH2:31][NH:32][C:33]([C:35]1([CH2:48][CH2:49][O:25][C:24]([C@H:21]2[CH2:20][CH2:19][C@H:18]([NH:17][C:15]([C:10]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:2]([F:27])([F:28])[F:1])=[CH:4][CH:5]=4)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16])[CH2:23][CH2:22]2)=[O:26])[C:47]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:41]2[C:36]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:34]
Reactant: O=C(NCC(F)(F)F)C1(CCO)c2ccccc2-c2ccccc21
Reactant: O=C(NC1CCC(C(=O)O)CC1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Product: O=C(N[C@H]1CC[C@H](C(=O)OCCC2(C(=O)NCC(F)(F)F)c3ccccc3-c3ccccc32)CC1)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
The 4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]cyclohexanecarboxylic acid (0.570 g) obtained in Example 7a) and 9-(2-hydroxyethyl)-9H-fluoren-9-carboxylic acid (2,2,2-trifluoroethyl)amide (0.500 g) obtained in Example 6d) were treated in a similar manner to Example 1g) to give the title compound (0.534 g) as a colorless solid (see Table 57).
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[Cl:8][CH2:9][CH2:10]O>>[OH:1][C:2]([CH3:7])([CH3:6])[C:3]([O:5][CH2:10][CH2:9][Cl:8])=[O:4]
Reactant: CC(C)(O)C(=O)O
Reactant: OCCCl
Product: CC(C)(O)C(=O)OCCCl

Procedure:
2-Chloroethyl 2-hydroxy-2-methylpropionate was prepared from 2-hydroxy-2-methylpropionic acid and excess 2-chloroethanol essentially by the method described in Step 1 of Example 1: b.p. 75°-77° C./6 mm Hg; 1H NMR δ1.47 (s, 6H), δ3.18 (s, 1H), δ3.72 (t, 2H, J= 5.6 Hz), δ4.43 (t, 2H, J=5.6 Hz); 13C NMR 27.1, 41.2, 64.8, 72.1, 176.8 ppm; HRMS calcd for C5H7ClO3Tms (M-CH3) 223.0557, obsd 223.0577.
Reaction SMILES: [F:1][CH2:2][C:3]1[CH:4]=[C:5]([C:13](OC)=[O:14])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[BH4-].[Na+].CO>C1COCC1>[F:1][CH2:2][C:3]1[CH:12]=[C:7]([CH:6]=[C:5]([CH2:13][OH:14])[CH:4]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(CF)cc(C(=O)OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(CO)cc(CF)c1
Yield: 79.6 %

Procedure:
Dimethyl 5-fluoromethylisophthalate (33) (3.16 g, 14.0 mmol) was dissolved in THF (10.5 mL). The air was evacuated from the reaction system, and then Ar was charged therein. To the solution were added NaBH4 (638 mg, 16.9 mmol), and then a mixted solution of THF:MeOH (8.8 mL:2.6 mL) slowly dropwise. The reaction mixture was refluxed for 1 hour. TLC was used to confirm the progress of the reaction. Then, the reaction was quenched with HCl (1 N, 14 mL). The mixture was extracted with EtOAc. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was purified by neutral silica gel column chromatography (hexane:EtOAc=5:1 to 2:1) to isolate methyl 3-fluoromethyl-5-hydroxymethylbenzoate (34) (2.21 g, 80%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH2:20](I)[CH:21]=[CH2:22]>C(O)C.CCOCC>[CH2:22]([O:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1)[CH:21]=[CH2:20]
Reactant: C=CCI
Reactant: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: C=CCOc1cccc([C@@H]2C[C@H]2CNC(=O)CCC)c1
Reaction time: 18 h
Yield: 34.4 %

Procedure:
To a rapidly stirred solution of (trans)-N-[[2-(3-hydroxyphenyl)cyclopropyl]methyl] butanamide (0.8 g, 3.4 mmol) and KOH (210 mg, 3.74 mmol) in ethanol (15 mL) was added allyl iodide (622 mg, 3.7 mmol). After stirring for 18 h, the suspension was diluted with Et2O (100 mL), and washed with H2O, 2N NaOH, brine, dried (K2CO3), and concentrated to a give a crude residue. The resulting material was purified by chromatography (silica gel, 40 % EtOAc/hexane) to afford 320 mg (34%) of the title compound: 1H NMR (300 MHz, CDCl3) δ0.70-0.94 (m, 5H), 1.12-1.32 (m, 1H), 1.58-1.84 (m, 3H), 2.20 (t, J=6.0 Hz, 2H), 3.15-3.36 (m, 2H), 4.48 (d, J=5.6 Hz, 2H), 5.24 (d, J=10.0 Hz, 1H), 5.40 (d, J=17.2 Hz, 1H), 5.56 (br s, 1H), 5.96-6.07 (m, 1H), 6.57-6.70 (m, 3H), 7.13 (t, J=7.2 Hz, 1H); IR (NaCl Film) 3296, 2962, 1644, 1607, 1548, 1494 cm-1 ; MS m/e 273; Analysis calc'd for C17H23NO2 0.20(H2O): C, 73.72; H, 8.52; N, 5.06; found: C, 73.77; H, 8.63; N, 5.00.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]2[C:13](=[O:14])OC(=O)[NH:10][C:9]=2[CH:16]=1)(=[O:4])=[O:3].[CH:17]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([CH2:19][CH3:20])[CH3:18]>CN(C)C=O.O>[NH2:10][C:9]1[CH:16]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[CH:7][C:8]=1[C:13]([NH:25][C:24]1[CH:26]=[CH:27][C:21]([CH:17]([CH2:19][CH3:20])[CH3:18])=[CH:22][CH:23]=1)=[O:14]
Reactant: CS(=O)(=O)c1ccc2c(=O)oc(=O)[nH]c2c1
Reactant: CCC(C)c1ccc(N)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)c1ccc(NC(=O)c2ccc(S(C)(=O)=O)cc2N)cc1
Temperature: 25 °C

