Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[F:23][C:21]1[CH:20]=[CH:19][C:3]2[NH:4][C:5]3[S:9][C:8]4[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=4[C:6]=3[C:14]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)=[N:1][C:2]=2[CH:22]=1
Reactant: CCOC(=O)c1c(Nc2ccc(F)cc2N)sc2ccccc12
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3cc(F)ccc3Nc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-4-fluoroanilino)benzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 9-fluoro-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[N:43]=[CH:44][O:45][C:46]=3[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:37]2=[O:53])[S:31][C:32]=1[C:33](O)=[O:34].[NH2:54][CH2:55][C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1>>[CH3:27][C:28]1[N:29]=[C:30]([N:36]2[CH2:40][CH2:39][N:38]([CH2:41][C:42]3[N:43]=[CH:44][O:45][C:46]=3[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:37]2=[O:53])[S:31][C:32]=1[C:33]([NH:54][CH2:55][C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1)=[O:34]
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2CCN(Cc3ncoc3-c3ccccc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ncoc3-c3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 13 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-((5-phenyloxazol-4-yl)methyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)-pyridine, the title compound was obtained as a colorless solid in 13% yield: mp 78-81° C. (dichloromethane/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.54 (d, J=4.8 Hz, 1H), 7.89 (s, 1H), 7.72-7.69 (m, 3H), 7.50-7.36 (m, 3H), 7.30-7.27 (m, 1H), 6.04-6.00 (m, 1H), 4.68 (s, 2H), 4.58 (d, J=5.8 Hz, 2H), 4.11-4.05 (m, 2H), 3.73-3.67 (m, 2H), 2.62 (s, 3H); MS (ES+) m/z 475.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[N:17]=2)[C:11]([O:13]C)=[O:12])[CH:7]=1.[OH-].[Na+].Cl>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[N:17]=2)[C:11]([OH:13])=[O:12])[CH:7]=1
Reactant: COC(=O)c1cc(C)nc(-c2cc(Cl)ccc2F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)O)cc(-c2cc(Cl)ccc2F)n1
Temperature: 60 °C
Yield: 66.2 %

Procedure:
Methyl 2-(5-chloro-2-fluorophenyl)-6-methylisonicotinate (1.86 g, 6.65 mmol) was dissolved in methanol (24 mL) and NaOH (16.6 ml, 33.3 mmol) was added. The reaction was heated at 60° C. for 1.5 hour, cooled to room temperature, acidified (pH˜2) with 6N HCl to give a precipitate which was filtered and dried to give 2-(5-chloro-2-fluorophenyl)-6-methylisonicotinic acid (1.17 g) as a off white solid which was used without further purification. ESI-MS: m/z 266.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](O)=[O:21])[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[F:26][C:27]([F:35])([F:34])[CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](=[O:21])[N:31]3[CH2:32][CH2:33][CH:28]([C:27]([F:35])([F:34])[F:26])[CH2:29][CH2:30]3)[C:14](=[O:23])[C@@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@H]1C(=O)N(CCC(=O)O)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Product: C[C@H]1C(=O)N(CCC(=O)N2CCC(C(F)(F)F)CC2)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 31 %

Procedure:
In analogy to the procedure described in Example 15, 3-[(S)-4-(3,4-dichloro-phenylcarbamoyl)-3-methyl-2-oxo-piperazin-1-yl]-propionic acid (intermediate 12) and 4-trifluoromethyl-piperidine hydrochloride gave the titled compound in 31% yield as white foam. MS: 509.13 (MH+, 2Cl).
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][C:13]1[S:17][C:16]2[CH2:18][CH2:19][CH2:20][C:15]=2[C:14]=1[C:21]#[N:22].[C:23]1([CH:29]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36]C=2)[C:30]([OH:32])=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:21]([C:14]1[C:15]2[CH2:20][CH2:19][CH2:18][C:16]=2[S:17][C:13]=1[NH:12][C:30](=[O:32])[CH:29]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:33]1[CH:34]=[CH:39][CH:38]=[CH:37][CH:36]=1)#[N:22]
Reactant: N#Cc1c(N)sc2c1CCC2
Reactant: O=C(O)C(Cc1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Product: N#Cc1c(NC(=O)C(c2ccccc2)c2ccccc2)sc2c1CCC2
Reaction time: 19 h
Yield: 23.9 %

