Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.CO.[OH-].[NH4+]>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a solution of N-tert-butyl-2-(1-methyl-1H-pyrazol-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (140 mg, 316 μmol) in dichloromethane (3.5 mL) was added trifluoroacetic acid (720 mg, 486 μL, 6.31 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained dissolved in dichloromethane (3 mL), methanol (1.5 mL), and ammonium hydroxide (0.65 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated in vacuo then triturated with ether and water. The solid was collected by filtration then dried in vacuo to give N-tert-butyl-2-(1-methyl-1H-pyrazol-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (44 mg, 140 μmol, 45%) as a brown solid. 1H NMR (400 MHz, methanol-d) δ ppm: 8.07 (s, 1H), 7.93 (s, 1H), 7.81 (s, 1H), 7.35 (d, J=2.2 Hz, 1H), 6.32 (d, J=2.2 Hz, 1H), 3.67 (s, 3H), 1.35 (s, 9H); MS (EI/CI) m/z: 314.1 [M+H].
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([O:12][CH2:13][C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)C=CC=CC=1.[Cl:25]CCCl.ClC(OC(Cl)C)=O>CO>[ClH:25].[S:15]1[CH:16]=[CH:17][CH:18]=[C:14]1[CH2:13][O:12][CH:10]1[CH2:11][NH:8][CH2:9]1
Reactant: ClCCCl
Reactant: c1ccc(C(c2ccccc2)N2CC(OCc3cccs3)C2)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Product: Cl
Product: c1csc(COC2CNC2)c1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A 50 mL flask was charged with 1-(diphenylmethyl)-3-(2-thienylmethoxy)azetidine (204 mg, 0.61 mmol; which may be prepared as described in Step 2) and 1,2-dichloroethane (2.7 mL). 1-Chloroethyl chloroformate (86 μL, 0.79 mmol) was added and the reaction mixture was stirred at 70° C. for 1.5 h. After cooling to room temperature, methanol (2.7 mL) was added and the reaction mixture was stirred at 70° C. for 1.5 h. The reaction mixture was concentrated to dryness. The crude mixture was triturated in pentane to give a dark wax (140 mg, quantitative) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7](C)=[N:6][CH:5]=[CH:4][N:3]=1.[Cl:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.N1C=CN=CC=1.[C:41]([Cl:45])(Cl)(Cl)Cl>>[Cl:9][CH2:1][C:2]1[C:7]([CH2:41][Cl:45])=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1nccnc1C
Reactant: ClC(Cl)(Cl)Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1cnccn1
Product: ClCc1nccnc1CCl
Yield: 11 %

Procedure:
To a solution of 2,3-dimethylpyrazine (6.27 g, 57.4 mmol) in 100 mL of carbon tetrachloride was added N-chlorosuccinimide (16.7 g) followed by benzoyl peroxide (278 mg, 2 mol %) and the solution was heated to reflux for 16 h. The reaction was cooled, more benzoyl peroxide (278 mg, 2 mol %) was added and the reaction was refluxed for 5 h. The reaction was monitored by TLC until the disappearance of starting pyrazine. The reaction flask was cooled in an ice bath, the solution filtered, and the eluent was concentrated and chromatographed on SiO2 using 15% EtOAc in hexane. Obtained 1.14 g of the product (11% yield). MS found: (M+H)+=178.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1Br.[CH3:12][N:13](C)C=O.O>ClCCl>[C:8]([C:5]1[CH:4]=[C:3]([C:12]#[N:13])[C:2]([NH2:1])=[CH:7][CH:6]=1)(=[O:10])[CH3:9]
Reactant: CN(C)C=O
Reactant: CC(=O)c1ccc(N)c(Br)c1
Solvent: O
Solvent: ClCCl
Product: CC(=O)c1ccc(N)c(C#N)c1
Reaction time: 0.33 h

