Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7].Cl[C:24]([O:26][CH3:27])=[O:25]>>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][C:24]([O:26][CH3:27])=[O:25])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CN
Reactant: COC(=O)Cl
Product: COC(=O)NCc1ccccc1-c1ccccc1C(=O)NCCC(C)C

Procedure:
From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid (3-methyl-butyl)amide (precursor 5c) and methyl chloroformate, according to the general working procedure followed by extraction with EA and purification by flash chromatography 29 mg of 2′-(methoxycarbonylaminomethyl)-biphenyl-2-carboxylic acid (3-methylbutyl)amide were obtained as a resin. MS (ES+): m/e=355 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[CH3:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18]>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:17]([CH3:18])[C:16]([CH3:15])=[C:20]([CH3:21])[N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Reactant: CC(=O)C(C)C(C)=O
Solvent: CC(=O)O
Product: Cc1nc2nc(SCc3ccccc3)nn2c(C)c1C
Temperature: 25 °C
Yield: 94.4 %

Procedure:
A solution of 51.6 g (0.250 mol) of 3-amino-5-benzylthio-1,2,4-triazole and 28.5 g (0.250 mol) of 3-methyl-2,4-pentanedione in 350 ml of glacial acetic acid was heated at reflux for 17 hours. Upo cooling to room temperature, the reaction mixture was poured onto ice. The pale yellow solid which separated was collected by filtration, washed with water and dried in vacuo to yield 67.1 g (94%) of the desired product as a pale yellow solid, m.p. 133.5°-135° C. The IR and 1H NMR spectra were consistent with the assigned structure.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[CH2:16]([O:9][C:8](=[O:10])[C:7]1[C:2]([CH3:1])=[CH:3][CH:4]=[N:5][CH:6]=1)[CH3:17]
Reactant: CCO
Reactant: Cc1ccncc1C(=O)O
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cnccc1C

Procedure:
To a flask containing 4-methylnicotinic acid 1.5 hydrochloride (9.6 g, 55.3 mmol), dissolved in dry absolute ethanol (120 mL) was added concentrated sulfuric acid (6 mL) via drop-wise addition. The material was heated to reflux temperature and stirred over night. The flask was cooled to ambient and about 85% of the solvent was removed on the rotovap. Ethyl acetate (40 mL) was added and the material was basified via drop-wise addition of an aqueous saturated sodium bicarbonate solution. Ethyl acetate (40 mL) and water (20 mL) was added and the material was shaken in a separatory funnel. The ethyl acetate phase was collected and washed with brine (60 mL). The aqueous phases were back extracted with ethyl acetate (2×50 mL), the organic phases were combined, dried (MgSO4), filtered and stripped affording ethyl-4-methylnicotinoate as a brown mobile oil. MS (M+H)+=166.
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=[O:10])[NH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:31]1[C:40]2[C:35](=[CH:36][C:37]([CH2:41]O)=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[N:31]1[C:40]2[C:35](=[CH:36][C:37]([CH2:41][N:2]3[C:3](=[O:10])[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:1]3=[O:11])=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: OCc1ccc2ncccc2c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2ncccc2c1
Temperature: 30 °C
Yield: 94.9 %