Procedure:
EDCI (59 mg; 0.308 mmol) was added to a solution of 2-Amino-3-cyano-5,6-dihydro-4H-cyclopenta[b]thiophene (25 mg; 0.152 mmol) and 2,3-diphenylpropionic acid (70 mg; 0.309 mmol). After stirring for 19 h, the reaction mixture was applied directly to a silica gel column (Merck Silica gel 60; eluent: 10%–33% ethyl acetate/hexanes) to provide 13.0 mg (23%) of N-(3-Cyano-5,6-dihydro-4H-cyclopenta[b]thiophen-2-yl)-2,2-diphenyl-acetamide as a white solid. EI-HRMS m/e calcd for C22H18N2OS (M+H+) 358.1140, found 358.1140.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:28]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1.C(OCC)(=O)C>[CH2:28]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41][O:42][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Oc1ccccc1F
Reactant: OCC1CCN(Cc2ccccc2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: Fc1ccc(OCC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Yield: 24 %

Procedure:
A mixture of 4 fluorophenol (6.01 g, 54 mmol), triphenylphosphine (6.87 g, 64 mmol), and 1-benzyl-4-hydroxymethylpiperidine (11.0 g, 54 mmol) in benzene (300 mL) was stirred at 10°-15° C. Diethyl azodicarboxylate (11.2 g, 10.1 mL, 64 mmol) was added dropwise. The reaction mixture was heated to reflux temperature and stirred for 24 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate; the organic solution was washed with water three times, a 2N sodium hydroxide solution three times, dried over magnesium sulfate and filtered. Solvent was removed in vacuo to give crude product. Column chromatography (ethyl acetate:hexanes::1:1) gave, after removal of solvent, a pale yellow oil (3.88 g, 24% yield): 7.40-7.25 (m, 5H), 7.0-6.7 (m, 4H), 3.75 (d, 2H, J=4), 3.50 (s, 2H), 2.9 (br d, 2H, J=4), 2.1-1.25 (m, 7H); IR (neat): 3084(m), 3062(m), 2921(s), 2802(s), 2758(s), 1601(m), 1505(s), 1467(s), 1454(s), 1394(s); HR-MS: Calcd. for C19H22FNO: 299.1684; Found: 299.1685.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[C:11]([C:12]([O-:14])=[O:13])[C:5]=2[N:4]=1.O.[OH-].[Li+]>C1COCC1.O>[CH3:1][N:2]([CH3:18])[C:3]1[NH:7][C:6]2[CH:8]=[C:9]([N+:15]([O-:17])=[O:16])[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[C:5]=2[N:4]=1
Reactant: CN(C)c1nc2c(C(=O)[O-])cc([N+](=O)[O-])cc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1nc2c(C(=O)O)cc([N+](=O)[O-])cc2[nH]1
Yield: 91.6 %

Procedure:
2-(dimethylamino)-6-nitro-1H-benzimidazole-4-carboxylate (1.5 g) and lithium hydroxide hydrate (2.4 g) in THF—H2O (1:1, 100 mL) was stirred at 50° C. for 2 hours. THF was removed under reduced pressure, and 1N hydrochloric acid was added to the residue with stirring under ice-cooling to adjust the pH to 5. The precipitate was collected by filtration and dried under reduced pressure to obtain the titled compound (1.38 g) as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[C:15]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[Si:19]([O:9][CH2:8][C:7]1[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Nc1ncccc1CO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCc1cccnc1N)(c1ccccc1)c1ccccc1
Reaction time: 15 h
Yield: 94.5 %

