Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5](O)=[O:6].C(OC(Cl)=O)C(C)C.C(N(CC)CC)C.[CH2:43]([NH:61]CCCCCCCCCCCCCCCCCC)[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]>O1CCCC1>[CH2:43]([NH:61][C:5](=[O:6])[CH2:4][CH2:3][CH:2]([CH:8]1[C:12]2([CH3:27])[CH:11]([CH:16]3[CH:15]([CH2:14][CH2:13]2)[C:20]2([CH3:26])[CH:19]([CH2:24][CH:23]([OH:25])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[CH3:1])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCNC(=O)CCC(C)C1CCC2C3CCC4CC(O)CCC4(C)C3CCC12C
Yield: 172.2 %

Procedure:
Lithocholic acid (81) (9.78 g, 26 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL). Isobutylchloroformate (3.55 g, 3.55 mL, 26 mmol) was added followed by the addition of triethylamine (5.26 g, 7.25 mL, 52 mmol) and dioctadecylamine (7 g, 26 g). The reaction mixture was brought to ambient temperature and allowed to stir over night. The reaction mixture was concentrated under vacuum, and the residue was dissolved in dichloromethane (250 mL). The organic layer was washed with 5% sodium bicarbonate, 3% aqueous HCl and water. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure to afford amide 88 (14.5 g) in 89% yield. This was used as such for the next step.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6]2.Cl.[N:13]1([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([Cl:29])=[O:28])=[CH:25][CH:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[ClH:29].[N:13]1([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:7]3[CH2:6][C:5]4[C:9](=[CH:10][CH:11]=[C:3]([F:2])[CH:4]=4)[CH2:8]3)=[O:28])=[CH:30][CH:31]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Fc1ccc2c(c1)CNC2
Reactant: O=C(Cl)c1ccc(OCCCN2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Product: O=C(c1ccc(OCCCN2CCCCC2)cc1)N1Cc2ccc(F)cc2C1
Yield: 27.3 %

Procedure:
A stirred mixture of 5-fluoroisoindoline hydrochloride (D8) (183 mg) and diethylaminoethylpolystyrene (626 mg, 3.2 mmol/g) in DCM (10 ml) at rt was treated with 4-(3-piperidin-1-ylpropoxy)-benzoyl chloride hydrochloride (223 mg) (D3). After 1 h the reaction mixture was chromatographed directly [silica gel, step gradient 0-10% MeOH (containing 10% 0.880 ammonia solution) in DCM)]. Fractions containing the required product were evaporated, redissolved in DCM, treated with excess hydrogen chloride (4M solution in dioxan) and then evaporated. The residue was triturated with acetone, filtered, washed with acetone and dried to yield the title compound (E11) (80 mg). MS electrospray (+ion) 383 (MH+). 1H NMR δ (DMSO-d6): 10.21 (1H, s), 7.61 (2H, d, J=8.8 Hz), 7.05-7.50 (3H, m), 7.01 (2H, d, J=8.8 Hz), 4.81 (4H, m), 4.13. (2H, t, J=6 Hz), 3.46 (2H, m), 3.15 (2H, m), 2.88 (2H, m), 2.21 (2H, m), 1.28-1.92 (6H, m).
