Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[C:15]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:18])[NH:16][NH2:17]>>[C:20]([O:19][C:15]([NH:16][N:17]=[CH:11][C:10]1[CH:13]=[CH:14][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:8][CH:9]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Product: CC(C)(C)OC(=O)NN=Cc1ccc(-c2ccccn2)cc1

Procedure:
WO97/40029 discloses a production method comprising reacting 4-(pyridin-2-yl)benzaldehyde with tert-butyl carbazate [tBuOC(═O)NHNH2 wherein tBu is tert-butyl] to give N-(tert-butoxycarbonyl)-N′-[4-(pyridin-2-yl)phenylmethylidene]hydrazine, therefor 4-(pyridin-2-yl)benzaldehyde is important as an intermediate for a pharmaceutical product.
Reaction SMILES: O.N[C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6].[K+].[Br-:12].N([O-])=O.[Na+].CCO>OS(O)(=O)=O.O>[Br:12][C@@H:3]([CH2:4][C:5](=[O:7])[NH2:6])[C:8]([OH:10])=[O:9]
Reactant: [Br-]
Reactant: NC(=O)C[C@H](N)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCO
Solvent: O
Product: NC(=O)C[C@H](Br)C(=O)O
Temperature: -10 °C

Procedure:
L-Asparagine monohydrate 1* (37.5 g, 0.25 mol) was dissolved in 3M H2SO4 (330 ml) and treated with KBr (39.3 g, 0.75 mol). The solution was stirred and cooled in an ice-MeOH bath to ca. -10° C. Some precipitation occurred. A solution of NaNO2 (21.6 g, 0.31 mol) in H2O (38 ml) was added dropwise over 80 minutes. The internal temperature was kept at -10° to -5° during the addition and for 90 minutes afterward. The mixture was filtered and the solid portion washed with ice cold H2O (3x) and dried overnight to give the product 2* (31.64 g, 65%) as an off-white solid: [α]D =-67.8° (C 4.51, EtOH). ##STR93##
Reaction SMILES: [C:1]([CH:6]1[CH2:15][CH2:14][C:13]2[NH:12][C:11](=[O:16])[N:10]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])[N:19]=[C:9]3[C:8]=2[CH2:7]1)([O:3]CC)=[O:2].Cl>[OH-].[Na+]>[C:1]([CH:6]1[CH2:15][CH2:14][C:13]2[NH:12][C:11](=[O:16])[N:10]3[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[F:26])[N:19]=[C:9]3[C:8]=2[CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Temperature: 60 °C
Reaction time: 0.67 h

Procedure:
To 20 mL of 1N NaOH was added 9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (400 mg). After the solid dissolved, the mixture was stirred for 40 minutes at 60° C., cooled and the pH adjusted to 3 with concentrated HCl. The solid was collected and dried to yield 9-Carboxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazolin-5(6H)-one (Compound 17). m.p.>325° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][C:21]([C:24]([OH:26])=O)([CH3:23])[CH3:22])[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCCCCC.C(OCC)(=O)C>C(OC(=O)C)C>[CH2:1]([O:8][C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][C:21]([C:24](=[O:26])[N:30]([CH2:31][CH3:32])[CH2:28][CH3:29])([CH3:22])[CH3:23])[CH:18]=2)[NH:13][C:12]=1[CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1[nH]c2ccc(OC(C)(C)C(=O)O)cc2c1C(=O)OCc1ccccc1
Reactant: CCNCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCN(CC)C(=O)C(C)(C)Oc1ccc2[nH]c(C)c(C(=O)OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 9.3 %

Procedure:
5-(1-Carboxy-1-methyl-ethoxy)-2-methyl-1H-indole-3-carboxylic acid benzyl ester (1.0 g, 2.76 mmol, 1.0 eq) was dissolved in ethylacetate (100 mL), and treated with diethylamine (0.241 g, 3.3 mmol, 1.2 eq) followed by HBTU (0.446 g, 3.3 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 24 hours and was followed by TLC (hexane/ethyl acetate 1/1). The reaction was quenched with aqueous sodium bicarbonate, extracted with ethyl acetate, and the organic layers dried over sodium sulfate, evaporated, and loaded on silica gel, followed by flash chromatography (hexane/ethyl acetate 1/1). 0.109 g of the product was obtained, 12% yield. LC/MS (ESI+) 422.52 (M+1) (C25H30N2O4).
Reaction SMILES: C(O[C:4](=O)[CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[CH3:12])C.[Br:14][C:15]1[CH:16]=[C:17]([NH2:22])[C:18]([NH2:21])=[CH:19][CH:20]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CS(O)(=O)=O>[Br:14][C:15]1[CH:20]=[CH:19][C:18]2[NH:21][C:4]([CH2:5][CH2:6][N:7]3[CH2:11][CH2:10][CH2:9][C@H:8]3[CH3:12])=[N:22][C:17]=2[CH:16]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CCOC(=O)CCN1CCC[C@H]1C
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: C[C@@H]1CCCN1CCc1nc2cc(Br)ccc2[nH]1
Temperature: 110 °C
Yield: 40 %

