Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[C:11](O)(=[O:15])[C:12](O)=[O:13]>Cl.O>[CH3:8][C:7]1[CH:6]=[C:5]2[C:4](=[CH:3][C:2]=1[CH3:1])[NH:10][C:12](=[O:13])[C:11](=[O:15])[NH:9]2
Reactant: Cc1cc(N)c(N)cc1C
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: Cc1cc2[nH]c(=O)c(=O)[nH]c2cc1C
Temperature: 25 °C
Yield: 938.5 %

Procedure:
A mixture of 2.72 g (2.0 mmol) of 4,5-dimethyl-1,2-phenylenediamine and 1.92 g (21.3 mmol) of oxalic acid in 30 mL of 2N HCl was refluxed for 2.5 h and cooled to room temperature. The mixture was diluted with 20 mL of H2O, filtered, washed with water, and dried to leave a pale-brown solid 3.57 g (94%); mp>250° C.; 1H NMR (DMSO-d6,2.161 (s,6), 6.869 (s,2), 11.78 (s,2).
Reaction SMILES: C(OC([N:8]1[CH:13]([CH3:14])[CH2:12][N:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24](Cl)[N:23]=3)[CH:17]=2)[CH2:10][CH:9]1[CH3:29])=O)(C)(C)C.[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[C:35]([Cl:40])[CH:34]=1>>[Cl:40][C:35]1[CH:34]=[C:33]([CH2:32][CH2:31][NH:30][C:24]2[N:23]=[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][N:11]4[CH2:10][CH:9]([CH3:29])[NH:8][CH:13]([CH3:14])[CH2:12]4)[CH:17]=3)[CH:27]=[CH:26][N:25]=2)[CH:38]=[CH:37][C:36]=1[OH:39]
Reactant: CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CC(C)N1C(=O)OC(C)(C)C
Reactant: NCCc1ccc(O)c(Cl)c1
Product: CC1CN(Cc2cccc(-c3ccnc(NCCc4ccc(O)c(Cl)c4)n3)c2)CC(C)N1

Procedure:
Intermediate 142 was coupled with 4-(2-amino-ethyl)-2-chloro-phenol following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 452. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.63 (s, 1H) 8.35 (d, 2H)) 7.93 (d, 1H) 7.74 (d, 1H) 7.62 (d, 1H) 7.17 (s, 1H) 7.07 (d, 1H) 6.74 (d, 1H) 4.60 (s, 2H) 3.60-3.70 (m, 6H) 3.35 (t, 2H) 2.92 (t, 2H) 1.44 (d, 6H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].[C:6]([C:10]1[CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([O:20][CH3:21])=[C:14]([S:16](Cl)(=[O:18])=[O:17])[CH:15]=1)([CH3:9])([CH3:8])[CH3:7]>C(#N)C>[C:6]([C:10]1[CH:11]=[C:12]([N+:22]([O-:24])=[O:23])[C:13]([O:20][CH3:21])=[C:14]([S:16]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:17])=[O:18])[CH:15]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1S(=O)(=O)Cl
Reactant: CC(C)(C)N
Solvent: CC#N
Product: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
t-Butylamine (9 ml) was added to a cooled solution of 5-t-butyl-2-methoxy-3-nitrophenyl sulfonyl chloride (7.4 g) in acetonitrile (40 ml). The mixture was stirred at ambient temperature for 1 hour and then the solvent was removed under vacuum. The residue was shaken with ethyl acetate (100 ml) and 4% citric acid (100 ml). The organic phase was separated and dried over sodium sulphate. Evaporation of solvent gave a solid residue which was recrystallized from aqueous ethanol to give the title compound (6.0 g);
Reaction SMILES: [NH2:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33].Br[CH2:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45].CCN(C(C)C)C(C)C>>[CH2:47]([O:46][C:44]([CH2:43][CH2:42][CH2:41][NH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][N:4]1[C:9](=[O:10])[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=2[F:19])=[C:7]([CH3:20])[N:6]([CH2:21][C:22]2[C:27]([C:28]([F:29])([F:31])[F:30])=[CH:26][CH:25]=[CH:24][C:23]=2[F:32])[C:5]1=[O:33])=[O:45])[CH3:48]
Reactant: CCOC(=O)CCCBr
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCCN[C@@H](Cn1c(=O)c(-c2cccc(OC)c2F)c(C)n(Cc2c(F)cccc2C(F)(F)F)c1=O)c1ccccc1
Temperature: 95 °C
Yield: 49.5 %

