Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:24])[CH3:23])[C:12]([CH:25]=[O:26])=[C:11]([I:27])[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=1>>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]([CH3:23])[CH3:24])[C:12]([C@H:25]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=3)[OH:26])=[C:11]([I:27])[C:10]1=2)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1nc2c(c(I)c1C=O)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2
Reactant: FC(F)(F)c1ccc(Br)nc1
Product: CC(C)c1nc2c(c(I)c1[C@@H](O)c1ccc(C(F)(F)F)cn1)[C@@H](O[Si](C)(C)C(C)(C)C)CC1(CCC1)C2

Procedure:
Obtained by starting from (S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-isopropyl-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-carbaldehyde and 2-bromo-5-(trifluoromethyl)pyridine.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[CH:20]=O)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=3[CH:20]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(OCc2nc(C(C)(C)C)cs2)c(C=O)c1
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 140 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
A mixture of 4-tert-butyl-2-(2-formyl-4-methoxyphenoxymethyl)thiazole (3.23 g) and acetic anhydride (3.2 ml) in xylene (30 ml) was stirred at 140° C. for 14 hours. After being cooled, the resulting mixture was concentrated to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with toluene. The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-(5-methoxybenzofuran-2-yl)thiazole (2.40 g).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[N:12]=[C:13]([O:22][CH2:23][C:24]4[N:25](COCC[Si](C)(C)C)[N:26]=[CH:27][N:28]=4)[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:1]1([C:7]2[N:11]3[N:12]=[C:13]([O:22][CH2:23][C:24]4[NH:25][N:26]=[CH:27][N:28]=4)[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:15][C:10]3=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1ncnc1COc1nn2c(-c3ccccc3)nnc2cc1-c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(-c2cc3nnc(-c4ccccc4)n3nc2OCc2ncn[nH]2)cc1
Temperature: 65 °C

Procedure:
The product from Example 72 Step b) (0.68 g) was suspended in ethanol (10 ml) with 2 N hydrochloric acid (21 ml) and heated at 65° C. for 5.5 h. Saturated sodium carbonate solution was added dropwise until a solid precipitated and this was collected by filtration and washed several. times with water in the sinter funnel. The solid was recrystallised from methanol to give the required product (0.245 g, m p.=248° C.). 1H NMR (360 MHz, d6-DMSO) δ 5.61 (2H, s), 7.48-7.63 (6H, m), 7.44-7.77 (2H, m), 8.40 (4H, m), 14.13 (1H, br s); MS (ES+) m/e 370 [MH]+. Anal. Found C, 65.02; H, 4.04; N, 26.35. C20H15N7O requires C, 65.03; H, 4.09; N, 26.54%.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:13][CH:12]=[CH:11][C:10]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)C1C=CC=CC=1>CO>[N:17]1[CH:18]=[CH:19][CH:20]=[C:15]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[C:9]=2[OH:8])[CH:16]=1
Reactant: c1ccc(COc2c(-c3cccnc3)cccc2-c2cccnc2)cc1
Solvent: CO
Product: Oc1c(-c2cccnc2)cccc1-c1cccnc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,6-Bis(3-pyridyl)phenyl benzyl ether (16.70 g, 49.35 mmol) was dissolved in MeOH (200 mL). Argon was bubbled through this solution for 10 min to remove oxygen. Then Pd/C (500 mg 5 w %) was added, and the reaction mixture was put into the Parr-reactor and shaken for 16 hr under a hydrogen atmosphere at 80 psi. After the hydrogenation, the resulting precipitate was redissolved by heating to reflux. The hot mixture was filtered over diatomaceous earth, and the filter cake thoroughly washed with hot MeOH. Upon cooling to room temperature, the product crystallized as a white crystalline material (12.25 g, 99%). M.p.=211° C. 1H-NMR (DMSO):δ=8.74 (d, 2H), 8.55 (dd, 2H), 7.95 (dt, 2H), 7.48 (m, 2H), 7.34 (d, 2H), 7.11 (t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-])=O)[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][CH2:20][CH3:21])[CH:18]=3)[S:13][C:6]=12.[BH4-].[Na+]>CO.C1COCC1.Cl[Ni]Cl>[F:1][C:2]1[CH:25]=[C:24]([CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]=[CH:16][N:17]([CH2:19][CH2:20][CH3:21])[CH:18]=3)[S:13][C:6]=12)[NH2:26]
Reactant: CCCn1cnc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
To a solution of the nitro compound 132 (4.13 g, 10.36 mmol) in MeOH/THF (100 ml/100 mL) was added NiCl2×6H2O (4.92 g, 20.73 mmol) and NaBH4 (1.54 mg, 41.44 mmol). The reaction mixture was allowed to stir for 1 hr, concentrated to dryness and the resultant solid was dissolved in 2 M HCl. The acidic solution was then made basic with aqueous ammonium hydroxide solution and extracted with EtOAc. The organic extract was dried over anhydrous sodium sulfate, filtered and evaporated The residue was purified by flash chromatography (eluents DCM-MeOH, 98:2, 95:5) to afford title compound 133 (3.31 g, 86% yield) as a pink solid. MS (m/z): 368.1 (M+H).
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]([C:44]1[CH:49]=[C:48]([F:50])[C:47]([F:51])=[CH:46][C:45]=1[OH:52])[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[Br:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[C:30]([C:44]1[CH:49]=[C:48]([F:50])[C:47]([F:51])=[CH:46][C:45]=1[OH:52])([CH2:5][OH:16])[C:31](=[O:43])[N:32]2[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)CN1C(=O)C(c2cc(F)c(F)cc2O)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: CCOC(=O)CN1C(=O)C(CO)(c2cc(F)c(F)cc2O)c2c(Br)cccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with ethyl [4-bromo-3-(4,5-difluoro-2-hydroxyphenyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (83%): MS (ES+) m/z 456.3 (M+1), 458.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[C:11]([F:13])([F:12])[F:10])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1)C(F)(F)F
Yield: 121.2 %