Procedure:
In a round-bottom flask was charged 3-(2-(R)-methyl-pyrrolidin-1-yl)-propionic acid ethyl ester (5.6 g, 30 mmol), 4-bromo-benzene-1,2-diamine (5.6 g, 30 mmol) and 56 mL of 5% P2O5 in CH3SO3H (Eaton's reagent). After briefly stirring, the homogeneous solution was heated to 110° C. for approximately 24-48 h. The reaction mixture was quenched with ice (˜50 g) and then the pH slowly adjusted to pH>11 with 50% NaOH. The product was extracted with isopropyl acetate (100 mL). The organic layer was then extracted with 5% NaHCO3, H2O and then distilled to dryness. The crude product was purified by column chromatography to provide the title compound (3.7 g). 1H NMR (500 MHz, [(CD3)2SO] δ 1.00 (d, 3H), 1.27 (m, 1H), 1.63 (m, 2H), 1.85 (m, 1H), 2.11 (m, 1H), 2.31 (m, 1H), 2.45 (m, 1H), 2.91-2.99 (m, 2H), 3.09 (m, 1H), 3.19 (m, 1H), 7.24 (m, 1H), 7.43 (d, 1H), 7.66 (s, 1H), some protons were not readily identified due to exchange broadening. 13C NMR (500 MHz, [(CD3)2SO+2 drops DCl] δ 15.3, 21.0, 23.2, 31.0, 48.3, 52.3, 64.3, 115.9, 116.6, 117.9, 128.8, 130.2, 132.2, 151.1 (some 13C peaks were not readily identified due to exchange broadening at 25° C., but were observed under acidic conditions, 2 drops DCl). APPI-MS: (M+1)+ at 308 m/z.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[CH:18]=2)=[CH:9][CH:8]=1.ClC1C=CC=C(C(OO)=[O:39])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.ClCCl>[O-:39][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:30])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=3)[CH:18]=2)=[CH:11][CH:12]=1
Reactant: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4ccccn4)cc3)c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(-c2cccc(/C=C/C(=O)Nc3ccc(-c4cccc[n+]4[O-])cc3)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 51.6 %

Procedure:
To a solution of (E)-N-[4-(2-pyridyl)phenyl]-3-(4-methylphenyl)cinnamamide (350 mg) in tetrahydrofuran (10 ml) and dichloromethane (30 ml) was added 3-chloro-perbenzoic acid (70%, 0.27 g) at 0° C., and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added sodium thiosulfate solution, and the mixture was stirred for a few minutes and extracted with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried with magnesium sulfate and concentrated. The residue was purified with column chromatography (ethanol/ethyl acetate=1:1) concentrated to give crystals, which were recrystallized from ethanol-chloroform to give (E)-N-[4-(1-oxidopyridin-2-yl)phenyl]-3-(4-methylphenyl)cinnamamide (Compound 189) (188 mg) as pale yellow crystals.
Reaction SMILES: C(Cl)CCl.[NH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CCN(C(C)C)C(C)C.OC1C2N=NNC=2C=CC=1.[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[O:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([C:49](O)=[O:50])=[CH:43]2>C(Cl)Cl>[S:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[O:39][C:40]1[CH:41]=[C:42]2[C:46](=[CH:47][CH:48]=1)[NH:45][C:44]([C:49]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:50])=[CH:43]2
Reactant: C1CCNCC1
Reactant: O=C(O)c1cc2cc(Oc3nc4ccccc4s3)ccc2[nH]1
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2cc(Oc3nc4ccccc4s3)ccc2[nH]1)N1CCCCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.9 %

