Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[N:10]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:15][CH2:14][CH:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:28]([C:13]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11][N:10]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:15][CH2:14]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(Cc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
Diisopropyl ethylamine (6.5 ml) in dry THF (25 ml) cooled the contents to about −10° C. then N-butyl lithium (1.6 M, 23 ml) was added drop wise under nitrogen atmosphere and maintain the same temperature for about 45 minutes and cooled to about −75° C. for about 15 minutes then 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (step 1, 5 g) in THF (30 ml) was added and stirred for about 30 minutes then increase the reaction temperature to −35° C. and stirred for about 45 minutes and again cooled to −75° C. then benzyl bromide (3.5 g in 20 ml THF) was added drop wise and slowly allowed the reaction to room temperature and stirred the reaction for about 12 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with sat. NaHCO3 followed by brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 3% ethyl acetate in hexane as eluent to furnish the title compound as a light yellow colour liquid. 1H NMR (300 MHz, CDCl3): 1.16-1.18 (t, 3H); 1.44 (s, 9H); 2.07-2.11 (m, 2H); 2.28 (s, 1H); 2.82 (s, 2H); 2.92-2.95 (m, 1H); 3.46-3.52 (m, 3H); 4.09-4.11 (m, 2H); 7.03-7.06 (m, 2H); 7.23-7.24 (m, 3H); ES Mass: 370 (100%) [M+Na].
Reaction SMILES: C1(NC([O:10][C@H:11]2[C@H:18]([OH:19])[CH2:17][O:16][C@@H:13]([O:14][CH3:15])[C@@H:12]2[OH:20])=O)C=CC=CC=1.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([O:20][C@@H:12]1[C@@H:11]([OH:10])[C@H:18]([O:19][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][O:16][C@H:13]1[O:14][CH3:15])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: CO[C@@H]1OC[C@@H](O)[C@H](OC(=O)Nc2ccccc2)[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CO[C@@H]1OC[C@@H](OCc2ccccc2)[C@H](O)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of methyl 3-O-phenylcarbamoyl-b-D-xylopyranoside (73.6 g, 0.26 mole) in DMF (300 ml) was added by portions 60% NaH in oil (36.0 g, 0.9 mole). After stirring at room temperature for 30 min, benzyl bromide (113 ml, 0.95 mole) was added dropwise to the reaction mixture. After the addition was completed, the stirring was continued for 3 hr. The reaction mixture was evaporated under reduced pressure and the oily residue was partitioned between ether (500 ml) and water (500 ml). The ether layer was dried over anhydrous sodium sulfate, evaporated to dryness under reduced pressure. The resulting amber viscous oil (150 g) was dissolved in 28% NaOMe--MeOH, (750 ml) and heated under reflux for 19 hrs. The reaction mixture was evaporated to dryness under reduced pressure. The oily residue was partitioned between ether (500 ml) and water (500 ml). The ether layer was washed with water (250 ml×2), and evaporated to dryness under reduced pressure. The residue was chromatographed on silica gel using CH2Cl2 /AcOEt (95:5) as an eluent to give methyl 2,4-di-O-benzyl-b-D-xylopyranoside (80.5 g, 90% yield) as amorphous powder; EI-MS: m/z 344 (M+); 1H-NMR (CDCl3)d: 2.54 (1H,d,J=2.5 Hz), 3.21 (1H,dd,J=7.5 & 9 Hz), 3.22 (1H,dd,J=10 & 12 Hz), 3.52 (3H,s), 3.49 (1H,m), 3.68 (1H,t,J=9 Hz), 3.93 (1H,dd,J=6 & 12 Hz), 4.25 (1H,d,J=7.5 Hz), 4.63 (1H,d,J=12 Hz), 4.66 (1H,d,J=11.5 Hz), 4.75 (1H,d,J=12 Hz), 4.90 (1H,d,J=12 Hz), 7.31 (10H,br.s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1Cl.[CH3:11][C@@H:12]1[CH2:17][NH:16][CH2:15][CH2:14][NH:13]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[N:16]1[CH2:15][CH2:14][NH:13][C@H:12]([CH3:11])[CH2:17]1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: C[C@@H]1CNCCN1
Product: C[C@@H]1CN(c2ncc(CO)cc2Cl)CCN1