Procedure:
To compound 3-[2(R)-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[2-fluoro-6-(trifluoromethyl)benzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 1f (5 g, 9.4 mmol) in 100 mL of acetontrile were added ethyl 4-bromobutyrate (4 mL, 28.2 mmol) and Hunig's base (1.6 mL, 9.4 mmol). After reflux at 95° C. overnight, the reaction mixture was cooled to ambient temperature and the volatiles were removed. The residue was chromatographed with 10:10:1 EtOAc/Hexane/Et3N to give 1g as a yellow oil (3.0 g, 4.65 mmol). MS (CI) m/z 646.2 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:25][N:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1.[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:39].[ClH:39].[OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4c([N+](=O)[O-])cccc24)C3=O)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1/C(=C/c2c[nH]c3c([N+](=O)[O-])cccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-2-[(7-nitro-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.030 g, 0.058 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The mixture was azeotroped twice with toluene under reduced pressure, and then the residual solid was suspended in a mixed solvent of methylene chloride and diethyl ether and thereby washed to obtain (Z)-6-hydroxy-2-[(7-nitro-1H-indol-3-yl)methylene]-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one dihydrochloride (0.018 g, 62%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]3[CH2:20][O:19]3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]([OH:19])[CH2:20][NH:28][CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCC3CO3)c2c1C
Reactant: NCc1cccnc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1oc2cccc(OCC(O)CNCc3cccnc3)c2c1C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
3-Methyl-4-oxiranylmethoxy-benzofuran-2-carboxylic acid ethyl ester (500 mg) (Naresh K. Sangwan et al., Eur. J. Med. Chem. (1987), 22(2), 153-6) and 3-picolylamine (1 ml) were dissolved in ethanol (5 ml) and stirred at 70° C. for two hours. The reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution and water. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to afford 4-[2-hydroxy-3-[(pyridin-3-ylmethyl)-amino]-propoxy]-3-methyl-benzofuran-2-carboxylicacid ethyl ester (330 mg) as a white powder. FAB-MS: m/z 385 (MH+); 1H-NMR (CDCl3): δ 1.44 (3H, t, J=7 Hz), 2.70 (3H, s),2.86 (1H, dd, J1=12 Hz, J2=7 Hz),2.97 (1H, dd, J1=12 Hz, J2=3.5 Hz), 3.85 (1H, d, J=14 Hz), 3.91 (1H, d, J=14 Hz), 4.13 (3H, m), 4.44 (2H, q, J=7 Hz), 6.63 (1H, d, J=8 Hz), 7.14 (1H, d, J=8 Hz), 7.26 (1H, m), 7.28 (1H, t, J=8 Hz), 7.68 (1H, br d, J=8 Hz),8.52 (1H, dd, J1=5 Hz, J2=2 Hz), 8.58 (1H, d, J=2 Hz).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[NH:11][C:10](=[O:13])[C:9]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[CH:8]2.[Cl:20][C:21]1[C:29]2[NH:28][N:27]=[CH:26][C:25]=2[C:24]2[CH2:30][N:31]([CH2:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C:32](=[O:55])[C@H:33]([CH2:35][C:36](=[O:54])N3CCC(N4CC5C(=CC=CC=5)NC4=O)CC3)[CH2:34][C:23]=2[CH:22]=1>>[Cl:20][C:21]1[C:29]2[NH:28][N:27]=[CH:26][C:25]=2[C:24]2[CH2:30][N:31]([CH2:56][C:57]([CH3:60])([CH3:59])[CH3:58])[C:32](=[O:55])[C@H:33]([CH2:35][C:36]([N:17]3[CH2:18][CH2:19][CH:14]([C:9]4[C:10](=[O:13])[NH:11][C:12]5[C:7]([CH:8]=4)=[CH:6][CH:5]=[CH:4][C:3]=5[F:2])[CH2:15][CH2:16]3)=[O:54])[CH2:34][C:23]=2[CH:22]=1
Reactant: O=c1[nH]c2c(F)cccc2cc1C1CCNCC1
Reactant: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C1=O
Agent: Cl
Product: CC(C)(C)CN1Cc2c(cc(Cl)c3[nH]ncc23)C[C@@H](CC(=O)N2CCC(c3cc4cccc(F)c4[nH]c3=O)CC2)C1=O
Yield: 36 %