Procedure:
To a solution of isoindoline-1,3-dione (6.47 g, 44.0 mmol) and triphenylphosphine (11.53 g, 44.0 mmol) in THF (70 mL) at a 0° C., was added a solution of quinolin-6-ylmethanol (7 g, 44.0 mmol) in THF (30 mL) and (E)-diisopropyl diazene-1,2-dicarboxylate (8.89 g, 44.0 mmol) dropwise over a period of 30 min. The mixture was then heated to 30° C. for 20 h. The reaction was cooled to rt and concentrated in vacuo. The resulting residue was purified by Analogix silica gel with gradient hexanes:EtOAc to provide 2-(quinolin-6-ylmethyl)isoindoline-1,3-dione (12.04 g) in 95% yield. LCMS (method A): [MH]+=2.99, tR=4.89 min.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:8])[O:4][C:5](=[O:7])[CH:6]=1.[N+:9]([C:12]1[S:16][CH:15]=[C:14]([CH:17]=O)[CH:13]=1)([O-:11])=[O:10].[O:19]1[CH2:24][C:23](=O)[CH2:22][C:21](=[O:26])[CH2:20]1>C(O)C>[CH3:8][N:3]1[C:2]2[NH:1][C:23]3[CH2:24][O:19][CH2:20][C:21](=[O:26])[C:22]=3[CH:17]([C:14]3[CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[S:16][CH:15]=3)[C:6]=2[C:5](=[O:7])[O:4]1
Reactant: O=Cc1csc([N+](=O)[O-])c1
Reactant: O=C1COCC(=O)C1
Reactant: Cn1oc(=O)cc1N
Solvent: CCO
Product: Cn1oc(=O)c2c1NC1=C(C(=O)COC1)C2c1csc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
The product from Example 45A (0.086 g, 0.75 mmol), 5-nitro-3-thiophenecarbaldehyde (0.12 g, 0.75 mmol) and 2H-pyran-3,5(4H,6H)-dione (0.085 g, 0.75 mmol) in ethyl alcohol (2 mL) were heated at 80° C. for 2 days in a sealed tube. The reaction mixture was allowed to cool to ambient temperature and was evaporated under reduced pressure. The residue was crystallized from methylene chloride/ethanol to provide the title product. 1H NMR (300 MHz, DMSO-d,) δ 3.23 (s, 3H), 4.1 (q, 2H), 4.53 (s, 2H), 4.88 (s, 1H), 7.7 (d, 1H), 7.92 (d, 1H), 10.8 (s, 1H); MS (ESI) m/z 348 (M−H)−, Anal. Calcd for C14H11N3O6S: C, 48.13; H, 3.15; N, 12.03. Found: C, 47.76; H, 3.25; N, 11.78.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([CH3:11])[N:10]=1)[C:6]#[N:7].Cl.[NH2:13][OH:14]>CO>[OH:14][NH:13][C:6](=[NH:7])[C:5]1[CH:8]=[C:9]([CH3:11])[N:10]=[C:3]([CH2:2][OH:1])[CH:4]=1
Reactant: NO
Reactant: Cc1cc(C#N)cc(CO)n1
Agent: Cl
Solvent: CO
Product: Cc1cc(C(=N)NO)cc(CO)n1
Temperature: 25 °C
Yield: 54.5 %

Procedure:
To a solution of crude 2-hydroxymethyl-6-methyl-isonicotinonitrile (544 mg, 2.38 mmol) in methanol (50 mL), potassium tert.-butylate (933 mg, 8.31 mmol) and hydroxylamine hydrochloride (495 mg, 7.13 mmol) is added. The solution is refluxed for 2 h. The resulting suspension is cooled to rt and filtered. The solvent filtrate is evaporated and the remaining residue is suspended in water, filtered off, washed with additional water and dried under HV to give N-hydroxy-2-hydroxymethyl-6-methyl-isonicotinamidine (235 mg) as a beige powder; LC-MS: tR=0.17 min, [M+1]+=182.01; 1H NMR (D6-DMSO): δ 2.45 (s, 3H), 4.52 (d, J=5.8 Hz, 2H), 5.37 (t, J=5.8 Hz, 1H), 5.90 (s, 2H), 7.36 (s, 1H), 7.56 (s, 1H), 9.92 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].N#N.[O-:11][CH2:12]C.[Na+].C(OCC)=O.Cl>C(O)C.O>[O:11]=[CH:12][CH:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:7]#[N:8]
Reactant: CC[O-]
Reactant: N#CCc1cccs1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCO
Solvent: O
Product: N#CC(C=O)c1cccs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Thiophen-2-yl-acetonitrile [20893-30-5] (6.7 mL, 62.6 mmol) was added to a N2 blanketed, 0° C., stirred solution of 21 wt % sodium ethoxide (25.7 mL, 68.9 mmol) in ethanol (100 mL). After 5 minutes, ethyl formate [109-94-4] (12.6 mL, 156.7 mmol) was added and the resultant solution was stirred for 20 minutes. The ice bath was then removed and replaced with a heating mantle. The reaction was heated to reflux for 2 h, cooled, and evaporated to provide a yellow solid. Crude product was dissolved in water, the solution chilled to 0° C. and acidified with aqueous hydrochloric acid to precipitate an off white powder. Product was isolated by filtration, washed with water, and dried to afford 7.4 g. LRMS (ESI) m/z 152.0 [(M+H)]+, calc'd for C7H6NOS: 151.19
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[N:14]=[N:15][N:16]([CH3:18])[CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:18][N:16]1[CH:17]=[C:13]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][OH:1])=[CH:4][CH:5]=2)[N:14]=[N:15]1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: Cn1cc(Br)nn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2ccc(CO)cc2)nn1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
A mixture of [4-(hydroxymethyl)phenyl]boronic acid (7.10 g), 4-bromo-1-methyl-1H-1,2-3-triazole (5.00 g), sodium carbonate (6.59 g) and tetrakis(triphenylphosphine)palladium(0) (3.59 g) in a mixed solvent of water (30.0 mL)-1,4-dioxane (100 mL) was heated with reflux for 16 hr under nitrogen atmosphere. The reaction mixture was allowed to be cooled to room temperature, the organic layer was concentrated under reduced pressure, and the residue was extracted with dichloromethane (×3). The combined extracts were dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (3.40 g).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:2]1.Cl[C:33]([C:35]([O:38][C:39](=[O:41])[CH3:40])([CH3:37])[CH3:36])=[O:34].CCN(CC)CC>C1COCC1>[CH3:36][C:35]([O:38][C:39](=[O:41])[CH3:40])([CH3:37])[C:33]([N:1]1[CH2:2][CH:3]([CH2:5][C:6]2[N:7]([CH3:31])[C:8]3[C:13]([N:14]=2)=[C:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:11]=[C:10]([N:21]2[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=[C:22]2[CH3:30])[N:9]=3)[CH2:4]1)=[O:34]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CNC3)n(C)c2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)OC(C)(C)C(=O)N1CC(Cc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.8 %