Reaction SMILES: OCC1C=NC2N3C=CN=C3C(=O)NC=2C=1.OCC1C=NC2N3C=NC=C3C(=O)NC=2C=1.O=C1[NH:39][C:38]2[CH:40]=[C:41]([C:44]([O:46][CH3:47])=[O:45])[CH:42]=[N:43][C:37]=2[N:36]2[CH:48]=[CH:49][N:50]=[C:35]12.[H-].[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)(C(F)(F)F)=O>C1COCC1.O.C(#N)C>[NH2:39][C:38]1[C:37]([N:36]2[CH:48]=[CH:49][N:50]=[CH:35]2)=[N:43][CH:42]=[C:41]([CH:40]=1)[C:44]([O:46][CH3:47])=[O:45]
Reactant: COC(=O)c1cnc2c(c1)[nH]c(=O)c1nccn12
Agent: O=c1[nH]c2cc(CO)cnc2n2ccnc12
Agent: O=c1[nH]c2cc(CO)cnc2n2cncc12
Agent: [Al+3]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnc(-n2ccnc2)c(N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
Compounds 64C1 and 64C2: 3-(Hydroxymethyl)imidazo[1,2-a]pyrido[3,2-e]pyrazin-6(5H)-one and 3-(Hydroxymethyl)imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one: Methyl 6-oxo-5,6-dihydroimidazo[1,2-a]pyrido[3,2-e]pyrazine-3-carboxylate (0.410 g, 1.68 mmol) was suspended in THF (20 mL) and sodium hydride (60% susp. in mineral oil, 0.112 g, 2.80 mmol) was added in one portion. The reaction mixture was stirred at room temperature for 1 h, cooled to −50° C. and LiAlH4 (2M in THF, 1.7 mL, 3.4 mmol) was added dropwise over 2 min. The reaction mixture was kept at −30-(−10)° C. for 3 h and more LiAlH4 (2M in THF, 0.7 mL and 1.0 mL, 3.4 mmol combined) was added. The reaction mixture was cooled to −60° C. and slowly quenched with MeOH, warmed to room temperature and TFA and water were added until a clear solution resulted. The solution was subjected to preparative HPLC (1-30% acetonitrile in water, TFA buffered) to afford the title compound as a grey solid (147 mg, 40%; −2:1 mixture of imidazole regioisomers). [M+H] calc'd for C10H8N4O2, 217; found, 217.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[N:24]([CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:23]([CH3:32])=[C:22]([S:33]([NH:36]C(=O)OCCCC)(=[O:35])=[O:34])[CH:21]=2)=[CH:12]1)(=[O:10])=[O:9]>CO.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]2[N:24]([CH2:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:23]([CH3:32])=[C:22]([S:33]([NH2:36])(=[O:34])=[O:35])[CH:21]=2)=[CH:12]1)(=[O:9])=[O:10]
Reactant: CCCCOC(=O)NS(=O)(=O)c1cc(-c2cn(S(=O)(=O)c3ccccc3Cl)c3ccccc23)n(CC2CCCCC2)c1C
Agent: Cl
Solvent: CO
Product: Cc1c(S(N)(=O)=O)cc(-c2cn(S(=O)(=O)c3ccccc3Cl)c3ccccc23)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
Crude intermediate 52 (0.50 mmol) was dissolved in dry MeOH/HCl under N2. The mixture was stirred overnight at rt, concentrated, treated with 3% aq. K2CO3, extracted with DCM, dried over Na2SO4, filtered, concentrated and purified by prep-HPLC to afford compound 53 (95 mg, 35%). 1H-NMR (DMSO-d6, 400 MHz) δ: 0.50-0.62 (2H, m), 0.83-0.95 (3H, m), 1.13-1.39 (3H, m), 1.41-1.50 (3H, m), 2.47 (3H, s), 3.81 (2H, d, J=5.6 Hz), 6.47 (1H, s), 7.00 (2H, s), 7.30-7.39 (2H, m), 7.50-7.54 (1H, m), 7.68-7.80 (4H, m), 8.00 (1H, s), 8.38-8.42 (1H, m). MS Calcd.: 545; MS Found: 546 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][N:11]2[C:10](=[O:13])[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[N:12]2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: O=c1ccc(-c2ccccc2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1ccc(-c2ccccc2)nn1CCc1ccc(F)cc1
Temperature: 23 °C
Reaction time: 72 h

Procedure:
