Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([NH:20][CH3:21])=[O:19])=[C:16]([CH3:24])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Cl:29][CH2:30][C:31]([N:33]=[C:34]=[O:35])=[O:32]>C1(C)C=CC=CC=1>[Cl:29][CH2:30][C:31]([NH:33][C:34]([N:20]([C:18](=[O:19])[C:17]1[CH:22]=[CH:23][C:14]([C:11]2[CH2:10][C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)([C:25]([F:28])([F:27])[F:26])[O:13][N:12]=2)=[CH:15][C:16]=1[CH3:24])[CH3:21])=[O:35])=[O:32]
Reactant: O=C=NC(=O)CCl
Reactant: CNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Solvent: Cc1ccccc1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)C(=O)NC(=O)CCl
Temperature: 50 °C
Reaction time: 24 h
Yield: 84.7 %

Procedure:
In a solution of 0.86 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl-N-methyl benzoic acid amide in 10 mL of toluene, 0.36 g of chloroacetyl isocyanate was added, and stirred at 50° C. for 24 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 0:1 to 3:2) to obtain 0.93 g of the aimed product as colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][CH:7]=[CH:6]2.O=P(Cl)(Cl)[Cl:16]>>[Cl:16][C:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: COc1ccc2c(=O)[nH]ccc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nccc2c1
Yield: 86 %

