Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([NH:7][C:8]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]1)=[O:6].[CH3:15]I>CN(C)C=O>[CH3:3][O:4][C:5]([N:7]([CH3:15])[C:8]1([C:11]([O:13][CH3:14])=[O:12])[CH2:10][CH2:9]1)=[O:6]
Reactant: CI
Reactant: COC(=O)NC1(C(=O)OC)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N(C)C1(C(=O)OC)CC1
Reaction time: 0.25 h

Procedure:
24.7 g of sodium hydride are added, in fractions, to a solution, cooled to 5° C., of 99.7 g of the compound obtained in Step 2 in 1.7 liters of anhydrous dimethylformamide. After 15 minutes at 5° C. and then 3 hours at ambient temperature, 38.2 ml of methyl iodide are added dropwise. After reacting for 20 hours, the mixture is evaporated. The residue is taken up in ether and then treated in conventional manner. Chromatography over silica gel (dichloromethane) allows the expected product to be isolated.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[CH:25]([N:28]1[C:32]2([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[C:31](=[O:38])[NH:30][CH2:29]1)([CH3:27])[CH3:26].C(N(CC)CC)C>C(O)C>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([N:6]2[C:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[N:35]2[CH2:36][CH2:37][C:32]3([N:28]([CH:25]([CH3:26])[CH3:27])[CH2:29][NH:30][C:31]3=[O:38])[CH2:33][CH2:34]2)=[CH:16][CH:15]=1
Reactant: Clc1ccc(-n2c(-c3ccccc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(C)N1CNC(=O)C12CCNCC2
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)N1CNC(=O)C12CCN(c1ncnc3c1nc(-c1ccccc1Cl)n3-c1ccc(Cl)cc1)CC2

Procedure:
A mixture of 6-chloro-9-(4-chlorophenyl)-8-(2-chlorophenyl)-9H-purine I-(4A-7)c (19 mg, 0.052 mmol), 1-isopropyl-1,3,8-triazaspiro[4.5]decan-4-one (Janssen, P. A. J., U.S. Pat. No. 3,238,216; 20 mg, 0.10 mmol) and triethylamine (11 μl) in ethanol (1 ml) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and then purified on a Biotage™ Flash 12S column using 3% methanol in methylene chloride as eluant to afford title compound 13A-1 (25 mg): +ESI MS (M+1) 536.3; 1H NMR (400 MHz, CD3OD) δ 8.22 (s, 1H), 7.59 (d, J=7.5 Hz, 1H), 7.46–7.35 (m, 5H), 7.29 (d, J=8.7 Hz, 2H), 4.27 (s, 2H), 4.25 (v br s, 4H), 3.15 (septuplet, J=6.6 Hz, 1H), 2.00–1.83 (m, 4H), 1.07 (d, J=6.6 Hz, 6H). A solution of the material in methylene chloride/ methanol was treated with excess 1 N HCl in diethyl ether, stirred, evaporated to dryness, and then triturated in diethyl ether to afford the hydrochloride salt of compound 13A-1 (23 mg, 77%): 1H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.53–7.40 (m, 5H), 7.35 (d, J=8.7 Hz, 2H), 4.20 (v br s), 3.94 (septuplet, J=6.6 Hz, 1H), 2.45 (m, 4H), 1.41 (d, J=6.6 Hz, 6H).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][C@H:24]([CH2:26]OS(C)(=O)=O)[O:23][C:22]3=[O:32])=[CH:17][C:16]=2[F:33])[CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[N-:34]=[N+:35]=[N-:36].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O.O>[N:34]([CH2:26][C@@H:24]1[O:23][C:22](=[O:32])[N:21]([C:18]2[CH:19]=[CH:20][C:15]([N:13]3[CH:14]=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2])[N:11]=[CH:12]3)=[C:16]([F:33])[CH:17]=2)[CH2:25]1)=[N+:35]=[N-:36]
Reactant: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)cn1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cn(-c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)cn1
Temperature: 80 °C
Yield: 82.3 %