Procedure:
A stirred mixture of 35.5 g of 4'-amino-3'bromoacetophenone, 17.8 g of cuprous cyanide and 180 ml of dry dimethylformamide was heated at reflux, under nitrogen for 6 hours. After cooling, the mixture was treated with 180 ml of a solution of ferric chloride (prepared from 400 g of ferric chloride hexahydrate, 100 ml of concentrated hydrochloric acid and 600 ml of water) and stirred for 20 minutes at 60°-70° C. A 500 ml portion of water and 400 ml of dichloromethane were added. To facilitate phase separation, the mixture was filtered and then the filtrate was extracted with two 400 ml portions of dichlorometbane. The organic extracts were combined, washed with 200 ml of water and 200 ml of saturated sodium bicarbonate solution and the solvent removed in vacuo at 80° C. The residue was evaporated twice from 100 ml portions of toluene, giving a yellow solid, which was crystallized from ethanol, giving 14.35 g of the desired compound, mp 155°-159° C.
Reaction SMILES: [NH2:1][C:2]1C(C#N)=[N:4][C:5]([C:14]2[CH:15]=[N:16][C:17]([O:20]C)=[CH:18][CH:19]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[OH-:24].[Na+].[O:26]1[CH2:31][CH2:30]OCC1>>[NH2:1][C:2]1[C:30]([C:31]([OH:26])=[O:24])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: C1COCCO1
Reactant: COc1ccc(-c2nc(C#N)c(N)nc2-c2ccccc2)cn1
Reactant: [OH-]
Agent: [Na+]
Product: Nc1nc(-c2ccccc2)c(-c2ccc(=O)[nH]c2)nc1C(=O)O
Temperature: 80 °C
Reaction time: 15 h

Procedure:
3-Amino-6-(6-methoxy-3-pyridyl)-5-phenyl-2-pyrazinecarbonitrile (800 mg) was dissolved in dioxane and conc. HC. The solution was stirred at 80° C. for 15 hours. Dioxane was evaporated out. The reaction mixture was cooled to room temperature and concentrated in vacuo to give residue. To the residue was added 1N NaOH to adjust the pH of the aqueous mixture to 6-7. The crystals were collected by filtration, and dried in vacuo to give 3-amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxylic acid as powder (600 mg).
Reaction SMILES: [CH3:1][C:2]([CH2:4][CH2:5][OH:6])=[CH2:3].[OH:7][CH:8]1[CH2:13][CH:12]([CH3:14])[CH2:11]CO1>>[CH3:1][C:2](=[CH:4][CH2:5][OH:6])[CH3:3].[CH:8](=[O:7])[CH2:13][CH:12]([CH3:14])[CH3:11]
Reactant: CC1CCOC(O)C1
Reactant: C=C(C)CCO
Product: CC(C)=CCO
Product: CC(C)CC=O
Reaction time: 4 h