Procedure:
A mixture of 8-azetidin-3-ylmethyl-2-(2-methylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (131 mg, 0.31 mmol), acetic acid 1-chlorocarbonyl-1-methylethyl ester (45 μL, 0.31 mmol) and NEt3 (40 μL, 0.31 mmol) in THF (3 mL) was allowed to stir at r.t. for 16 h then concentrated in vacuo. The resulting residue was partitioned between DCM and H2O, the organic phase dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording the title compound as a white solid (125 mg, 73%). LCMS (method H): RT 2.50 min [M+H]+ 547.5
Reaction SMILES: C([O:3][C:4](=[O:21])/[CH:5]=[CH:6]/[CH:7]=[C:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.[OH-].[K+]>CO>[C:9]1([C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:21])=[O:3])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)/C=C/C=C(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/C=C(c1ccccc1)c1ccccc1
Yield: 86.7 %

Procedure:
A solution of (E)-5,5-diphenyl-2,4-pentadieneoic acid ethyl ester (15 g) in methanol (80 mL) was treated with a 4N Potassium hydroxide solution (20 mL) and the mixture was stirred at reflux for 45 minutes. Most of the methanol was removed under reduced pressure, then the residual solution was poured over ice containing 3N hydrochloric acid (30 mL). The resulting solid was collected by filtration washed with water and dried. Crystallization of the crude material from 2-propanol furnished 11.7 g of (E)-5,5-diphenyl-2,4-pentadienoic acid mp 193°-194° C. Recrystallization from the same solvent did not affect the melting Point. Anal. Calculated for C17H14O2 : C, 81.57: H, 5.63 Found: C, 81.43; H. 5.81.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1)[CH3:2].[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24]([Cl:26])=[O:25]>C1C=CC=CC=1>[ClH:26].[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:24]([C:20]3[O:19][CH:23]=[CH:22][CH:21]=3)=[O:25])[CH2:15][CH2:14]2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(CCCN2CCNCC2)cc1
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccccc1
Product: CCOc1ccc(CCCN2CCN(C(=O)c3ccco3)CC2)cc1
Product: Cl

Procedure:
The compound was obtained by following the same process as in Example 2 from a mixture of 1-[3-(p-ethoxyphenyl)propyl]piperazine [b.p. 162° - 165°C (4 mmHg), dihydrochloride, m.p. 232° - 239°C], 2-furoyl chloride and benzene.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[Cl:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14](Cl)[C:13]([CH3:20])=[C:12]([CH3:21])[N:11]=1>>[Cl:9][C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[C:14]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[C:13]([CH3:20])=[C:12]([CH3:21])[N:11]=1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Reactant: NCCCCCCO
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCCCO)c1C
Yield: 36.1 %

