Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:36]=[C:35]([O:37][CH3:38])[C:19]3[N:20]([CH3:34])[C:21]([C:23]4[N:31]([CH2:32][CH3:33])[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:36]=[C:35]([O:37][CH3:38])[C:19]3[N:20]([CH3:34])[C:21]([C:23]4[N:31]([CH2:32][CH3:33])[C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)cc(OC)c3n2C)cc2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](N)C4)cc(OC)c3n2C)cc2cccnc21
Reaction time: 0.5 h

Procedure:
To a solution of (R)-tert-butyl(1-(2-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-7-methoxy-1-methyl-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate (4.4 g, 8.26 mmol) in dichloromethane (DCM) (20 ml) was added TFA (9 ml, 118 mmol) dropwise. The reaction mixture was stirred for 1 hour 30 minutes. LC/MS showed that that desired product had formed with no starting material remaining. The reaction mixture was concentrated under vacuum to afford an oil. The oil was dissolved in methanol and split into two equal batches and passed through two separate 70 g SCX cartridges. The columns were washed with MeOH (2CV) and the product collected from both columns as the free base with 2M ammonia in methanol (3CV). The product was concentrated under vacuo and dried under vacuum to afford the title compound as a white solid (3.46 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[NH:12][CH2:11][CH2:10]2.[H-].[Na+].[CH2:23]([O:25][C:26](=[O:30])[CH:27](Br)[CH3:28])[CH3:24].O>CN(C=O)C>[CH2:23]([O:25][C:26](=[O:30])[CH:27]([N:12]1[CH2:11][CH2:10][C:9]2[C:14](=[CH:15][CH:16]=[C:7]([O:6][CH2:5][C:4]3[CH:18]=[CH:19][CH:20]=[C:2]([F:1])[CH:3]=3)[CH:8]=2)[C:13]1=[O:17])[CH3:28])[CH3:24]
Reactant: O=C1NCCc2cc(OCc3cccc(F)c3)ccc21
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)N1CCc2cc(OCc3cccc(F)c3)ccc2C1=O
Temperature: 70 °C
Yield: 69.3 %

Procedure:
A mixture of 6-(3-fluoro-benzyloxy)-3,4-dihydro-2H-isoquinolin-1-one (0.100 g, 0.369 mmol) and sodium hydride (55%, 22 mg, 0.51 mmol) in N,N′-dimethylformamide was heated at 70° C. for 1 h. Then ethyl-2-bromopropionate (0.072 mL, 0.55 mmol) was added and the resulting mixture was heated at 80° C. overnight. After cooling to room temperature, water was added and the reaction was extracted with dichloromethane. After drying of the organic layer with MgSO4, filtration and evaporation, the residue was purified by chromatography (SiO2, hexane/ethyl acetate 1:0 to 3:2 v:v gradient) to give the title compound as a white solid (0.095 g, 69%). MS: m/e=372.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24](F)=[CH:23][N:22]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8].[CH3:28][S:29](C)=O.C[S-].[Na+]>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:29][CH3:28])=[CH:23][N:22]=2)=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1)c1ccc(F)cn1
