Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:4]2([CH2:8][CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][CH2:5]2)[CH2:3][N:2]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:45][O:46][C:47]([NH:49][C@H:50]([C:54](O)=[O:55])[CH:51]([CH3:53])[CH3:52])=[O:48].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:45][O:46][C:47]([NH:49][C@H:50]([C:54]([N:6]1[CH:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:8][C:4]2([CH2:3][N:2]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])[CH2:1]2)[CH2:5]1)=[O:55])[CH:51]([CH3:52])[CH3:53])=[O:48]
Reactant: CCOC(=O)C1CC2(CN1)CN(C(=O)OC(C)(C)C)C2
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CC2(CN(C(=O)OC(C)(C)C)C2)CN1C(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
To a solution of 2-(1,1-dimethylethyl) 7-ethyl 2,6-diazaspiro[3.4]octane-2,7-dicarboxylate (145) (500 mg, 1.76 mmol), HATU (735 mg, 1.93 mmol) and N-[(methyloxy)carbonyl]-L-valine (339 mg, 1.93 mmol) in anhydrous CH2Cl2 (10 mL) was added Hunig's base (0.68 mL, 3.87 mmol) and the reaction stirred at room temperature under nitrogen for 2 h. The reaction was concentrated in vacuo and purified by C18 reverse-phase chromatography eluting with 10-90% ACN/water/0.2% NH4OH to afford the title compound as an off-white solid (398 mg, 51% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CN.CO>>[C:1]([O:5][C:6](=[O:42])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH2:16])=[CH:11][CH:10]=1)[CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCCCNC(=O)OCc1ccccc1)Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: CN
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCCNC(=O)OCc1ccccc1)Cc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 74 %

Procedure:
The compound (173 mg) obtained in Example 42-2 was added with a 40% methylamine/methanol solution (3.0 ml), followed by stirring at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off and the residue was then added with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The extract was dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off, thereby obtaining the subject compound (98.9 mg) as a colorless viscous liquid.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([NH2:5])=[O:4].O[Cl:15]>C(Cl)Cl>[Cl:15][NH:5][C:3](=[O:4])[CH:2]([CH3:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: OCl
Reactant: CCCCCCCCC(C)C(N)=O
Solvent: ClCCl
Product: CCCCCCCCC(C)C(=O)NCl
Temperature: 2 °C
Reaction time: 0.25 h
Yield: 94.4 %

Procedure:
2-Methyl decanamide (50 g, 270 mmol) was suspended in 300 ml of methylene chloride, cooled to 2° C. and aqueous HOCl (14.72 g, 280 mmol) was added over about 10 minutes. The mixture was stirred in the cold for 15 minutes, then at room temperature for 45 minutes. The methylene chloride layer was separated, dried over magnesium sulfate, and the solvent removed on a rotary evaporator in a warm water bath to give 56 g (94% yield) of white solid product, m.p. 56°-57° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13](=O)[CH2:14][CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+].CC1C=CC(C2SC(CCCCC(OCC)=O)=CC=2)=CC=1.[OH-].[Na+]>FC(F)(F)C(O)=O.O1CCCC1.O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCC(=O)c1ccc(-c2ccc(C)cc2)s1
Agent: CCOC(=O)CCCCc1ccc(-c2ccc(C)cc2)s1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccc(CCCCC(=O)O)s2)cc1
Reaction time: 96 h
Yield: 73.8 %

