Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]=[C:3]([C:10]1[N:14]([CH3:15])[CH:13]=[N:12][N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[N:24]=1>CC#N>[Br:22][C:23]1[N:24]=[C:25]([CH2:29][O:1][N:2]=[C:3]([C:10]2[N:14]([CH3:15])[CH:13]=[N:12][N:11]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: BrCc1cccc(Br)n1
Reactant: Cn1cnnc1C(=NO)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1cnnc1C(=NOCc1cccc(Br)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.5 %

Procedure:
To a stirred solution of N-hydroxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)-1-phenylmethanimine (0.45 g, 2.22 mmol, 1.0 eq.) in 20 ml of MeCN was added Cs2CO3 (0.795 g, 2.44 mmol, 1.1 eq.) followed by Kl (0.0365 g, 0.22 mmol, 0.1 eq.) in one portion. The resulting suspension was stirred for 5 mins before addition of 2-bromo-6-(bromomethyl)pyridine (0.586 g, 2.33 mmol, 1.05 eq.) in one portion. The reaction was stirred for 4 h at room temperature. The solid was removed by filtration and washed with 250 ml of fresh MeCN. The filtrate was evaporated, and 500 ml of EtOAc were added. The organic layer was washed with H2O and dried over MgSO4 then concentrated. Chromatography of the crude on silica gel gave N-[(6-bromopyridin-2-yl)methoxy]-1-(4-methyl-4H-1,2,4-triazol-3-yl)-1-phenylmethanimine (0.748 g, 90% yield) as a yellow oil.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[SH:34][CH2:35][CH2:36][OH:37]>C(Cl)Cl>[OH:37][CH2:36][CH2:35][S:34][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2
Reactant: OCCS
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1ccc2c(c1)C(SCCO)c1ccccc1CO2
Temperature: 25 °C

Procedure:
In 400 ml of methylene chloride was suspended 40.0 g of Compound b obtained in Reference Example 2. Trifluoroacetic anhydride, 21.0 ml, was added to the suspension followed by stirring at room temperature for an hour. Them, 10.7 ml of 2-mercaptoethanol was added to the mixture followed by stirring for further 4 hours. After 100 ml of methylene chloride was added to the reaction mixture, the mixture was washed with saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained crude product was recrystallized from toluene to give 37.6 g of methyl 11-(2-hydroxyethyl)thio-6,11-dihydrodibenz[b,e]oxepin-2-carboxylate as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[NH:33][C:34]([NH:36][C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=1[F:44])=[O:35])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]2[NH:16][CH:15]=[C:14]([C:17]([NH:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)=[O:18])[CH:13]=2)[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:22][CH2:21][CH2:20][NH:19][C:17]([C:14]1[CH:13]=[C:12]([C:8]2[CH:7]=[C:6]([O:5][C:4]3[CH:30]=[CH:31][C:32]([NH:33][C:34]([NH:36][C:37]4[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=4[F:44])=[O:35])=[C:2]([F:1])[CH:3]=3)[CH:11]=[CH:10][N:9]=2)[NH:16][CH:15]=1)=[O:18]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCNC(=O)OC(C)(C)C)c[nH]4)c3)cc2F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCN)c[nH]4)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of tert-butyl (2-{[(5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrol-3-yl)carbonyl]amino}ethyl)carbamate (300 mg, 0.49 mmol) in 10 ml of methylene chloride was added 3 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 30 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8˜9. The precipitates were filtered, washed with water and dried in vacuo to give N-(2-aminoethyl)-5-{4-[3-fluoro-4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as beige solid. Yield: 200 mg, 80%.
Reaction SMILES: Br[C:2]1[C:7]([NH:8][C:9]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:10]=2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([NH:8][C:9]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:10]=2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:2]=[N:3][C:4]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1ccc(Nc2cc(Cl)cnc2Br)c(C(=O)OC(C)(C)C)c1
Reactant: OB(O)c1ccccc1
Product: Cc1ccc(Nc2cnc(-c3ccccc3)c(Cl)c2)c(C(=O)OC(C)(C)C)c1

