Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:25]C)[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21].Cl.[C:28](#N)[CH3:29]>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]([CH2:28][CH3:29])[C:5](=[O:25])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21]
Reactant: COCCOc1nc(N)c2nc(OC)n(Cc3cccc(C#N)c3)c2n1
Reactant: CC#N
Agent: Cl
Product: CCn1c(=O)n(Cc2cccc(C#N)c2)c2nc(OCCOC)nc(N)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-((6-Amino-8-methoxy-2-(2-methoxyethoxy)-9H-purin-9-yl)methyl)benzonitrile (9) (50 mg) was dissolved in acetonitrile (2 mL). A 6N aqueous HCl solution (2 mL) was added and the mixture was stirred at ambient temperature overnight. After evaporation to dryness, the residue was dissolved in DMF (1 mL). Potassium carbonate (100 mg) and ethyl iodide (0.02 mL) were added and the mixture was stirred at ambient temperature for 5 hours. After dilution with water (20 mL) the product was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried with Na2SO4 and evaporated under vacuum. Purification by flash chromatography on silica gel (eluent: 0-10% MeOH in ethyl acetate) gave 3-((6-amino-7-ethyl-2-(2-methoxyethoxy)-8-oxo-7,8-dihydropurin-9-yl)methyl)benzonitrile (10) (35 mg) as a colorless glass.
Reaction SMILES: Cl.[CH2:2]([N:4]1[N:8]=[N:7][C:6]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=4[O:26][CH3:27])[S:18][C:14]=3[C:13](=[O:28])[N:12]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[C:11]2=[O:35])=[N:5]1)[CH3:3].[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[C:53]([CH:57]=[CH:58][CH:59]=3)[C:54](O)=[O:55])=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:36]([O:38][C:39]1[C:48]([O:49][CH3:50])=[CH:47][C:46]2[C:45]([C:51]3[CH:52]=[C:53]([C:54]([N:32]4[CH2:33][CH2:34][CH:29]([N:12]5[C:13](=[O:28])[C:14]6[S:18][C:17]([C:19]7[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=7[O:26][CH3:27])=[CH:16][C:15]=6[N:10]([CH2:9][C:6]6[N:7]=[N:8][N:4]([CH2:2][CH3:3])[N:5]=6)[C:11]5=[O:35])[CH2:30][CH2:31]4)=[O:55])[CH:57]=[CH:58][CH:59]=3)=[N:44][C@@H:43]3[CH2:60][CH2:61][S:62][CH2:63][C@@H:42]3[C:41]=2[CH:40]=1)[CH3:37]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4cc(F)ccc4OC)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6cc(F)ccc6OC)cc5n(Cc5nnn(CC)n5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-(5-fluoro-2-methoxyphenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (190 mg; compound B79) is reacted with 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (145 mg; compound C8) and HBTU (304 mg) in DCM/DMF (15 ml/2 ml) in the presence of DIPEA (377 mg) according to the procedure described in example 2 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: Cyclohexane/EtOAc/DCM, 100/0/0 to 50/40/10 to 30/60/10 to 0/90/10 (v/v/v)] and preparative HPLC as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]([O:28][CH3:29])=[O:27])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:33]>O1CCCC1.[NH4+].[Cl-]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:33])[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]([O:28][CH3:29])=[O:27])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NCc3ccccn3)nc2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)Cc3ccccn3)nc2c1
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-[(pyridin-2-ylmethyl)amino]quinoxaline-6-carboxylate (200 mg, 0.51 mmol) in tetrahydrofuran (50 mL) was added NaH (107 mg, 4.65 mmol) at 0° C., and the reaction mixture was stirred for 30 minutes. Iodomethane (954 mg, 6.72 mmol) was added, and the reaction mixture was stirred overnight at room temperature. The resulting solution was diluted with NH4Cl solution (80 mL), extracted with ethyl acetate (3×40 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to give methyl 2-(4-fluorophenyl)-3-[methyl(pyridin-2-ylmethyl)amino]quinoxaline-6-carboxylate as a yellow solid (120 mg, 57%).