Procedure:
(5R)-3-(4-(4-t-Butyldimethylsilyloxymethylimidazol-1-yl)-3-fluorophenyl)-5-methanesulfonyloxymethyloxazolidin-2-one (13.6 g) was dissolved in dry N,N-dimethylformamide (110 ml). Sodium azide (3.53 g) was added, and the mixture was heated at 80° C. for 3.5 hours. The mixture was cooled, diluted with water (1.1 L) containing sodium bicarbonate (2 g), and extracted with ethyl acetate (2×800 ml). Combined organics were washed with water (2×300 ml), then brine, and dried over magnesium sulfate. The solution was evaporated to a small volume (˜100 ml), and insolubles filtered. The ethyl acetate soluble material was columned on silica (100 g), eluting with ethyl acetate. Product fractions were combined and evaporated to give a gum (10.0 g).
Reaction SMILES: [C:1]([O:8]C([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.[NH2:12][CH2:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1>O1CCOCC1.[OH-].[Na+]>[C:4]([O:3][C:1]([NH:12][CH2:13][CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)=[O:8])([CH3:5])([CH3:6])[CH3:7]
Reactant: NCCc1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl dicarbonate (1.64 g; 7.5 mmol) is dissolved in 1,4-dioxane (5 mL) and the solution is added to a well-stirred solution of 4-(2-aminoethyl)benzoic acid (1.0 g; 5 mmol) in 1M aqueous sodium hydroxide solution (25 mL) and 1,4-dioxane (10 mL), and the mixture is then stirred at ambient temperature for 3 hours. The 1,4-dioxane is removed by evaporation in vacuo, and then ethyl acetate (200 mL) is added to the residue. The pH of the aqueous phase is adjusted to 1.5 with 2M aqueous HCl solution. The organic phase is separated off and the aqueous phase is then extracted with ethyl acetate (100 mL). The combined organic extracts are washed with water, dried over Na2SO4 and evaporated to a volume of 10 mL. Heptane is added to the residue and then the solid precipitate is filtered off to yield the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:11][CH:10]=2)[N:6]([C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:5]=1)([CH3:3])=[CH2:2]>C1COCC1.CO.[Pd]>[CH:1]([C:4]1[CH:8]=[C:7]([C:9]2[CH:22]=[CH:21][C:12]([O:13][CH2:14][CH2:15][NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:11][CH:10]=2)[N:6]([C:23]2[CH:24]=[N:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc(-c2ccc(OCCNS(C)(=O)=O)cc2)n(-c2ccc(OC)nc2)n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C(C)C)cc2-c2ccc(OCCNS(C)(=O)=O)cc2)cn1
Yield: 57.9 %

Procedure:
A mixture of 10% Pd-C 50% wet (20 mg) and N-(2-{4-[3-isopropenyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide (118 mg) in THF (1 ml) and MeOH (1 ml) was hydrogenated under H2 1atm at ambient temperature for 1 day. The catalyst was removed by filtration. The filtrate and combined washings were concentrated in vacuo. The residue was purified by preparative thin layer silica gel chromatography developed by AcOEt/n-hexane=70%. The separated silica gel was extracted with 10% MeOH/CHCl3 and the solvent was evaporated in vacuo. The residue was recrystallized from AcOEt-IPE to give N-(2-{4-[3-isopropyl-1-(6-methoxy-3-pyridinyl)-1H-pyrazol-5-yl]phenoxy}ethyl)methanesulfonamide (68.6 mg) as white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:17])(O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Br:15])[CH:2]=1.[CH3:18][C:19]([CH:22]=[O:23])([CH3:21])[CH3:20].B(F)(F)F.CCOCC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:19]([CH:22]1[O:17][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Br:15])[O:23]1)([CH3:21])([CH3:20])[CH3:18]
Reactant: CC(C)(C)C=O
Reactant: OC(O)(Cc1ccccc1Br)c1cccnc1
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)C1OC(c2cccnc2)C(c2ccccc2Br)O1
Reaction time: 8 h

Procedure:
8 g (0.027 mol) of 1-(pyrid-3-yl)-2-(2-bromophenyl)-ethanediol and 4.5 g (0.0525 mol) of pivaldehyde were dissolved in 100 ml of methylene chloride. This was achieved by adding 4.35 ml (0.0525 mol) of boron trifluoride etherate dropwise at room temperature and stirring overnight. Thereafter, the mixture was poured onto ice water and was neutralized with NaHCO3 solution. The organic phase was washed with water, dried over Na2SO4 and filtered, and the filtrate was evaporated down. The crude product was purified by chromatography.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:14][CH2:15][C:16]2[CH:36]=[CH:35][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24](/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:25][C:26]=3[CH3:27])=[C:18]([O:37][CH3:38])[CH:17]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=1)=O.[Cl-].[CH2:40]([C:42]1[S:43][CH:44]=[C:45]([CH2:47][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:46]=1)[CH3:41].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:40]([C:42]1[S:43][CH:44]=[C:45](/[CH:47]=[CH:1]\[C:3]2[C:4]([O:14][CH2:15][C:16]3[CH:36]=[CH:35][C:19]([O:20][CH2:21][C:22]4[N:23]=[C:24](/[CH:28]=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:25][C:26]=4[CH3:27])=[C:18]([O:37][CH3:38])[CH:17]=3)=[N:5][N:6]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:7]=2)[N:46]=1)[CH3:41]
Reactant: CCc1nc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cs1
Reactant: CCOC(=O)/C=C/c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3C=O)cc2OC)c(C)o1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3/C=C\c3csc(CC)n3)cc2OC)c(C)o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 13.3 %