Procedure:
The autoclave was charged with 350 ml of a dioctyl phthalate solution containing 4.0 mg (0.00054 mml) of Rh4 (CO)12 and 0.173 g (0.856 mml) of ##STR23## and with 130 g (1.512 moles) of 2-methyl-1-buten-4ol. After thoroughly purging the autoclave with a mixed H2 /CO gas (1/1 in molar ratio), the reaction was carried out at a pressure of 140 kg/cm2 (absolute pressure) resulting from a mixed H2 /CO gas (1/1 in molar ratio) and at a temperature of 100° C., with stirring, for 4 hours. After the reaction, a very small amount of the reaction mixture was taken out and analyzed by gas chromatography, to show that 0.045 mole of the 2-methyl-1-buten-4-ol remained unreacted (the conversion being 97%), that the yield of 2-hydroxy-4-methyltetrahydropyran was 1.320 moles, and that the yields of 2-methyl-2-buten-4-ol and isovaleraldehyde were 0.058 and 0.073 mole, respectively.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:22]([C:23](=[O:26])[C:24]=2[OH:25])=[CH:21][CH:20]=[C:19]([O:27][CH2:28][O:29][CH3:30])[CH:18]=3)=[CH:11][C:10]=1[O:31][CH2:32][O:33][CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[CH2:45][O:46][CH3:47]>C(Cl)Cl.CCOCC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[C:22]([C:23](=[O:26])[C:24]=2[O:25][CH2:45][O:46][CH3:47])=[CH:21][CH:20]=[C:19]([O:27][CH2:28][O:29][CH3:30])[CH:18]=3)=[CH:11][C:10]=1[O:31][CH2:32][O:33][CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCOc1ccc2c(=O)c(O)c(-c3ccc(OCc4ccccc4)c(OCOC)c3)oc2c1
Reactant: COCCl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1ccc2c(=O)c(OCOC)c(-c3ccc(OCc4ccccc4)c(OCOC)c3)oc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To 2-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-3-hydroxy-7-(methoxymethoxy)-4H-chromen-4-one (55 mg, 0.12 mmol) in 2 mL of DCM was added DIPEA (31 mg, 0.24 mmol), followed by slow addition of chloro(methoxy)methane (15 mg, 0.18 mmol). The reaction mixture was stirred at rt under Ar atmosphere for 3 h and diluted with ether (30 mL). It was washed with water (3×30 mL) and dried over MgSO4 and concentrated. The crude product was purified with silica chromatography (hexane/EtOAc) to afford 2-(4-(benzyloxy)-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4H-chromen-4-one as a white solid (55 mg, 90%). 1H NMR (400 MHz, CDCl3) δ 8.14 (d, J=8.8 hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.71 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.46-7.44 (m, 2H), 7.39 (m, 2H), 7.34-7.31 (m, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 5.30 (s, 2H), 5.28 (s, 2H), 5.24 (s, 2H), 5.21 (s, 2H), 3.55 (s, 3H), 3.51 (s, 3H), 3.18 (s, 3H); MS (ESI) m/z 509 (M+H+).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]1[C@H:14]2[C:15](=[O:39])[CH:16]=[C:17]3[C@:36]([CH3:37])([C@@H:13]12)[C@@H:35]1[C@H:20]([C@H:21]2[C@:32]([CH3:38])([CH2:33][CH2:34]1)[C@@H:24]([CH:25]([CH3:31])[CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH2:23][CH2:22]2)[CH:19]=[CH:18]3>C(Cl)(Cl)Cl>[O:12]1[C:14]2=[C:13]3[C@:36]([CH3:37])([CH2:17][CH2:16][C:15]2=[O:39])[C@@H:35]2[C@H:20]([C@H:21]4[C@:32]([CH3:38])([CH2:33][CH2:34]2)[C@@H:24]([CH:25]([CH3:31])[CH:26]([O:29][CH3:30])[O:27][CH3:28])[CH2:23][CH2:22]4)[C@@H:19]2[O:9][C@:18]123
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC(OC)C(C)[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@]45OC4=C5[C@](C)(CCC4=O)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
A mixture of 0.836 g (0.5 mmole) of m-chloroperbenzoic acid and 70 ml of chloroform was added to a mixture of 0.772 g (2.0 mmoles) of 1α,2α-epoxy-21,21-dimethoxy-20-methylpregna-4,6-dien-3-one and 20 ml of chloroform and the whole mixture was stirred at room temperature for 1 day. The reaction mixture thus obtained was worked up in the same manner as Example 7 to recover 0.498 g of 1α,2α;6α,7α-diepoxy-21,21-dimethoxy-20-methylpregn-4-en-3-one (yield: 62%).
Reaction SMILES: [Si]([O:18][C:19]1[CH:59]=[CH:58][C:22]([O:23][CH2:24][C@@H:25]([OH:57])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:56]=[CH:55][C:33]([NH:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([NH:43][CH2:44][C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=4[C:51]([F:54])([F:53])[F:52])=[O:42])[CH2:37][CH2:36]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[F:53][C:51]([F:52])([F:54])[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][NH:43][C:41]([N:38]1[CH2:39][CH2:40][CH:35]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([CH2:29][CH2:28][NH:27][CH2:26][C@H:25]([OH:57])[CH2:24][O:23][C:22]3[CH:21]=[CH:20][C:19]([OH:18])=[CH:59][CH:58]=3)=[CH:56][CH:55]=2)[CH2:36][CH2:37]1)=[O:42]
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H](O)CNCCc2ccc(NC3CCN(C(=O)NCc4ccccc4C(F)(F)F)CC3)cc2)cc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NCc1ccccc1C(F)(F)F)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 58.3 %