Procedure:
1-Chloro-6-methoxy-isoquinoline was prepared according to the following procedure. To a solution of 3-methoxy cinnamic acid (25 g, 140.3 mmol) and triethylamine (39.1 mL, 280.6 mmol) in THF (200 mL) was added ethyl chloroformate (20 ml, 210 mmol) dropwise at 0° C. After stirring at this temperature for 1 hour, aqueous NaN3 (14.7 g, 226 mmol in 80 mL H2O) was added dropwise and the reaction mixture was stirred for 16 hours at ambient temperature. Water (220 mL) was added to the mixture and the volatiles were removed in vacuo. The resulting slurry was extracted with toluene (3×110 mL) and the combined organic layers were dried over MgSO4, filtered and concentrated. The dried solution was added dropwise to a heated solution of diphenylmethane (120 mL) and tributylamine (68 mL) at 190° C. The toluene was distilled off during the addition. After complete addition, the reaction temperature was raised to 210° C. for 2 hours. Upon cooling via an ice bath, the precipitated product was collected by filtration, washed with hexanes, and dried to yield the desired product as an off-white solid (14.04 g, 57%): LCMS found 176.1 [M+H]+. 6-Methoxy-2H-isoquinolin-1-one (14.04 g, 80.15 mmol) in POCl3 (30.5 ml) was heated to gentle reflux for 1 hour and the mixture was then concentrated in vacuo. The residue was poured into ice water and brought to pH 10 by the addition of 10 M NaOH. The resulting mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (0-20% EtOAc/hexane) to afford 13.31 g (86%) of the desired 1-chloro-6-methoxy-isoquinoline intermediate as a white solid. LCMS found 194.19 [M+H]+.
Reaction SMILES: [C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([NH2:24])[C:14]=2[CH3:25])=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].[CH:30](=O)[CH3:31].C(O)(=O)C>CO>[C:1]1([C@@H:7]([NH:10][C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([NH:24][CH2:30][CH3:31])[C:14]=2[CH3:25])=[O:12])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[C@H](NC(=O)c1c(C)n(N)c(=O)c2ccccc12)c1ccccc1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCNn1c(C)c(C(=O)N[C@@H](CC)c2ccccc2)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-amino-3-methyl-1-oxo-1,2-dihydro-isoquinoline-4-carboxylic acid ((S)-1-phenyl-propyl)-amide (3.04 g, 9.06 mmol) and sodium cyanoborohydride (1.00 g, 15.9 mmol) in methanol (25 mL), acetaldehyde (2.00 mL, 35.6 mmol) was added followed by dropwise addition of acetic acid (2.5 mL, 44 mmol) (caution: exothermic reaction with gas evolution). The obtained clear colorless solution was stirred at r.t. for 30 min. More sodium cyanoborohydride (1 g), acetaldehyde (1 ml), and acetic acid (2 ml) were added and stirring continued for 2 hour. LC-MS indicated a full conversion to the title product with formation of traces of the double alkylation product (UV 1.3%, tR=1.5, m/z (MH+) 392.4). The reaction mixture was partitioned between 5% aq. NaHCO3 (100 ml, pH=7) and ethyl acetate (3×50 mL), the combined organic solutions were washed with water 3 times, and evaporated to give 3.2 g of colorless solid residue. The crude product was transferred into 100 g prepacked SiO2 column with 1,2-dichloroethane and flash chromatographed with gradient 20% to 50% ethyl acetate in heptane. The title product came out with 40-50% ethyl acetate to give 2.73 g of colorless foam after evaporation and drying in high vacuo at 60° C. for 2 hours. LC-MS (m/z) 364.6 (MH+); tR=1.33. LC— high res. MS: calculated for C22H26N3O2 (MH+) 364.2020. found 364.2006. 1H NMR (250 MHz, 70° C., DMSO-d6, DMSO-d5=2.5 ppm): 0.96 (t, J=7.3 Hz, 3H, Me of Et), 1.13 (t, J=7.3 Hz, 3H, Me of EtNH), 1.72-1.94 (m, 2H, CH2 of Et), 2.38 (s, 3H, Me), 2.97 (quintet, J=7.1 Hz, 2H, CH2 of EtNH), 5.0 (q (unres. dt), J=6.8 Hz, J=8.2 Hz, 1H, CHNHCO), 6.05 (t, J=6.6 Hz, 1H, NHEt), 7.27 (m, 1H), 7.31-7.5 (m, 5H), 7.62 (m, 1H), 8.26 (d, J=8 Hz, 1H, C8-H), 8.68 (br. d, J=8.1 Hz, 1H). 13C APT (125 MHz, 25° C., DMSO-d6=39.88 ppm): 11.65 (CH3 of Et), 12.99 (CH3 of NHEt), 16.55 (br, CH3), 29.58 (CH2 of Et), 44.99 (CH2 of NHEt), 55.29 (CHNHCO), 114.3 (C), 123.73 (br, CH), 123.82 (C), 126.4 (CH), 126.93 (CH of Ph), 127.21 (CH), 127.47 (C8-H), 128.64 (CH of Ph), 132.89 (br, CH), 134.3 (C), 139.21 (C3), 143.92 (C1 of Ph), 160.82 (CON), 166.12 (CONH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:38])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][NH:22]C(OCC2C=CC=CC=2)=O)=[N:19][C:18]([C:33](=[O:37])[N:34]([CH3:36])[CH3:35])=[N:17]1.[BrH:39].C(O)(=O)C>CCOCC>[BrH:39].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:38])[C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[C:20]([CH2:21][NH2:22])=[N:19][C:18]([C:33](=[O:37])[N:34]([CH3:35])[CH3:36])=[N:17]1
Reactant: CN(C)C(=O)c1nc(CNC(=O)OCc2ccccc2)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CN(C)C(=O)c1nc(CN)n(-c2ccc(Cl)cc2C(=O)c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2',5-dichloro-2-(3-dimethylcarbamoyl-5-carbobenzoxyaminomethyl-1,2,4-triazol- 1-yl)benzophenone (3.6 g) and 30% hydrogen bromide-acetic acid (9 ml) is stirred at room temperature for 2 hours. The reaction mixture is mixed with ether, and the precipitate is isolated by decantation and washed thrice with ether, whereby 2',5-dichloro-2-(3-dimethylcarbamoyl-5-aminomethyl-1,2,4-triazol- 1-yl)-benzophenone hydrobromide is obtained. This hydrobromide (1.2 g) is added to a solution of chloroacetyl chloride (1.2 g) in benzene (40 ml) to give a solution, which is mixed with dimethylformamide (20 ml). The resultant mixture is stirred at room temperature for 3 hours. The reaction mixture is mixed with ethyl acetate and neutralized with aqueous sodium bicarbonate. The organic layer is separated, washed with water, dried, and evaporated under reduced pressure to remove the solvent. The residue is treated with ethanol/n-hexane to give 2',5-dichloro-2-[3-dimethylcarbamoyl-5-(2-chloroacetylamino)methyl-1,2,4-triazol- 1-yl]-benzophenone (12.9 g), which is recrystallized from ethyl acetate to give colorless needles melting at 80°-82° C.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([CH:16]1[CH2:21][CH2:20][O:19][CH2:18][C:17]1=O)[CH2:12][CH2:13][CH:14]=[CH2:15]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:1]=[C:17]1[CH:16]([CH2:11][CH2:12][CH2:13][CH:14]=[CH2:15])[CH2:21][CH2:20][O:19][CH2:18]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C=CCCCC1CCOCC1=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCCCC1CCOCC1=C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaHMDS (5.35 ml, 10.70 mmol) was added to methyltriphenylphosphonium bromide (3822 mg, 10.70 mmol) in THF (53.500 ml) at RT. The reaction was stirred at RT for 1 hr before 4-(pent-4-en-1-yl)dihydro-2H-pyran-3(4H)-one (900 mg, 5.35 mmol) in THF (2 mL) was added at 0° C. The reaction mixture was stirred at room temperature for 2 hr. The mixture was cooled and quenched with aqueous NH4Cl. The reaction mixture was extracted with diethyl ether (3×20 mL). The combined organic fractions were washed with water and brine (saturated, 100 mL), dried, filtered and the solvent was evaporated under reduced pressure (400 mmhg). The residue was purified by column chromatography on silica gel to provide the title compound. 1H NMR (500 MHz, CDCl3) δ 5.75-5.89 (m, 1H), 4.92-5.06 (m, 2H), 4.86 (s, 1H), 4.77 (t, 1H, J=1.5 Hz), 4.12 (d, 1H, J=12.1 Hz), 3.86-3.96 (m, 2H), 3.57-3.65 (m, 1H), 2.15-2.24 (m, 1H), 2.00-2.12 (m, 2H), 1.81-1.91 (m, 1H), 1.64-1.76 (m, 1H), 1.21-1.52 (m, 4H).
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[N:34][CH:35]=2)=[CH:18][C:17]=1[F:37])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.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>[F:37][C:17]1[CH:18]=[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)=[CH:28][C:29]=2[C:30]2[CH:35]=[N:34][CH:33]=[N:32][CH:31]=2)[C:20]([F:22])=[CH:21][C:16]=1[S:13]([NH:7][C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(=[O:14])=[O:15]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(F)c(Oc2cnc(Cl)cc2-c2cncnc2)cc1F
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: O
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1cscn1)c1cc(F)c(Oc2cnc(-c3cccc(F)c3)cc2-c2cncnc2)cc1F
Reaction time: 0.17 h
Yield: 46.2 %