Reactant: CS(C)=O
Agent: C[S-]
Agent: [Na+]
Solvent: O
Product: CSc1ccc(C(=O)Nc2ccc(F)cc2C(=O)Nc2ccc(Cl)cn2)nc1
Temperature: 50 °C
Yield: 86 %

Procedure:
A mixture of 5-fluoro-2-[(5-fluoropyridin-2-yl)-carbonylamino]-N-(5-chloropyridin-2-yl)benzamide (502 mg, 1.29 mmol), DMSO (4 mL) and sodium thiomethoxide (95 mg, 1.36 mmoL) was heated to 50° C. for 18 h. The reaction was cooled, added water, filtered, and dried. The solid was triturated with CH2Cl2 and filtered to give the title compound as a white solid (461 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][N+:13]([O-])=[CH:14][CH:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.CC(C)([O-])C.[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: [O-][N+]1=CC2CN=C(c3ccccc3F)c3cc(Cl)ccc3N2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: Fc1ccccc1C1=NCc2cncn2-c2ccc(Cl)cc21

Procedure:
A solution of 50 mg of 8-chloro-6-(2-fluorophenyl)-3a,4-dihydro-1H-imidazo[1,5-a][1,4]benzodiazepine 2-oxide in 3 ml of methanol containing 25 mg of potassium t-butoxide was heated to reflux for 10 min. The mixture was evaporated partially and the residue was partitioned between methylene chloride and sodium bicarbonate solution. The organic phase was dried and evaporated. Crystallization of the residue from ether yielded product with mp 148°-151° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2=[CH:7][C:8]3[CH:22]=[N:21][CH:20]=[N:19][C:9]=3[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=O)[C:11]=3[N:5]2[CH2:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:36][C:37]([CH:39]1[CH2:41][CH2:40]1)=[NH:38].C(O)(=O)C>CN(C=O)C>[CH:39]1([C:37]2[N:38]=[C:16]([C:12]3[C:11]4[N:5]5[CH2:4][N:3]=[C:2]([CH3:1])[C:6]5=[CH:7][C:8]5[CH:22]=[N:21][CH:20]=[N:19][C:9]=5[C:10]=4[CH:15]=[CH:14][CH:13]=3)[O:18][N:36]=2)[CH2:41][CH2:40]1
Reactant: CC1=NCN2C1=Cc1cncnc1-c1cccc(C(=O)O)c12
Reactant: N=C(NO)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC1=NCN2C1=Cc1cncnc1-c1cccc(-c3nc(C4CC4)no3)c12
Temperature: 85 °C
Yield: 59 %

Procedure:
To a suspension of 6-methyl-9H-imidazo[1,5-a]pyrimido[5,4-d][1]benzazepine-10-carboxylic acid (1.0 g, 3.4 mmol) in DMF (15 mL) was added 1,1′-carbonyldiimidazole (0.61 g, 3.76 mmol) followed by N-hydroxy-cyclopropanecarboxamidine and the resulting solution was heated at 85° C. for 1.5 h. Then acetic acid (3.4 mL) was added and the resulting mixture heated at 130° C. for 40 min. After cooling, the mixture was evaporated and dissolved n DCM (15 mL). This DCM extract was washed with sodium hydrogen carbonate (saturated solution, 40 mL) and then the aqueous phase was washed with DCM (20 mL). The combined DCM layers were then dried over MgSO4 and evaporated. The residue was recrystallized from ethyl acetate: hexane to afford the product (720 mg, 59%) as white crystals, mp 216-218° C., m/z 356 (M).