Procedure:
A mixture of (5,6-dichloro-pyridin-3-yl)-methanol (356 mg, 2.0 mmol, Aldrich) and (R)-(−)-2-methyl-piperazine (240 mg, 2.4 mmol, Aldrich reacted under the conditions of Example 3a to give the title compound. MS (ESI, pos. ion) m/z: 242 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:16]([NH:23][C@H:24]([C:26](O)=[O:27])[CH3:25])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:19]([O:18][C:16](=[O:17])[NH:23][C@H:24]([C:26](=[O:27])[NH:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][N:11]=1)[CH3:25])([CH3:20])([CH3:21])[CH3:22]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(F)cc1Nc1ccncn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1ccncn1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
To 4-fluoro-N2-pyrimidin-4-ylbenzene-1,2-diamine (0.247 g, 1.21 mmol), Boc-alanine (0.24 g, 1.27 mmol), and HOAT (0.165 g, 1.21 mmol) in DCM at 0° C. under nitrogen was added N-(3-dimethylaminopropyl)-n′-ethylcarbodiimide hydrochloride (0.244 g, 1.27 mmol). The reaction was stirred and allowed to warm to RT overnight. The mixture was diluted with DCM (20 mL) and washed with 0.5M NaHCO3 (20 mL). The organic extract was dried (Na2SO4), concentrated in vacuo and purified by column chromatography (Si—PCC, gradient 0-8% (9:1 MeOH/0.880 NH3) in DCM). Product containing fractions were evaporated to give the title compound, (0.272 g, 60%) LCMS (Method J): RT=1.93 min, [M+H]+=376.20
Reaction SMILES: Cl.O.[Cl:3][C:4]1[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:5]=1[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCN(CC)CC>CO.[Fe]>[Cl:3][C:4]1[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:5]=1[N:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCN(CCCCCC)c1ccc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CCCCCCN(CCCCCC)c1ccc(N)cc1Cl
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
A mixture of concentrated hydrochloric acid (1.0 mL), water (50 mL) and iron powder (5.58 g, 100 mmol) was stirred at 65° C. for 15 min. The aqueous layer of the mixture was poured out, and a solution of 2-chloro-N,N-dihexyl-4-nitroaniline (3.41 g, 10 mmol) in MeOH (100 mL) was added to the above processed iron powder. The mixture was acidified to pH 3 with hydrochloric acid and stirred at 65° C. for 45 min. The mixture was then cooled to rt, adjusted to pH 10 with Et3N and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in 150 mL of DCM. The solution was washed with water (100 mL×3) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound as colorless oil (3.00 g, 97%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:5]=2[C:6]=1[N+:7]([O-:9])=[O:8].O.[OH-].[Na+]>C(OCC)(=O)C>[CH3:1][C:2]1[O:3][C:4]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:5]=2[C:6]=1[N+:7]([O-:9])=[O:8]
Reactant: Cc1oc2ccc([N+](=O)[O-])cc2c1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1oc2ccc(N)cc2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 70 h
Yield: 44.9 %