Reaction SMILES: [C:1]([O:23][CH2:24][CH:25]=[CH2:26])(=[O:22])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC1C=CC(OC)=CC=1)=[O:11])=[O:5].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:24]([O:23][C:1](=[O:22])[CH2:2][CH2:3][C:4]([O:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])[CH:25]=[CH2:26]
Reactant: C=CCOC(=O)CCC(=O)OCCCC(=O)OCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: C=CCOC(=O)CCC(=O)OCCCC(=O)O

Procedure:
According to a similar procedure to that described in Example 13-(2), allyl 4-[(4-methoxybenzyl)oxy]-4-oxobutyl succinate (546 mg, 1.50 mmol) obtained from Example 14-(4) was treated with anisole (0.50 ml) and trifluoroacetic acid (5 ml), to afford 4-[4-(allyloxy)-4-oxobutyryloxy]butyric acid, and then treated with oxalyl chloride (290 mg) to give crude allyl 4-chloro-4-oxobutyl succinate.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].[C:33]1(=O)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:8]2[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C@@H:2]([NH:1][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][CH2:9]2)=[CH:17][CH:16]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C([C@H](Cc1ccccc1)NC1CCCCC1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
(S)-2-Amino-1-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3-phenyl-propan-1-one (0.500 g, 1.15 mmol, Example 52) and cyclohexanone (0.119 mL, 1.15 mmol, Aldrich, Milwaukee, Wis.) were mixed in CH2Cl2 (6 mL). After stirring at ambient temperature under nitrogen atmosphere for 30 minutes, the solution was cooled to 0° C. in an ice-water bath. To this solution was added sodium triacetoxyborohydride (0.365 g, 1.72 mmol). The resulting reaction mixture was stirred for, in succession, 30 minutes at 0° C. and 12 hours at ambient temperature. Twenty milliliters of saturated aqueous NaHCO3 solution was added to the reaction mixture and the resulting mixture was stirred for 10 minutes. The two layers were separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic solution was dried over Na2SO4. The solution was concentrated in vacuo affording a viscous oil. The crude product was purified by flash chromatography (40% EtOAc in hexanes) affording 444 mg (75%) of the pure titled compound as a white foam: mp 60-64° C. APCI-MS m/z 518.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[C:19]1([N:25]=[C:26]=[S:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][C:4]([C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])=[CH:3][C:2]=1[NH:1][C:26]([NH:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[S:27]
Reactant: S=C=Nc1ccccc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1ccccc1
Yield: 57.2 %

Procedure:
Prepared according to the procedure described for Example 60 using 3-amino-4-methoxy-N-phenyl-benzamide (0.245 g, 1.01 mmol) and phenyl isothiocyanate (0.12 mL, 1.00 mmol) to give the product (0.216 g); m.p. 174-176° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.Br[N:10]1[C:14](=O)CC[C:11]1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.Cl>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][N:10]([CH3:14])[CH3:11])[N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Cl)n1
Agent: Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CN(C)Cc1cccc(Cl)n1
Reaction time: 8 h
Yield: 42 %

Procedure:
To 2-chloro-6-methylpyridine (38.3 g, 0.30 mole) in 300 ml of carbon tetrachloride is added N-bromosuccinimide (67.0 g, 0.375 mole) and benzoyl peroxide (1.0 g). The mixture is stirred at reflux for 22 hours. Then it is cooled to 10° and is filtered. Into the carbon tetrachloride solution of crude 2-chloro-6-bromomethylpyridine is bubbled dimethylamine with ice bath cooling. The mixture is allowed to stand at room temperature overnight. After removal of the dimethylamine hydrobromide by filtration the carbon tetrachloride filtrate is concentrated in vacuo to a dark oil. The oil is taken up in hexane and the product is extracted into 6 N hydrochloric acid (0.30 mole). The acid extract is made alkaline with sodium hydroxide and the product is extracted into benzene. After removal of the benzene the product is distilled. The yield is 42%, b.p. 108°-110° at 3.3 mm, n25D 1.5206.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[OH:32][CH2:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:37]4[CH2:38][CH2:39][CH:34]([CH2:33][OH:32])[CH2:35][CH2:36]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: OCC1CCNCC1
Product: OCC1CCN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)CC1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and 4-hydroxymethylpiperidine (55.9 mg; 0.48 mmol) to give Example 139 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, dd, J=4.48, 1.64 Hz), 7.97-7.86 (3H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.5, 1.7 Hz), 7.55-7.48 (4H, m), 4.43 (1H, t, J=5.3 Hz), 3.55 (2H, s), 3.28 (2H, t, J=5.8 Hz), 2.84 (2H, d, J=10.8 Hz), 1.96 (2H, t, J=11.3 Hz), 1.66 (2H, d, J=12.6 Hz), 1.37 (1H, d, J=10.8 Hz), 1.25-1.12 (2H, m). LC/MS (Method C): 512 (M+H)+. HPLC (Method E) Rt 2.16 min (Purity: 99.2%).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[F:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: Oc1ccc(F)cc1
Product: CCCCOC(=O)c1nc(Oc2ccc(F)cc2)c2ccccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and 4-fluoro phenol in analogy to Example D-20 d); MS-(+)-ion: M+1=356.1.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH:13]([CH2:17][CH2:18][OH:19])[CH2:14][CH2:15][OH:16]>[N+]([O-])([O-])=O.[Ag+]>[OH:16][CH2:15][CH2:14][N:13]([CH2:17][CH2:18][OH:19])[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: OCCNCCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Product: N#Cc1cc([N+](=O)[O-])ccc1N(CCO)CCO
Temperature: 100 °C
Reaction time: 1 h
Yield: 60.4 %

Procedure:
2-Chloro-5-nitrobenzonitrile (25.5 g) and silver nitrate (28.5 g) were added to diethanolamine (102 g) and the mixture was stirred at 100° C. for 1 h. The reaction mixture was cooled to room temperature and the solid was filtered off. To the filtrate was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give 2-bis(2-hydroxyethyl)amino-5-nitrobenzonitrile (21.2 g).
Reaction SMILES: Br[CH:2]=[CH:3][CH3:4].II.[CH3:7][O:8][C:9](=[O:28])[CH2:10][CH:11]1[C:15]2=[CH:16][C:17]3[C:18](Br)=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][C:22]=3[N:14]2[CH2:13][CH2:12]1>C1COCC1.[Zn+2].[Br-].[Br-].[Pd].[Cu]I>[CH3:7][O:8][C:9](=[O:28])[CH2:10][CH:11]1[C:15]2=[CH:16][C:17]3[C:18]([C:3]([CH3:4])=[CH2:2])=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][C:22]=3[N:14]2[CH2:13][CH2:12]1
Reactant: COC(=O)CC1CCn2c1cc1c(Br)cc(S(C)(=O)=O)cc12
Reactant: CC=CBr
Agent: [Cu]I
Agent: [Pd]
Agent: II
Solvent: C1CCOC1
Product: C=C(C)c1cc(S(C)(=O)=O)cc2c1cc1n2CCC1CC(=O)OC
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Alpha-bromopropene (514 μL, 5.2 mmol) was added portionwise, in order to maintain 55° C. exotherm, to Mg (126 mg, 5.2 mmol) (in THF 4 mL) and a trace of iodine. The mixture was heated and stirred for 30 minutes. Dried ZnBr2 (1.16 g, 5.2 mmol) in THF (4 mL) was added and the mixture was heated at 55° C. for 1 hour. The reaction mixture was cooled to room temperature, and Pd (dppf) CH2Cl2 (19 mg) was added followed by CuI (7 mg) after a further 5 minutes. The product of Step 1 (200 mg, 0.52 mmol) in 3 ml THF was then added. The reaction mixture was heated to 75° C. for 15 minutes. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to give the title compound (130 mg).