Procedure:
To a suspension of (2-aminopyridin-3-yl)methanol (2.19 g, 17.6 mmol) and 1H-imidazole (6.00 g, 88.2 mmol) in DMF (10 mL) was added dropwise tert-butylchlorodiphenylsilane (5.49 mL, 21.2 mmol). The reaction was stirred for 15 hours. The solvent was removed under reduced pressure and the residue was diluted with DCM (4 0 mL). The organic layer was washed with 1N HCl (10 mL), water (10 mL) and brine (10 mL) and then concentrated to give crude product (6.03 g, 94.3% yield). MS (apci) m/z=363.1 (M+H).
Reaction SMILES: Cl.[CH:2]1([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][CH:22]3OCC[O:23]3)[C:9]=2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[CH2:35][NH:36][CH3:37])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C1COCC1>[CH:2]1([C:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=3)[N:10]([CH2:21][CH:22]=[O:23])[C:9]=2[C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=2[CH2:35][NH:36][CH3:37])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CNCc1cc(OC)ccc1-c1c(C2CCCCC2)c2ccc(C(=O)OC)cc2n1CC1OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: CNCc1cc(OC)ccc1-c1c(C2CCCCC2)c2ccc(C(=O)OC)cc2n1CC=O

Procedure:
Aqueous HCl (25 eq, 3 M) was added to a solution of methyl 3-cyclohexyl-1-(1,3-dioxolan-2-ylmethyl)-2-{4-methoxy-2-[(methylamino)methyl]phenyl}-1H-indole-6-carboxylate in THF (0.02 M), and the mixture heated at reflux for 24 h. The volatiles were reduced in vacuo, and the residue partitioned between EtOAc and saturated aqueous NaHCO3 (ensuring that the aqueous phase is basic). The aqueous phase was extracted with EtOAc and the combined organics washed with water and brine, before being dried (Na2SO4), filtered and concentrated in vacuo to give the title compound in essentially quantitative yield; MS (ES+) m/z 449 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH2:10]=[CH:11][CH3:12]>>[N:1]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: C=CC
Product: c1ccc2ncccc2c1
Temperature: 220 °C

Procedure:
Twenty grams of nitrobenzene, 1.1 grams of iodo (4-iodophenyl) bis(triphenylphosphine)palladium catalyst and 39 grams of liquified propylene was placed in a 300 ml. stainless steel rocking autoclave and cooled to -78° C. The vessel was sealed and heated to 220° C. This temperature was maintained for 24 hours. The autoclave was then cooled and vented. The reaction mixture removed from the autoclave was analyzed by gas chromatography and found to contain 0.32 grams of quinoline (1.9% efficiency) 5.8 grams of aniline (44.0% efficiency) and 2.8 grams of unreacted nitrobenzene.
Reaction SMILES: [Mg:1].[CH2:2](Cl)[CH2:3][CH2:4][CH3:5].[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][Na])[CH3:8]>CCCCCCC>[CH2:2]([Mg:1][CH2:10][CH:9]([CH2:7][CH3:8])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:3][CH2:4][CH3:5]
Reactant: [Mg]
Reactant: CCCCC(CC)C[Na]
Reactant: CCCCCl
Solvent: CCCCCCC
Product: CCCC[Mg]CC(CC)CCCC
Reaction time: 8 h

