Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si](O[C@@H](CC)C(O)=O)(C(C)(C)C)(C1C=CC=CC=1)[C:2]1C=CC=CC=1.[NH2:25][CH2:26][CH2:27][CH2:28][C@:29]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:33]([C:34](=[O:39])[C@@H:35]([O:37][CH3:38])[CH3:36])[N:32]=[C:31]([C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=2[F:47])[S:30]1>>[NH2:25][CH2:26][CH2:27][CH2:28][C@:29]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[N:33]([C:34](=[O:39])[C@@H:35]([O:37][CH3:38])[CH2:36][CH3:2])[N:32]=[C:31]([C:40]2[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:41]=2[F:47])[S:30]1
Reactant: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1
Reactant: CC[C@H](O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Product: CC[C@H](OC)C(=O)N1N=C(c2cc(F)ccc2F)S[C@@]1(CCCN)c1ccccc1

Procedure:
Prepared as in Example 71 using (S)-2-(tert-butyldiphenylsilyloxy)butanoic acid in place of (S)-2-(tert-butyldiphenylsilyloxy)propanoic acid. MS APCI (+) m/z 434 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.48 (m, 3H), 7.35 (app t, 2H, J=8 Hz), 7.28 (m, 1H), 7.13 (m, 2H), 4.53 (dd, 1H, J=7 Hz, 4 Hz), 3.40 (s, 3H), 3.26 (m, 1H), 2.86 (m, 2H), 2.42 (m, 1H), 1.94 (m, 2H), 1.74 (m, 2H), 0.96 (t, 3H, J=8 Hz). Stereochemistry was assigned by comparison to (S)-1-((S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methoxypropan-1-one.
Reaction SMILES: BrC1C(N)=NC=C(C(F)(F)F)C=1.C(OC(N=C=S)=O)C.Cl.NO.[Br:24][C:25]1[C:26]2[N:27]([N:35]=[C:36]([NH2:38])[N:37]=2)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1.[CH3:39][S:40]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)(=[O:42])=[O:41]>>[Br:24][C:25]1[C:26]2[N:27]([N:35]=[C:36]([NH2:38])[N:37]=2)[CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=1.[CH3:39][S:40]([C:43]1[CH:48]=[CH:47][C:46]([C:25]2[C:26]3[N:27]([N:35]=[C:36]([NH2:38])[N:37]=3)[CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=2)=[CH:45][CH:44]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: CCOC(=O)N=C=S
Agent: Cl
Agent: NO
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)cn3nc(N)nc23)cc1