Procedure:
Title compound was prepared from 8-fluoro-3-(piperidin-4-yl)quinolin-2(1H)-one hydrochloride in a manner analogous to the preparation of 4-Chloro-9-(2,2-dimethyl-propyl)-7-(S)-{2-oxo-2-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-ethyl}-6,7,9,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-8-one. Material was obtained as white solid in 36% yield. MS m/e (M+H)+=592.2. 1H NMR (500 MHz, DMSO-D6): δ13.54 (s, 1H), 11.78 (s, 1H), 8.36 (s, 1H), 7.76 (d, J=5.19, 1H), 7.46 (d, J=7.93, 1H), 7.34 (dd, J1=0.53, J2=8.70, 1H), 7.24 (s, 1H), 7.14 (m, 1H), 53.6 (d, J=16.48, 1H), 4.63 (d, J=17.40, 1H), 4.55 (d, J=11.29, 1H), 4.12 (m, 1H), 3.87 (m, 1H), 3.58 (d, J=13.12, 1H), 3.17 (m, 1H), 3.05 (m, 4H), 2.88 (m, 1H), 2.65 (m, 1H), 2.34 (d, J=15.87 1H), 1.92 (d, J=12.51, 1H, 1.84 (d, J=11.29, 1H), 1.57 (m, 1H), 1.40 (m, 1H), 0.72 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[NH:6]2.Br[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH2:13][CH2:14][CH3:15])[N:6]2[CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=1
Reactant: CC(=O)Nc1ccc(OCCBr)cc1
Reactant: CCCc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: CCCc1cc2c(Cl)c(C#N)ccc2n1CCOc1ccc(NC(C)=O)cc1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-propyl-1H-indole-5-carbonitrile and N-{4-[(2-bromoethyl)oxy]phenyl}acetamide: 1H NMR (400 MHz, DMSO-d6) δ 9.72 (s, 1H), 7.90 (s, 1H), 7.80 (d, J=8.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.39 (d, J=9.0 Hz, 2H), 6.71 (d, J=9.0 Hz, 2H), 4.63 (t, J=4.9 Hz, 2H), 4.18 (t, J=4.9 Hz, 2H), 2.82 (t, J=4.9 Hz, 2H), 1.94 (s, 3H), 1.73-1.49 (m, 2H), 0.94 (t, J=4.9 Hz, 3H); MS (ES) m/z 396 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]1([CH3:24])[CH:19]=CC(S(Cl)(=O)=O)=C[CH:15]=1.C(O)(C)(C)C>N1C=CC=CC=1>[NH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([O:6][C:14]([CH3:24])([CH3:19])[CH3:15])=[O:5])=[C:2]([CH3:1])[CH:10]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: Cc1cc(N)ccc1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 104.4 %