Procedure:
To a solution of ethyl 5-[5-(4-methylphenyl)thiophen-2-yl]-5-oxovalerate (4.50 g) in trifluoroacetic acid (7.66 ml) was added triethylsilane(5.7 ml) at room temperature, and the mixture was stirred for 4 days. To the reaction mixture was added ethyl acetate, and the mixture was made alkaline with saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1:9) to give crude ethyl 5-[5-(4-methyl-phenyl)thiophen-2-yl]valerate. To a solution of the crude ethyl 5-[5-(4-methylphenyl)thiophen-2-yl]valerate in tetrahydrofuran (50 ml) was added 1N sodium hydroxide (20 ml) at room temperature, and the mixture was stirred for 24 hours. To the reaction mixture was added water, and the mixture was washed with diethylether. The aqueous layer was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure to precipitate crystals, which were collected by filtration and washed with hexane to give 5-[5-(4-methylphenyl)-thiophen-2-yl]valeric acid (2.88 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[C:6]([C:7]2[CH:12]=[C:11]([CH2:13][OH:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:5][CH2:4][CH2:3]1.[H-].[Na+].[Br:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30](F)[CH:29]=1>CN(C=O)C.O>[Br:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([O:14][CH2:13][C:11]2[CH:10]=[CH:9][C:8]([C:15]3[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=3[F:23])=[C:7]([C:6]3[C:2]([CH3:24])([CH3:1])[CH2:3][CH2:4][CH:5]=3)[CH:12]=2)[CH:29]=1
Reactant: Fc1cc(Br)ccn1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2C2=CCCC2(C)C)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(COc3cc(Br)ccn3)cc2C2=CCCC2(C)C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A dry round bottom flask containing 14.3 (0.0937 g, 0.287 mmol) in dry DMF (1 mL) was cooled in an ice bath. After 10 minutes, sodium hydride (60% wt. in oil) (15.4 mg, 0.385 mmol) was added carefully, and the mixture was stirred at 0° C. After 10 minutes, 4-bromo-2-fluoropyridine (commercially available from Synthonix Corporation) (0.0511 g, 0.290 mmol) was added. The reaction was allowed to stir overnight at room temperature. After 18 hours, the reaction was diluted with water and extracted five times with EtOAc. The combined organic layers were then washed one time with brine and dried over anhydrous magnesium sulfate. The solid was filtered off, and the solvent was concentrated. The residue was purified by silica gel flash chromatography (0-45% EtOAc/hexane) to afford 95.A (105.9 mg, 76% yield). 1H NMR (400 MHz) (CDCl3) δ ppm 8.02 (1H, d, J=4.7 Hz), 7.41 (1H, m), 7.35 (2H, m), 7.08 (2H, m), 7.00 (1H, m), 6.79 (2H, dt, J=5.1, 2.5 Hz), 5.52 (1H, s), 5.42 (2H, s), 3.76 (3H, s), 2.25 (2H, td, J=6.9, 2.5 Hz), 1.67 (2H, t, J=7.0 Hz), 0.87 (6H, s).
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][C:15]1[C:16]([CH3:26])=[N:17][O:18][C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[CH3:27][C:28]1[N:29]=[C:30]([N:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])[S:31][C:32]=1[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH3:27][C:28]1[N:29]=[C:30]([N:38]2[CH2:42][CH2:41][N:40]([CH2:14][C:15]3[C:16]([CH3:26])=[N:17][O:18][C:19]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:39]2=[O:43])[S:31][C:32]=1[C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: Cc1noc(-c2ccccc2)c1CBr
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(Cc3c(C)noc3-c3ccccc3)C2=O)nc1C
Yield: 87 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 4-(bromomethyl)-3-methyl-5-phenylisoxazole to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 87% yield: MS (ES+) m/z 427.2 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12](O)=[O:13])=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].[CH3:29][S:30][CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:29][S:30][CH2:31][CH2:32][NH:33][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:13]
Reactant: CSCCN
Reactant: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Nc2nc3ccc(C(F)(F)F)cc3s2)nc2cc(C(=O)NCCSC)ccc21
Yield: 37.9 %