Procedure:
8-Bromo-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 3-bromo-5-trifluoromethyl-pyridin-2-ylamine, ethoxycarbonylisothiocyanate, and hydroxylamine hydrochloride in a manner analogous to Steps 2a-b. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.24 (s, 1H), 8.08 (s, 1H), 6.62 (bs, 2H). MS=282.9 (MH)+. 102b) 8-(4-Methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 8-bromo-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and (4-methylsulfonylphenyl)boronic acid in a manner analogous to Step 2c to afford a white solid (67%) MP=236-237° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.28 (s, 1H), 8.42 (d, J=7.8 Hz, 2H), 8.07 (s, 1H), 8.06 (d, J=7.8 Hz, 2H), 6.58 (bs, 2H), 3.29 (s, 3H). MS=356.33 (MH)+. 102c) [8-(4-Methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 8-(4-methanesulfonyl-phenyl)-6-trifluoromethyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(3-bromo-phenyl)-4-methyl-piperazine in a manner analogous to Step 2d and was isolated as a yellow solid (2% yield). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.84 (s, 1H), 8.28 (d, J=8.3 Hz, 2H), 8.14 (d, J=7.2 Hz, 2H), 7.81 (s, 1H), 6.95 (m, 2H), 6.64 (d, 1H), 3.32 (bm, 4H), 3.14 (s, 3H), 2.67 (bm, 4H), 2.44 (s, 3H). MS=531.1 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[C:4]([CH2:17][CH2:18][O:19][CH3:20])[C:3]=1[C:21](=O)[CH3:22].C(N(CC)CC)C.C(Cl)(=O)OC.[BH4-].[Na+].Cl>O1CCCC1.CO.O>[CH2:21]([C:3]1[C:2]([OH:1])=[CH:7][C:6]([OH:8])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:4]=1[CH2:17][CH2:18][O:19][CH3:20])[CH3:22]
Reactant: COCCc1c(C(C)=O)c(O)cc(O)c1-c1cccc(OC)c1
Agent: COC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(O)cc(O)c(-c2cccc(OC)c2)c1CCOC
Temperature: 25 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
Compound 116 obtained in Example 116 was dissolved in tetrahydrofuran (10 mL), and triethylamine (0.35 mL, 2.5 mmol) and methyl chlorocarbonate (0.18 mL, 2.3 mmol) were added thereto and stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in tetrahydrofuran (10 mL), and under stirring with ice-cooling, aqueous solution (5 mL) of sodium borohydride (150 mg, 4.0 mmol) was dropwise added thereto, and stirred for 1 hour. Water was added to the reaction solution, and extracted twice with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate/n-hexane 1/1) to obtain a crude product. Methanol solution (10 mL) of 7 mol/L hydrochloric acid was added to the resulting crude product, and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified through silica gel column chromatography (ethyl acetate/n-hexane=1/4 to 1/1) to obtain Compound 118 (53 mg, 18%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21]C=2)=[O:16])[CH2:10][C:11]([OH:13])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:25](N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>CCOC(C)=O.O.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:10][CH2:11][OH:13])[CH2:14][C:15]([N:17]([CH3:25])[C:18]2[CH:19]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:16])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)CC(CC(=O)NCc1ccccc1)c1ccc(Cl)c(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: CN(C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.3 %

Procedure:
3,4-Dichloro-beta-[2-[(phenyl)methylamino]-2-oxoethyl]benzenepropanoic acid (0.98 g) in EtOAc (25 mL) was treated with carbonyldiimidazole (0.653 g) and N,N-dimethylaminopyridine (trace). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (0.668 g) in H2O (10 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was then diluted with Et2O and washed with 1N HCl (20 mL), sat. NaHCO3 (20 mL) and water (20 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound (0.908 g). Mass spectrum (CI): 352.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([O:14][CH3:15])[N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:62](=[NH:75])([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:62](=[N:75][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([O:14][CH3:15])[N:13]=1)[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6])([C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1)[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: COc1cc(C(=O)N(C)OC)cc(Cl)n1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)N(C)OC)cc(N=C(c2ccccc2)c2ccccc2)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
2-Chloro-6,N-dimethoxy-N-methyl-isonicotinamide (1.0 g, 4.35 mmol) was added to a mixture of Pd(OAc)2 (0.05 g, 0.22 mmol), BINAP (0.27 g, 0.43 mmol), benzophenone imine (0.88 mL, 5.22 mmol), and cesium carbonate (7.08 g, 21.7 mmol) in toluene (16 mL) and heated to 100° C. for 12 h. Pd(OAc)2 (0.05 g, 0.22 mmol) was added to the reaction mixture and stirred for an additional 1 h at 100° C. The reaction mixture was cooled to room temperature, quenched with EtOAc (200 mL), and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (ethyl acetate/hexanes 65:35) to afford the title compound as a yellow oil (1.53 g, 94%). MS: 376.3 (MH+); HPLC Rf: 6.92 min. (HPLC method 4).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:17]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:17][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)=[CH:3][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(-c2ccc(C)c(F)c2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1cccc(-c2ccc(CBr)c(F)c2)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 3-fluoro-3′-methoxy-4-methyl-bipheny (0.5 g, 1.7 mmol, 1.0 eq) in chloroform (30 mL), was added N-bromo succinimide (0.3 g, 1.7 mmol followed by catalytic amount of dibenzoyl peroxide. The reaction mixture was refluxed by irradiating with a tungsten lamp for 3 hours. After the reaction was completed, it was cooled to room temperature and washed with water. The combined organic layers were dried over anhydrous sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 5% ethyl acetate in hexane to obtain the title compound (0.45 g, 89%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O)=[O:2].[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([N:17]1[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]1)=[O:10])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1cccc(OCC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)COc2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 29 %