Procedure:
Obtained (0.005 g, 3% of yield) following the procedure described in Example 8 (step A) starting with 0.230 g (0.58 mmol) of Intermediate 20A and 0.106 g (0.87 mmol) of phenylboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21]SC1C=CC=CC=1.BrCC1[C:40]2[C:35](=[CH:36][CH:37]=[C:38](C3C=CC=CC=3OC)[CH:39]=2)[NH:34]C(C)(C)C=1.C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]([CH3:20])([CH3:19])[CH:13]=[C:12]2[CH2:21][NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COc1ccccc1-c1ccc2c(c1)C(CSc1ccccc1)=CC(C)(C)N2
Reactant: COc1ccccc1-c1ccc2c(c1)C(CBr)=CC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Product: COc1ccccc1-c1ccc2c(c1)C(CNc1ccccc1)=CC(C)(C)N2

Procedure:
6-(2-Methoxyphenyl)-2,2-dimethyl-4-phenylsulfanylmethyl-1,2-dihydroquinoline 80 mg of 4-bromomethyl-6-(2-methoxyphenyl)-2,2-dimethyl-1,2-dihydroquinoline, 46 mg of potassium carbonate, and 23 μL of thiophenol reacted to give 12 mg of the title compound as a foam.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].OC(C(F)(F)F)=O.[NH2:30][CH2:31][C:32]([CH3:37])([CH3:36])[C:33]([OH:35])=[O:34].C[O-].[Na+]>CCO>[CH2:16]([C:10]1[CH:9]=[C:8]2[C:13]([C:14]([OH:15])=[C:5]([C:3]([NH:30][CH2:31][C:32]([CH3:37])([CH3:36])[C:33]([OH:35])=[O:34])=[O:4])[N:6]=[CH:7]2)=[CH:12][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(CN)C(=O)O
Reactant: COC(=O)c1ncc2cc(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CC(C)(CNC(=O)c1ncc2cc(Cc3ccccc3)ccc2c1O)C(=O)O
Temperature: 150 °C
Yield: 38.6 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (19 mg, 0.065 mmol), 3-amino-2,2-dimethyl-propionic acid TFA salt (60 mg, 0.26 mmol) and NaOMe (28 mg, 0.52 mmol) in EtOH (2 mL) was heated at 150° C. in a microwave reactor for 6 h. The solvent was evaporated, and the residue was partitioned between water (30 mL) and EtOAc (30 mL). 1 M HCl was added with vigorous stirring until pH was ˜2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by column chromatography (0-30% EtOAc/hexanes+2% AcOH) to give 9.5 mg of the title compound. MS: (+) m/z 379.17 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([NH:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:19](O)=[O:20])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:26][NH2:27]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([NH:15][C:16]3[CH:17]=[C:18]([C:19](=[O:20])[NH:27][CH3:26])[CH:22]=[CH:23][C:24]=3[CH3:25])=[O:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1ccc(-c2ccc(Cl)cc2)s1
Reactant: CN
Product: CNC(=O)c1ccc(C)c(NC(=O)c2ccc(-c3ccc(Cl)cc3)s2)c1
Yield: 73 %

Procedure:
The title compound (Example 186) was prepared by reacting 3-(5-(4-chlorophenyl)thiophene-2-carboxamido)-4-methylbenzoic acid C with methylamine using the method described in Example 128 to afford a white solid in 73% yield. HPLC Ret. Time=3.51 min, LCMS [M+H]+ 385.08.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][N:12]3[CH:21]=2)=[CH:5][CH:4]=1.C(O)C.C(O)(=O)C>[Pd].[OH-].[NH4+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:14][CH2:13][N:12]3[CH:21]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cn3ccc4ccccc4c3n2)cc1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(-c2cn3c(n2)-c2ccccc2CC3)cc1
Reaction time: 3 h