Procedure:
1-Ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methylsulfanyl-ethyl)-amide (67.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethyl-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (150.0 mg), 2-methylsulfanyl-ethylamine (45.0 mg), HBTU (200.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 481; and 1H NMR (DMSO-d6, 400 MHz): δ 8.59 (1H, br. s), 8.26 (1H, br. s), 8.11 (1H, br. s), 7.76-7.68 (2H, m), 7.56 (1H, m), 4.25 (2H, bs. s), 3.51-3.46 (2H, q), 3.32 (2H, s), 2.70-2.66 (2H, t), 2.12 (3H, s), 1.35-1.32 (3H, t).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][OH:12])=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18].[CH:19]([Mg]Cl)([CH3:21])[CH3:20].[Cl-].[NH4+]>O1CCCC1.C(OCC)C.O.C(OCC)(=O)C.[Cu]I>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[C:10](\[CH:19]([CH3:21])[CH3:20])/[CH2:11][OH:12])=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18]
Reactant: COCCCOc1cc(C#CCO)ccc1OC
Reactant: CC(C)[Mg]Cl
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COCCCOc1cc(/C=C(/CO)C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
A dried 50 ml Schlenk tube is charged under an argon atmosphere with a solution of 4.034 mmol of 3-[4-methoxy-3-(3-methoxypropoxy)phenyl]prop-2-yn-1-ol in 20 ml of tetrahydrofuran. The solution is admixed with 0.403 mmol of solid copper(I) iodide and the suspension is cooled to 0° C. Subsequently 6.05 ml of a 2.0 molar isopropyl-magnesium chloride solution in diethyl ether are added. The resulting mixture is stirred at 0° C. over 3.5 hours. The reaction mixture is then poured onto saturated aqueous ammonium chloride solution at 0° C. and then diluted with water and ethyl acetate. The phases are separated; the aqueous phase is extracted with ethyl acetate (2×). The combined organic phases are washed with brine, dried over sodium sulphate, filtered and concentrated by evaporation on a rotary evaporator. The title compound A2 is obtained as a yellow oil (967 mg) from the residue by means of flash chromatography (SiO2 60 F, 2:1 ethyl acetate-hexane). Rf=0.48 (2:1 ethyl acetate-heptane); Rt=3.97 (gradient I).
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=2[O:2]1.[Cl:12][C:13]1[N:14]=[C:15](Cl)[C:16]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:17]=2[N:18]=1>>[Cl:12][C:13]1[N:14]=[C:15]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]3[O:11][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:17]=2[N:18]=1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CCc1cc2c(Cl)nc(Cl)nc2s1
Product: CCc1cc2c(NCc3ccc4c(c3)OCO4)nc(Cl)nc2s1

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxybenzylamine with 2,4-dichloro-6-ethyl-thieno-[2,3-d]-pyrimidine gives 2-chloro-6-ethyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine Mp. 148° C.
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](SC2C=CC(S(O)(=O)=O)=CC=2)=[CH:4][C:3]=1OC1C=CC(S(O)(=O)=O)=C(N)C=1.N1C(Cl)=NC(Cl)=NC=1Cl.NC1C=C(S(O)(=O)=O)C=CC=1>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cc(Oc2cc(Sc3ccc(S(=O)(=O)O)cc3)c3c(c2N)C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)O
Agent: Clc1nc(Cl)nc(Cl)n1
Agent: Nc1cccc(S(=O)(=O)O)c1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
1-Amino-2-(3'-amino-4'-sulfophenoxy)-4-(4'-sulfophenylthio)anthraquinone (6 parts), cyanuric chloride (1.8 parts) and 1-aminobenzene-4-β-sulfatoethylsulfone (2.8 parts) were subjected to condensation reactions one after another in an aqueous medium in a conventional manner, followed by a successive condensation reaction with 3-aminobenzenesulfonic acid (1.7 parts) at 50° to 70° C. under a weak acid condition. Thereafter, salting out of the reaction mixture gave an anthraquinone compound of following formula (free acid form). ##STR117##
Reaction SMILES: ClC1C=CC(C([N:8]2[CH2:13][CH2:12][C:11]3[C:14]4[C:15]([S:43][C:10]=3[CH2:9]2)=[N:16][C:17]([CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])=[C:18]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:19]=4[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([O:30][CH3:31])[CH:21]=2)=O)=CC=1.[OH-].[K+].C(O)C>O>[CH2:41]([N:38]([CH2:37][C:17]1[N:16]=[C:15]2[S:43][C:10]3[CH2:9][NH:8][CH2:13][CH2:12][C:11]=3[C:14]2=[C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([O:30][CH3:31])[CH:21]=2)[C:18]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:39][CH3:40])[CH3:42]
Reactant: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC(C)C)c(OC)c1)CCN(C(=O)c1ccc(Cl)cc1)C3
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(CN(CC)CC)nc2sc3c(c2c1-c1ccc(OC(C)C)c(OC)c1)CCNC3
Reaction time: 5 h
Yield: 92.8 %

