Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH:31]([CH3:35])[N:30]1[CH2:36][C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1>>[CH3:35][CH:31]1[CH2:32][CH2:33][CH2:34][CH:29]([CH3:28])[N:30]1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH:41]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:42][CH:43]=1
Reactant: CC1CCCC(C)N1Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CN3C(C)CCCC3C)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-[(2,6-dimethyl-piperidin-1-yl)-methyl]-aniline
Reaction SMILES: [I:1][C:2]1[C:3]2[S:11][C:10]([CH3:12])=[N:9][C:4]=2[C:5](=O)[NH:6][CH:7]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:5]1[C:4]2[N:9]=[C:10]([CH3:12])[S:11][C:3]=2[C:2]([I:1])=[CH:7][N:6]=1
Reactant: Cc1nc2c(=O)[nH]cc(I)c2s1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc2c(Cl)ncc(I)c2s1

Procedure:
7-Iodo-2-methyl-5H-thiazolo[4,5-c]pyridin-4-one (880 mg, 3.01 mmol) was suspended in POCl3 (8.25 ml, 90.4 mmol) and refluxed for 4 hrs. The black reaction mixture was evaporated and poured as a dichloromethane solution in ice water. The aqueous layer was neutralized with solid NaHCO3 to pH 7 and extracted three times with dichloromethane. The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (dichloromethane/methanol 100:0->95:5 gradient). The desired product was obtained as a light yellow solid (280 mg, 30%), MS: m/e=311.0 (M+H+).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Cl:7][C:8]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH3:30])[C:9]=1[C:10]([C:12]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH3:20])=[C:14]([O:21][CH3:22])[C:13]=1[O:23][CH3:24])=[O:11].C([O-])(O)=O.[Na+]>O1CCCC1>[Cl:7][C:8]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([CH3:30])[C:9]=1[CH:10]([OH:11])[C:12]1[C:17]([CH3:18])=[CH:16][C:15]([O:19][CH3:20])=[C:14]([O:21][CH3:22])[C:13]=1[O:23][CH3:24]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)ccc(Cl)c2C)c(OC)c1OC
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cc(C)c(C(O)c2c(Cl)ccc(Cl)c2C)c(OC)c1OC
Reaction time: 1 h

Procedure:
Under protective gas conditions, at about −78° C., 1 ml of a 1-molar solution of LiAlH4 in tetrahydrofuran was added dropwise to a solution of 0.37 g of 2,5-dichloro-6,6′-dimethyl-2′, 3′, 4′-trimethoxybenzophenone in 20 ml of anhydrous tetrahydrofuran, and the mixture was stirred for about 1 hour. At 20-25° C., sat. NaHCO3 solution was added to the reaction solution, the solution was extracted with ethyl acetate and the organic phase was washed with water and sat. NaCl solution and dried, and the solvent was then distilled off. The residue gave, after purification by column chromatography (mobile phase: ethyl acetate/cyclohexane 1:9), 150 mg of the title compound as a yellow viscous oil.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[C:8]([Cl:20])=[N:9][C:10]([Cl:19])=[N:11][C:12]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)C.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:19][C:10]1[N:9]=[C:8]([Cl:20])[C:7]([O:6][CH2:5][CH2:4][OH:3])=[C:12]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:11]=1
Reactant: CCOC(=O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCCOc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 0 °C
Yield: 94.7 %