Procedure:
To a one liter autoclave are charged 7.1 g. of 2-(4-methoxyphenyl)imidazo[2,1-a]isoquinoline, 210 ml. of ethanol, 150 ml. of acetic acid and 0.55 g. of 10% palladium on charcoal. After flushing and filling the autoclave with hydrogen, the mixture is hydrogenated at 90° C. and 10 atmospheres for 3 hours. After absorption of 1.5 atmospheres of hydrogen gas, the autoclave is cooled and vented and 200 ml. of CHCl3 is added to the reaction mixture. The catalyst is filtered off, and the solution is evaporated to dryness, giving a solid residue which is suspended in 10% ammonium hydroxide, then extracted with dichloromethane. After drying over Na2SO4, the organic solvent is evaporated off and the residue is crystallized from ethanol giving 4.55 g. of the title product, which melts at 179°-81° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10]([O:12][C:13](OCC)([O:19]CC)[C:14](OCC)=O)[CH3:11]>>[CH2:10]([O:12][C:13]([C:14]1[O:9][C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=2[N:1]=1)=[O:19])[CH3:11]
Reactant: CCOC(=O)C(OCC)(OCC)OCC
Reactant: Cc1cccc(O)c1N
Product: CCOC(=O)c1nc2c(C)cccc2o1
Temperature: 110 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To 2-amino-3-methylphenol (1 g, 8.1 mmol) was added ethyl triethoxyacetate (5.4 g, 3 eq). The mixture was stirred at 110° C. overnight. The reaction mixture was cooled and triturated with hexane. Filtration gave 1.36 g of 4-methyl-benzooxazole-2-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][C:15]([CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[C:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:17]=2)[CH:12]=[C:11]1[C:42](=O)[CH:43]([CH3:45])[CH3:44])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Si:25]([O:24][CH2:23][C:15]1[C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][C:18]2[N:10]3[CH2:9][CH2:8][N:7]=[C:42]([CH:43]([CH3:45])[CH3:44])[C:11]3=[CH:12][C:13]=2[CH:14]=1)([C:38]([CH3:41])([CH3:39])[CH3:40])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)C(=O)c1cc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc2n1CCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of tert-butyl(2-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-2-isobutyryl-6-(methylsulfonyl)-1H-indol-1-yl)ethyl)carbamate (250 mg, 0.37 mmol) in CH2Cl2 (5.0 mL) was added trifluoroacetic acid (1.0 mL) and the mixture was allowed to stir at rt for 1 h. The excess amount of TFA was removed by azeotropic evaporation with toluene under reduced pressure. The residue was redissolved in CH2Cl2 (5 mL) and Et3N (0.5 mL) was added. The reaction mixture was stirred at rt for 45 min and concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluting with CH2Cl2/methanol (98/2) to provide 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-3,4-dihydropyrazino[1,2-a]indole (135 mg, 65% yield). LC-MS m/z 559 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][N:33]=2)=[CH:27][CH:26]=1)[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:24]=[CH:23][C:22]3[O:21][CH2:20][O:19][C:18]=3[CH:17]=2)[CH2:11][CH2:10]1)=[O:8])=[O:4].[CH3:41][NH:42][CH3:43].O>C(#N)C>[CH3:41][N:42]([CH3:43])[CH2:2][C:3]([N:5]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][N:33]=2)=[CH:27][CH:26]=1)[CH2:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:24]=[CH:23][C:22]3[O:21][CH2:20][O:19][C:18]=3[CH:17]=2)[CH2:11][CH2:10]1)=[O:8])=[O:4]
Reactant: CNC
Reactant: O=C(CN(C(=O)CCl)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Solvent: CC#N
Solvent: O
Product: CN(C)CC(=O)N(CC(=O)N1CCN(Cc2ccc3c(c2)OCO3)CC1)c1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-N-[4-(5-nitropyridin-2-yloxy)phenyl]-N-[2-(4-piperonylpiperazin-1-yl)-2-oxoethyl]acetamide (0.300 g, 0.528 mmol) in acetonitrile (3 mL) was added at room temperature dimethylamine (0.150 mL, 1.63 mmol), and the resulting solution was stirred for 2 hours at 50° C. Water was added to the reaction mixture, and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate, evaporated, and the residue was purified by silica gel column chromatography (dichloromethane:methanol=10:1), to thereby yield 0.270 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1)([O-:3])=[O:2].Cl.[CH3:22]O>>[CH3:22][O:19][C:18](=[O:20])[CH2:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:12][CH:13]=1
Reactant: O=C(O)Cc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A mixture of [4-(2-nitro-phenylamino)-phenyl]-acetic acid (1.0 g, 3.68 mmol) and HCl conc. (0.4 mL) in MeOH (20 mL) is stirred and refluxed for 1 h, allowed to cool to rt, and concentrated in vacuo. The residue is diluted with CH2Cl2, washed with an aqueous saturated solution of NaHCO3, H2O, and brine, then dried (Na2SO4), filtered and concentrated. Silica gel column chromatography purification (Hexane/EtOAc, 4:1) of the crude product affords the title compound as a red oil: ES-MS: 287.0 [M+H]+; single peak at tR=5.01 min (System 1); Rf=0.20 (Hexane/EtOAc, 4:1).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15](=[O:17])[CH3:16])[CH:8]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:18].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O.C(=O)([O-])O.[Na+]>C1COCC1>[Br:18][CH2:16][C:15]([C:7]1[CH:8]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=1)=[O:17]
Reactant: CC(=O)c1cc(C(C)(C)C)cc(C(C)(C)O)c1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(C(=O)CBr)cc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.7 %