Procedure:
To a solution of EDC (370 mg, 1.9 mmol), piperidine (0.24 mL, 0.21 g, 2.4 mmol), DIEA (0.33 mL, 0.25 g, 1.9 mmol) and hydroxybenzotriazole (257 mg, 1.9 mmol) in DCM (15 mL) was added 5-(benzothiazol-2-yloxy)-1H-indole-2-carboxylic acid (500 mg, 1.6 mmol) and the reaction mixture was stirred (rt, 48 h). The reaction mixture was partitioned between saturated NaHCO3 (10 mL) and DCM (20 mL). The organic layer was separated and the aqueous layer was extracted with DCM (2×25 mL). The organic layer was dried, filtered and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using EtOAc:hexane (0-70%) to provide the title compound as a colorless solid (374 mg, 63%). MS (ESI): mass calcd. for C21H19N3O2S, 377.1; m/z found, 378.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.77 (5, 1H), 7.74 (d, J=7.6, 1H), 7.67-7.59 (m, 2H), 7.48 (d, J=8.8, 1H), 7.37 (t, J=7.1, 1H), 7.27-7.20 (m, 2H), 6.78 (d, J=1.3, 1H), 3.99-3.74 (m, 4H), 1.90-1.64 (m, J=11.3, 5.8, 6H).
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C[Si]([C:35]#[N:36])(C)C.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([C:35]#[N:36])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(C(=O)Cl)cc1
Reactant: C[Si](C)(C)C#N
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CCCCCCCc1ccc(C(=O)C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Heptylbenzoyl cyanide was synthesized according to the general procedure reported by G. A. Olah et al [supra]. Under dry conditions, 2.5518 g of 4-heptylbenzoyl chloride (99%, Aldrich) (10.69 mmol), 30 mL of methylene chloride, freshly distilled from phosphorus pentoxide under nitrogen, and 1.65 mL of trimethylsilyl cyanide (12 mmol) were added to a 100-mL round bottom flask. To this solution 0.27 mL of tin (IV) chloride (2.3 mmol) was added. The reaction mixture was stirred for 2 hr at room temperature. During the 2 hr, the color of the solution changed from a pale yellow to dark brown. After 2 hr of stirring, the reaction was quenched with 81 mL of ice-cold water and then extracted with two 81-mL portions of methylene chloride. The methylene chloride extracts were combined, washed with two 81-mL portions of ice-cold water, dried with MgSO4, and filtered. The methylene chloride was removed by rotary evaporation to yield 2.097 g of a dark brown oil. This oil was distilled at 106°-109.5° C. (0.2 mm) to yield 1.214 g (50%) of 4-heptylbenzoyl cyanide as a colorless oil that solidified on standing in the freezer: IR (CCl4) (partial) 2930, 2860, 2220, 1680, 1610 cm-1.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[NH2:15][C:16]1[C:21]2[C:22](=[O:30])[C:23]3[S:29][CH:28]=[CH:27][C:24]=3[CH2:25][S:26][C:20]=2[CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:15][C:16]1[C:21]2[C:22](=[O:30])[C:23]3[S:29][CH:28]=[CH:27][C:24]=3[CH2:25][S:26][C:20]=2[CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: Nc1cccc2c1C(=O)c1sccc1CS2
Reactant: CC(O)(C(=O)O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Product: CC(O)(C(=O)Nc1cccc2c1C(=O)c1sccc1CS2)C(F)(F)F
Temperature: -10 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
In dimethylacetamide (10 ml) was dissolved 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (0.79 g, 5.0 mmol), and thionyl chloride (0.36 ml, 5.0 mmol) was added thereto at −15  C., followed by stirring at −15 to −5° C. for one hour. To the resulting mixture was added 9-amino-4,10-dihydrothieno[3,2-c][1]benzothiepin-10-one obtained in Reference Example 5 (0.62 g, 2.5 mmol), and the mixture was stirred overnight at room temperature. After the reaction mixture was concentrated under reduced pressure, the obtained oily residue was dissolved in ethyl acetate (50 ml). The organic layer was washed successively with a 5% aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained oily residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1), followed by trituration with hexane to give 9-(3,3,3-trifluoro-2-hydroxy-2-methylpropanoylamino)-4,10-dihydrothieno[3,2-c][1]benzothiepin-10-one (0.60 g, 63%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:28][CH2:29][C@@H:30]1[C@@H:34]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH:44]([CH3:46])[CH3:45])=[O:42])[C@@H:33]([OH:47])[CH2:32][O:31]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[Si:11]([O:28][CH2:29][C@@H:30]1[C@@H:34]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH:44]([CH3:45])[CH3:46])=[O:42])[C:33](=[O:47])[CH2:32][O:31]1)([C:24]([CH3:26])([CH3:27])[CH3:25])([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)OC(=O)CCCCCC[C@H]1[C@@H](O)CO[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)OC(=O)CCCCCC[C@H]1C(=O)CO[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.05 h
Yield: 99.2 %