Procedure:
Using the general method of Example 89 Part A, 6-aminohexan-1-ol (15.91 g, 135.7 mmol) was reacted with 2,4-dichloro-5,6-dimethyl-3-nitropyridine (30 g, 136 mmol) to provide 14.79 g of 6-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]hexan-1-ol as a yellow solid.
Reaction SMILES: [O:1]=[C:2]1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[NH2:39][CH2:40][CH2:41][N:42]1[CH2:46][CH2:45][NH:44][C:43]1=[O:47].OS([O-])(=O)=O.[Na+].[CH3:54][CH2:55][OH:56]>>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C:21]2[CH:22]=[C:23]3[C:18]([C:17]([OH:32])=[C:16]([C:15]([NH:14][CH2:13][CH2:12][N:3]4[CH2:21][CH2:20][NH:19][C:2]4=[O:1])=[O:38])[C:33](=[O:34])[N:3]3[CH2:12][CH2:13][NH:14][C:55]([C:54]3[C:16]([C:33]([NH:39][CH2:40][CH2:41][N:42]4[CH2:46][CH2:45][NH:44][C:43]4=[O:47])=[O:34])=[CH:17][CH:18]=[CH:23][CH:22]=3)=[O:56])=[N:19][CH:20]=2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Reactant: CCO
Reactant: NCCN1CCNC1=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: O=C(NCCN1CCNC1=O)c1ccccc1C(=O)NCCn1c(=O)c(C(=O)NCCN2CCNC2=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 1-(2-aminoethyl)-2-imidazolidinone (0.0078 g, 0.03 mmol, 50% W/W in IPA) for 30 min.@150° C. The reaction was further microwaved for 30 min. (150° C. after the addition of an additional 0.6 equivalents (0.015 mL) of the amine, cooled to ambient temperature, and treated with 1N NaHSO4. The resulting suspension was filtered and the filtrate was concentrated in vacuo. The filtrate residue was purified by reversed phase HPLC. Pure fractions were combined and concentrated to afford the title compound as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 3.16-3.22 (m, 6 H), 3.26-3.38 (m, 11 H), 3.49 (dq, J=12.61, 6.42 Hz, 3 H), 4.11 (s, 3 H), 4.38 (t, J=6.41 Hz, 2 H), 6.29 (s, 1 H), 6.37 (s, 1 H), 7.09 (t, J=8.88 Hz, 1 H), 7.28-7.39 (m, 2 H), 7.41 -7.47 (m, 2 H), 8.32 (s, 1 H), 8.35-8.40 (m, 1 H), 8.43-8.47 (m, 1 H), 8.51 (s, 1 H), 10.37 (s, 1 H); ES+ MS: 728 (M+H+).
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][CH:32]=O)[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:18]([O:22][C:23](=[O:34])[NH:24][C@H:25]1[CH2:26][CH2:27][C@H:28]([CH2:31][CH2:32][N:6]2[CH2:5][CH2:4][N:3]([C:9]3[C:13]4[CH:14]=[N:15][CH:16]=[CH:17][C:12]=4[O:11][N:10]=3)[CH2:8][CH2:7]2)[CH2:29][CH2:30]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: c1cc2onc(N3CCNCC3)c2cn1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCN(c3noc4ccncc34)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution in CH2Cl2 (10 ml) of 3-piperazin-1-yl-isoxazolo[4,5-c]pyridine dihydrochloride (840 mg, 3.0 mmol) and trans-[4-(2-oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (904 mg, 3.7 mmol; intermediate H; prepared according to WO2007/093540) was treated with Et3N (629 mg, 6.2 mmol) before addition of Na(AcO)3BH (1.03 g, 5 mmol). The reaction mixture was stirred 16 h at r.t., then sat. aq. NaHCO3 was added and the product was extracted with 2 portions of CH2Cl2. After drying (MgSO4) and evaporation of the solvent the product was purified by flash chromatography (50 g SiO2, EtOAc/MeOH 100:0→80:20) to obtain 930 mg (71%) of the title compound as an off white solid. m/z=430.3 ([M+H]+).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[CH3:3].C(N(CC)CC)C.Cl.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][CH:32]=1>CN(C)C(=O)C.C1COCC1>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[C:6](=[O:15])[N:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:4]([C@@H:2]([NH:1][C:30](=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[N:33][CH:32]=1)[CH3:3])=[CH:13]2
Reactant: O=C(Cl)c1cccnc1