Procedure:
A mixture of ethyl (2E)-3-{4-[(4-([(4-formyl-1-phenyl-1H-pyrazol-3-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-propenoate (0.87 g), [(2-ethyl-1,3-thiazol-4-yl)methyl]triphenylphosphonium chloride (1.06 g), anhydrous potassium carbonate (0.36 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to give ethyl (2E)-3-[4-({4-[({4-[(Z)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-propenoate as colorless crystals (0.14 g, yield 17%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 119-120° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]([CH3:18])[CH2:8][C:7]=12.CI.[CH3:21]N(C)C=O.[H-].[Na+]>O>[CH3:21][O:1][CH2:2][C:3]1[N:4]=[CH:5][N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[N:9]([CH3:18])[CH2:8][C:7]=12
Reactant: CN1Cc2c(CO)ncn2-c2ccccc2C1=O
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COCc1ncn2c1CN(C)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1.1 g (4.5 mmol) of 4,5-dihydro-3-(hydroxymethyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one, 0.3 ml (5.0 mmol) of methyl iodide and 10 ml of dry dimethylformamide is treated with 0.2 g (4.5 mmol) of sodium hydride (55 percent oil dispersion, washed with n-hexane) and the mixture is stirred at room temperature for about 16 hours. The mixture is poured into 70 ml of water and extracted three times with chloroform. The chloroform solution is washed once with water, dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel while eluting with chloroform containing 5% of methanol. Recrystallization of the material obtained from ethyl acetate/hexane yields 4,5-dihydro-3-(methoxymethyl)-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one of melting point 115°-116°.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:9]=1[CH:10]=O)=[O:5])[CH3:2].CC(C)([O-])C.[K+].O.Cl>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)COc1c(C=O)cccc1OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cccc(OC)c2o1
Yield: 19.5 %

Procedure:
A solution of 2-ethoxycarbonylmethoxy-3-methoxybenzaldehyde (2.00 g) and potassium tert-butoxide (963 mg) in tetrahydrofuran (20 ml) was stirred for 1 hour under ice-cooling. Water was added to the reaction mixture, and the solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (n-hexane:ethyl acetate=7:1, v/v) to give 2-ethoxycarbonyl-7-methoxybenzofuran (360 mg).
Reaction SMILES: [CH2:1]([C:9]1([CH2:23]CCCCCCC)[C:21]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)CCCCCCC.C1(C)C=CC=CC=1.[Li]CCCC.CN([CH:46]=[O:47])C>CCCCCC>[CH:46]([C:19]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH3:23])([CH3:1])[C:21]=2[CH:20]=1)=[O:47]
Reactant: CN(C)C=O
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC1(C)c2ccccc2-c2ccc(C=O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.77 %