Procedure:
According to Reference Example 8-12, by use of 4-fluorobenzaldehyde (500 mg, 4.03 mmol), (trifluoromethyl)trimethylsilane (715 μL, 4.83 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 403 μL, 0.403 mmol) and tetrahydrofuran (10 mL), the mixture was stirred and reacted at room temperature for 30 minutes. Thus, 1-fluoro-4-(2,2,2-trifluoro-1-hydroxyethyl)benzene (Compound CS) (948 mg, yield: quantitative) was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:46]/[O:47][CH3:48])/[C:8]([NH:10][CH:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([O:30]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:29])=[C:15]([C:18]4[C:21](=[O:22])[C:20](=[O:23])[C:19]=4[O:24][CH:25]([CH3:27])[CH3:26])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:46]/[O:47][CH3:48])/[C:8]([NH:10][CH:11]2[C:44](=[O:45])[N:13]3[C:14]([C:28]([OH:30])=[O:29])=[C:15]([C:18]4[C:21](=[O:22])[C:20](=[O:23])[C:19]=4[O:24][CH:25]([CH3:27])[CH3:26])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3c(OC(C)C)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(c3c(OC(C)C)c(=O)c3=O)CS[C@H]12)c1csc(N)n1
Reaction time: 1 h

Procedure:
Diphenylmethyl 7-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[3,4-dioxo-2-(2-propoxy)-1-cyclobutenyl]-3-cephem-4-carboxylate (33 mg) was added to a stirred, cooled (ice/H2O bath) solution of trifluoroacetic acid (100 μL) and anisole (50 μL). The cooling bath was removed, and stirring was continued for 1 hr at ambient temperatures. The solution was diluted with diethyl ether to precipitate the trifluoroacetic acid salt of the title compound as a yellow powder.
Reaction SMILES: [F:1][C:2]1[C:7]2[C:8]([C:18](=[O:21])[NH:19][CH3:20])=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[CH3:31])[C:25]([OH:27])=O.[CH3:32][C:33]1[CH:38]=[C:37]([CH3:39])[N:36]=[C:35]([C:40]2([NH2:43])[CH2:42][CH2:41]2)[N:34]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:39][C:37]1[CH:38]=[C:33]([CH3:32])[N:34]=[C:35]([C:40]2([NH:43][C:25]([C:24]3[CH:28]=[CH:29][C:30]([CH3:31])=[C:22]([C:3]4[CH:4]=[CH:5][C:6]5[O:10][C:9]([C:11]6[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=6)=[C:8]([C:18]([NH:19][CH3:20])=[O:21])[C:7]=5[C:2]=4[F:1])[CH:23]=3)=[O:27])[CH2:41][CH2:42]2)[N:36]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)c(F)c12
Reactant: Cc1cc(C)nc(C2(N)CC2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5nc(C)cc(C)n5)CC4)ccc3C)c(F)c12
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-fluoro-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (50 mg, 0.12 mmol), crude 1-(4,6-dimethylpyrimidin-2-yl)cyclopropanamine (150 mg) in 2 ml DMF at room temperature was added BOP (106 mg, 0.24 mmol, 2.0 eq.) and triethyl amine (0.050 ml, 0.36 mmol, 3.0 eq.), and the mixture stirred overnight under an N2 atmosphere. The mixture was poured into crushed ice, and solid precipitate was filtered and dried. The product obtained was further purified by column chromatography using Silica gel (230-400) and CHCl3-MeOH (95:5) as a mobile phase. Yield: 40 mg (60%). 1H NMR (400 MHz, CDCl3): δ 8.00-7.97 (m, 2H), 7.80-7.76 (m, 2H), 7.41-7.37 (m, 3H), 7.21-7.15 (m, 3H), 6.77 (s, 1H), 6.22 (br. s., 1H), 3.01 (d, J=5.0 Hz, 3H), 2.37 (s, 6H), 2.26 (s, 3H), 1.76-1.73 (m, 2H), 1.56-1.54 (m, 2H). 