Procedure:
1-[3-tert-Butyl-5-(1-hydroxy-1-methylethyl)phenyl]ethanone (O2.100; 50 mg) was initially charged in THF (5 ml) while stirring at RT, and admixed with phenyltrimethylammonium tribromide (80 mg). After stirring at RT for 3 h, the mixture was left to stand overnight and admixed with water and saturated sodium hydrogencarbonate solution. Then it was extracted three times with EA, and the combined EA phases were dried over sodium sulfate, filtered and concentrated. The residue was purified using silica gel (10 g cartridge, n-heptane/EA gradient). 42 mg of the title compound were obtained. LC-MS rt: 1.10 min [M+H—H2O]+: 295.1 (met. b)
Reaction SMILES: C(OC([NH:6][NH:7][C:8]([CH:10]([N:12]([S:21]([CH3:24])(=[O:23])=[O:22])[C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])[CH3:11])=[O:9])=O)C>C(O)C.[OH-].[Na+]>[NH:7]([C:8]([CH:10]([N:12]([S:21]([CH3:24])(=[O:23])=[O:22])[C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:20])[CH3:11])=[O:9])[NH2:6]
Reactant: CCOC(=O)NNC(=O)C(C)N(c1c(C)cccc1C)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(C)c1N(C(C)C(=O)NN)S(C)(=O)=O

Procedure:
A solution of N-[1-(2-(ethoxycarbonyl)hydrazinocarbonyl)ethyl]-2',6'-dimethylmethanesulphonanilide (5.6 g) in ethanol (75 ml) and 10% sodium hydroxide solution (75 ml) was heated on a steam bath for 21/2 hours, and then the ethanol was evaporated off. The aqueous solution remaining was acidified with dilute hydrochloric acid, heated on a steam bath for 1 hour, and then filtered. The filtrate was just neutralised with dilute sodium hydroxide solution, saturated with sodium chloride and extracted with chloroform. The chloroform solution was dried and evaporated, and the residue gave colourless crystals of N-[1-(hydrazinocarbonyl)ethyl]-2',6'-dimethylmethanesulphonanilide from a solution in toluene/60°-80° petrol. Yield 2.6 g (58%). Melting point 115°-118°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=1>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:28][C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][N:30]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Reactant: Nc1ccc(Br)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (1.97 g, 9.2 mmol) was dissolved in 150 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (3.7 mL, 45.8 mmol) followed by the dropwise addition of oxalyl chloride (2 mL, 22.9 mmol). A precipitate forms immediately. The reaction was stirred vigorously at 0° C. for 2 hours, then at ambient temperature for one hour. Added 100 mL diethyl ether, filtered off solids washing with diethyl ether. Concentrated the filtrates to an off-white oil. Redissolved oil in 100 mL dry DCM under Ar, cooled to 0° C., added 3 mL pyridine followed by 2-amino-5-bromopyridine (1.32 g, 7.6 mmol). The reaction was allowed to warm to ambient temperature, stirred for 3 hours then concentrated. Redissolved in 250 mL EtOAc, washed with 10% HCl (3×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated to yield title compound as a yellow sticky solid. (2.74 g, 97%) APCI (AP−): 368.0, 370.0 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]=O)=[C:9]([O:16][CH3:17])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:18].[H-].[Na+].[CH3:21][N:22]1[CH:26]=[C:25]([C:27]2[C:32]3[N:33]=C(S(C)(=O)=O)[N:35]=[CH:36][C:31]=3[CH:30]=[CH:29][N:28]=2)[CH:24]=[N:23]1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:35]=[CH:36][C:31]4[CH:30]=[CH:29][N:28]=[C:27]([C:25]5[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=5)[C:32]=4[N:33]=3)=[C:9]([O:16][CH3:17])[CH:8]=2)=[CH:5][N:4]=[C:3]1[CH3:18]
Reactant: COc1cc(-c2cnc(C)n2C)ccc1NC=O
Reactant: Cn1cc(-c2nccc3cnc(S(C)(=O)=O)nc23)cn1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(-c2cnc(C)n2C)ccc1Nc1ncc2ccnc(-c3cnn(C)c3)c2n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 14 %