Procedure:
A dry 100 mL round-bottom flask was charged with 15 mL of anhydrous CH2Cl2 and oxalyl chloride (2.8 mL, 2.0M in CH2Cl2, 5.6 mmol) and this solution was cooled to -78° C. A solution of DMSO (0.78 mL, 11.0 mmol) in 5 mL of CH2Cl2 was added dropwise and the resulting solution was stirred for 3 min. To this mixture, a solution of the alcohol 4 (1.92 g, 3.65 mmol) in 30 mL of CH2Cl2 was added dropwise and stirring was continued for 15 min. Triethylamine (1.5 mL, 11.0 mmol) was then introduced dropwise and the mixture was allowed to warm to room temperature over 15 min. The reaction mixture was poured into 50 mL of water, the layers were separated and the aqueous layer was extracted with 50 mL of CH2Cl2. The combined organic extracts were washed with water and brine, and dried over anhydrous MgSO4. Filtration, solvent removal and chromatography of the crude on silica gel afforded the ketone 5 (1.9 g, 99% yield) as pale yellow oil: Rf 0.7 (60% EtOAc/hexane); 13C-NMR (CDCl3) δ217.04, 173.21, 135.59, 132.99, 129.83, 129.77, 127.75, 127.72, 83.48, 71.34, 67.34, 65.79, 47.87, 34.61, 29.23, 28.83, 28.29, 26.89, 26.75, 24.90, 21.84, 19.19.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][C:10]=1[F:39].C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:64][C:65]1[CH:72]=[CH:71][C:68]([C:69]#[N:70])=[CH:67][C:66]=1[O:73][CH3:74]>>[C:69]([C:68]1[CH:71]=[CH:72][C:65]([NH:64][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[C:10]([F:39])[CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:66]([O:73][CH3:74])[CH:67]=1)#[N:70]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)c(F)cc12
Reactant: COc1cc(C#N)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)c(F)cc32)C1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 47 (0.7 g, 1.2 mmol), was reacted with diisopropylethylamine (0.78 g, 6.0 mmol), diphenylphosphinic chloride (0.57 g, 2.4 mmol), then reacted with 4-amino-3-methoxy-benzonitrile prepared in Example 57 (0.54 g, 3.6 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-5-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a off white solid (Yield 0.24 g, 33%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].C([Li])CCC.[CH3:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28](=[O:42])[CH:29]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[CH2:30][S:31]2)=[CH:26][CH:25]=1.O>O1CCCC1>[Si:7]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([C:28]2([OH:42])[C:27]3[C:32](=[CH:33][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[S:31][CH2:30][CH:29]2[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH:16]=[CH:15][CH:14]=1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: COc1ccc(C2CSc3cc(OC)ccc3C2=O)cc1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C2CSc3cc(OC)ccc3C2(O)c2cccc(CO[Si](C)(C)C(C)(C)C)c2)cc1
Reaction time: 0.83 h
Yield: 28.1 %

Procedure:
To a solution of (3-bromobenzyloxy)-t-butyldimethylsilane (2.207 g, 7.326 mmol) in dry tetrahydrofuran (20 ml) was added n-butyl lithium (4.18 ml, 6.66 mmol, 1.59M tetrahydrofuran solution) at −78° C. over 25 minutes and stirred for 50 minutes. Then to the reaction mixture was added 7-methoxy-3-(4-methoxyphenyl)thiochroman-4-one (1 g, 3.33 mmol) dissolved in tetrahydrofuran at the same temperature over 10 minutes. The reaction mixture was stirred for 20 minutes at −78° C., followed at −15° C. for 12 h and at 0° C. for 8 h. When the reaction was completed, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (n-hexane:ethyl acetate=8:2) to give 0.49 g (yield: 28%) of the title compound as a colorless oil. In this reaction 0.55 g (55%) of the unreacted starting compound was recovered.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]1[NH:13][C:14](=[O:26])[C:15]([C:24]#[N:25])=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1.[H-].[Na+].Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>C1COCC1>[C:24]([C:15]1[C:14](=[O:26])[N:13]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:12]([C:7]2[C:8]3[C:3](=[C:2]([Br:1])[CH:11]=[CH:10][CH:9]=3)[CH:4]=[CH:5][CH:6]=2)=[N:17][C:16]=1[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)#[N:25]
Reactant: N#Cc1c(-c2ccccc2)nc(-c2cccc3c(Br)cccc23)[nH]c1=O
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1c(-c2cccc3c(Br)cccc23)nc(-c2ccccc2)c(C#N)c1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 105.6 %