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].ClC(OCCCC)=O.Cl.C(N(CC)CC)C.Cl.[CH3:40][O:41][C:42](=[O:47])[C@H:43]([CH2:45][OH:46])[NH2:44].Cl>C(#N)C.CO.C(N(CC)CC)C>[CH3:40][O:41][C:42](=[O:47])[C@H:43]([CH2:45][OH:46])[NH:44][C:1](=[O:22])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)O
Reactant: COC(=O)[C@@H](N)CO
Agent: CCCCOC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCCC/C=C\C/C=C\C/C=C\C/C=C\CCCC(=O)N[C@@H](CO)C(=O)OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
Arachidonic acid (152 g, 0.5 mmol) and triethylamine (52 mg, 0.51 mmol) were dissolved in 3 ml of dry acetonitrile and chilled to −15° C., and 70 mg (0.51 mmol) of butyl chloroformate was added. After 30 min, the mixture free of the precipitated triethylamine hydrochloride was pipetted in a solution of L-serine methyl ester hydrochloride (156 mg, 1 mmol) and 0.14 ml of triethylamine in 1 ml of methanol, stirring was continued for 15 min at −15° C., then that mixture was allowed to warm to room temperature. After 2 h, 0.5 M HCl was added, and the mixture was extracted with ether (20 ml). The extract was washed with water, then dried with Na2SO4, and evaporated in vacuo. The residue was dissolved in 2 ml of chloroform and purified by column (2×2 cm) chromatography on aluminum oxide (basic, Brockmann II). Elution of the column with chloroform-methanol (9:1 v/v) and evaporation of the appropriate fractions gave 186 mg (95%) of desired N-arachidonoyl-L-serine methyl ester as oil: TLC (system A) Rf 0.5.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7](=[O:9])[CH3:8])=[CH:5][CH:6]=1.[N:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.O1CCOCC1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:10]1[CH:15]=[CH:14][C:13]([C:2]2[S:3][C:4]([C:7](=[O:9])[CH3:8])=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccncc1
Reactant: CC(=O)c1ccc(Br)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)c1ccc(-c2ccncc2)s1
Temperature: 90 °C
Reaction time: 18 h
Yield: 85.4 %

Procedure:
To a 100 mL round bottom flask was added a solution of 2-bromo-5-acetylthiophene (0.500 g, 2.438 mmol) and pyridine-4-boronic acid (0.560 g, 4.555 mmol) in a solution of 1,4-dioxane (20.00 mL, 256.3 mmol) and water (4.00 mL, 222 mmol). Cesium carbonate (2.383 g, 7.314 mmol) was added followed by [1,1′-bis(diphenylphosphino)ferrocene]palladium(II)dichloride (0.2407 g, 0.293 mmol). The reaction mixture was fitted with an air condenser and heated to 90° C. and allowed to stir for 18 h. The reaction was cooled to ambient temperature and quenched by the addition of a saturated aqueous solution of sodium bicarbonate (10.00 mL) and extracted with EtOAc (10.00 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure The crude material was dry loaded onto silica gel and then purified using a ISCO (24 g cartridge, gradient hexanes to 100% EtOAc over 30 min) to afford the title compound (0.423 g, 81%) as a yellow solid. LC/MS (AA) ES+ 204. 1H NMR (dmso-d6, 400 MHz): δ 8.65-8.64 (m, 2H), 8.02 (d, 1H), 7.92 (d, 1H), 7.76-7.75 (m, 2H), 2.58 (s, 3H).