Procedure:
2-(3-formylphenoxy)acetic acid (48)/(1 eq), tert-butyl piperazine-1-carboxylate (1.5 eq) were taken in DCM to which HATU (1.3 eq) and DIPEA (2 eq) along with cat. DMAP were added and the traction mixture was stirred at rt for 16 h when TLC indicated completion of reaction. The reaction mixture was diluted with DCM and the organic extract was washed with water, dried and purified by column chromatography using silica gel (100-200 mesh) to afford the pure product (29%) as a colorless oil. LCMS: 91.65% (M++1-Boc).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][NH:12][C:13]([O:15][CH3:16])=[O:14])=[S:10])=[CH:4][CH:3]=1.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19].C(N(CC)CC)C>C1C=CC=CC=1>[CH2:22]([O:21][C:17](=[O:20])[CH2:18][CH2:19][S:10][C:9](=[N:11][NH:12][C:13]([O:15][CH3:16])=[O:14])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[CH3:23]
Reactant: C=CC(=O)OCC
Reactant: COC(=O)NNC(=S)Cc1ccc(C)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCSC(Cc1ccc(C)cc1)=NNC(=O)OC

Procedure:
A mixture of 30 g of 2-[2-(4-methylphenyl)-1-thioxoethyl]hydrazinecarboxylic acid, methyl ester, 25 g of ethyl acrylate, 500 μl of triethylamine and 250 ml of benzene was heated at reflux for 24 hours, cooled and concentrated in vacuo. The resulting oil was purified by dry column chromatography on silica gel, eluting with dichloromethane. The desired fractions were collected and evaporated, giving [1-[(3-ethoxy-3-oxopropyl)thio]-2-(4-methylphenyl)ethylidene]hydrazinecarboxylic acid, methyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH2:20])=[C:17](Br)[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(C)=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([S:21][CH3:22])=[C:8]([S:10]([C:13]2[CH:14]=[N:15][C:16]([NH2:20])=[C:17]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH3:23])[CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cnc(N)c(Br)c2)c(SC)s1
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1cc(S(=O)(=O)c2cnc(N)c(-c3ccccc3C)c2)c(SC)s1
Temperature: 80 °C
Yield: 29 %

Procedure:
The procedure as in Example 1: step c was followed using 4-(6-Amino-5-bromo-pyridine-3-sulfonyl)-5-methylsulfanyl-thiophene-2-carboxylic acid methyl ester (25 mg, 0.06 mmol, Example 124: step a), 2-methyl phenyl boronic acid (33 mg, 0.25 mmol), Pd(PPh3)4 (14 mg, 0.01 mmol), aqueous Na2CO3 (2M, 400 μL, 0.5 mmol), ethanol (400 μL) and toluene (800 μL). The reaction was heated to 80° C. for 12 hours. The residue was dissolved into EtOAc and washed with brine. The organic layers were dried (MgSO4) and removal of the solvents in vacuo was followed by preparative SiO2 TLC purification (20% MeOH in DCM) that yielded the title compound (7.4 mg, 29%) as a white solid. ESI-MS (m/z): Calcd. for C19H18N2O4S3: 420.0 (M+1) found: 420.2.
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18].[CH3:19][O-:20].[Na+]>CN(C=O)C.[Cu]Br>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:6]3[CH:5]=[CH:4][C:3]([OH:18])=[C:2]([O:20][CH3:19])[C:7]=3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: Oc1ccc(-c2cc3c(Br)c(O)ccc3o2)cc1
Reactant: C[O-]
Agent: [Cu]Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1c(O)ccc2oc(-c3ccc(O)cc3)cc12
Temperature: 150 °C
Yield: 36.6 %