Procedure:
1,6-Dihydro-2-(5-bromo-1-naphthalenyl)-6-oxo-4-phenyl-5-pyrimidinecarbonitrile (4.0 g, 9.9 mmol) was added portionwise to a suspension of sodium hydride (60% dispersion in mineral oil, washed with hexane, 0.6 g, 14.9 mmol) in dry THF (80 mL). After 5 minutes the mixture became a homogeneous solution. Neat t-butyl bromoacetate (2.9 g, 14.9 mmol) was added in one portion and the mixture was refluxed for 18 hours. Additional t-butyl bromoacetate (0.4 g, 2.0 mmol) was added and reflux was continued for 2 hours. The reaction mixture was cooled to room temperature and quenched with water. The mixture was partitioned between water (50 mL) and CHCl3 (100 mL), and the aqueous layer was extracted with CHCl3 (2×50 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, and concentrated in vacuo to give an orange foam (5.4 g). The material was purified by radial preparative thin-layer (Chromatotron) chromatography with elution by EtOAc/hexanes (20:80) to give the pure product (3.0 g, 59%).
Reaction SMILES: [CH:1]1([C:7]#[N:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.[Cl:9][C:10]1([Cl:19])[C:14]([Cl:15])=[C:13]([Cl:16])[C:12]([Cl:17])=[C:11]1[Cl:18]>>[Cl:15][C:14]12[C:10]([Cl:9])([Cl:19])[C:11]([Cl:18])([CH:3]3[CH:4]1[CH2:5][CH2:6][CH:1]([C:7]#[N:8])[CH2:2]3)[C:12]([Cl:17])=[C:13]2[Cl:16]
Reactant: N#CC1CC=CCC1
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Product: N#CC1CCC2C(C1)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 25 °C

Procedure:
3-Cyclohexene-1-carbonitrile (Aldrich Chemical Corp.) (56 g.), and 200 g. of hexachlorocyclopentadiene were mixed, heated at 160°-170° C. for 6 hours, and then allowed to cool to room temperature. The reaction mixture was then vacuum distilled. Unreacted hexachlorocyclopentadiene was first removed and then the crude adduct produced was collected, 175°-170° C. at 0.3 m.m. Hg. The thick liquid was crystallized very slowly in Skelly "B". The crude solid melted at 140°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[N:5]([C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)C(OC(C)(C)C)=O.[ClH:27].CCOCC>C(Cl)Cl>[ClH:27].[CH3:1][O:2][C:3](=[O:26])[C@H:4]([CH2:22][CH2:23][S:24][CH3:25])[NH:5][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](CCSC)N(C(=O)OC(C)(C)C)C(=O)c1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1
Reaction time: 8 h

Procedure:
N-BOC-4-aminobenzoyl methionine methyl ester (3.53 g, 9.59 mmol) was placed into CH2Cl2 (30-35 ml) and to it was added 3M HCl/ Et2O (38.4 ml). After standing a white precipitate formed. After 2 hours the solution was decanted, and the crystals were collected by centrifugation. The crystals were then washed several times with fresh ether and dried overnight on the vacuum pump. Meanwhile, the filtrate was left to stand overnight to allow additional product to precipitate. The second fraction was washed with ether and dried overnight on the vacuum pump. The total yield of pure fully deprotected material was 2.87 g (93.9%) yield. mp 158-164° C.; 1H NMR (CDCl3) 2.10 (3H, s), 2.12-2.29 (1H, m), 2.52-2.71 (1H, m), 2.59 (2H, t, J=7.6 Hz), 3.75 (3H, s), 4.79 (1H, m), 7.02 (2H, d, J=8.6 Hz), 7.55 (2H, d, J=8.6 Hz); 13C NMR (CDCl3) 15.23, 31.43, 31.53, 52.91, 52.43, 124.35, 130.56, 135.31, 135.76, 168.95, 173.87; HRMS calc. for C13H18N2O3S, 282.1038, found 282.1009.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[S:14][C:9]=3[N:10]=[C:11]([NH2:13])[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[NH2:13][C:11]1[N:12]=[C:7]([N:1]2[CH2:6][CH2:5][N:4]([C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=3)=[O:32])[CH2:3][CH2:2]2)[C:8]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[S:14][C:9]=2[N:10]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Nc1nc(N2CCNCC2)c2nc(-c3cccnc3)sc2n1
Product: Nc1nc(N2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)c2nc(-c3cccnc3)sc2n1
Yield: 38 %

Procedure:
This compound was prepared from 7-(piperazin-1-yl)-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-chlorophenyl isocyanate in a yield of 38%, according to the procedure for the synthesis of example 42.