Procedure:
To a solution of 2-methyl-3,5-dinitrobenzofuran (4.4 g, 19.8 mmol) in ethyl acetate (250 mL) was added stannous chloride (dihydrate, 8.99 g, 39.8 mmol). The mixture was stirred at room temperature for 70 hours. Water (100 mL) and 1N NaOH (100 mL) were added. The mixture was extracted with ethyl acetate (4×150 mL). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo and the residue was chromatographed (silica, 20-30% ethyl acetate in hexanes) to give 2-methyl-3-nitro-5-benzofuranamine as a yellow solid (1.71 g, 45%): 1H-NMR (270 MHz, CDCl3) δ 7.38 (d, 1H, J=2.8 Hz), 7.25 (d, 1H, J=8.8 Hz), 6.72 (dd, 1H, J=8.8, 2.8 Hz), 2.87 (s, 3H); HPLC (Method A) tR=1.36 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C:11]([CH2:13][CH2:14]OS(C)(=O)=O)=[CH:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[C:21]1([CH3:29])[CH2:26][CH2:25][CH2:24][C:23]([CH3:28])(C)[NH:22]1.[CH3:30][C:31]#[N:32]>>[CH2:1]([N:8]1[CH2:12][C:11]([CH2:13][CH2:14][N:22]2[C@H:21]([C:29]3[C:11]([CH3:12])=[CH:10][CH:30]=[CH:31][N:32]=3)[CH2:26][CH2:25][CH2:24][C@@H:23]2[C:28]2[C:4]([CH3:5])=[CH:3][CH:2]=[CH:1][N:8]=2)=[CH:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: CS(=O)(=O)OCCC1=CNN(Cc2ccccc2)C1
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1CCC1=CNN(Cc2ccccc2)C1
Yield: 93 %

Procedure:
A mixture of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2′]terpyridine (0.320 g, 1.20 mmol), methanesulfonic acid 2-(2-benzyl-1H-pyrazol-4-yl)-ethyl ester (0.540 g, 1.60 mmol) and 2,2,6,6-tetramethylpiperidine (0.255 g, 1.80 mmol) in CH3CN (5 mL) was stirred and heated at reflux overnight. The solvent was then removed, water (20 mL) was added, and the mixture was extracted with CH2Cl2 (3×20 mL). The extracts were combined and dried over Na2SO4. After filtration the solvent was removed by evaporation under vacuum, and the residue was purified by flash chromatography on a silica gel column (500:15:1 CH2Cl2/CH3OH/NH4OH), affording (2′R,6′S)-1′-[2-(2-benzyl-1H-pyrazol-4-yl)-ethyl]-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine as a pale yellow oil (0.420 g, 93%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:34][C:35]1[O:39][C:38](B(O)O)=[CH:37][CH:36]=1>COCCOC.O.C(OCC)(=O)C.C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][C@H:20]1[NH:21][C@@H:22]([CH3:24])[CH2:23][N:18]([C:16]2[CH:15]=[CH:14][C:13]([O:26][CH3:27])=[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([C:38]4[O:39][C:35]([CH3:34])=[CH:36][CH:37]=4)=[CH:3][CH:4]=3)(=[O:10])=[O:9])[CH:17]=2)[CH2:19]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1
Reactant: Cc1ccc(B(O)O)o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccc(C)o2)cc1

Procedure:
4-Bromo-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (32.96 g, 72.5 mmol) was suspended in 1,2-dimethoxyethane (300 ml) and treated with sodium carbonate (38.4 g, 363 mmol) dissolved in water (150 ml). (5-Methyl-2-furanyl)boronic acid (13.7 g, 109 mmol) and bis(triphenylphosphine)palladium(II) chloride (108 mg, 0.15 mmol) were added and the mixture was heated at reflux for 1.5 hours. The mixture was cooled and diluted with ethyl acetate, charcoal added and the mixture was stirred with charcoal for 45 minutes. The mixture was filtered through celite, the filtrate separated and washed with saturated sodium bicarbonate solution, water (×3), brine, dried over anhydrous sodium sulfate and concentrated to a crude solid, titrated with pentane and filtered. The combined residues were purified by flash chromatography (Biotage Flash 75+L, dichloromethane to 1:10 2M ammonia in methanol: dichloromethane) followed by trituration with pentane to give the title compound (E247). MS (ES+) m/e 456 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([N:9]=O)=[N:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][CH:12]([CH2:21][CH3:22])[CH2:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C(O)(=O)C>[CH3:11][CH:12]([CH2:21][CH3:22])[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:18]=[N:9][C:7]2[S:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=2)=[CH:19][CH:20]=1
Reactant: CCC(C)Cc1ccc(N)cc1
Reactant: O=Nc1ncc([N+](=O)[O-])s1
Solvent: CC(=O)O
Product: CCC(C)Cc1ccc(N=Nc2ncc([N+](=O)[O-])s2)cc1