Procedure:
A solution of 4-bromo-2-(4-Hydroxyphenyl)-benzofuran-5-ol 130 (0.100 g, 0.32 mmol) and copper (I) bromide (0.047 g, 0.32 mmol) in DMF (4 mL) was treated with sodium methoxide (0.73 mL, 3.2 mmol, 25% by weight in MeOH) and heated at 150° C. for three hours under a nitrogen atmosphere; The reaction was quenched at room temperature with 1 N HCl and extracted with ethyl acetate (3×). The combined organic extracts were washed once with a saturated sodium bicarbonate solution, then dried over magnesium sulfate and filtered. Then the material was purified by column chromatography using 30% ethyl acetate in hexane as the eluent to yield 132 (0.030 g, 36.6%) as a brown solid: Mp. 165–1.68° C.; 1H NMR (DMSO-d6) δ 7.72 (d, 2 H, J=8.6 Hz), 7.23 (s, 1 H), 7.1 (d, 1H J=8.7 Hz), 6.86 (d, 2 H, J=8.6 Hz, 6.76 (d, 1 H, J=8.6 Hz), 3.94 (s, 3 H); MS 257 (M+H)+.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[Si:12]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH:34]1[CH:39]([O:40][Si:41]([C:54]([CH3:57])([CH3:56])[CH3:55])([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38][C:37](=[C:58](O)[CH3:59])[C:36](=[CH2:61])[CH:35]1[O:62][Si:63]([C:76]([CH3:79])([CH3:78])[CH3:77])([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-].[Na+]>C(Cl)Cl.C(OCC)C>[Si:12]([O:29][CH2:30][CH2:31][CH2:32][O:33][CH:34]1[CH:39]([O:40][Si:41]([C:54]([CH3:57])([CH3:56])[CH3:55])([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38][C:37](=[CH:58][CH2:59][Cl:1])[C:36](=[CH2:61])[CH:35]1[O:62][Si:63]([C:76]([CH3:79])([CH3:78])[CH3:77])([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=C1C(=C(C)O)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(OCCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CSC
Solvent: ClCCl
Product: C=C1C(=CCCl)CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(OCCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -25 °C
Yield: 95.3 %

Procedure:
N-chlorosuccinimide (140 mg) was suspended in 10 ml of methylene chloride, and 74 mg of dimethyl sulfide was added at 0° C. The mixture was stirred, and cooled to -25° C. A solution of 958 mg of (4-(3-tert-butyldiphenylsilyloxypropoxy)-3,5-bis-(tert -butyldiphenylsilyloxy)-2-methylenecyclohexylidene) ethanol in 2 ml of methylene chloride was added dropwise, followed by stirring at 0° C. for 2 hours. A sodium chloride aqueous solution was added to the reaction mixture, and extraction was conducted with diethyl ether. The extract was washed with a sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. There resulted 931 mg of (4-(3-tert-butyldiphenylsilyloxypropoxy)-3,5-bis-(tert-butyldiphenylsilyloxy)-2-methylenecyclohexylidene)ethyl chloride.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[C:8]([S:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].C(Cl)(Cl)Cl.CC(O)C>O1CCCC1.Cl>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]2[C:8]([S:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[N:7][N:6]=[C:5]2[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:12][CH:13]=1
Reactant: CCCCc1nnc(SCC(=O)OC)n1Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCCCc1nnc(SCC(=O)OC)n1Cc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2.46 g (6.76 mmole) of 3 -n- butyl-5-(carbomethoxymethylthio)-4-(4-nitrobenzyl)-4H-1,2,4-triazole in 32 ml of tetrahydrofuran stirred in an ice bath was added gradually over 15 minutes a solution of 15.2 g (67.6 mmole) of stannous chloride dihydrate in 19 ml of concentrated HCl. The ice bath was removed, and the mixture was stirred at room temperature for 1.5 hours. It was then poured into a vigrously stirred mixture of 68 ml of 50% NaOH and 270 g. of ice. This was rapidly extracted with 3×300 ml of ether. The combined ether extracts were washed with 150 ml of H2O, then dried (MgSO4), filtered, and concentrated to give 566 mg (25%) of a white waxy solid, homogeneous by TLC in 97:3 CHCl3 -iPrOH; mass spectrum (FAB) m/e 335 (M+1)+. This material was used directly in the next reaction.
Reaction SMILES: [CH:1]1([NH:6][C:7]([NH2:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH:1]1([NH:6][C:7]2[O:8][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:17]([CH3:19])[N:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NC(=O)NC1CCCC1
Product: CCOC(=O)c1oc(NC2CCCC2)nc1C
Yield: 16.4 %