Procedure:
A mixture of the compound (8.9 g) obtained in Example 48A, 4N KOH (18 ml) and ethanol (150 ml) was stirred under refluxing conditions for 5 hours. The reaction mixture was poured over water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (4:1, v/v) to yield ethyl 2-diethylaminomethyl-4-(4-isopropoxy-3-methoxyphenyl)-5,6,7,8-tetrahydrothieno[2,3-b:5,4-c']dipyridine-3-carboxylate (6.5 g, 88%), which was then recrystallized from ethyl acetate-hexane to yield colorless prismatic crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[CH:12]=2)[NH:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:23]([S:26][CH2:27][CH:28]([CH3:32])[C:29](Cl)=[O:30])(=[O:25])[CH3:24]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:15][CH3:16])[CH:12]=2)[N:7]1[C:29](=[O:30])[CH:28]([CH3:32])[CH2:27][S:26][C:23](=[O:25])[CH3:24])=[O:5])[CH3:2]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CCOC(=O)C1Cc2cc(OC)ccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)C1Cc2cc(OC)ccc2N1C(=O)C(C)CSC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the stirred mixture of 4.0 g of 5-methoxyindoline-2-carboxylic acid ethyl ester, 5.0 g of powdered potassium carbonate and 50 ml of methylene chloride, 3.3 g of 3-acetylthio-2-methylpropanoyl chloride in 10 ml of methylene chloride are added during 1 minute. After stirring for 2 hours at reflux the mixture is cooled to room temperature and partitioned between 50 ml of water and 100 ml of diethyl ether. The organic layer is washed with 50 ml of water, 50 ml of 1N hydrochloric acid and 50 ml of saturated aqueous sodium chloride, dried and evaporated, to give the 1-(3-acetylthio-2-methylpropanoyl)-5-methoxyindoline-2-carboxylic acid ethyl ester as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[CH:14]=2)[N:5]=[C:4]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)[CH:3]=1.[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>O1CCOCC1>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:2]2[N:7]=[C:6]([N:8]3[CH2:12][CH2:11][CH2:10][CH:9]3[C:13]3[O:17][N:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[CH:14]=3)[N:5]=[C:4]([NH:24][C:25]3[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=3)[CH:3]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(Nc2cc(Cl)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)nc(N3CCCC3c3cc(-c4ccccn4)no3)n2)n[nH]1
Temperature: 160 °C
Yield: 24.7 %

Procedure:
A mixture of 6-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)-2-[2-{3-(pyrid-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Example 17) (250 mg, 0.6 mmol) and N-(tert-butoxycarbonyl)piperazine (222 mg, 6.0 mmol) in 1,4-dioxane (4 ml) was heated at 160° C. in a sealed vessel under microwave irradiation for 90 minutes. The crude reaction mixture was purified by reverse phase HPLC using a C18 column eluting with water/acetonitrile/TFA (95:5:0.2 decreasing in polarity to 0:100:0.2). Product containing fractions were combined and passed through an isolute SCX-2 ion exchange column. The column was eluted with methanol to elute any neutrals, followed by 7M methanolic ammonia to elute the product. The solvent was removed by evaporation to afford the desired product (85 mg, 25%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.CCCCC.[CH2:28]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][CH:42]=[O:43])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:17])[CH2:16][CH:42]([OH:43])[CH2:41][CH:38]2[CH2:37][CH2:36][N:35]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:40][CH2:39]2)=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: O=CCC1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)CC(O)CC2CCN(Cc3ccccc3)CC2)cc1
Yield: 62.7 %

Procedure:
50 ml of tetrahydrofuran was added to 3.80 g of N-t-butoxycarbonyl-4-acetylaniline, and 19.0 ml of a 1.7M t-butyl lithium·pentane solution was added dropwise thereto under an argon stream at -78° C. Subsequently, a solution of 3.50 g of (1-benzylpiperidin-4-yl)acetaldehyde dissolved in 10 ml of tetrahydrofuran was added to the mixture, and the resulting mixture was stirred until its temperature was returned to room temperature. Then, a saturated ammonium chloride aqueous solution was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. Then, the solvent was removed by distillation under reduced pressure, and the obtained residue was applied to silica gel column chromatography to obtain 4.57 g of the title compound as white powder.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=1)=O.[C:13]([NH2:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:13]2[O:20][CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=3)[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)c1ccccc1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Product: N#Cc1ccc(-c2coc(-c3ccccc3)n2)cc1
Temperature: 135 °C
Yield: 66 %