A mixture of 6-phenyl-3(2h)-pyridazinone (306 mg, 1.78 mmol), 1-(2-bromo-ethyl)-4-fluoro-benzene (397 μl, 1.95 mmol), and potassium carbonate, −325 mesh (614 mg, 4.44 μmol) in DMF (5 mL) was stirred for 3 days at 23° C. The mixture was partitioned between CH2Cl2 (30 mL) and 5% NaHCO3 (15 mL). The aqueous was further extracted with CH2Cl2 (2×5 mL) and the combined organics was dried over MgSO4, and concentrated under reduced pressure To give a clear oil. MS (ESI pos. ion) m/z (MH+): 295. Calc'd exact mass for C18H15FN2O: 294. 1H NMR (400 MHz, Chloroform-d) δ ppm 3.16 (t, J=7.53 Hz, 2 H) 4.47 (t, J=7.78 Hz, 2 H) 6.88-7.06 (m, 3 H) 7.15-7.25 (m, 2 H) 7.35-7.53 (m, 3 H) 7.59-7.74 (m, 3 H). 13C NMR (101 MHz, Chloroform-d) δ ppm 32.60, 52.08, 114.07, 114.28, 124.73, 127.81, 128.32, 128.89, 129.01, 129.20, 129.27, 132.63, 132.67, 133.57, 143.32, 158.60, 159.33, 161.76.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[CH2:30][CH3:31]>C(#N)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:29][CH2:30][CH3:31])[C:5]=1[O:21][CH3:22])[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCOc1c(-c2ccc3c(c2)COC3=O)ccc(OCC)c1OC
Temperature: 70 °C
Yield: 22 %

Procedure:
To a stirring solution of 5-(4-ethoxy-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.266 mmol) in acetonitrile was added potassium carbonate (110 mg, 0.798 mmol) and propyl bromide (130 mg, 1.066 mmol) and the resultant reaction mixture was heated to 70° C. for 2 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. Purification of the residue by flash column chromatography (silica gel, 0-25% ethyl acetate in pet ether) afforded the title compound as a solid (20 mg, 22%).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([CH:18]=[CH:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:25])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccccc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-phenyl-5-(1-hexenyl)pyridine (Example 15) according to the procedure described in Example 1, Step H. 1H NMR (300 MHz, CDCl3): δ7.40 (m, 3 H), 7.18 (m, 2 H), 4.33 (d, J=5 Hz, 2 H), 3.42 (septet, J=7 Hz, 1 H), 3.23 (septet, J=7 Hz, 1 H), 2.26 H), 1.31 (m, 13 H), 1.12 (m, 8 H), 0.80 (t, J=7 Hz, 3 H). FAB-MS: calculated for (C24H35NO) 353, found 354 (M+H). Anal. Calcd for C24H35NO: C, 81.53; H, 9.98; N, 3.96. Found: C, 79.06; H, 9.65; N, 3.61. mp 71-72° C. Rf=0.1 (10% ethyl acetate/hexane).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([C:21]([OH:23])=[O:22])[CH2:9][C:10]([C@@H:12]([NH2:20])[CH2:13][CH2:14][CH2:15][N:16]=[C:17]([NH2:19])[NH2:18])=[O:11])=[CH:3][CH:2]=1.Cl.C(=O)([O-])O.[Na+].[CH2:30]([O:37][C:38](SC1N=C(C)C=C(C)N=1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>O1CCOCC1.O>[CH2:30]([O:37][C:38]([NH:20][CH:12]([CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[NH:18])[C:10](=[O:11])[CH2:9][CH:8]([CH2:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)[C:21]([OH:23])=[O:22])=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccccc2)n1
Reactant: NC(N)=NCCC[C@H](N)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N=C(N)NCCCC(NC(=O)OCc1ccccc1)C(=O)CC(Cc1ccccc1)C(=O)O
Yield: 60.7 %

Procedure:
Arphamenine A hydrochloride (150 mg), sodium hydrogen carbonate (176 mg) and S-benzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (230 mg) were dissolved in 20 ml of dioxane-water (1:1), and the resultant solution was stirred at room temperature overnight. After the reaction was completed, the reaction solution was adjusted to pH 2.0 with 1N hydrochloric acid, followed by extraction with n-butanol. The extract in n-butanol was washed with water and concentrated to dryness. The residue obtained was chromatographed in a column of silica-gel (20 g) by eluting with a mixture of chloroform and methanol, while changing the ratio of chloroform to methanol in said mixture gradiently from 15:1 to 2:1. The desired reaction product was eluted out in fraction Nos. 60 to 120 [in chloroformmethanol (2:1)] of the eluate. These fractions were combined together and concentrated to dryness to afford 116 mg of the titled compound as a colorless powder. This product gave a value of m/z 455 (MH+) in mass spectrometry.