Procedure:
To a dry 500 mL flask equipped with an argon inlet, a rubber septum, and a distillation head was charged 22.54 g (48.0 mmol) of 9,9-dioctyl-2-bromofluorene and 100 mL of toluene. Toluene was then removed by distillation to dry the flask and starting material. The residue was allowed to cool to room temperature and 250 mL of anhydrous ether was added. The resultant solution was then chilled to −78 ° C. and treated dropwise over 15 minutes with 30.6 mL (49.06 mmol) of 1.6M BuLi in hexane. Upon addition of the butyl lithium solution the reaction mixture initially turned purple and subsequently turned red. Anhydrous DMF (8 mL) was added and the resulting mixture was stirred at −78 ° C. for 1 hour and then warmed up to room and stirred for an additional hour. The mixture was quenched with 50 mL of 10% HCl and transferred into a separatory funnel. The organic phase was washed with 10% HCl (1×), water (2×) and brine (1×), and then dried over MgSO4. Solvent removal afforded 12 g of crude product. Purification by column chromatography (gradient from 96:4 heptanes: EtOAc in heptanes to 90:10 heptanes:EtOAc) afforded 10.2 g of 2-formyl-9,9-dimethylfluorene (49.77% yield). EI-MS: 418 (M+), 362,193 (100). 1H NMR (CDCl3) δ 10.09 (s, 1H), 7.87 (m, 4H), 7.41 (b, 3H), 2.05 (m, 4H), 1.30-1.05 (m, 22H), 0.83 (t, 5H), 0.61 (t, 3H). 13C NMR (CDCl3) δ 192.22, 152.11, 151.55, 147.54, 139.53, 135.39, 130.40, 128.78, 127.10, 123.09, 120.98, 120.91, 119.93, 70.98, 55.32, 40.24, 31.88, 29.92, 29.17, 23.78, 22.59, 14.03.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]1[CH:10]=[C:11]([CH:45]=[CH:46][CH:47]=1)[C:12]([NH:14][C:15]1[S:16][C:17]2[CH2:44][CH2:43][CH2:42][CH2:41][C:18]=2[C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)=[O:21])=[O:13])[CH:5]1[CH2:7][CH2:6]1.Br[CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH:5]1([N:4]([CH2:8][C:9]2[CH:10]=[C:11]([CH:45]=[CH:46][CH:47]=2)[C:12]([NH:14][C:15]2[S:16][C:17]3[CH2:44][CH2:43][CH2:42][CH2:41][C:18]=3[C:19]=2[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=3)=[CH:25][CH:24]=2)=[O:21])=[O:13])[CH2:3][CH2:2][NH:1][CH2:49][C:50]([O:52][CH2:53][CH3:54])=[O:51])[CH2:7][CH2:6]1
Reactant: CCOC(=O)CBr
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CN(CCN)C5CC5)c4)sc4c3CCCC4)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CNCCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1.0 g of methyl 4-(2-{4-[({2-[(3-{[(2-aminoethyl)(cyclopropyl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate, 0.20 mL of ethyl bromoacetate, 212 mg of potassium carbonate, and 20 mL of DMF was stirred overnight at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, thereby obtaining 140 mg of methyl 4-{2-[4-({[2-({3-[(cyclopropyl {2-[(2-ethoxy-2-oxoethyl)amino]ethyl}amino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH:11][C@H:12]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=1)[C:13]([NH:15][N:16]1[CH2:20][CH2:19][C@H:18]([N:21]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH2:17]1)=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:41]=O>>[CH3:41][CH:9]([NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:10][NH:11][C@H:12]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=1)[C:13]([NH:15][N:16]1[CH2:20][CH2:19][C@H:18]([N:21]([CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)[C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[CH2:17]1)=[O:14]
Reactant: CC(C)C(=O)N(C1CCCCC1)[C@H]1CCN(NC(=O)[C@@H](Cc2ccc(Cl)cc2)NCCNC(=O)OC(C)(C)C)C1
Reactant: C=O
Product: CC(CN[C@H](Cc1ccc(Cl)cc1)C(=O)NN1CC[C@H](N(C(=O)C(C)C)C2CCCCC2)C1)NC(=O)OC(C)(C)C

Procedure:
The title compound was prepared following the procedure described in Step A of Example 3 using (2R)-2-[2-(BOC)aminoethyl]amino-N-{(3S)-3-[cyclohexyl(isobutyryl)amino]pyrrolidine-1-yl}-3-(4-chlorophenyl)propionamide prepared in Step A of Example 360 and formaline.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][CH:19]([CH2:24][CH:25]1[CH2:28][CH2:27][CH2:26]1)[C:20]([NH:22][CH3:23])=[O:21]>>[CH:25]1([CH2:24][CH:19]([NH:18][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:20](=[O:21])[NH:22][CH3:23])[CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Reactant: CNC(=O)C(N)CC1CCC1
Product: CNC(=O)C(CC1CCC1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 69, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 50 mg, 0.21 mmol) and 2-amino-3-cyclobutyl-N-methyl-propionamide (41.2 mg, 0.32 mmol) as starting materials and isolated (20 mg, 25.16%) as white solid; LC-MS (UV peak area, ESI) 99.32%, 373.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH:9]=[N:10][S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[S:11]1[C:7]2=[CH:6][CH:5]=[CH:4][C:3]([OH:2])=[C:8]2[CH:9]=[N:10]1
Reactant: COc1cccc2sncc12
Agent: Cl
Solvent: c1ccncc1
Product: Oc1cccc2sncc12
Temperature: 150 °C
Yield: 32.1 %