Procedure:
To a reaction mixture derived by cooking magnesium metal powder (0.30 g atoms) and n-butyl chloride (0.25 moles) together in 175 ml refluxing heptane was added a solution of 2-ethylhexylsodium (310 ml of 0.65N conc.) in heptane,2 the temperature of reaction not exceeding 42° C. On filtration of the reaction mixture, a solution which was 0.64N in total alkalinity and 0.34M in Mg was obtained. The solution was concentrated to 0.64M (2.2 wt. % Mg) in Mg (Na=0.0025M). Some precipitation of solids occurred in the solution on standing overnight (Mg=0.55M). Sufficient triisobutylaluminum in hexane solution was added to give a final Al concentration corresponding to 3 mole % on the total Mg. All solids immediately dissolved and a very fluid solution resulted. The viscosity of this solution was found to be only 1.25 cps (40° ), a significantly lower value than that listed for a commercial n-butylethylmagnesium in heptane solution at the same magnesium concentration (about 15 cps). Again, the viscosity lowering effect of the 2-ethylhexyl group, as well as its solubilizing properties, was noted. (Di-n-butylmagnesium alone possesses only a very low order [<0.2M] of solubility in hydrocarbon solvents.)
Reaction SMILES: [CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(F)(F)F.[CH3:17]COCC.C([O-])(O)=O.[Na+]>CO>[CH2:1]([C:8](=[CH2:12])[C:9]([O:11][CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCC
Reactant: C=C(Cc1ccccc1)C(=O)O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C=C(Cc1ccccc1)C(=O)OC
Yield: 95 %

Procedure:
α-Benzylacrylic acid (1.00 g, 6.17 mmol) in methanol (20 ml) was treated with BF3.Et2O (2 ml). The mixture was heated to reflux for 14 h, cooled, and poured into saturated NaHCO3 solution. Extraction with ether followed by drying over Na2SO4 and evaporation afforded 1.03 g (95%) of a mobile oil. 1H NMR (CDCl3) δ7.17-7.35 (m,5H), 6.23 (m,1H), 5.47 (m,1H), 3.74 (s,3H), 3.63 (s,2H).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].BrC1C2[O:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:12][C:11]=2[CH:10]=[C:9]([O:24][CH3:25])[CH:8]=1.ICC>C1COCC1>[CH2:3]([C:2]1[C:1]2[O:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[N:12][C:11]=2[CH:10]=[C:9]([O:24][CH3:25])[CH:8]=1)[CH3:4]
Reactant: [Li]CCCC
Reactant: COc1ccc(-c2nc3cc(OC)cc(Br)c3o2)cc1
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cc(OC)cc2nc(-c3ccc(OC)cc3)oc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
n-Butyllithium (2.5 N, 0.43 mL, 1.08 mmol) was added dropwise into a cold (−78° C.) mixture of 7-bromo-5-methoxy-2-(4-methoxyphenyl)-1,3-benzoxazole (300 mg, 0.90 mmol) and THF (2 mL). The mixture was allowed to stir for 0.5 h. Iodoethane (0.14 mL, 1.8 mmol) was added dropwise into the mixture. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with aqueous ammonium chloride, poured into water, and extracted with EtOAc. The organic extracts were washed with brine and dried over MgSO4. Evaporation and flash chromatography (20% EtOAc/petroleum ether) gave (231 mg, 91% yield) of the product as a light brown solid: m.p. 85° C.; MS m/e 284 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][CH:12]=[CH2:13])[CH:5]=1.[CH3:15]I>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:15])=[C:6]([CH2:11][CH:12]=[CH2:13])[CH:5]=1
Reactant: C=CCc1cc(C(=O)OC)ccc1O
Reactant: CI
Product: C=CCc1cc(C(=O)OC)ccc1OC

Procedure:
3-Allyl-4-methoxybenzoic acid methyl ester was prepared from 3-Allyl-4-hydroxybenzoic acid methyl ester according to Method C using methyl iodide as an alkylating agent in quantative yield. This product was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.[CH2:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][N:11]1[C:20]1([Cl:29])[N:25]=[CH:24]N=C2C=CC=C12>CN(C)C=O>[ClH:29].[CH3:9][C:4]1[CH:3]=[C:2]([F:1])[CH:8]=[CH:7][C:5]=1[NH:6][C:20]1([N:11]2[CH2:12][CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10]2)[N:25]=[C:24]2[CH:8]=[CH:2][CH:3]=[C:4]2[CH:5]=[N:6]1
Reactant: ClC1(N2CCc3ccccc3C2)N=CN=C2C=CC=C21
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: Cc1cc(F)ccc1NC1(N2CCc3ccccc3C2)N=CC2=CC=CC2=N1
Product: Cl
Yield: 75.6 %