Procedure:
To a solution of (2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-acetic acid ethyl ester (188 mg, 0.56 mmol) in THF (2.5 mL) at −78° C. was added DIBAL-H (2.0 mL, 2.0 mmol, 1M solution in THF) and the resulting mixture warmed to 0° C. over 30 minutes. The reaction mixture was quenched with methanol and Rochelle's salt (1M aqueous solution) and the aqueous extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo affording 2-(2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-ethanol as an oil (156 mg, 95%). LCMS: RT=2.60 min, [M+H]+=294/296/298.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]=[CH2:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:10][Si:11]([CH3:21])([CH3:20])[O:12][SiH:13]([CH3:19])[O:14][Si:15]([CH3:18])([CH3:17])[CH3:16].[SiH4]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl.C(O)(C)C>[CH3:10][Si:11]([CH3:20])([CH3:21])[O:12][Si:13]([CH3:19])([CH2:9][CH2:8][CH2:7][O:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])[O:14][Si:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: C=CCOC(=O)C(=C)C
Reactant: C[SiH](O[Si](C)(C)C)O[Si](C)(C)C
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Agent: [SiH4]
Solvent: CC(C)O
Product: C=C(C)C(=O)OCCC[Si](C)(O[Si](C)(C)C)O[Si](C)(C)C
Temperature: 70 °C

Procedure:
Into 63 parts of allyl methacrylate admixed with 0.04 part of chloroplatinic acid in the form of an isopropyl alcohol solution and heated at 60° 70° C. were added dropwise gradually 111 parts of 1,1,1,3,5,5,5-heptamethyl trisiloxane and, after completion of the dropwise addition of the silane compound, the mixture was heated at 90° C. for further 2 hours to complete the reaction. Thereafter, the reaction mixture was distilled under reduced pressure to be freed from the unreacted reactants and then filtered to give 1,1,1,3,5,5,5- heptamethyl-3-(3-methacryloxypropyl) trisiloxane, which is referred to as the compound B-1 hereinbelow, in a yield of 165 parts corresponding to 95% of the theoretical yield.
Reaction SMILES: S(Cl)([Cl:3])=O.[O:5]1[CH2:9][CH2:8][N:7]=[C:6]1[C:10]1[CH:31]=[CH:30][C:13]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH2:28]O)=[CH:12][CH:11]=1>C(Cl)Cl>[Cl:3][CH2:28][C:23]1[C:24]([CH3:27])=[N:25][O:26][C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][C:13]1[CH:30]=[CH:31][C:10]([C:6]2[O:5][CH2:9][CH2:8][N:7]=2)=[CH:11][CH:12]=1
Reactant: Cc1noc(CCCCCCCOc2ccc(C3=NCCO3)cc2)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1noc(CCCCCCCOc2ccc(C3=NCCO3)cc2)c1CCl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 2.1 ml of thionyl chloride in 5.0 ml of methylene dichloride cooled in an ice-bath was added over a 30 minute period a suspension of 5 g of 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methyl-4-isoxazolemethanol (Example 29) in 20 ml of methylene dichloride. The reaction mixture was stirred at 0° C. for 2 hours and then at room temperature for 3 hours. The solvent was then removed in vacuo and the residue triturated with ether. The solid product was collected and recrystallized from acetonitrile to give 4.5 g of 4-chloromethyl-5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole in the form of its monohydrochloride salt, tan solid, m.p. 103°-104° C.