Procedure:
10 mg (0.02 mmol) of tert-butyl((4-((6-chloro-4-(pyrimidin-5-yl)pyridin-3-yl)oxy)-2,5-difluorophenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 3.6 mg (0.03 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 2 mg (10 mol %) of Pd(PPh3)4, 5.4 mg (0.05 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](=[N:9][O:10][CH2:11][CH2:12][OH:13])[CH3:8])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O[C:21]1[CH:53]=[CH:52][C:24]([CH2:25][CH:26]2[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]2=[O:51])=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7](=[N:9][O:10][CH2:11][CH2:12][O:13][C:21]2[CH:53]=[CH:52][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[N:28]([C:32]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)([C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:27]3=[O:51])=[CH:23][CH:22]=2)[CH3:8])[N:4]=[C:3]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=NOCCO)c1cn(C)c(-c2ccccc2)n1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(=NOCCOc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1)c1cn(C)c(-c2ccccc2)n1
Yield: 82.2 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 396 mg of 2-[1-(1-methyl-2-phenylimidazol-4-yl)ethylideneaminooxy]ethanol (prepared as described in Preparation 25), 694 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 440 mg of triphenylphosphine and 292 mg of diethyl azodicarboxylate, 866 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5].I[CH:19]([OH:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[OH:21][CH2:19][CH2:20][S:1][CH2:2][CH2:3][C:4]([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:6])[CH3:5]
Reactant: CC(O)I
Reactant: CC(C)(CCS)NC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(CCSCCO)NC(=O)OCc1ccccc1
Temperature: 85 °C
Yield: 27.9 %

Procedure:
To a solution of benzyl 4-mercapto-2-methylbutan-2-ylcarbamate (3.30 g, 12.2 mmol) in N,N-dimethylformamide (50 ml) was added iodoethanol (1.4 ml, 18.0 mmol) and cesium carbonate (390 mg, 1.20 mmol). The solution was heated to 85° C. for 16 hours, cooled to room temperature, and concentrated in vacuo. The residue was purified by flash chromatography (30% to 100% ethyl acetate in hexanes) to afford the title compound as a clear oil (1.01 g, 3.40 mmol, 26%). 1H NMR (400 MHz, CDCl3) δ 1.31 (s, 6H), 2.0-2.1 (m, 2H), 2.47-2.51 (m, 2H), 2.72 (m, 2H), 3.70 (m, 2H), 4.7 (s, 1H), 5.06 (s, 2H), 7.3-7.4 (m, 5H); LRMS (ESI/APCI) m/z 298 [M+H]+, 320 [M+Na]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].Cl>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(NC(=O)OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Yield: 87.3 %