19F NMR (376.57 MHz, CDCl3): δ−109.83, −119.22 LCMS: (ES+) m/z=567.2 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([OH:19])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.CO.C(Cl)(=O)C([Cl:30])=O>>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([C:17]([Cl:30])=[O:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(Cl)[C@@H]1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-Piperidine-1,3-dicarboxylic acid 1-benzyl ester (XXVIII) (8.00 g, 30.4 mmol) was taken in neat oxalyl chloride (20 ml), 0.2 ml of DMF were added and the mixture was stirred at room temperature for 1 hour. The completion of reaction was monitored by TLC which showed the formation of a non-polar spot after treatment of a small amount with methanol. The reaction mixture was concentrated under reduced pressure to provide (R)-3-chlorocarbonyl-piperidine-1-carboxylic acid benzyl ester (XXIX) (8.33 g) which was directly used in the next reaction.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1.CCN(C(C)C)C(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12][S:29]([CH3:28])(=[O:31])=[O:30])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[O:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CC1OB(O)c2cc(OS(C)(=O)=O)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(1,6-dihydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (500 mg, 2 mmol), DIPEA (774 mg, 6 mmol) in DCM (10 mL) was slowly added MsCl (366 mg, 3.2 mmol) at −78° C. The reaction mixture was stirred overnight at room temperature, quenched with saturated NH4Cl and washed with saturated NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was used directly in next step reaction without further purification. MS (ESI) m/z=329 [M+H]+
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[NH2:14].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH3:21][O:20][C:16]1[CH:15]=[C:13]([N:14]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:12]=[C:11]([O:10][CH3:9])[C:17]=1[O:18][CH3:19]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: ClCCNCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: COc1cc(N2CCNCC2)cc(OC)c1OC
Reaction time: 16 h
Yield: 37.4 %

Procedure:
A solution of 44.3 g (0.25 mol) of bis(2-chloroethyl)amine hydrochloride and 45.5 g (0.25 mol) of 3,4,5-trimethoxyaniline in 550 mL of absolute ethanol was heated at reflux for 16 h under a nitrogen atmosphere. The mixture was cooled and 50.0 g (0.36 mol) of potassium carbonate was added and heating was continued for 16 h. The hot mixture was filtered, the filtrate was concentrated under reduced pressure and the residue was triturated with ethyl acetate. The collected solid was re-crystallized from 2-propanol/methanol. The solid was dissolved in 5.9N sodium hydroxide and the solution was continuously extracted with chloroform for 5 h. The organic layer was dried (MgSO4), concentrated under reduced pressure, and the residue was triturated with cyclohexane/petroleum ether (30°-60°) to give 23.6 g (38%) of white solid, mp 73°-77° C.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:24])=[C:4]([CH:18]=[C:19]([N+:21]([O-:23])=[O:22])[CH:20]=1)[CH2:5][N:6]([CH3:17])[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Si:25]([O:32][CH2:33][C@H:34](O)[CH3:35])([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Si:25]([O:32][CH2:33][C@@H:34]([O:24][C:3]1[C:2]([F:1])=[CH:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][C:4]=1[CH2:5][N:6]([CH3:17])[C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH3:35])([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26]
Reactant: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1O)C(=O)OCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1c(F)cc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 95.2 %