Reaction SMILES: C[Si]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8](Br)[CH:7]=1)(C)C.[Mg].[CH3:14][O:15][CH2:16][O:17][C:18]1[CH:38]=[CH:37][C:21]2[C:22](=[O:36])[CH:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=3)[CH2:24][O:25][C:20]=2[CH:19]=1>O1CCCC1>[OH:5][C:6]1[CH:11]=[CH:10][C:9]([C:22]2([OH:36])[C:21]3[CH:37]=[CH:38][C:18]([O:17][CH2:16][O:15][CH3:14])=[CH:19][C:20]=3[O:25][CH2:24][CH:23]2[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][O:34][CH3:35])=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)Oc1cccc(Br)c1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2=O)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(O)cc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Under nitrogen atmosphere, 3-bromomagnesium phenyl trimethylsilyl ether prepared from 3-bromophenyl trimethylsilyl ether (2.35 g, 9.57 mmol) and magnesium turning (0.23 g, 9.57 mmol) in dry tetrahydrofuran (3 ml) was cooled to -78° C. 7-Methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran-4-one (1 g, 2.9 mmol) dissolved in dry tetrahydrofuran (2 ml) was slowly added dropwise thereto, and the mixture was stirred for one hour. The reaction solution was quenched with saturated aqueous ammonium chloride solution and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to remove the organic solvent. The concentrate was then subjected to column chromatography (n-hexane:ethyl acteate=4:1) to obtain 903 mg (yield: 74%) of the title compound as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][Si](C)(C)C)[CH:3]=1.[OH-].[K+]>CO.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]=[CH2:9])[CH:3]=1
Reactant: C[Si](C)(C)C#Cc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=Cc1cccc(Br)c1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
To a solution of 1-bromo-3-trimethylsilylethynylbenzene (20.5 g, 81.0 mmol) in degassed methanol (500 ml), there was added potassium hydroxide (31 mg, 0.55 mmol) in water (1 ml). The solution was stirred at room temperature until G.C. analysis indicated the reaction was complete (5.0 h). The reaction mixture was diluted with an equal volume of water, and extracted with n-pentane (5×500 ml). The combined organic layers were dried (MgSO4) and the solvent removed under reduced pressure to yield a yellow liquid. The liquid was distilled via bulb-to-bulb vacuum distillation to yield the product (1c) (13.0 g, 90%) as a clear liquid: bp 40° CC/1 torr; 1H NMR (200 MHz, CDCl3) c3.35(s), 7.23(t), 7.40(m), 7.65(t).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[CH:31]1[CH2:32][CH2:33][N:34]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:35][CH2:36]1
Reactant: Fc1ccc(C2CCNCC2)c(F)c1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC(c2ccc(F)cc2F)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 4-(2,4-difluorophenyl)piperidine (1.2 equiv) to give 214 (11.8 mg, M+1 493.1)
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[C@@H:12]2[CH2:13][C:14]([CH2:16][C@H:9]1[CH2:10][CH2:11]2)=O)=[O:7])([CH3:4])[CH3:3].[NH2:17][CH2:18][C:19]1[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH3:26][O:25][C:23]([C:22]1[CH:27]=[CH:28][C:19]([CH2:18][NH:17][CH:14]2[CH2:16][CH:9]3[N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH:12]([CH2:11][CH2:10]3)[CH2:13]2)=[CH:20][CH:21]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Reactant: COC(=O)c1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COC(=O)c1ccc(CNC2CC3CCC(C2)N3C(=O)OC(C)(C)C)cc1
Reaction time: 1 h
Yield: 88.2 %