Reaction SMILES: CCN(C(C)C)C(C)C.[Li]CCCC.[Cl:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].CN([CH:31]=[O:32])C>C1COCC1>[Cl:15][C:16]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:23]([F:27])[C:24]([CH:31]=[O:32])=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1c(F)cccc1Cl
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1c(Cl)ccc(C=O)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution DIPEA (6.6 mL, 46.0 mmol) in THF (15 mL) was added nBuLi (27 mL, 43.0 mmol, 1.6 M in hexane) at −78° C. and the reaction mixture was warmed to 0° C. over a period of 1 h. Then the reaction mixture was cooled to −78° C. and a solution of ethyl 2-chloro-6-fluorobenzoate (3.50 g, 19.0 mmol) in THF (56 mL) was added to the reaction mixture dropwise over 30 mins. The resulting mixture was stirred at −78° C. for 2 h before DMF (14 mL, 186 mmol) was added to the reaction mixture. The resulting mixture was stirred at −78° C. for 1 h and then gradually warmed to 0° C. over 1 h. The reaction mass was quenched with 10% aq. AcOH and was extracted with EtOAc. The organic layer was washed with water and brine, separated, dried, filtered and concentrated to provide ethyl 6-chloro-2-fluoro-3-formylbenzoate. 1H NMR (300 MHz, DMSO-d6): δ 10.27 (s, 1H), 8.05-8.00 (t, J=7.8 Hz, 1H), 7.72-7.69 (d, J=8.4 Hz, 1H), 4.53-4.46 (q, J=6.9, 14.4 Hz, 2H), 1.41-1.37 (t, J=6.6 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-formylbenzoate (4.04 g, 17.52 mmol) and hydroxylamine (50% aq, solution, 4.29 mL, 70 mmol) in MeOH (60 mL) was stirred at 55° C. for 1.5 h. Then the mixture was concentrated and the residue was diluted with EtOAc and was washed with water and brine. The organic layer was separated, dried, filtered and concentrated to provide ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate. 1H NMR (300 MHz, DMSO-d6): δ 11.89 (s, 1H), 8.20 (s, 1H), 7.88-7.83 (t, J=8.1 Hz, 1H), 7.49-7.46 (d, J=8.4 Hz, 1H), 4.44-4.37 (q, J=7.5, 14.1 Hz, 2H), 1.34-1.29 (t, J=7.2 Hz, 3H). A mixture of ethyl 6-chloro-2-fluoro-3-((hydroxyimino)methyl)benzoate (4.21 g, 17.14 mmol), Zn (4.48 g, 68.56 mmol), and 10N HCl in EtOH (51.42 mL, 514.2 mmol) in MeOH (200 mL) was heated at reflux for 3 h. Additional Zn (2.24 g, 34.25 mmol) was added to the reaction mixture and it was heated at reflux for 2 h and then stirred at rt for 16 h. Then the reaction mixture was concentrated. The residue was diluted with EtOAc and was treated with a saturated solution of NaHCO3. The mixture was filtered and the organic layer was separated, dried, filtered and concentrated to provide 3.5 g of the title product. 1H NMR (300 MHz, CDCl3): δ 7.54 (t, J=7.8 Hz, 1H), 7.28 (d, J=7.8 Hz, 1H), 4.45 (q, J=7.5, 14.1 Hz, 2H), 4.11 (d, J=3.6 Hz, 2H), 3.37 (br s, 2H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]2[OH:14])[N:4]=[C:3]([C:15]([NH2:17])=[O:16])[N:2]=1.O.P(Cl)(Cl)(Cl)=O.[P:24](OC)([O:28]C)([O:26]C)=[O:25]>>[CH:1]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11][O:12][P:24]([OH:28])([OH:26])=[O:25])[C@@H:8]([OH:13])[C@H:7]2[OH:14])[N:4]=[C:3]([C:15]([NH2:17])=[O:16])[N:2]=1
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Reactant: COP(=O)(OC)OC
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: NC(=O)c1ncn([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The manufacture and synthesis Ribavirin (ICN Pharmaceuticals, Costa Mesa Calif.) are described in U.S. Pat. No. 4,211,771, incorporated herein by reference. A dry 1 L ml 3-neck round bottom flask, equipped with a stir bar, gas inlet adapter, and thermometer, was charged with 50 g Ribavirin (0.204 moles), 500 ml trimethyl phosphate, and 0.367 ml de-ionized water (0.0204 moles). The mixture was cooled under nitrogen with an ice/water bath. When the temperature reached 10° C., 23.3 ml phosphorous oxychloride was added, the flask was removed from