Procedure:
To a solution of 27B (400 mg, 1.197 mmol), 33A (251 mg, 1.316 mmol) and triphenylphosphine (345 mg, 1.316 mmol) in THF (10 mL) at 0° C., was added DIAD (0.256 mL, 1.316 mmol) dropwise. The reaction mixture was allowed to slowly warm to rt and stirred for 16 h, then was concentrated. The crude product was purified by flash chromatography (0 to 40% ethyl acetate/hexanes) to give 33B (577 mg, 1.139 mmol, 95% yield) as colorless oil. MS (ESI) m/z: 507.1[M+1]+. 1H NMR (400 MHz, chloroform-d) δ ppm 7.78-7.94 (2H, m) 7.27-7.43 (5H, m) 5.17 (2H, d, J=20.1 Hz) 4.46-4.74 (3H, m) 3.65-3.81 (2H, m) 2.97 (3H, d, J=15.8 Hz) 1.31 (3H, t, J=7.0 Hz) 0.81 (9H, d, J=7.0 Hz) −0.05-0.04 (6H, m) rotamers.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([NH:9][C:10]([C:12]1[S:30][C:15]2[N:16]=[C:17]([NH2:29])[N:18]=[C:19]([C:20]3[CH:25]=[C:24]([OH:26])[C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[C:14]=2[CH:13]=1)=[O:11])[CH3:8].O.[CH2:32]([O:34][CH:35]([O:38][CH2:39][CH3:40])[CH2:36]Br)[CH3:33]>C(#N)C>[CH2:7]([NH:9][C:10]([C:12]1[S:30][C:15]2[N:16]=[C:17]([NH2:29])[N:18]=[C:19]([C:20]3[CH:25]=[C:24]([O:26][CH2:36][CH:35]([O:38][CH2:39][CH3:40])[O:34][CH2:32][CH3:33])[C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[C:14]=2[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCNC(=O)c1cc2c(-c3cc(O)c(Cl)cc3Cl)nc(N)nc2s1
Reactant: CCOC(CBr)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCNC(=O)c1cc2c(-c3cc(OCC(OCC)OCC)c(Cl)cc3Cl)nc(N)nc2s1

Procedure:
Potassium tert-butoxide was added to a suspension of 2-Amino-4-(2,4-dichloro-5-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl amide in acetonitrile, bromoacetaldehyde diethyl acetal was added and the suspension heated under reflux for ˜8 hrs. The resulting suspension was allowed to cool and water added, the mixture was extracted with ethyl acetate and the extracts washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a red/brown gum. The crude product was purified by chromatography on silica eluting with mixtures of ethyl acetate and hexane.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1.[C:23](=[O:25])=[O:24]>>[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([C:3]2[CH:4]=[CH:5][C:6]([C:23]([OH:25])=[O:24])=[C:7]([F:8])[C:2]=2[F:1])=[CH:10][CH:11]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Reactant: O=C=O
Product: CCCCCCCOc1ccc(-c2ccc(C(=O)O)c(F)c2F)cc1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
0.1 mol of 2,3-difluoro-4'-heptyloxybiphenyl is metalated according to 1b). The mixture is stirred for 3 hours at -78° C. and the reaction mixture is then tipped in one swing onto 200 g of pulverized dry ice. The mixture is subsequently worked up as customary.
Reaction SMILES: C1(OC(=O)N[C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH2:16]([C:14]1[CH:15]=[C:10]([CH2:14][CH2:13][NH:12][C:11]([N:33]2[CH2:34][CH2:35][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[O:23][CH3:22])[CH2:31][CH2:32]2)=[O:19])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: COc1ccccc1N1CCNCC1
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Product: CCc1cc(CCNC(=O)N2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Yield: 63 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C(O[C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:5][C:6]1[CH2:10][CH2:9][CH2:8][N:7]=1)C.F[B-](F)(F)F>C(N)(C)C>[CH:6]([N:7]=[C:4]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH:5]=[C:6]1[CH2:10][CH2:9][CH2:8][NH:7]1)([CH3:10])[CH3:5]
Reactant: CCOC(=CC1=NCCC1)c1ccccc1
Agent: F[B-](F)(F)F
Solvent: CC(C)N
Product: CC(C)N=C(C=C1CCCN1)c1ccccc1