Procedure:
A solution of N-Boc nortropinone (2.4 g, 10.9 mmol) and methyl 4-aminomethylbenzoate (1.6 g, 10.9 mmol) in dichloroethane (20 mL) was stirred as acetic acid (0.85 g, 14.2 mmol) was added. After 1 hour, sodium triacetoxyborohydride (2.7 g, 13.1 mmol) was added and the reaction was stirred for 17 hours. The reaction was treated with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2×). The combined organic extracts were dried and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexane gave 3.6 g of 1,1-dimethylethyl 3-[[[4-(methoxycarbonyl)phenyl]methyl]amino]-8-azabicyclo[3.2.1]octane-8-carboxylate.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[C:6]([CH:11]([CH3:16])[CH:12]([NH2:15])[CH2:13][NH2:14])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:17](N1C=CN=C1)(N1C=CN=C1)=[S:18]>C(Cl)Cl.C(Cl)(Cl)Cl.O>[N:1]1[C:10]2[C:5](=[C:6]([CH:11]([CH:12]3[CH2:13][NH:14][C:17](=[S:18])[NH:15]3)[CH3:16])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CC(c1cccc2ncccc12)C(N)CN
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CC(c1cccc2ncccc12)C1CNC(=S)N1
Yield: 93.1 %

Procedure:
3-Quinolin-5-yl-butane-1,2-diamine (Intermediate E3) (1.8 g, 8.35 mmol) in CH2Cl2 (20 mL) was treated with a solution of 1,1′-thiocarbonyldiimidazole (1.52 g, 8.54 mmol) in CH2Cl2 (40 mL) at 0° C. for 1 h. The mixture was diluted with chloroform (40 mL) and water (60 mL). The aqueous layer was extracted with chloroform (3×30 mL) and CH2Cl2 (6×30 mL). The organic solution was dried over MgSO4, filtered and evaporated to give a residue. The material was purified by chromatography on SiO2 with 3% NH3-MeOH:CH2Cl2 to give 4-(1-quinolin-5-yl-ethyl)-imidazolidine-2-thione (Intermediate E4) 2 g (93%).
Reaction SMILES: [C:1]([NH:9][C:10]1[N:14]([C@@H:15]2[CH2:20][CH2:19][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16]2)[C:13]2[CH:25]=[C:26]([CH2:29]O)[CH:27]=[CH:28][C:12]=2[N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:35][C:36]1([CH3:44])[CH2:41][CH2:40][CH2:39][C:38]([CH3:43])([CH3:42])[NH:37]1>C(Cl)Cl>[C:1]([NH:9][C:10]1[N:14]([C@@H:15]2[CH2:16][CH2:17][C@H:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:19][CH2:20]2)[C:13]2[CH:25]=[C:26]([CH2:29][N:37]3[C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][CH2:41][C:36]3([CH3:44])[CH3:35])[CH:27]=[CH:28][C:12]=2[N:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccccc3)nc3ccc(CO)cc32)CC1
Reactant: CC1(C)CCCC(C)(C)N1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@H]1CC[C@@H](n2c(NC(=O)c3ccccc3)nc3ccc(CN4C(C)(C)CCCC4(C)C)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
cis-Methyl 4-(2-benzamido-6-(hydroxymethyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (0.05 g, 0.123 mmol) was suspended in DCM (1.2 mL) and cooled to 0° C. under nitrogen atmosphere. To this mixture was added thionyl chloride (0.292 g, 2.454 mmol), and the mixture was stirred for 30 minutes. The resulting mixture was concentrated under reduced pressure and dried under high vacuum. The residue was suspended in 2 mL of DMSO and cooled in an ice bath under nitrogen atmosphere. To this mixture was added 2,2,6,6-tetramethylpiperidine (0.173 g, 1.227 mmol) dropwise, and the reaction was stirred in an ice bath for 30 minutes and at RT for another 30 minutes. The reaction mixture was diluted with DCM (20 mL) and washed with water (10 mL). The organic layer was collected, dried over sodium sulfate, and concentrated under vacuum. The residual yellow oil was triturated with 10% water/MeOH to afford cis-methyl 4-(2-benzamido-6-((2,2,6,6-tetramethylpiperidin-1-yl)methyl)-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate (20 mg, 30.8% yield). MS m/z=531.2 [M+H]. Calc'd for C32H42N4O3: 530.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04 (s, 12H) 1.54-1.73 (m, 6H) 1.73-1.99 (m, 4H) 2.25-2.41 (m, 2H) 2.46-2.54 (m, 2H) 2.84-3.02 (m, 1H) 3.81 (s, 3H) 3.93 (s, 2H) 4.73-5.08 (m, 1H) 7.25 (d, J=8.31 Hz, 1H) 7.39-7.62 (m, 4H) 7.74 (s, 1H) 8.23-8.35 (m, 2H) 12.76 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2Br)=[O:10])=[N:6][CH:7]=1.[CH3:18][C:19]1[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][N:20]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH:25][C:24]2[C:19]([CH3:18])=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1nc(C(=O)Nc2ccc(F)cn2)c(Br)s1
Reactant: Cc1ncccc1N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1nc(C(=O)Nc2ccc(F)cn2)c(Nc2cccnc2C)s1
Yield: 68.2 %