Procedure:
After 4-fluoro-2-methylaniline(0.25 ml, 2.20 mmol) was added to a mixture solution of 4-(1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chlorocyclopenta[d]pyrimidine(0.58 g, 2.0 mmol) and dimethylformamide(5 ml), 0.34 g of the titled compound was obtained in accordance with the same procedure as in Step 2 of Example 1.
Reaction SMILES: O=[C:2]1[O:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=[CH:12][C:4]=2[NH:3]1>CN(C)C1C=CN=CC=1.CN(C)C=O.CO.C(OCC)(=O)C>[NH2:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:5]=1[C:6]([O:7][CH3:2])=[O:8]
Reactant: O=C(O)c1ccc2[nH]c(=O)oc(=O)c2c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(=O)O)ccc1N
Yield: 83.8 %

Procedure:
150 mg (1.21 mmol) of 4-dimethylaminopyridine are added to 2.5 g (12.1 mmol) of 2,4-dioxo-1,4-dihydro-2H-3,1-benzoxazine-6-carboxylic acid [described in J. Med. Chem., (1981), 24(6), 735-742] in solution in 10 ml of dimethylformamide and 10 ml of methanol, and the mixture is heated at 60° C. for 3 hours. The reaction medium is concentrated under reduced pressure. The residue is taken up in water and extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The solid obtained is taken up in ethyl acetate, filtered and dried. 1.98 g of a white powder are obtained.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:21][CH3:22])=[C:7]([CH:10]=[C:11]([C:13]2[C:14]([O:19][CH3:20])=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:12]=1)[CH:8]=[O:9])([CH3:4])([CH3:3])[CH3:2].C[Si]([N:27]([Si](C)(C)C)[C:28]1[CH:29]=[C:30]([Mg]Cl)[CH:31]=[CH:32][CH:33]=1)(C)C>C1COCC1>[NH2:27][C:28]1[CH:33]=[C:32]([CH:8]([C:7]2[CH:10]=[C:11]([C:13]3[C:14]([O:19][CH3:20])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]=2[O:21][CH3:22])[OH:9])[CH:31]=[CH:30][CH:29]=1
Reactant: COc1ncccc1-c1cc(C=O)c(OC)c(C(C)(C)C)c1
Reactant: C[Si](C)(C)N(c1cccc([Mg]Cl)c1)[Si](C)(C)C
Solvent: C1CCOC1
Product: COc1ncccc1-c1cc(C(O)c2cccc(N)c2)c(OC)c(C(C)(C)C)c1
Reaction time: 8 h
Yield: 54.7 %

Procedure:
step 1—To a solution of 3-tert-butyl-2-methoxy-5-(2-methoxy-pyridin-3-yl)-benzaldehyde (B-2a, R4=tert-Bu, R6═H, 110 mg, 0.368 mmol) in THF (5 mL) at 0° C. was added a solution of 3-(bis-(trimethylsilyl)amino)phenyl magnesium chloride (1.0 M in THF, 0.750 mL, 0.750 mmol). The reaction was gradually warmed RT and stirred overnight. The reaction mixture was quenched with 1N aqueous HCl solution and extracted with EtOAc. The organic layer was washed sequentially with water and brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (25 to 50% EtOAc) to afford 79 mg (55%) of (3-amino-phenyl)-[3-tert-butyl-2-methoxy-5-(2-methoxy-pyridin-3-yl)-phenyl]-methanol (34) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5].[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:10])[CH3:11])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)=CCCC(C)CCO
Solvent: c1ccncc1
Product: CC(=O)OCCC(C)CCC=C(C)C