Procedure:
2-Methyl-4-nitrobenzoic acid (700 mg, 3.86 mmol) was dissolved in pyridine (8 mL), p-toluenesulfonyl chloride (1.47 g, 7.74 mmol) was added, then tert-butanol (0.369 mL, 3.86 mmol) was added under ice cooling, and the mixture was stirred at 0° C. for 2 hours and at room temperature for 2 hours. tert-Butanol (0.369 mL, 3.86 mmol) was further added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, water was added, then the mixture was extracted with ethyl acetate (×3), and the organic layer was washed with 1 N hydrochloric acid, a 1 N aqueous sodium hydroxide solution, water, and saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, a solution of the resulting residue in ethyl acetate (40 mL) was added to 10% palladium-carbon (dry; 222 mg), the atmosphere in the system was replaced with a hydrogen atmosphere, and then the mixture was stirred at room temperature for 2 hours. The atmosphere in the system was replaced with a nitrogen atmosphere, and then the mixture was filtered through celite. The solvent was evaporated under reduced pressure to give the title compound (835 mg; yield, 100%) as a brown solid.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[O:8]1[CH:12]=[N:11][N:10]=[C:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]>C1(C)C=CC=CC=1>[N:5]([S:2]([O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:9]1[O:8][CH:12]=[N:11][N:10]=1)(=[O:4])=[O:3])=[C:6]=[O:7]
Reactant: Oc1ccccc1-c1nnco1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: O=C=NS(=O)(=O)Oc1ccccc1-c1nnco1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
By the procedure of Example 1, 7.1 g of chlorosulfonyl isocyanate was added to a suspension containing 8.1 g of 2-(1,3,4-oxadiazol-2-yl)phenol [prepared by the procedure of J. Maillard et al., Bull. Soc. Chim. France, 3, 529 (1961)] in 125 ml of dry toluene. The reaction mixture was stirred at 25° C. for 1 hour, then heated at 100° to 110° C. for about 0.5 hour. The resulting suspension containing a viscous oil was cooled to 25° C., filtered, and the filtrate was concentrated in vacuo to yield 8 g of the title compound as a viscous, crude oil. The IR spectrum showed an isocyanate absorption at 2220 cm-1.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([OH:19])[C:6]2[N:11]=C(C3C=CC=C(C)C=3)O[C:7]=2[N:8]=1.[CH3:20][O:21][C:22]1[C:30]([CH3:31])=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[CH3:32]>>[CH3:20][O:21][C:22]1[C:30]([CH3:31])=[CH:29][C:25]([C:26]2[O:27][C:7]3[N:8]=[C:3]([S:2][CH3:1])[N:4]=[C:5]([OH:19])[C:6]=3[N:11]=2)=[CH:24][C:23]=1[CH3:32]
Reactant: COc1c(C)cc(C(=O)Cl)cc1C
Reactant: CSc1nc(O)c2nc(-c3cccc(C)c3)oc2n1
Product: COc1c(C)cc(-c2nc3c(O)nc(SC)nc3o2)cc1C

Procedure:
2-(4-Methoxy-3,5-dimethyl-phenyl)-5-methylsulfanyl-oxazolo[5,4-d]pyrimidin-7-ol was prepared according to the procedure described in example 1, steps (a) to (d), using 4-methoxy-3,5-dimethylbenzoyl chloride in step (a).
Reaction SMILES: [NH:1]([CH2:3][C:4]([OH:6])=[O:5])[CH3:2].[CH3:7][CH:8]([CH3:25])[C:9]([O:11][CH2:12][CH2:13][O:14][C:15](ON1C(=O)CCC1=O)=[O:16])=[O:10]>>[CH3:2][N:1]([C:15]([O:14][CH2:13][CH2:12][O:11][C:9](=[O:10])[CH:8]([CH3:7])[CH3:25])=[O:16])[CH2:3][C:4]([OH:6])=[O:5]
Reactant: CC(C)C(=O)OCCOC(=O)ON1C(=O)CCC1=O
Reactant: CNCC(=O)O
Product: CC(C)C(=O)OCCOC(=O)N(C)CC(=O)O
Yield: 88.4 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, sarcosine (0.23 g, 2.63 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl 2-methylpropanoate (0.6 g, 2.1 mmol) were reacted to provide 0.459 g (85% yield) of the title compound (38) as a colorless liquid after work-up and mass-guided preparative HPLC purification. 1H NMR (CD3OD, 400 MHz): δ=6.88 (q, 1H), 4.12 (m, 2H), 2.9 (2s, 3H), 2.59 (m, 1H), 1.5-1.4 (2d, 3H), 1.1 (m, 6H). MS (ESI) m/z 270.06 (M+Na)+; 246.12 (M−H)−.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH:28]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:4][N:3]=1.O=P(Cl)(Cl)[Cl:31].CN(C)C1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:31][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([C:18]2[CH:19]=[N:20][CH:21]=[C:22]([CH:28]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cncc(-c2nnc(O)c3c(-c4ccccc4)cccc23)c1
Solvent: CN(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cncc(-c2nnc(Cl)c3c(-c4ccccc4)cccc23)c1
Temperature: 100 °C
Yield: 95.3 %