Procedure:
By the procedure of Example 4, 10 g (78 mmol) of cyclopentyl urea was reacted with 10.7 g (65 mmol) of ethyl 2-chloroacetoacetate at 140°-150° C. for 4 hours. The product was separated, then purified by Kugelrohr distillation (135° C. @ 0.5 mm Hg) and then recrystallized from hexane to yield 2.54 g of a light yellow solid product (m.p.=50°-52° C.) identified in Table I.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([CH2:19][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].[BH4-].[Na+]>CO>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([CH2:19][CH:20]([OH:21])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCN(c2nc(CC(=O)c3ccccc3)cc3ccccc23)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCN1CCN(c2nc(CC(O)c3ccccc3)cc3ccccc23)CC1
Yield: 87.6 %

Procedure:
To a solution of the resulting 1-(4-ethylpiperazin-1-yl)-3-phenacylisoquinoline (0.92 g) in methanol (30 ml) was added sodium borohydride (0.12 g) at room temperature. One hr later, the reaction mixture was concentrated. The resulting residue was partitioned between ethyl acetate and water, and extracted with ethyl acetate. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed, to give the title compound (0.81 g) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.O=P(Cl)(Cl)Cl.O.CN([CH:21]=[O:22])C>>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[C:7]=1[CH:21]=[O:22]
Reactant: COc1cc(Br)cc(OC)c1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Br)c(C=O)c(OC)c1
Temperature: 100 °C
Yield: 65 %

Procedure:
A solution of 1-bromo-3,5-dimethoxybenzene (10.0 g, 46.1 mmol) in DMF (40 mL) was treated with POCl3 (6.32 mL, 69.1 mmol) at 0° C. and heated to 100° C. for 6 h. The reaction was cooled to room temperature and water (40 mL) was added. The resulting mixture was heated to 50° C. 1 h. The reaction was cooled down and extracted with ethyl acetate. The organic layer was separated, dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (silica, hexanes/ethyl acetate=2:1) to give the title compound (7.26 g, 65%). 1H NMR (300 MHz, CDCl3) δ 10.24 (s, 1H), 6.81 (s, 1H), 6.42 (s, 1H), 3.96 (s, 3H), 3.93 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[Cl:14][C:15]1[N:20]=[C:19](Cl)[CH:18]=[C:17]([CH3:22])[N:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:14][C:15]1[N:16]=[C:17]([CH3:22])[CH:18]=[C:19]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[N:20]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(trifluoromethyl)phenylboronic acid (116.52 g, 613.5 mmol) in 1,2-dimethoxyethane (1200 mL) was added 2,4-dichloro-6-methylpyrimidine (100 g, 613.5 mmol). To this stirring solution was added a solution of sodium carbonate (195.07 g, 1840.5 mmol) dissolved in water (600 mL) giving some precipitation of the base and then bis(triphenylphosphine)palladium (II) dichloride (2.15 g, 3.07 mmol). The mixture was brought to 50° C. over about 1 hr then stirred at this temperature overnight. The reaction mixture cooled to approx. 30° C., filtered and washed with DCM (approx. 500 mL). The filtrate was evaporated to remove the bulk of the organic solvents. To the residues was added DCM (250 mL) and the phases were separated. The aqueous phase was extracted with DCM (2×250 mL) and the combined extracts were washed with brine (250 mL), dried over magnesium sulphate, filtered and evaporated to a brown gummy solid. The solid was stirred in iso-hexane (150 mL) at 60° C. until the solid had dissolved. The heat was turned off and the flask allowed to cool in the heat-on block naturally. When the solution was at 30° C. seed crystals were added causing immediate crystallisation. The mixture was stood overnight then the crystalline material was crushed and filtered. The solids were washed with cold iso-hexane (2×50 mL) and dried to give the title compound (D5) as a slightly sticky tan solid, (96.17 g) consistent by NMR with that prepared by Method 1.