Procedure:
A solution of 7-methanesulfonyl-1H-benzo[d][1,3]oxazine-2,4-dione (0.98 g, 3.8 mmol) and 4-sec-butylaniline (0.57 g, 3.8 mmol) in N,N-dimethylformamide (30 mL) was stirred at 115° C. for 16 hours, cooled to room temperature, diluted with water (50 mL), extracted with ethyl acetate (2×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column chromatography (SiO2, hexane/ethyl acetate=2:1) to provide 2-amino-N-(4-sec-butyl-phenyl)-4-methanesulfonyl-benzamide. Yield: 0.466 g (33%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[S:13](Cl)(=[O:15])=[O:14].[OH:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH2:21]>CO>[OH:17][C:18]1[CH:19]=[C:20]([NH:21][S:13]([C:4]2[CH:5]=[CH:6][C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=2[O:2][CH3:1])(=[O:15])=[O:14])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC)c1OC
Reactant: COc1ccc(N)cc1O
Solvent: CO
Product: COc1ccc(NS(=O)(=O)c2ccc(OC)c(OC)c2OC)cc1O
Reaction time: 1 h

Procedure:
To a solution of 2,3,4-trimethoxybenzenesulfonyl chloride (500 mg, 1.88 mmol) in methanol (10 mL) is added 3-hydroxy-4-methoxyaniline (523 mg, 3.76 mmol) at ambient temperature. The reaction is stirred for 1 h, the solvent is then evaporated and the crude product is purified by flash chromatography over silica.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]3[C:12]([CH:13]=[CH:14][C:4]=2[N:3]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[H-].[Na+].[CH3:17]I.Cl>O1CCCC1.O>[CH3:1][C:2]1[N:3]([CH3:17])[C:4]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:5]=2[N:6]=1
Reactant: CI
Reactant: Cc1nc2ccc3ccccc3c2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c3ccccc3ccc2n1C
Reaction time: 0.33 h

Procedure:
To a solution of 8.56 g of 2-methyl-1H-naphth[1,2-d]imidazole in 100 ml of tetrahydrofuran was added over a period of 15 minutes 2.25 g of 50% sodium hydride in oil and the mixture allowed to stir for 20 minutes. Methyl iodide (2.93 ml) was added over a 5-minute period and the reaction mixture allowed to stir at room temperature overnight. The reaction mixture was poured into water and the pH adjusted to 2 with 12N hydrochloric acid. The aqueous acid was extracted with chloroform (2×100 ml) and the pH adjusted to 10 with ammonium hydroxide. The aqueous base was extracted with chloroform (2×100 ml) and the combined extracts dried and concentrated to give 7.75 g of the isomers as a tan solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C(OC(C1NC2C(C=1)=C([N+]([O-])=O)C=CC=2)=O)C.C(O[C:27]([C:29]1[NH:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[C:33]([N+:38]([O-])=O)[CH:32]=2)=O)C.[OH-].[Na+]>C1COCC1.O>[CH3:27][C:29]1[NH:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[C:33]([NH2:38])[CH:32]=2
Reactant: CCOC(=O)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Agent: CCOC(=O)c1cc2c([N+](=O)[O-])cccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc2ccc(N)cc2[nH]1
Temperature: 0 °C
Yield: 8 %

Procedure:
To a suspension of LiAlH4 (7.8 g, 0.21 mol) in THF (300 mL) was added dropwise a mixture of 4-nitro-1H-indole-2-carboxylic acid ethyl ester and 6-nitro-1H-indole-2-carboxylic acid ethyl ester (B-4-b) (6 g, 25.7 mmol) in THF (50 mL) at 0° C. under N2. The mixture was heated at reflux overnight and then cooled to 0° C. H2O (7.8 mL) and 10% NaOH (7.8 mL) were added to the mixture at 0° C. The insoluble solid was removed via filtration. The filtrate was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to afford 2-methyl-1H-indol-6-ylamine (B-4) (0.3 g, 8%). 1H NMR (CDCl3) δ 7.57 (br s, 1 H), 7.27 (d,J=8.8 Hz, 1 H), 6.62 (s, 1 H), 6.51-6.53 (m, 1 H), 6.07 (s, 1 H), 3.59-3.25 (br s, 2 H), 2.37 (s, 3H); ESI-MS 147.2 m/z (MH+).