Procedure:
To a solution of ethyl 5-(4-hydroxy-5-phenylphthalazin-1-yl)nicotinate (3.50 g, 9.42 mmol) in toluene (35 mL) was added POCl3 (26.4 mL, 283 mmol) followed by N,N-dimethylbenzenamine (1.5 mL, 9.42 mmol). The resulting mixture was heated in a sealed tube at 100° C. for 12 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with saturated NaHCO3 (2×50 mL) solution. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield ethyl 5-(4-chloro-5-phenylphthalazin-1-yl)nicotinate (3.50 g) as a yellow solid with LC-MS purity of 47% which was taken for the next step without further purification. LCMS (Condition 12): retention time 0.97 min, [M+1]=390.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:17][C:6]2=[CH:7][C:8]3[C:9]([CH3:16])=[CH:10][C:11]([CH3:15])=[N:12][C:13]=3[CH:14]=[C:5]2[CH:4]=[CH:3]1.CN1C=CN=C1.Cl[O-].[Na+].S([O-])([O-])(=[O:30])=S.[Na+].[Na+]>C(OCC)(=O)C.O>[O:30]1[C@@H:4]2[C:5]3[C:6]([O:17][C:2]([CH3:18])([CH3:1])[C@H:3]12)=[CH:7][C:8]1[C:9]([CH3:16])=[CH:10][C:11]([CH3:15])=[N:12][C:13]=1[CH:14]=3
Reactant: O=S([O-])([O-])=S
Reactant: Cc1cc(C)c2cc3c(cc2n1)C=CC(C)(C)O3
Agent: Cn1ccnc1
Agent: [Na+]
Agent: [O-]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C)c2cc3c(cc2n1)[C@H]1O[C@H]1C(C)(C)O3
Yield: 68 %

Procedure:
To a solution of 2,2,7,9-tetramethyl-2H-pyrano[2,3-g]quinoline (4.64 g, 19.4 mmol) in ethyl acetate (70 mL), N-methyl imidazole (0.303 mL, 3.88 mmol) and Ph,Ph salen manganese complex (201 mg, 0.194 mmol) were added at room temperature and sodium hypochlorite aqueous solution (25.6 g, 1.513 mol/kg, 38.8 mmol) was added dropwise in water bath, and the resulting mixture was stirred in water bath for 1 hour. Further, in water bath, sodium hypochlorite aqueous solution (25.6 g, 1.513 mol/kg, 38.8 mmol) was added, and the resulting mixture was stirred in water bath for 1 hour. Upon the completion of the reaction, sodium thiosulfate aqueous solution was added to the reaction solution, the resulting mixture was filtered through celite and extracted. The organic phase was washed with sodium hydrogencarbonate aqueous solution and then with sodium chloride aqueous solution, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=1/3) and the aimed product was obtained (yield: 68%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].Cl[CH:12]([O:14]C)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([C:5]([OH:9])=[CH:4][C:3]=1[CH3:10])[CH:12]=[O:14]
Reactant: Cc1cc(O)cc(C)c1Cl
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(O)c(C=O)c(C)c1Cl
Temperature: 2 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-chloro-3,5-dimethylphenol (16 g, 0.1 mole) in dichloromethane (100 ml) was stirred and cooled to 2° C. in an ice bath. Titanium tetrachloride (35 g, 0.18 mole) was added dropwise over a period of 10 minutes and dichloromethylmethyl ether (11.5 g, 0.1 mole) was added slowly to the dark red solution, the temperature being kept below 10° C. throughout. After the solution had been stirred at 5° C. for 30 minutes the temperature was allowed to rise and to remian at 20° C. for 30 minutes. Finally the solution was warmed at 35° C. for 15 minutes and then poured into ice water (200 ml). The mixture was shaken vigorously until almost colourless and then the dichloromethane layer was separated and the aqueous phase was extracted with more dichloromethane (2×50 ml). The combined organic layers were washed with water thoroughly (4×200 ml) and then dried over anhydrous magnesium sulphate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure using a rotary evaporator. The product, 3-chloro-6-hydroxy-2,4-dimethylbenzaldehyde was isolated as a white solid (13 g, 70%), mp 89°-90° C. Proton magnetic resonance spectrum (CDCl3 ; δ in ppm): 2.40 (3H, s); 2.64 (3H, s); 6.71 (1H, s); 10.23 (1H, s); 11.91 (1H, s).
Reaction SMILES: II.Br[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1.[Mg].Cl[Si:23]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[CH:28][CH:27]=1)([CH3:25])[CH3:24]>O1CCCC1.C(OCC)C>[CH2:33]([O:32][C:29]1[CH:30]=[CH:31][C:26]([Si:23]([CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)([CH3:24])[CH3:25])=[CH:27][CH:28]=1)[CH3:34]
Reactant: Fc1ccc(CCCBr)cc1Oc1ccccc1
Reactant: CCOc1ccc([Si](C)(C)Cl)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOc1ccc([Si](C)(C)CCCc2ccc(F)c(Oc3ccccc3)c2)cc1
Temperature: 10 °C