Procedure:
A solution of diethyl 2-benzyloxycarbonylaminomalonate (50 g) in anhydrous DMF (300 mL) was added portionwise with sodium hydride (60%, 6.47 g) with ice cooling and stirring, then the mixture was stirred at room temperature for 30 minutes, and subsequently added with ethyl 2-bromoacetate (22.6 g), and the mixture was stirred overnight. The reaction mixture was poured into diluted hydrochloric acid, the mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography, in which elution was performed with n-hexane/ethyl acetate (5:1) for purification, and then crystallized from ethyl acetate/n-hexane to obtain the title compound (46.7 g, yield: 83%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C([Li])CCC.F[C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[C:22]1[O:23][CH2:24][C:25]([CH3:28])([CH3:27])[N:26]=1.Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:17]2[CH:18]=[C:19]([F:21])[CH:20]=[CH:15][C:16]=2[C:22]2[O:23][CH2:24][C:25]([CH3:28])([CH3:27])[N:26]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(S)cc1
Reactant: CC1(C)COC(c2ccc(F)cc2F)=N1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc(F)cc2Sc2ccc(F)cc2)=N1
Temperature: 25 °C
Yield: 76.5 %

Procedure:
To 4-fluorothiophenol (9.26 g; 72.2 mmol.) in dry THF under nitrogen and cooled to -78° C. was added n-butyllithium (45.2 ml of 1.6M) dropwise affording a white slurry. To this mixture was added 2-(2,4-difluorophenyl)-4,4-dimethyloxazoline (7.63 g; 36.1 mmol.) in 20 ml of dry THF dropwise. The reaction mixture was allowed to warm to room temperature overnight. An additional 50 ml of THF was added to afford a solution and the reaction stirred over the weekend. The mixture was poured into water, acidified to pH 5 with 1N HCl. The mixture was extracted twice with diethyl ether and the organics combined, washed with water and then 0.2N NaOH. The organic layer was washed again with water and then brine, dried over MgSO4, and concentrated to afford 13.2 g of crude product which after recrystallization from hexane afforded 8.82 g of the subtitle compound.
Reaction SMILES: [OH-].[Na+].[O:3]([CH2:10][C:11]([NH:13][CH:14]1[CH2:17][N:16]([C:18](=[C:35]([CH3:40])[CH2:36][O:37]C=O)[C:19]([O:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:15]1=[O:41])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OCC)(=O)C>C1COCC1>[O:3]([CH2:10][C:11]([NH:13][CH:14]1[CH2:17][N:16]([C:18](=[C:35]([CH3:40])[CH2:36][OH:37])[C:19]([O:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[C:15]1=[O:41])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(COC=O)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(CO)=C(C(=O)OC(c1ccccc1)c1ccccc1)N1CC(NC(=O)COc2ccccc2)C1=O
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
To 6 ml of 0.1 N aqueous sodium hydroxide at 0° was added a solution of 338 mg (0.6 mmol) of benzhydryl 2-(3-phenoxyacetamido-2-oxoazetidin-1-yl)-3-methyl-4-formyloxy-2-butenoate in 10 ml of cold THF. After 30 minutes, ethyl acetate was added. The organic layer was separated, washed with dilute acid and brine, dried, and evaporated in vacuo to dryness to provide 250 mg of a multi-component mixture. Separation by preparative thin layer chromatography (silica gel plates developed with 3:1/ethyl acetate:hexane) provided 35 mg of the title product: nmr (CDCl3) δ 2.28 (s, 3, CH3), 4.72 (s, 2, --CH2OH), 3.60 (m, 2, C4 --H), 5.02 (m, 1, C3 --H), 4.55 (s, 2, side chain CH2), and 7.2 (b, ArH).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[C:7]([O:9][CH:10]([CH3:12])[CH3:11])[CH:6]=[CH:5][C:4]=1B(O)O.Cl.Cl.COC1C=CC([C:28]2[CH:29]=[C:30]3[C:35]4=[C:36]([CH2:38][CH2:39][CH2:40][N:34]4[CH2:33][C@@H:32]4[CH2:41][NH:42][CH2:43][C@@H:31]34)[CH:37]=2)=C(C(F)(F)F)C=1>>[CH:10]([O:9][C:7]1[CH:6]=[CH:5][C:4]([C:28]2[CH:29]=[C:30]3[C:35]4=[C:36]([CH2:38][CH2:39][CH2:40][N:34]4[CH2:33][C@@H:32]4[CH2:41][NH:42][CH2:43][C@@H:31]34)[CH:37]=2)=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=1)([CH3:12])[CH3:11]
Reactant: CC(C)Oc1ccc(B(O)O)c(C(F)(F)F)c1
Reactant: COc1ccc(-c2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)c(C(F)(F)F)c1
Agent: Cl
Product: CC(C)Oc1ccc(-c2cc3c4c(c2)[C@@H]2CNC[C@H]2CN4CCC3)c(C(F)(F)F)c1