Procedure:
One equivalent of 5-nitro-2-nitroso-thiazole was dissolved in a minimum quantity of glacial acetic acid and one equivalent of (+)-4-(2-methylbutyl)aniline (ex. 4) was added. The solution was allowed to react overnight and the resultant coupled helichromic dye was recovered by precipitation with water. Chromatography on alumina afforded the pure dye compound.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[CH2:22]([O:24][C:25]([C:27]1[C:28]2[N:29]=[CH:30][CH:31]=[N:32][C:33]=2[C:34]([C:37]2[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[C:39]([O:45][CH3:46])[CH:38]=2)=[CH:35][CH:36]=1)=[O:26])[CH3:23].C([O-])(O)=O.[Na+]>CC#N.CCOC(C)=O>[CH2:22]([O:24][C:25]([C:27]1[C:28]2[N:29]=[CH:30][CH:31]=[N:32][C:33]=2[C:34]([C:37]2[CH:38]=[C:39]([O:45][CH3:46])[CH:40]=[C:41]([O:43][CH3:44])[C:42]=2[F:21])=[CH:35][CH:36]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2)c2nccnc12
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2cc(OC)cc(OC)c2F)c2nccnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 46.8 %

Procedure:
SelectFluor (105 mg, 0.30 mmol) was added to a cold (−5° C.) solution of 8-(3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 115.1) (100 mg, 0.30 mmol) in CH3CN (2 mL), under an argon atmosphere. The reaction mixture was allowed to warm to rt over 6 h and stirred at that temperature for additional 12 h and diluted in EtOAc and a saturated aqueous solution of NaHCO3. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 3:2) to provide 50 mg of the title compound as an off-white solid. Title compound: ESI-MS: 357.2 [M+H]+; tR=4.58 min (System 1); TLC: Rf=0.24 (Hex/EtOAc, 3:2).
Reaction SMILES: [CH:1]([N:4]([C:8](Cl)=[O:9])[C:5](Cl)=[O:6])([CH3:3])[CH3:2].I.[CH3:12][S:13][C:14](=[NH:20])[NH:15][N:16]=[C:17]([CH3:19])[CH3:18]>C(N(CC)CC)C>[CH:1]([N:4]1[C:8](=[O:9])[NH:20][CH:14]([S:13][CH3:12])[N:15]([N:16]=[C:17]([CH3:19])[CH3:18])[C:5]1=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)N(C(=O)Cl)C(=O)Cl
Reactant: CSC(=N)NN=C(C)C
Agent: I
Solvent: CCN(CC)CC
Product: CSC1NC(=O)N(C(C)C)C(=O)N1N=C(C)C