Procedure:
A small crystal of iodine was added to a mixture of 0.75 g (0.0024 mole) of 1-bromo-3-(4-fluoro-3-phenoxyphenyl)propane and 0.11 g (0.0045 mole) of magnesium powder in 1 ml of tetrahydrofuran. This mixture was heated in a water bath for about three hours. After heating, the clear solution was light grey-brown in color. The solution was cooled to 10° C., and 0.51 g (0.0022 mole) of chloro(4-ethoxyphenyl)dimethylsilane was added. This mixture was stirred for one-half hour and was then heated for an hour. Following dilution with diethyl ether, the reaction mixture was washed successively with 10% hydrochloric acid and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, leaving a colorless oil weighing 0.95 g as the residue. This oil was purified using a Chromatotron (eluant=ethyl acetate/hexane (2:98)), producing (4-ethoxyphenyl)[3-(4-fluoro-3-phenoxyphenyl)propyl]dimethylsilane as a colorless oil. The proton and 13C nmr spectra were consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][C:5]=1[O:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24].[OH-].[K+]>C1COCC1.O>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[C:5]([O:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24])[CH:6]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C=CCCCOc1cc(OCCCCCCCC)ccc1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCOc1cc(OCCCCCCCC)ccc1C(=O)O
Reaction time: 6 h
Yield: 90.9 %

Procedure:
77.5 g (0.22 mol) of 4-Octyloxy-2-(pent-4-en-1-yloxy)benzoic acid methyl ester obtained in Step 2 is dissolved in 700 mL of THF. A solution of 66.6 (1.19 mol) of KOH in 200 mL of water is added. The mixture is heated to reflux and stirred for 6 h. The mixture is allowed to return to room temperature, then the solvents are distilled off and ice/water is added. After acidification with concentrated HCl, the mixture is extracted with several times with CH2Cl2. The resulting organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The product recrystallised from hexane gives a pure product as white crystals (66.9 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:15]3=[C:16]([CH2:19][C:20]4([OH:27])[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)[CH:17]=[CH:18][N:14]3[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].[BH3-]C#[N:30].[Na+]>CO>[NH2:30][CH:23]1[CH2:24][CH2:25][C:20]([CH2:19][C:16]2[CH:17]=[CH:18][N:14]3[C:15]=2[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)=[N:11][CH:12]=[N:13]3)([OH:27])[CH2:21][CH2:22]1
Reactant: [BH3-]C#N
Reactant: O=C1CCC(O)(Cc2ccn3ncnc(Nc4ccc(F)c(Cl)c4)c23)CC1
Agent: [Na+]
Solvent: CO
Product: NC1CCC(O)(Cc2ccn3ncnc(Nc4ccc(F)c(Cl)c4)c23)CC1
Reaction time: 12 h
Yield: 15 %

Procedure:
To a solution of 4-[4-(3-chloro-4-fluoro-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl]-4-hydroxy-cyclohexanone (24 mg, 0.06 mmole) in dry MeOH (0.5 mL) was added powdered 3 A molecular sieves (24 mg), (10 eq) NH4OAc (48 mg, 0.06 mmole), and NaCNBH3 (4 mg, 0.06 mmole); the reaction stirred under nitrogen for 12 hr. The reaction mixture was filtered and a 15% NaOH solution was added. After 10 min, the mixture was diluted with DCM (50 mL) and washed with water. The organic phase was dried (Na2SO4) and the solvent was removed. The material was purified and separated by preparative HPLC to afford the title compound (3.5 mg, 15%) and the cis isomer (7.9 mg, 32%). The title compound: MS: 390 (M+H)+; HPLC Ret Time: 2.070 min (XTERRA 4.6×50 mm S5 column, 3 min gradient, 4 mL/min). The cis isomer: MS: 390 (M+H)+; HPLC Ret Time: 2.190 min (XTERRA 4.6×50 mm S5 column, 3 min gradient, 4 mL/min).