Procedure:
4-[4-(2-{[(2S)-3-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-2-hydroxypropyl]amino}ethyl)anilino]-N-[2-(trifluoromethyl)benzyl]-1-piperidinecarboxamide (0.211 g, 0.24 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol containing 1% ammonium hydroxide) to give the title compound (0.085 g, 0.14 mmol).
Reaction SMILES: [ClH:1].[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[OH:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)[CH:20]=1)[C:14](OC)=[O:15].O>CN(C)C=O.CO>[ClH:1].[OH:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[C:19]([N:21]2[CH:22]=[CH:23][CH:24]=[CH:25]2)[CH:20]=1)[C:14]([N:4]=[C:3]([NH2:5])[NH2:2])=[O:15]
Reactant: N=C(N)N
Reactant: COC(=O)c1cc(CO)cc(-n2cccc2)c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: NC(N)=NC(=O)c1cc(CO)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
To a solution of guanidine hydrochloride (62.1 g) in N,N-dimethylformamide (150 ml) was added 28% sodium methoxide in methanol (106 ml) under nitrogen. After being stirred for 30 minutes at room temperature, to the reaction mixture was added a solution of methyl 3-hydroxymethyl-5-(pyrrol-1-yl)benzoate (30.0 g) in N,N-dimethylformamide (150 ml). After being stirred for 21 hours at room temperature, the reaction mixture was poured into water (1.5 l) with stirring. The resulting precipitate was collected by filtration, washed with water and purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (10:1). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was dissolved in ethanol (70 ml) and crystallized from slight excess 4N-hydrogen chloride-ethyl acetate. The crystalline was recrystallized from an aqueous ethanol to afford 2-[3-hydroxymethyl-5-(pyrrol-1-yl)benzoyl]guanidine hydrochloride (7.3 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH:7]([NH:23][C:24](=[O:42])[CH:25]([NH:30]C(C(N1CCCCCC1)=O)=O)[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O1[CH2:48][CH2:47][CH2:46][CH2:45]1>[Pd]>[C:1]([O:5][C:6](=[O:43])[CH:7]([NH:23][C:24](=[O:42])[CH:25]([NH:30][C:24]([N:23]1[CH2:45][CH2:46][CH2:47][CH2:48][CH2:6][CH2:7]1)=[O:42])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)CC(NC(=O)C(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Reactant: C1CCOC1
Agent: [Pd]
Product: CC(C)CC(NC(=O)N1CCCCCC1)C(=O)NC(Cc1ccc(O)cc1)C(=O)OC(C)(C)C
Yield: 95 %

Procedure:
A solution of the product from Example 1 (0.20 g, 0.35 mmol) in 16 mL of tetrahydrofuran was hydrogenated at 52 psi over 20% Pd/C for 48 hours. The reaction mixture was filtered through Celite using methanol and concentrated. The resulting foam was purified by chromatography (silica gel, 1:1 heptane/ethyl acetate). The product was isolated as a foam and dried under vacuum to give the title compound (0.16 g, 95%).
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C:5]3=O)[CH2:3]1)[CH2:9]2.[NH2:13][CH2:14][C:15]([N:17]([CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C=O)C.ClCCCl>[CH:24]1([N:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:15](=[O:16])[CH2:14][NH:13][CH:5]2[CH:4]3[CH2:10][CH:8]4[CH2:9][C:2]([OH:1])([CH2:11][CH:6]2[CH2:7]4)[CH2:3]3)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NCC(=O)N(c1ccccc1)C1CCCCC1
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(CNC1C2CC3CC1CC(O)(C3)C2)N(c1ccccc1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
To a solution of 5-hydroxy-2-adamantanone (80 mg, 0.48 mmol) in a mixed solvent of 1,2-dichloroethane and DMF (6 mL and 0.5 mL, respectively) at room temperature was added compound 2-amino-N-cyclohexyl-N-phenylacetamide (92 mg, 0.40 mmol). The reaction mixture was stirred for 15 minutes before cooling to 0° C. Sodium triacetoxyborohydride (128 mg, 0.60 mmol) was slowly added, followed by addition of glacial acetic acid (22 μL, 0.40 mmol). The reaction mixture was allowed to warm to room temperature, and then stirred for 24 hours. Concentration under reduced pressure, and purification on silica gel (5% methanol/dichloromethane) afforded N-cyclohexyl-2-[(5-hydroxyadamantan-2-yl)amino]-N-phenylacetamide CVT-6441 (90 mg, 60% yield). (M+1)=383.24.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7](O)=[CH:8][CH:9]=1)=[O:3].Br[CH2:12][CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-:17].[K+].[K+].O>CC(C)=O>[CH3:15][CH2:14][CH2:13][CH2:12][O:17][CH2:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCOCC(=O)c1ccccc1
Yield: 98.8 %

Procedure:
A suspension of 4-hydroxyacetophenone (27.2 g, 0.2 mole), 1-bromobutane (41.8 g, 0.305 mole) and potassium carbonate (41.4 g, 0.3 mole) in acetone (400 ml) were heated under reflux for 48 hours. Water (200 ml) was then added and the mixture extracted with ethyl acetate (300 ml) and washed with water (2×150 ml). The organic solution was dried and evaporated under reduced pressure to give an orange liquid which solidified on cooling to give the product (38.0 g, 99%) which was used in the next reaction without further purification.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([NH:7][C:8]([NH2:10])=[O:9])=[CH:3][CH:2]=1.[C:12](Cl)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:14])[CH3:13].CC(C1C=CC=CC=1)=C>CC(CC(C)C)=O>[CH3:13][C:12]([NH:10][C:8]([NH:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)=[O:9])([CH3:14])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(Cl)c1ccccc1
Reactant: Cc1ccc(NC(N)=O)cc1
Agent: C=C(C)c1ccccc1
Solvent: CC(=O)CC(C)C
Product: Cc1ccc(NC(=O)NC(C)(C)c2ccccc2)cc1
Reaction time: 5 h