Procedure:
The mixture of the 2-bromo-1-(4-cyanophenyl)ethanone (4 g, 17.85 mmol) and benzamide (5.41 g, 44.6 mmol) was heated to 135° C. for 3 hours. Then the reaction mixture was cooled, and partitioned between diethyl ether and water. The aqueous layer was extracted with ether twice, and the combined organic layers were washed with 1N NaOH, 1N HCl, water, and brine, dried over MgSO4. After concentration, the solid residue was dissolved in CHCl3. The insoluable solid was filtered through a frits funnel and discarded. The CHCl3 solution was filtered through a pad of silica and evaporate to dryness to give 2.9 g (66% yield) of 4-(2-phenyl-1,3-oxazol-4-yl)benzonitrile. LCMS: m/z 247.1 (M+H)+.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH2:17][C:18]([NH:20][O:21]C(OCC)(C)C)=[O:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1.Cl>CCOC(C)=O>[F:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)[CH2:17][C:18]([NH:20][OH:21])=[O:19])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: CCOC(C)(C)ONC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OCCCCF)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CN(CC(=O)NO)S(=O)(=O)c2ccc(OCCCCF)cc2)cc1

Procedure:
A solution of 0.22 g of 2-{[4-(4-fluorobutoxy)-benzenesulfonyl](4-methoxy-benzyl)amino}-N-(1-ethoxy-1-methyl-ethoxy)acetamide in 30 ml of AcOEt is treated with 7 ml of 5N aqueous HCl for 10 min. at r.t. and the mixture is extracted with AcOEt. The combined extracts are washed with sat. NaHCO3 and brine, dried over MgSO4 and concentrated under reduced pressure to give solids which are washed with ether to afford 2-{[4-(4-fluorobutoxy)-benzenesulfonyl]-(4-methoxy-benzyl)amino]-N-hydroxy-acetamide; NMR (CDCl3): 1.83-2.05 (m, 4H), 3.69 (s, 2H), 3.78 (s, 3H), 4.09 (t, 2H, J=5.56 Hz), 4.25 (s, 2H), 4.48 (t, 1H, J=5.52 Hz), 4.55-4.65 (m, 1H), 6.84 (d, 2H, J=8.56 Hz), 7.00 (d, 2H, J=9.04 Hz), 7.02 (br s, 1H), 7.15 (d, 2H, J=8.56 Hz), 7.77 (d, 2H, J=8.56 Hz), 8.85 (br s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][C@@H:5]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([CH:25]([F:27])[F:26])[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][C:11]=2[CH3:33])=[O:9])[C@H:4]([CH3:34])[CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:30]1([CH2:29][O:28][C:20]2[CH:21]=[CH:22][C:23]([CH:25]([F:27])[F:26])=[CH:24][C:19]=2[C:18]2[C:13]3[NH:12][C:11]([CH3:33])=[C:10]([C:8]([NH:7][C@@H:5]4[CH2:6][C@@H:2]([NH:1][C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:3][C@H:4]4[CH3:34])=[O:9])[C:14]=3[N:15]=[CH:16][N:17]=2)[CH2:32][CH2:31]1
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1C[C@@H](N)C[C@H]1C
Reactant: COCC(=O)Cl
Product: COCC(=O)N[C@H]1C[C@@H](C)[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from N-[(1R*,2R*,4S*)-4-amino-2-methylcyclopentyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f69) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([S:18][C:19]3[CH:20]=[C:21]([C:25]([OH:30])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=3)=[CH:7][CH:8]=2)[N:3]=1.Cl[CH2:32][CH:33]=O.C(=O)(O)[O-].[Na+].O>O1CCOCC1>[C:12]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([S:18][C:19]4[CH:20]=[C:21]([C:25]([OH:30])([CH2:28][CH3:29])[CH2:26][CH3:27])[CH:22]=[CH:23][CH:24]=4)=[CH:7][CH:8]=3)[N:3]3[CH:32]=[CH:33][N:1]=[C:2]3[CH:11]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc(N)nc3c2)c1
Reactant: O=CCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCC(O)(CC)c1cccc(Sc2ccc3c(-c4ccccc4)cc4nccn4c3c2)c1
Temperature: 80 °C

Procedure:
To 10q (200 mg, 0.48 mmol) in 1,4-dioxane (4 mL) was added chloroacetaldehyde (0.07 mL, 0.53 mmol), sodium bicarbonate (243 mg, 2.89 mmol), and water (2 mL). The mixture was heated to 80° C. for 5 hours, and then cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 10r.