Procedure:
A solution of N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)formamide (Preparation 55, 37 mg, 0.151 mmol) in THF (1 mL) was treated with sodium hydride (10 mg, 0.250 mmol) at 0° C. After stirring for 20 minutes at room temperature, the mixture was cooled to 0° C. and 8-(1-methyl-1H-pyrazol-4-yl)-2-(methylsulfonyl)pyrido[3,4-d]pyrimidine (Preparation 35, 50 mg, 0.173 mmol) was added. The reaction was allowed to reach room temperature and stirred for 18 hours. Aqueous NaOH (2M, 0.5 mL) and MeOH (0.5 mL) were added and the resulting mixture stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layers were washed with water, brine, dried and evaporated. The residue was purified by silica gel column chromatography eluting with 0 to 10% MeOH in EtOAc to give the title compound (9 mg, 14%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:29]([N:31]1[CH2:35][CH2:34][C@H:33]([F:36])[CH2:32]1)=[O:30])[C@H:10]([CH:12]1[CH2:17][CH2:16][CH:15]([NH:18]C(=O)OCC2C=CC=CC=2)[CH2:14][CH2:13]1)[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:29]([N:31]1[CH2:35][CH2:34][C@H:33]([F:36])[CH2:32]1)=[O:30])[C@H:10]([CH:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1)[CH3:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](C1CCC(NC(=O)OCc2ccccc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H](C1CCC(N)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1

Procedure:
To a solution of the slower eluting diastereomer of the material prepared in Step A (0.60 g, 1.2 mmol) in methanol (100 mL) was added 10% palladium on carbon (0.20 g). The mixture was placed under 3 atm of hydrogen gas for 3 h, then filtered through Celite. The solution was then concentrated in vacuo, affording the title compound as a clear oil. LC/MS 372.3 (M+H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])=[O:12]>C(O)C>[CH3:21][O:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C:11](=[O:12])[CH2:10][NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COc1ccccc1NC(=O)CCl
Solvent: CCO
Product: COc1ccccc1NC(=O)CNCc1ccccc1

Procedure:
To ethanol (100 mL) add benzylamine (35 g, 0.33 mol) and 2-chloro-N-(2-methoxyphenyl)acetamide (22 g, 0.11 mol). Stir and heat the reaction at 50° C. Monitor the progress of the reaction by thin-layer chromatography. Upon completion of the reaction remove the precipitate that has formed by suction filtration and discard. Evaporate the filtrate and partition the residue between ethyl acetate and 2N NaOH(aq). Separate the organic layer and dry it over Na2SO4. Remove the drying agent by filtration and remove the solvent in vacuo. Chromatograph the residue on silica gel (400 g) using hexane/EtOAc (3/1) as eluent to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][CH2:6][CH:5]([CH2:8][OH:9])[CH2:4][O:3]1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=1[CH3:22]>CS(C)=O>[CH3:1][C:2]1([CH3:10])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:14]2[CH:19]=[CH:18][N+:17]([O-:20])=[C:16]([CH3:21])[C:15]=2[CH3:22])[CH2:4][O:3]1
Reactant: Cc1c(Cl)cc[n+]([O-])c1C
Reactant: CC1(C)OCC(CO)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1c(OCC2COC(C)(C)OC2)cc[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.8 %

Procedure:
To a dimethyl sulfoxide (30 ml) solution of the (2,2-dimethyl-1,3-dioxan-5-yl)methanol (3.27 g, 22.4 mmol) separately obtained in the same manner as in the step (11a) in example 11, sodium hydride, in oil (837 mg, 20.9 mmol as the content was regarded as 60%) was added at room temperature. The mixture was stirred at room temperature for 15 minutes in a nitrogen atmosphere. To the mixture, 4-chloro-2,3-dimethylpyridine 1-oxide (3.03 g, 19.2 mmol) was added, and the mixture was stirred at 60° C. for 3 hours and 20 minutes. After cooled to room temperature, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography (NH silica gel: 250 g, elution solvent: ethyl acetate, ethyl acetate/methanol=10/1) to obtain the title compound (3.84 g, yield: 74.8%) as a pale brown solid.