Procedure:
Using 2-trifluoromethyl-4-isopropoxyphenyl boronic acid and following the procedures described in EXAMPLE 34, (±)-trans tert-butyl 2-bromo-5,6,8a,9,11,11a-hexahydro-4H-pyrido[3,2,1-ij]pyrrolo[3,4-c]quinoline-10(8H)-carboxylate from EXAMPLE 7, Part A was converted into the title compound of EXAMPLE 35 as a yellow semi-solid. 1H NMR (500 MHz, CDCl3) δ 1.26 (s, 1H), 1.30 (d, 6H, J=6.1 Hz), 1.85-2.05 (m, 2H), 2.15 (m, 1H), 2.74 (m, 4H), 2.96 (t, 1H, J=7 Hz), 3.23 (m, 1H), 3.32 (m, 4H), 3.57 (t, 1H, J=7 Hz), 4.58 (sept, 1H, J=6.1 Hz), 6.59 (s, 1H), 6.77 (s, 1H), 6.99 (dd, 1H, J=2.5, 8.4, Hz), 7.18 (s, 1H), 7.24 (m, 1H). LRMS (ES)+: 417 (M+H)+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2.[CH2:14](Br)[CH:15]=[CH2:16]>CN(C=O)C>[CH2:16]([O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: Oc1cccc2cccnc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cccc2cccnc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a suspension of sodium hydride (60% oil dispersion, 3.0 g, 75 mmol) in DMF (100 mL) at 0° C. under argon, was added a solution of 8-hydroxyquinoline (9.2 g, 64 mmol) in DMF (20 mL) dropwise. The mixture was allowed to stir for 0.5 h, then allyl bromide (6.6 mL, 77 mmol) was added dropwise. The mixture was stirred at room temperature for 20 h, then was poured into ice/water (400 mL) and extracted with ether (3×300 mL). Combined organic extracts were washed with water (500 mL) and evaporated in vacuo. The crude residue was purified by silica gel chromatography (ethyl acetate in hexane 25%-75% gradient) to give 8-allyloxyquinoline (8.5 g, 72%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:17](N)=[NH:18]>COCCO>[CH3:12][O:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:18][CH:17]=[N:1]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)O)c(N)c1
Reactant: N=CN
Solvent: CC(=O)O
Solvent: COCCO
Product: COc1ccc2c(O)ncnc2c1
Temperature: 130 °C
Reaction time: 15.25 h
Yield: 89.8 %

Procedure:
Step 1 A mixture of 2-amino-4-methoxybenzoic acid (0.5 g, 2.99 mmol) and formamidine acetate (0.623 g, 5.98 mmol) in 2-methoxyethanol (4 mL) was heated at 130° C. After 15.25 h, the mixture was cooled to rt. The resulting precipitate was collected by filtration, washed with methanol and dried to provide 7-methoxyquinazolin-4-ol as a tan solid (473 mg, 90%). 1H NMR (400 MHz, DMSO-d6) δ 12.08 (1 H, br. s.), 8.06 (1 H, s), 8.03 (1 H, d, J=9.5 Hz), 7.03-7.14 (2 H, m), 3.90 (3 H, s).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([CH3:10])=[O:11])=[CH:6][CH:7]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Cc1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 54 %

Procedure:
To a solution of 1-(4-hydroxyphenyl)propan-2-one (2.2 g, 0.01 mol) in dimethylformamide (10 mL) was added 1,3-dibromopropane (7.6 mL, 0.07 mol), potassium carbonate (2.3 g, 0.01 mol) and potassium iodide (0.7 g, 0.004 mol). The mixture was stirred at room temperature for 72 hours. Water was added into the reaction vessel and the crude was extracted with ethyl acetate. The organic layer was washed with water and brine, dried, filtered and evaporated to dryness. The crude obtained was purified by column chromatography with silica gel, eluting with hexane/ethyl acetate (from 100% to 10%), obtaining the title compound (54%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][Cl:26]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:23][CH2:24][CH2:25][Cl:26])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: ClCCCOc1ccc(OCc2ccccc2)cc1

Procedure:
Following the procedure described in example 1§E, but starting from 4-benzyloxyphenol (2 g), potassium carbonate (6.90 g) and 1-bromo-3-chloropropane (4.94 mL) in N,N-dimethylformamide (10 mL) affords 2.07 g of O-benzyl-4-(3-chloropropoxy)phenol as a white solid.