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7](=[O:35])[C:8]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33]O)=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[CH:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=1>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:35])[C:8]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][Br:2])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[CH:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CO)cc2)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CBr)cc2)cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of PBr3 (4.8 mL of 1.0 M in CH2Cl2) was added dropwise to 12 (5.0 g, 11.9 mmol) dissolved in CH2Cl2 (20 mL) at temperature with good stirring. After 1 h, the solution was extracted with water (2×60 mL) and brine (20 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered through a small bed of silica gel (20 g) and solvent was evaporated. The resulting tacky syrup was dried under high vacuum for 48 h at room temperature to yield the title compound (5.7 g, 99%): mp 79-81° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.42 (t, J=2.4 Hz, 1H), 6.28 (d, J=2.0 Hz, 2H), 4.73 (d, J=4.8 Hz, 2H), 3.68 (s, 3H), 3.58 (s, 6H); Anal. (C25H23BrO5) C: calculated, 61.12; found, 62.26; H: calculated 4.80; found 4.88.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][N:7]=[C:6]2[O:23]C1C=CC=CC=1.Cl.C(=O)([O-])O.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[N:9]=[CH:8][NH:7][C:6]2=[O:23]
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Yield: 94.7 %

Procedure:
A mixture of 6-methoxy-7-(3-morpholinopropoxy)-4-phenoxyquinazoline (980 mg, 2.48 mmol) and 2M hydrochloric acid (25 ml) was heated at 100° C. for 2 hours and allowed to cool. The solution was basified with solid sodium hydrogen carbonate, and the product was extracted with methylene chloride. The organic phase was passed through phase separating paper and the solvent removed by evaporation to give 6-methoxy-7-(3-morpholinopropoxy)-3,4dihydroquinazolin-4-one (750 mg, 95%) as a pale brown solid which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:11][C:10]=1[CH:24](O)[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:33])=O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:16]=2[F:23])=[CH:11][C:10]=1[CH:24]([Cl:33])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c(-c2ccc(OCc3ccccc3)c(C(O)CC(C)(C)C)c2)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(F)c(-c2ccc(OCc3ccccc3)c(C(Cl)CC(C)(C)C)c2)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-(benzyloxy)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-3-yl)-3,3-dimethylbutan-1-ol (1.00 g) in toluene (10 mL) was added thionyl chloride (437 mg), and the mixture was stirred at 70° C. for 1 hr. The solvent was evaporated under reduced pressure to give the title compound as a crude product. This compound was used for the next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[NH:13][CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[S:10]2)=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1.[CH:21]1(Br)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([N:13]2[CH2:12][C:11]3([CH2:17][CH2:16][CH2:15][CH2:14]3)[S:10][C:9]2=[N:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=2[CH:18]([CH3:20])[CH3:19])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)c1cc(I)ccc1N=C1NCC2(CCCC2)S1
Reactant: BrC1CCCC1
Product: CC(C)c1cc(I)ccc1N=C1SC2(CCCC2)CN1C1CCCC1

Procedure:
2-Isopropylaniline was converted to 4-iodo-2-isopropylaniline according to Method A5a. The aniline was converted to 4-iodo-2-isopropylphenyl isothiocyanate according to Method A2b. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 4-iodo-2-isopropylphenyl isothiocyanate according to Method C1a to give 2-(4-iodo-2-isopropylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 3-cyclopentyl-2-(4-iodo-2-isopropylphenylimino)-1-thia-3-azaspiro[4.4]nonane. The phenyl iodide was reacted with CuCN according to Method D7a to afford 3-cyclopentyl-2-(4-cyano-2-isopropylphenylimino)-1-thia-3-azaspiro[4.4]nonane.
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16](S(C)(=O)=O)[N:15]=1)[CH3:12]>O1CCCC1>[CH2:11]([O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:15]=1)[CH3:12]
Reactant: CCOc1cc(C)nc(S(C)(=O)=O)n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1cc(C)nc(Cc2ccccc2)n1

Procedure:
To benzyl alcohol (Compound II-64) (0.35 g, 0.0016×2.0 mol) in tetrahydrofuran, sodium hydride (0.085 g, (60% in mineral oil), 0.0016×1.3 mol) and 4-ethoxy-6-methyl-2-(methylsulfonyl)pyrimidine (Compound III-44) (0.35 g, 0.0016 mol) prepared as described in Reference synthesis example 1 below were successively added and the solution was allowed to react for about 1 hour at room temperature.