Procedure:
Analogously to Example 1, N-isopropyl-bis-(chlorocarbonyl)-amine (prepared analogously to Synthesis 1970, pages 542-543; boiling point 66-67° C/12 mm Hg) and acetone-S-methylisothio-semicarbazone hydroiodide, with addition of triethylamine, yielded 1-isopropyl-3-isopropylideneamino-4methylmercapto-tetrahydro-1,3,5-triazine-2,6-dione as a pale yellow powder of melting point 110-112° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CO[CH:21](OC)[N:22](C)[CH3:23].CN(C)[CH:29]=[O:30]>>[CH3:21][N:22]([C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[C:9]([C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[CH:12][CH:11]=1)[CH:29]=[O:30])[CH3:23]
Reactant: CN(C)C=O
Reactant: CSc1ccc(CC(=O)c2ccc(F)cc2)cc1
Reactant: COC(OC)N(C)C
Product: CSc1ccc(C(C=O)=C(c2ccc(F)cc2)N(C)C)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 25.8 g (99.2 mMol) of 1-(4-fluorophenyl)2-(4-methylthiophenyl)ethan-1-one from Step 3 in 200 ml of dimethylformamide was added 33 ml (30 g, 250 mMol) of dimethylformamide dimethyl acetal. The resulting mixture was stirred at 90° C. for 2 hours. Evaporation of the volatiles gave 1-(N,N-dimethylamino)-1-(4-fluorophenyl)-2-(4-methylthiophenyl)prop-1-en-3-one as a yellow solid (32.5 g).
Reaction SMILES: O.OC1C2N=NNC=2C=CC=1.[C:12]1([CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:28][O:29][C:30]([CH:32]1[NH:37][CH2:36][C:35]2[N:38]=[CH:39][N:40]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[C:44]([CH3:51])[CH:43]=3)[C:34]=2[CH2:33]1)=[O:31]>C(#N)C>[CH3:28][O:29][C:30]([CH:32]1[N:37]([C:19](=[O:21])[CH:18]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:36][C:35]2[N:38]=[CH:39][N:40]([CH2:41][C:42]3[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[C:44]([CH3:51])[CH:43]=3)[C:34]=2[CH2:33]1)=[O:31]
Reactant: COC(=O)C1Cc2c(ncn2Cc2ccc([N+](=O)[O-])c(C)c2)CN1
Reactant: O=C(O)C(c1ccccc1)c1ccccc1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CC#N
Product: COC(=O)C1Cc2c(ncn2Cc2ccc([N+](=O)[O-])c(C)c2)CN1C(=O)C(c1ccccc1)c1ccccc1
Temperature: 2 °C
Reaction time: 0.25 h

Procedure:
A mixture of 16.7 g dicyclohexycarbodiimide, 10.9 g hydroxybenzotriazole hydrate, 17.2 g diphenylacetic acid and 150 mL acetonitrile is stirred at 2° C. for 15 min then treated with a solution of 25.4 g methyl-1-(3-methyl-4-nitrophenyl)methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate in 125 mL acetonitrile. The resulting suspension is stirred 48 hr at 25° C., filtered and the filtrate is evaporated, dissolved in dichloromethane, washed with 10% Na2CO3, dried and evaporated. Chromatography on silica gel (chloroform-methanol, 99:1) gives a crisp foam which crystallizes when triturated with methanol. MS (FAB) 525 (M+1).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:15][C@@H:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[C:10]1([CH3:26])[CH3:25])=O)(C)(C)C.CCN(CC)CC>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([NH:15][C@@H:16]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[C:10]1([CH3:25])[CH3:26]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H]1C[C@@H](NC(=O)OC(C)(C)C)C1(C)C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H]1C[C@@H](N)C1(C)C
Yield: 100 %

Procedure:
A stirred solution of (S)-methyl 2-((1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxamido)-4-methylpentanoate (step 1, 0.200 g, 0.54 mmol) in TFA:DCM (1:4) (4 ml) at 0° C.-room temperature for about 1 hour. After completion of the reaction, the solvent was evaporated and the crude was dissolved in DCM and basified with Et3N (0.5 ml, 3.24 mmol) then the resulting solution as such used for next reaction immediately. Wt: 0.145 g (Based on 100% yield calculated and proceeded for next reaction).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][CH:18]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:9]([O:13][C:14]([N:16]1[CH2:20][CH2:19][C:18]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(Cl)c(Cl)c2)C1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23 %