Procedure:
100 Grams of 3,7-dimethyloct-6-en-1-ol is dissolved in 150 ml. of pyridine and 100 ml. of acetic anhydride and left at room temperature for about 48 hours. Then the mixture is extracted with ether and the ethereal extracts washed with water, 10% aqueous HCl and brine to yield 1-acetoxy-3,7-dimethyloct-6-ene which is purified by distillation.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15](C)[CH:16]([C:21]2[CH:26]=[CH:25][C:24]([O:27]C)=[CH:23][CH:22]=2)[C:17](NO)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].N1C=CN=C1.CN([CH:46]=[O:47])C>CCOCC>[CH3:46][O:47][C:17](=[O:18])[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:23][CH:22]=1)[NH:15][S:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=1)(=[O:13])=[O:14]
Reactant: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)NO)c2ccc(OC)cc2)cc1
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 6.62 g (0.017 mmol) of [}[4-(2-butynyloxy)phenyl]sulfonyl}amino](4-hydroxyphenyl)acetate from Example 178 in 50 mL of DMF was added 3.08 g (0.020 mmol) of tert-butyldimethylsilyl chloride followed by 2.89 g (0.043 mmol) of imidazole. The reaction was stirred at room temperature for 5 h and then diluted with ether. The resulting mixture was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to give 7.06 g of [4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-(4-but-2-ynyloxy-benzenesulfonylamino)-acetic acid methyl ester as a white solid. Electrospray Mass Spec 504.4 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[S:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@@H:21](O)[CH3:22]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@H:21]([O:1][C:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[S:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11])[CH3:22]
Reactant: C[C@H](O)c1ccccc1Cl
Reactant: COC(=O)c1sc([N+](=O)[O-])cc1O
Product: COC(=O)c1sc([N+](=O)[O-])cc1O[C@H](C)c1ccccc1Cl

Procedure:
Methyl 3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-nitro-2-thiophenecarboxylate was prepared from methyl 3-hydroxy-5-nitro-2-thiophenecarboxylate and (1S)-1-(2-chlorophenyl)ethanol by a procedure analogous to Intermediate 29, Step A. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.65 (dd, 1H, J=1.7, 7.8 Hz), 7.47 (dd, 1H, J=1.5, 7.7 Hz), 7.40 (dt, 1H, J=1.3, 7.5 Hz), 7.34 (dt, 1H, J=1.9, 7.5 Hz), 5.98 (q, 1H, J=6.0 Hz), 3.85 (s, 3H), 1.59 (d, 3H, J=6.2 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:22])[C@@H:12]([NH2:21])[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].[C:23]([O:27][C:28]([NH:30][CH:31]([C:35]1[CH:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][CH:36]=1)[C:32](O)=[O:33])=[O:29])([CH3:26])([CH3:25])[CH3:24].Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:22])[C@@H:12]([NH:21][C:32](=[O:33])[CH:31]([NH:30][C:28]([O:27][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:29])[C:35]2[CH:40]=[CH:39][C:38]([S:41][CH3:42])=[CH:37][CH:36]=2)[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](N)[C@@H](C)c2ccccc2)n1
Reactant: CSc1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)C(NC(=O)OC(C)(C)C)c2ccc(SC)cc2)[C@@H](C)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 80 %

Procedure:
A solution of 2-((2S,3S)-2-amino-3-phenyl-butyrylamino)-thiazole-4-carboxylic acid methyl ester (75 mg, 0.24 mmol) and tert-butoxycarbonylamino-(4-methylsulfanyl-phenyl)-acetic acid (77 mg, 0.26 mmol) in dichloromethane (10 mL) at 0° C. was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50 mg, 0.26 mmol). The reaction was allowed to slowly warm to room temperature and stirred for 60 hours. The mixture was then partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel gradient eluted up to 7:3 ethyl acetate/hexane. The material obtained after chromatography was further treated by precipitation of dichloromethane solution with excess of hexanes to give 2-{(2S,3S)-2-[2-tert-butoxycarbonylamino-2-(4-methylsulfanyl-phenyl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester as a white amorphous solid (115 mg, 80%).