Procedure:
A solution of 5-bromo-2-methyl-thiazole-4-carboxylic acid (5-fluoro-pyridin-2-yl)-amide (0.24 g, 0.76 mmol) and 2-methyl-pyridin-3-ylamine (0.099 g, 0.92 mmol) in dry dioxane (12 ml) was degassed by sonication and argon bubbling. 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.149 g, 0.26 mmol) and palladium dibenzylideneacetone chloroform complex (0.081 g, 0.08 mmol) were added and the mixture was stirred until dissolution was complete. Finally, the mixture was treated with cesium carbonate (0.495 g, 1.52 mmol) and irradiated in a microwave oven at 100° C. for 10 min, 130° C. for 10 min and 150° C. for 10 min. The solvent was removed under vacuum and the residue purified by flash chromatography (heptane, ethyl acetate) to yield the title compound (0.178 g, 68%) as a light brown solid, MS (ISP): m/e=344.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([CH:22]=[N:23][OH:24])=[C:13]([CH2:25][O:26][CH3:27])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrN1C(=O)CCC1=O.[CH2:36]([O:38][C:39]#[CH:40])[CH3:37].C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][C:14]([C:22]3[CH:37]=[C:36]([O:38][CH2:39][CH3:40])[O:24][N:23]=3)=[C:13]([CH2:25][O:26][CH3:27])[C:12]2=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#COCC
Reactant: COCc1c(C=NO)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(-c2ncc3[nH]c4ccc(OCc5ccccc5)cc4c3c2COC)no1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.1 g (3.0 mmol) of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carbaldehyde oxime is dissolved in 40 ml of dry DMF and combined with 0.56 g (3.1 mmol) of N-bromosuccinimide (dissolved in 5 ml of DMF). The reaction mixture is stirred for 15 minutes at room temperature and then combined with 1.5 eq. of ethoxyacetylene and 2 ml of triethylamine. The reaction mixture is agitated overnight at room temperature, then poured on ice water and extracted with ethyl acetate. The organic phase is dried over magnesium sulfate, filtered, the solvent drawn off, and the residue purified by column chromatography on silica gel with ethyl acetate. Melting point: 139°-140° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.Br[CH:11]([CH3:15])[C:12](=O)[CH3:13]>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:11]([CH3:15])=[C:12]([CH3:13])[N:1]=2)[CH:4]=[C:5]([Br:9])[CH:6]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: CC(=O)C(C)Br
Solvent: CCO
Product: Cc1nc2c(N)cc(Br)cn2c1C
Temperature: 25 °C

Procedure:
A solution of 2,3-diamino-5-bromopyridine (4.0 g, 21.29 mmol) and 3-bromo-2-butanone (3.7 g, 24.48 mmol) in ethanol (40 ml) was refluxed overnight. After cooling to room temperature, the crystalline product was filtered and washed with ethanol and ether. The crystals were dissolved in methylene chloride and neutralized by aqueous NaHCO3. The organic layer was separated, dried over Na2SO4 and evaporated in vacuo. Yield 2.3 g.
Reaction SMILES: CC([CH:5]1[CH2:10][N:9]([CH2:11][CH2:12][C:13]2[CH:22]=[CH:21][C:16]3[C:17](=[O:20])[O:18][CH2:19][C:15]=3[C:14]=2[CH3:23])[CH2:8][CH2:7][N:6]1C([O-])=O)(C)C.[ClH:27]>O1CCOCC1>[ClH:27].[CH3:23][C:14]1[C:15]2[CH2:19][O:18][C:17](=[O:20])[C:16]=2[CH:21]=[CH:22][C:13]=1[CH2:12][CH2:11][N:9]1[CH2:10][CH2:5][NH:6][CH2:7][CH2:8]1
Reactant: Cc1c(CCN2CCN(C(=O)[O-])C(C(C)(C)C)C2)ccc2c1COC2=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(CCN2CCNCC2)ccc2c1COC2=O