Procedure:
Benzyl bromide (0.19 mL, 1.60 mmol) was added to a solution of 3-(3,4-dichloro-benzoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (138 mg, 0.40 mmol) in THF (5 mL), and then lithium bis(trimethylsilyl)amide (1.0 M, in THF, 1.2 mL, 1.20 mmol) was slowly added at room temperature. The reaction mixture was stirred at room temperature for 1.5 hours, then was quenched by addition of saturated aqueous NH4Cl, diluted with water, and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography (10% to 20% of EtOAc in hexane) to give 40 mg (23% yield) of 3-benzyl-3-(3,4-dichloro-benzoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a colorless oil.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH2:5]([N:9]([CH2:16][CH2:17][CH2:18][CH3:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8].Cl.[OH-].[Na+]>O>[CH2:5]([N:9]([CH2:16][CH2:17][CH2:18][CH3:19])[C:10]1[CH:15]=[CH:14][C:13]([N:1]=[O:3])=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8]
Reactant: O=N[O-]
Reactant: CCCCN(CCCC)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCN(CCCC)c1ccc(N=O)cc1
Yield: 48 %

Procedure:
A solution was prepared by dissolving 18.5 g (0.26 mol) of sodium nitrite, of a purity of 97%, in 30 ml of water. This solution was added dropwise to a solution composed of 51.3 g (0.25 mol) of N,N-dibutylaniline, 200 g of water and 105 ml of conc HCl (35 to 38%) at a temperature between 10° and 20° C. for one-half hour. After stirring the solution obtained for one hour, the solution was neutralized to pH 8 with a 15% aqueous solution of sodium hydroxide. The crystals obtained were filtered, washed sufficiently on filter paper and thereafter dried with hot-air at 50° C. for 48 hours. 28.1 g of N,N-dibutyl-p-nitrosoaniline with a melting point of 122°~124° C. was obtained. The yield was 48.0%.
Reaction SMILES: Cl[CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4].[C:18]([O-:21])(=[O:20])[CH3:19].[K+].C(OCC)(=O)C.O>CN(C=O)C>[C:18]([O:21][CH:2]([CH3:17])[C:3]([C:5]1[C:6]([CH:14]([CH3:16])[CH3:15])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12)=[O:4])(=[O:20])[CH3:19]
Reactant: CC(=O)[O-]
Reactant: CC(Cl)C(=O)c1c(C(C)C)nn2ccccc12
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC(C)C(=O)c1c(C(C)C)nn2ccccc12
Yield: 86.8 %

Procedure:
A solution of 2-chloro-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one (1.0 g, 1 equivalent) and potassium acetate (0.6 g, 1.5 equivalents) in 5 mL of DMF was stirred at room temperature for 2 days. The solution was worked up with ethyl acetate and water to give a crude oil. The oil was purified by silica gel flash column chromatography to furnish 1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1-oxopropan-2-yl acetate (0.95 g, 86% yield) as a paste. Compound 1067.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[C:24]3[C:23](=[O:25])[N:22]([CH3:26])[C:21](=[O:27])[N:20]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:19]=3[S:18][C:17]=2[CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:1]([NH:8][C:9]1[CH:10]=[C:11]([S:15][C:16]2[C:24]3[C:23](=[O:25])[N:22]([CH3:26])[C:21](=[O:27])[N:20]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:19]=3[S:18][C:17]=2[CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Sc3cccc(N)c3)c(Cc3cccc4ccccc34)sc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cccc(Sc2c(Cc3cccc4ccccc34)sc3c2c(=O)n(C)c(=O)n3CC(C)C)c1
Reaction time: 1 h

Procedure:
Acetic anhydride (0.034 ml) was added to a solution of 5-[(3-aminophenyl)thio]-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl) thieno[2,3-d]pyrimidine-2,4-(1H, 3H)-dione (60 mg) and triethylamine (0.067 ml ) in anhydrous dichloromethane (2 ml) at room temperature. After 1 hour, work-up and purification as in Example 32 gave the title compound (15 mg).