Reactant: C[C@H](N)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: C[C@H](NC(=O)c1cccnc1)c1cc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of (S)-3-(1-aminoethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one (1) (50 mg, 0.17 mmol) in a mixture of N,N-dimethylacetamide (1 mL) and THF (3 mL), triethylamine (0.07 mL, 0.50 mmol) and nicotinoyl chloride hydrochloride (32 mg, 0.18 mmol) were added and the resulting mixture was stirred at RT for 30 min. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo and purified by ISCO column chromatography (silica gel cartridge, 0-10% MeOH-DCM) to afford the product, (S)-N-(1-(8-chloro-1-oxo-2-phenyl-1,2-dihydroisoquinolin-3-yl)ethyl)nicotinamide (compound 51). ESI-MS m/z: 404.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([OH:11])[C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1.C(N(C(C)C)C(C)C)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[CH:4]([O:11][S:23]([CH3:22])(=[O:25])=[O:24])[C:5]1[S:6][C:7]([CH3:10])=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)C(O)c1ccc(C)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(OS(C)(=O)=O)c1ccc(C)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
To a solution of hydroxy-(5-methyl-thiophen-2-yl)-acetic acid methyl ester (I265) (1.84 g, 9.89 mmol) in dry DCM, cooled at 0° C. under nitrogen atmosphere, N-ethyl-N-isopropylpropan-2-amine (2.54 mL, 14.8 mmol) and methanesulfonyl chloride (1.16 mL, 14.8 mmol) are added and the reaction is stirred at RT for 2 hours. DCM is added and the organic phase is washed with aq. NaHCO3, water and brine, dried over Na2SO4 and evaporated to obtain intermediate I268 as a dark brown oil (2.1 g, 80% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10]2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:29])[C:25]([O:27]C)=[O:26])[C:4]=12.C([O-])([O-])=O.[K+].[K+]>O.CO>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([N:9]2[CH:13]=[N:12][C:11]([NH:14][C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])=[N:10]2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:29])[C:25]([OH:27])=[O:26])[C:4]=12
Reactant: COC(=O)C(=O)c1c[nH]c2c(-n3cnc(NC(=O)C(C)(C)C)n3)ncc(OC)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cnc(-n2cnc(NC(=O)C(C)(C)C)n2)c2[nH]cc(C(=O)C(=O)O)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a mixture of methyl 2-(4-methoxy-7-(3-pivalamido-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetate (40 mg, 0.100 mmol) in water (1 mL) and MeOH (1 mL) was added K2CO3 (83 mg, 0.599 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. MeOH was removed under reduced pressure. The water layer was acidified to PH=5-6 using 1N HCl and concentrated under reduced pressure. The resulting residue was washed with water, filtered and dried to give 2-(4-methoxy-7-(3-pivalamido-1H-1,2,4-triazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-oxoacetic acid (30 mg, 78%) as white solid. LCMS: m/e 387.18 (M+H)+, ret time 2.46 min (method 4).
Reaction SMILES: NC1C=C(C=CC=1)O[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:14])=O)[CH:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([F:26])[CH:20]=1.ClC1C=CN=C(C#N)C=1>>[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([C:12]#[N:14])[CH:7]=2)=[C:21]([F:26])[CH:20]=1
Reactant: NC(=O)c1cc(Oc2cccc(N)c2)ccn1
Reactant: Nc1ccc(O)c(F)c1
Agent: N#Cc1cc(Cl)ccn1
Product: N#Cc1cc(Oc2ccc(N)cc2F)ccn1

Procedure:
4-(4-Amino-2-fluorophenoxy) pyridine-2-carbonitrile (2H) was prepared by a method analogous to that described for 4-(3-aminophenoxy) pyridine-2-carboxamide (2C), starting from 4-amino-2-fluorophenol and 4-chloro-2-cyanopyridine, MS ES: 230 (M+H)+, calcd 230, RT=2.18 min.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH:43]([N:46]([CH:50]([CH3:52])[CH3:51])[CH2:47][CH2:48][NH2:49])([CH3:45])[CH3:44]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:49][CH2:48][CH2:47][N:46]([CH:50]([CH3:52])[CH3:51])[CH:43]([CH3:45])[CH3:44])=[O:41]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: CC(C)N(CCN)C(C)C
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(Oc3ccc(NC(=O)NCCN(C(C)C)C(C)C)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (134 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diisopropyl-1,2-ethanediamine (65 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (64 mg, yield 43%).