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]([OH:18])[CH2:16][OH:17])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1.O.[C:23]1(C)[CH:28]=CC(S(O)(=O)=O)=C[CH:24]=1.COC(OC)(C)C.CN(C=O)C>CCOC(C)=O>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]4[CH2:16][O:17][C:23]([CH3:28])([CH3:24])[O:18]4)=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C(O)CO)ccc12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: COC(C)(C)OC
Solvent: O
Product: CC1(C)OCC(c2ccc3c(c2)[nH]c2c(C(N)=O)ccc(Br)c23)O1
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-7-(1,2-dihydroxyethyl)-9H-carbazole-1-carboxamide (Example 68-1, 50 mg, 0.143 mmol) and p-toluenesulfonic acid monohydrate (8.2 mg, 0.043 mmol) in 2,2-dimethoxypropane (1.76 mL, 14.32 mmol) was stirred at rt. DMF (0.5 mL) was added and the mixture was stirred overnight. The mixture was diluted with EtOAc and washed with NaHCO3 (aq) and brine, then dried and concentrated. The residue was purified by column chromatography (eluting with a gradient from 75:25 to 50:50 hexane-EtOAc) to provide 4-bromo-7-(2,2-dimethyl-1,3-dioxolan-4-yl)-9H-carbazole-1-carboxamide as a light yellow solid (40 mg, 75% purity, 54%). Mass spectrum m/z 389, 391 (M+H)+.
Reaction SMILES: CCO[CH:4]=[C:5]([C:11]([O:13]CC)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[N:33]3[C:28]([CH:29]=[CH:30][CH:31]=[CH:32]3)=[C:27]([O:34][CH3:35])[C:26]=2[CH3:36])=[O:24])=[CH:19][CH:18]=1.C(OC(C)C)(C)C.CCCCC>C1(C)C=CC=CC=1.C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:35][O:34][C:27]1[C:26]([CH3:36])=[C:25]([C:23]([C:20]2[CH:21]=[C:22]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]3=[O:13])=[O:24])[N:33]2[C:28]=1[CH:29]=[CH:30][CH:31]=[CH:32]2
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1c(C)c(C(=O)c2ccc(N)cc2)n2ccccc12
Solvent: Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCC
Product: CCOC(=O)c1c[nH]c2ccc(C(=O)c3c(C)c(OC)c4ccccn34)cc2c1=O
Temperature: 110 °C

Procedure:
0.36 ml of diethyl ethoxymethylene malonate is added, under an inert atmosphere at ambient temperature, to 0.4 g (1.43 mmol) of (4-aminophenyl)(1-methoxy-2-methylindolizin-3-yl)methanone in 6 ml of toluene. The reaction medium is heated at 110° C. for 1 h 45 and then concentrated under reduced pressure. The residue obtained is dissolved in 8.2 ml of diphenyl ether and then heated at 230° C. for 1 h 20. After the addition of diisopropyl ether and pentane at ambient temperature, the precipitate formed is filtered off and rinsed with pentane. The residue obtained is purified by silica gel column chromatography, elution being carried out with a dichloromethane/methanol (90/10) mixture. 142 mg of a yellow powder are obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].BrCCOC1CCCCO1.[CH2:17]([O:24][C:25]1[C:26]([CH2:61][CH3:62])=[C:27]([CH2:45][C:46]2[O:50][C:49](=[O:51])[N:48]([CH2:52][CH2:53][O:54]C3CCCCO3)[N:47]=2)[C:28]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.C(=O)([O-])O.[Na+]>CO.CN(C)C=O>[CH2:17]([O:24][C:25]1[C:26]([CH2:61][CH3:62])=[C:27]([CH2:45][C:46]2[O:50][C:49](=[O:51])[N:48]([CH2:52][CH2:53][OH:54])[N:47]=2)[C:28]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCc1c(OCc2ccccc2)cc(OCc2ccccc2)c(-c2ccccc2)c1Cc1nn(CCOC2CCCCO2)c(=O)o1