Procedure:
1,1-Dimethylethyl-4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate (245 mg) was treated with 4N HCl in dioxane solution and the reaction was monitored until completion. The mixture was concentrated to afford 4-methyl-5-(2-piperazin-1-ylethyl)-2-benzofuran-1(3H)-one hydrochloride. The hydrochloride can be converted to free base as needed by partitioning between organic solvent (EtOAc, DCM, or 30% IPA/CHCl3) and saturated Na2CO3 solution.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[C@H:6]([CH3:23])[CH2:7][C@H:8]([NH2:22])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH3:3].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([F:37])[C:34]=1[O:35][CH3:36])[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:2]([O:4][C:5](=[O:24])[C@H:6]([CH3:23])[CH2:7][C@H:8]([NH:22][C:29](=[O:30])[C:28]1[CH:32]=[C:33]([F:37])[C:34]([O:35][CH3:36])=[C:26]([F:25])[CH:27]=1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)[CH3:3]
Reactant: COc1c(F)cc(C(=O)O)cc1F
Reactant: CCOC(=O)[C@H](C)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(F)c(OC)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.9 %

Procedure:
To a solution of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride salt (200 mg, 0.58 mmol) in CH2Cl2 (2 mL) and DMF (2 mL) at rt is added 3,5-difluoro-4-methoxy benzoic acid (108 mg, 0.58 mmol) followed by an addition of TEA (0.32 mL, 2.3 mmol) and HATU (262 mg, 0.69 mmol). The mixture is stirred at r.t. for 4 hours and quenched with saturated NaHCO3 and diluted in ethyl acetate. The organic layer is washed with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained material is purified by preparative silica gel thin-layer chromatography plates (eluent: EtOAc/hepane=3/2) to give 265 mg of (2R,4S)-5-biphenyl-4-yl-4-(3,5-difluoro-4-methoxy-benzoylamino)-2-methyl-pentanoic acid ethyl ester.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=2)O1>>[NH2:39][C:36]1[N:37]=[CH:38][C:33]([C:2]2[N:7]=[C:6]3[S:8][C:9]([NH:11][C:12](=[O:24])[C:13]4[CH:18]=[CH:17][C:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[CH:15][CH:14]=4)=[N:10][C:5]3=[CH:4][CH:3]=2)=[CH:34][CH:35]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(Br)nc3s2)cc1
Product: CC(C)(CO)c1ccc(C(=O)Nc2nc3ccc(-c4ccc(N)nc4)nc3s2)cc1
Yield: 22 %

Procedure:
The titled compound (yield=22%, white solid) was prepared using a procedure analogous to that described in connection with 10 (Example 10) except that 2F (Example 2) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine were used as starting materials. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (s, 6H) 3.17 (s, 2H) 3.49 (s, 1H) 7.03 (d, J=9.35 Hz, 1H) 7.58 (d, J=8.59 Hz, 2H) 7.89 (br. s., 2H) 8.08 (dd, J=11.12, 8.59 Hz, 3H) 8.24 (d, J=8.59 Hz, 1H) 8.62 (dd, J=9.35, 2.27 Hz, 1H) 8.72 (d, J=1.77 Hz, 1H) 13.02 (s, 1H); ESI-MS: m/z 420.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3](CC2C=CC(OC)=CC=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].C(O)(C(F)(F)F)=O.C(S(O)(=O)=O)(F)(F)F.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16]
Reactant: COc1ccc(Cn2cc3c(c2Cl)c(=O)n(C)c(=O)n3CC(C)C)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)[nH]cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-chloro-1-isobutyl-6-(4-methoxybenzyl)-3-methyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (14 mg, 0.032 mmol) in CH2Cl2 (0.5 mL) is added TFA (100 μL) and TFMSA (50 μL). The mixture is stirred at r.t. for 2 h, and then carefully basified with saturated NaHCO3 aqueous solution, followed by extractions with CH2Cl2. The combined organic phase is dried over sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give crude product, which is used in the next step without further purification. MS (ESI) m/z 256.1 [M+H]+.