Procedure:
11.25 parts of p-tolylurea, 7.72 parts of cumyl chloride and 23.64 g of α-methylstyrene were added to 80 parts of methylisobutyl ketone, and the reaction was performed at 60° C. for 5 hours. After the reaction, the solvent was evaporated off at reduced pressure. The residue was washed with n-hexane, and recrystallized from a mixture of water and methanol to afford 5.4 parts of N-(α,α-dimethylbenzyl)-N'-(p-tolyl)urea.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[O:3].O=S(Cl)Cl.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.N1C=CC=CC=1>C1COCC1>[CH3:27][O:26][C:23]1[CH:22]=[CH:21][C:20]([N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:1](=[O:6])[C:2](=[O:3])[CH3:4])=[CH:25][CH:24]=1
Reactant: COc1ccc(Nc2ccc(OC)cc2)cc1
Reactant: CC(=O)C(=O)O
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: COc1ccc(N(C(=O)C(C)=O)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
Pyruvic acid (1.00 g, 11.34 mmol) was placed in a 250 mL three-necked round-bottomed flask fitted with a stirring bar, reflux condenser and a nitrogen inlet, and dissolved in 30 mL anhydrous THF at room temperature. Then, SOCl2 (2.03 g, 17.01 mmol) was added dropwise with stirring in 3 hours at room temperature. Bis(4-methoxyphenyl)amine (2.00 g, 8.72 mmol) was added under nitrogen protection. Pyridine (4.14 g, 52.3 mmol) were added to the mixture at 0° C. The reaction mixture was heated to reflux for 12 hours. The reaction was quenched by adding 30 mL of 2N HCl solution. The mixture was extracted with EtOAc (3×20 mL). The organic layers were separated, washed with brine (20 mL) and dried over anhydrous MgSO4. The solvent was removed under reduced pressure to give a yellow residue. The solvent was removed and residue was subjected to flash column chromatography (silica gel, EtOAc/hexanes=3/7 v/v) to give a white solid product, N,N-bis(4-methoxyphenyl)-2-oxopropanamide, 2.15 g, 82.4% yield. MS: m/z 322 [M+Na]+.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 22.3 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.078 mmol), β-alanine (692 mg, 7.8 mmol), and NaOMe solution (12 mL, 5.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After cooling to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-30% EtOAc/CH2Cl2+1% AcOH). The product isolated was then dissolved in saturated NaHCO3 and washed with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and the resulting precipitate was isolated by filtration to give 7.7 mg of the title compound. MS: (+) m/z 444.37 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([O:32][CH2:33][CH3:34])[C:30]=1F)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[N:24][NH:25][N:26]=3)[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2].C(OC1C=C(C=C(OCC)C=1[N:46]1[CH:50]=[CH:49][CH:48]=[CH:47]1)C=O)C.C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:28]=[C:29]([O:32][CH2:33][CH3:34])[C:30]=1[N:46]1[CH:50]=[CH:49][CH:48]=[CH:47]1)[CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[N:23]=[N:24][NH:25][N:26]=3)[CH:17]=2)[CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOc1cc(CN2CCC(NC(=O)c3cccc(-c4nn[nH]n4)c3)CC2)cc(OCC)c1F
Reactant: CCOc1cc(C=O)cc(OCC)c1-n1cccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc(-c4nn[nH]n4)c3)CC2)cc(OCC)c1-n1cccc1

Procedure:
In analogy to the procedure described in example 50k), N-piperidin-4-yl-3-(1H-tetrazol-5-yl)-benzamide (example 178) was reacted with 3,5-diethoxy-4-pyrrol-1-yl-benzaldehyde (example 40b), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 516.2 (MH+).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>ClCCl>[NH2:26][C:25]1[CH:27]=[CH:28][C:22]([CH2:21][CH2:20][NH:19][S:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])=[CH:23][CH:24]=1
Reactant: NCCc1ccc(N)cc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1

Procedure:
47.5 ml of triethylamine and then, in portions, 72 g of 4-chlorobenzenesulphonyl chloride, are added at ambient temperature to a solution of 46.5 g (340 mmol) of 4-(2-aminoethyl)aniline in a liter of dichloromethane. The mixture is then stirred for one night and subsequently filtered. The solid obtained is washed with water and dried using a dessicator to yield the expected product.