Agent: BrCCOC1CCCCO1
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CO
Product: CCc1c(OCc2ccccc2)cc(OCc2ccccc2)c(-c2ccccc2)c1Cc1nn(CCO)c(=O)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
In the same manner as in the step 1 in Example 317, 5-{[3,5-bis(benzyloxy)-2-ethyl-6-phenylphenyl]methyl}-3-(2-tetrahydropyran-2-yloxyethyl)-3H-1,3,4-oxadiazol-2-one was obtained from 5-{[3,5-bis(benzyloxy)-2-ethyl-6-phenylphenyl]methyl}-3H-1,3,4-oxadiazol-2-one (280 mg, 0.57 mmol) obtained in the step 2 in Example 315, using potassium carbonate (200 ng, 1.4 mmol), 2-(2-bromoethoxy)tetrahydro-2H-pyran (0.13 mL, 0.86 mmol) and N,N-dimethylformamide (3.0 mL). The resulting 5-{[3,5-bis(benzyloxy)-2-ethyl-6-phenylphenyl]methyl}-3-(2-tetrahydropyran-2-yloxyethyl)-3H-1,3,4-oxadiazol-2-one was dissolved in methanol (3.0 mL), and methanol solution (2.0 mL) of 10% hydrogen chloride was added thereto and stirred at room temperature for 30 minutes. The reaction solution was neutralized with aqueous saturated sodium hydrogencarbonate solution added thereto, and then extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated away under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate/hexane=1/1 to 1/0) to obtain 5-{[3,5-bis(benzyloxy)-2-ethyl-6-phenylphenyl]methyl}-3-(2-hydroxyethyl)-3H-1,3,4-oxadiazol-2-one (260 mg, 85%).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:11]1[CH:12]=[C:13]([C:19]2[CH:24]=[C:23]([CH3:25])[C:22]([OH:26])=[C:21]([CH3:27])[CH:20]=2)[N:14]=[N:15][C:16]=1[O:17][CH3:18].O.C([O:33][C:34]1[N:39]=[C:38]([O:40]C(C)(C)C)[C:37](B(O)O)=[CH:36][N:35]=1)(C)(C)C>>[OH:26][C:22]1[C:23]([CH3:25])=[CH:24][C:19]([C:13]2[N:14]=[N:15][C:16]([O:17][CH3:18])=[C:11]([C:3]3[NH:4][C:5]4[C:10]([C:2]=3[C:37]3[C:38](=[O:40])[NH:39][C:34](=[O:33])[NH:35][CH:36]=3)=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:12]=2)=[CH:20][C:21]=1[CH3:27]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1[nH]c2ccccc2c1Br
Reactant: CC(C)(C)Oc1ncc(B(O)O)c(OC(C)(C)C)n1
Solvent: O
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1[nH]c2ccccc2c1-c1c[nH]c(=O)[nH]c1=O

Procedure:
111 mg of 4-[5-(3-bromo-1H-indol-2-yl)-6-methoxy-pyridazin-3-yl]-2,6-dimethyl-phenol is treated analogously to example 6 (c), using 2,4-di(tert-butoxy)pyrimidin-5-yl boronic acid hydrate. Yield 100 mg. LC-MS (ES+) 455 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH3:16])[CH2:14][CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1.[CH2:17]([NH2:20])[CH:18]=[CH2:19].C(=O)([O-])O.[Na+]>>[CH2:17]([NH:20][C:2]1[N:3]=[C:4]([NH:12][CH:13]([CH3:16])[CH2:14][CH3:15])[C:5]2[S:10][CH:9]=[C:8]([CH3:11])[C:6]=2[N:7]=1)[CH:18]=[CH2:19]
Reactant: C=CCN
Reactant: CCC(C)Nc1nc(Cl)nc2c(C)csc12
Agent: O=C([O-])O
Agent: [Na+]
Product: C=CCNc1nc(NC(C)CC)c2scc(C)c2n1
Yield: 80.2 %

Procedure:
In a sealed tube were heated 307 mg (1.2 mmol) of 2-chloro-7-methyl-4-(1-methylpropylamino)thieno[3,2-d]pyrimidine and 1.10 g (19.2 mmol) of allylamine at 160° C. for 16 hours. After completion of the reaction, the reaction mixture was allowed to resume room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane=1/10) to give 266 mg (yield: 80.1%) of the title compound.