Procedure:
To a sealed tube was added 4-methoxy-benzo[d]isothiazole (760 mg, 4.60 mmol) and pyridine hydrochloride (5.5 g, 48 mmol). The reaction was heated to 150° C. for 18 h and was then cooled to rt. The mixture was partitioned between dichloromethane and water. The organic phase was separated and the aqueous layer was extracted with 2×30 mL dichloromethane. The combined organic phases were dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography eluting silica gel with EtOAc:hexane [0:100 to 3:7] to yield the title compound as a solid (223 mg, 32%); Mass spectrum (ion spray): m/z=151.9 (m+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]=[CH:20][C:21]([OH:23])=O)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH:19]=[CH:20][C:21]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[O:23])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)O)cc2)=C(C)C1=O
Reactant: C1CCNCC1
Product: COC1=C(OC)C(=O)C(Cc2ccc(C=CC(=O)N3CCCCC3)cc2)=C(C)C1=O
Yield: 55.2 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]acrylic acid (200 mg, 0.58 mmol) obtained in Example 2 and piperidine (65 mg, 0.76 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (129 mg, 0.32 mmol, yield 54%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[CH3:8].[NH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=O)=[C:14]([OH:21])[CH:13]=1.O>C(OCC)(=O)C>[NH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]2[NH:10][C:4]3[CH:3]=[C:2]([CH3:1])[C:7]([CH3:8])=[CH:6][C:5]=3[N:9]=2)=[C:14]([OH:21])[CH:13]=1
Reactant: Cc1cc(N)c(N)cc1C
Reactant: Nc1ccc(C(=O)O)c(O)c1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc2nc(-c3ccc(N)cc3O)[nH]c2cc1C
Temperature: 130 °C
Yield: 28 %

Procedure:
To polyphosphoric acid at 130° C. were added 4,5-dimethylbenzene-1,2-diamine (500 mg, 3.67 mmol) and 4-amino-2-hydroxybenzoic acid (562 mg, 3.67 mmol), and the resulting mixture was then heated to 130° C. for 16 h. The solution was then poured into water and the resulting precipitate was dissolved in ethyl acetate and washed with Na2CO3. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous MgSO4 and evaporated. The resulting solid was purified by column chromatography eluting with ethyl acetate/hexanes 50:50 v/v to afford 260 mg (28%) of the title compound (LCMS RT=6.14 min, MH+ 254.1)
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH2:13]([O:16][C:17]1[C:24]([OH:25])=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20])[CH:14]=[CH2:15]>>[CH2:13]([O:16][C:17]1[C:24]([O:25][CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=[O:20])[CH:14]=[CH2:15]
Reactant: BrCc1ccc2ccccc2c1
Reactant: C=CCOc1c(O)cccc1C=O
Product: C=CCOc1c(C=O)cccc1OCc1ccc2ccccc2c1
Yield: 95 %

Procedure:
2-Bromomethylnaphthalene was reacted with 2-allyloxy-3-hydroxybenzaldehyde using the conditions described in Example 1 to give 2-allyloxy-3-(naphth-2-ylmethoxy)benzaldehyde as an oil in 95% yield. A mixture of the product so obtained (1.3 g), p-toluenethiol (0.8 g), sodium hydride (55% w/w dispersion in oil, 0.28 g) and dimethylformamide (10 ml) was heated to 100° C. for 1.3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 4:1 v/v mixture of methylene chloride and ethyl acetate as eluent. There was thus obtained 2-hydroxy-3-(naphth-2-ylmethoxy)benzaldehyde (0.7 g), m.p. 105° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH2:8].Br[C:10]([CH3:19])([CH:16]([CH3:18])[CH3:17])[C:11]([N:13]=[C:14]=[S:15])=[O:12]>C(Cl)Cl>[CH:16]([C:10]1([CH3:19])[S:15][C:14]([NH:8][CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:13][C:11]1=[O:12])([CH3:18])[CH3:17]
Reactant: NCc1ccccn1
Reactant: CC(C)C(C)(Br)C(=O)N=C=S
Solvent: ClCCl
Product: CC(C)C1(C)SC(NCc2ccccn2)=NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42.5 %

Procedure:
Pyridin-2-ylmethanamine (0.22 mL, 2.1 mmol) was added to 2-bromo-2,3-dimethylbutanoyl isothiocyanate (240 mg, 1.1 mmol) at room temperature. The reaction was exothermic, and was stirred at room temperature for 15 min. CH2Cl2 (2 ml) was added, and the resulting precipitate was removed by filtration. The CH2Cl2 solution was concentrated, and the mixture was purified by silica gel column (gradient 1% (10% NH3 in MeOH) to 30% (10% NH3 in MeOH) in CH2Cl2) to give the title compound as an off-white solid (123 mg). Mass Spec.=m/z+ion 264.1 (M+H)