Procedure:
By refluxing the solution of 9.1 g (0.03 mole) of 2-(2-ethoxy-2-phenyl-ethenyl)-1-pyrroline-tetrafluoroborate in 30 ml of isopropylamine for 1 hour and processing analogously to Example 1, there is obtained crude 2-[2-(isopropylimino)-2-phenylethylidene]-pyrrolidine. The crude base is dissolved in isopropanol, and 2.8 g of methanesulphonic acid is added, whereupon 2-[2-(isopropylimino)-2-phenyl-ethylidene]-pyrrolidine-(1:1)-methanesulphonate, m.p. 175°-176° (decomposition) crystallises out.
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]([CH3:14])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1>>[CH3:14][C:5]1[S:4][C:3]([CH2:2][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[N:7][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1sc(CCl)nc1-c1ccccc1
Reactant: O=Cc1ccc(O)cc1
Product: Cc1sc(COc2ccc(C=O)cc2)nc1-c1ccccc1

Procedure:
According to the method described for Reference Example 45, 2-chloromethyl-5-methyl-4-phenylthiazole was allowed to react with p-hydroxybenzaldehyde to give 4-(5-methyl-4-phenyl-2-thiazolylmethoxy)benzaldehyde. Recrystallization from ethyl acetate--isopropyl ether gave colorless prisms, m.p.81°-82° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[N:6][CH:7]=1.[Cl:17]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:7]([Cl:17])=[N:6][C:5]([CH:8]([C:9]([F:10])([F:11])[F:12])[C:13]([F:16])([F:14])[F:15])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Nc1ccc(C(C(F)(F)F)C(F)(F)F)nc1
Solvent: CC#N
Product: Nc1ccc(C(C(F)(F)F)C(F)(F)F)nc1Cl
Yield: 85.8 %

Procedure:
In 10 ml of acetonitrile was dissolved 0.56 g (2.3 mmol) of 5-amino-2-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pyridine, to which was added 0.31 g (2.3 mmol) of N-chlorosuccinimide (NCS). The mixture thus obtained was heated under reflux for one hour to make progress a reaction. The solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel column chromatography (hexane/ethyl acetate=2:1) to obtain 0.55 g of 3-amino-2-chloro-6-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]pyridine (Compound No. 4-2) (yield: 86%).
Reaction SMILES: [CH:1]1([C:4]2[O:8][C:7]([C:9]3[C:10]([NH2:25])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[N:20]([CH3:24])[CH:19]=[CH:18]5)[CH:14]=3)=[N:6][N:5]=2)[CH2:3][CH2:2]1.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.O>[CH:1]1([C:4]2[O:8][C:7]([C:9]3[C:10]([NH2:25])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[N:20]([CH3:24])[CH2:19][CH2:18]5)[CH:14]=3)=[N:6][N:5]=2)[CH2:3][CH2:2]1
Reactant: Cn1ccc2cc(-c3cnc(N)c(-c4nnc(C5CC5)o4)c3)ccc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CN1CCc2cc(-c3cnc(N)c(-c4nnc(C5CC5)o4)c3)ccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of 3-(5-cyclopropyl-[1,3,4]oxadiazol-2-yl)-5-(1-methyl-1H-indol-5-yl)-pyridin-2-ylamine (160 mg, 0.48 mmol) in TFA at 0° C. was added triethylsilane (0.2 mL, 1.20 mmol) drop-wise over a period of 5 min, and stirred for 2 h at 0° C. The reaction mixture was diluted with water (20 mL) and neutralized with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (3×20 mL). The organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude product. The crude product was purified by column chromatography using 100-200 mesh silica gel and compound was eluted with 40% ethyl acetate in petroleum ether to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13]>O.CC(C)=O>[Cl:9][C:10]1[CH:11]=[C:12]([NH:13][C:5]2[C:4]([NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:10]([Cl:9])[CH:11]=3)=[N:3][C:2](=[O:1])[C:7](=[O:8])[CH:6]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Oc1cccnc1O
Solvent: O
Solvent: CC(C)=O
Product: O=C1C=C(Nc2cccc(Cl)c2)C(Nc2cccc(Cl)c2)=NC1=O
Reaction time: 2 h
Yield: 36 %

Procedure:
2,3-dihydroxypyridine (0.0027 mol), m-chloroaniline (0.0054 mol), and NaIO3 (0.0009 mol) were dissolved in 160 ml of water/acetone (80:1, v/v) solvent. The reaction mixture was stirred for 2 hours, and maintained still overnight. It was then filtered and recrystallized with chloroform. The final product was 5,6-di(m-chlorophenylamino)-2,3-pyridindione in a yellow powder. The yield was 36%-57%.