Reaction SMILES: [CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([Cl:21])[C:10]([Cl:20])=[C:11]([O:16][CH2:17][C:18]#[N:19])[CH:12]=3)[C:7]2=[O:22])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+].Cl>CN(C=O)C>[CH:1]1([CH:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([Cl:21])[C:10]([Cl:20])=[C:11]([O:16][CH2:17][C:18]4[NH:25][N:24]=[N:23][N:19]=4)[CH:12]=3)[C:7]2=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)CC2
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C1c2c(cc(OCc3nnn[nH]3)c(Cl)c2Cl)CCC1C1CCCC1
Temperature: 0 °C

Procedure:
To 2-cyclopentyl-6-cyanomethoxy-7,8-dichloro-1- tetralone (5.6 g., 0.0165 mole) in DMF (25 ml.) is added sodium azide (12.6 g., 0.0194 mole) and ammonium chloride (1.05 g., 0.0194 mole). The mixture is heated at 85°-90° C. for one hour, cooled and poured into ice water. The mixture is acidified with 6 N HCl. The dark gummy solid that forms is triturated with butyl chloride to obtain a solid, which is crystallized from a mixture of butyl chloride and methanol to obtain 2-cyclopentyl-6-(5-tetrazolylmethoxy)- 7,8-dichloro-1-tetralone.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)=[CH:4][C:3]=1[O:24][Si](C(C)C)(C(C)C)C(C)C.CN1CCOCC1.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.O>[OH:24][C:3]1[CH:4]=[C:5]([CH2:6][NH:7]/[CH:8]=[C:9]2\[C:10](=[O:21])[NH:11][C:12](=[O:20])[C:13]3[C:18]\2=[CH:17][C:16]([I:19])=[CH:15][CH:14]=3)[CH:22]=[CH:23][C:2]=1[NH:1][C:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)[Si](Oc1cc(CN/C=C2\C(=O)NC(=O)c3ccc(I)cc32)ccc1N)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C1NC(=O)c2ccc(I)cc2/C1=C/NCc1ccc(NC(=O)c2ccccc2)c(O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
To a solution of (4Z)-4-[({4-amino-3-[(triisopropylsilyl)oxy]benzyl}amino)methylene]-6-iodoisoquinoline-1,3(2H,4H)-dione (65 mg, 0.11 mmol) in tetrahydrofuran (6 mL) is added 4-methylmorpholine (36 μL, 0.33 mmol), and the mixture is cooled to 0° C. in an ice-water bath. Benzoyl chloride (38 μL, 0.33 mmol) is added and the mixture is allowed to stir at room temperature for one hour. To the mixture is then added 1.0 M tetrabutylammonium fluoride solution in tetrahydrofuran (1 mL, 1 mmol). After heating for 10 minutes at 55° C., water is added. The precipitated solid is collected by filtration, washed with water and acetonitrile, and dried under house vacuum to give N-[2-hydroxy-4-({[(Z)-(6-iodo-1,3-dioxo-2,3-dihydroisoquinolin-4(1H)-ylidene)methyl]amino}methyl)phenyl]benzamide (34 mg, 58%).
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([Cl:11])=[N:9][OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:14][S:15]([O:10][N:9]=[C:8]([Cl:11])[C:7]1[CH:12]=[CH:13][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)(=[O:17])=[O:16]
Reactant: CC(C)c1ccc(C(Cl)=NO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(C(Cl)=NOS(C)(=O)=O)cc1
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
Into a solution of 6.7 g of 4-isopropylbenzohydroximoyl chloride in 175 ml of benzene was added in one portion 5.2 g of triethylamine. To this solution was added dropwise during 15 minutes (mildly exothermic reaction) 4.0 g of methanesulfonyl chloride. The mixture was stirred for 30 minutes and filtered. The filtrate was concentrated and the residue recrystallized twice from ethanol to give 8.1 g of N-(methanesulfonyloxy)-4-isopropylbenzimidoyl chloride, m.p. 79.5°-82°. The ir spectrum was consistent with the assigned structure.