the ice bath, and the mixture was stirred under nitrogen. After 30 min., the flask was cooled in the ice/water bath. When the temperature reached 10° C., the mixture was poured into a 2 L beaker containing 1000 ml ice water. The pH was adjusted to pH=9.0 using 4 M LiOH and the mixture was stirred overnight. After final adjustment to pH 9, the white precipitate that has formed is filtered away using a 0.2 mm filter. The mixture was evaporated at 40° C. under reduced pressure to 1 L. The solution was added to 1 L hot ethanol dropwise. The white precipitate was collected on a 2 L glass fritted funnel, coarse grade, washing the solid with two 100 ml portions of ethanol, re-suspending the solid each time. The product was dried under vacuum overnight, yield: 89 g. The solid was dissolved in 200 ml de-ionized water, and 5 g activated carbon was added. The mixture was filtered through a 0.2 mm filter, washing the carbon with 50 ml de-ionized water. The filtered solution was added dropwise to 1200 ml hot ethanol The mixture was cooled to room temperature, and the precipitate was collected on the 2 L glass fritted funnel. The solid was washed with 2×100 ml ethanol in the funnel, and dried under vacuum. Yield: 66.6 g. The dried product was dissolved in 200 ml de-ionized water. Amberlite IR-120 H.C.P. resin (H+ form) was added until the pH of the mixture reached pH=2.18. The resin was filtered off using a 0.2 mm filter, and the final solution was lyophilized. Yield: 54.8 g (0.160 moles), 78.5%, Ribavirin 5'-monophosphate. Elemental analysis indicates the product contains 1 mole water/mol ribavirin 5'-monophosphate.
Reaction SMILES: [CH:1]1([NH:6][C:7](=[O:35])[C@H:8]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[N:21](C(OC(C)(C)C)=O)[CH:22]=[C:23]([C:24]([O:26]C)=[O:25])[C:16]=23)[C:9]([OH:12])([CH3:11])[CH3:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([NH:6][C:7](=[O:35])[C@H:8]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[NH:21][CH:22]=[C:23]([C:24]([OH:26])=[O:25])[C:16]=23)[C:9]([OH:12])([CH3:11])[CH3:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cn(C(=O)OC(C)(C)C)c2nccc(CN[C@@H](C(=O)NC3CCCC3)C(C)(C)O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(O)[C@@H](NCc1ccnc2[nH]cc(C(=O)O)c12)C(=O)NC1CCCC1
Temperature: 53 °C
Reaction time: 16 h

Procedure:
To (R)-1-tert-butyl 3-methyl 4-((1-(cyclopentylamino)-3-hydroxy-3-methyl-1-oxobutan-2-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-1,3-dicarboxylate was added MeOH (1 mL) and aqueous NaOH (12N, 2mL). The reaction mixture was stirred at 53° C. for 16 h and the resulting product was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-90%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound. [M+H] calc'd for C19H26N4O4, 375; found, 374.5.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12]([C:14]([NH:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][C:21]([C:26]([OH:28])=O)=[CH:20]4)=[O:15])=[CH:11][C:10]=2[CH:29]=1)=[O:4].[CH2:30]([NH2:33])[CH2:31][NH2:32]>>[NH2:32][CH2:31][CH2:30][NH:33][C:26]([C:21]1[NH:22][C:23]2[C:19]([CH:20]=1)=[CH:18][C:17]([NH:16][C:14]([C:12]1[O:13][C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][NH2:1])=[CH:29][C:10]=3[CH:11]=1)=[O:15])=[CH:25][CH:24]=2)=[O:28]
Reactant: NCC(=O)Nc1ccc2oc(C(=O)Nc3ccc4[nH]c(C(=O)O)cc4c3)cc2c1
Reactant: NCCN
Product: NCCNC(=O)c1cc2cc(NC(=O)c3cc4cc(NC(=O)CN)ccc4o3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 340 mg (0.05 mmol) 131 resin 8 mL 1,2-ethylenediamine was added. The resin was agitated for 1 hr at ambient temperature then it was filtered off, washed twice with DMF. The filtrates were pooled and were evaporated to dryness. The remaining oily residue was dissolved in DMF and evaporated again in order to get rid of the amine traces. The crude material was dissolved in 5 mL aqueous 0.1% TFA solution and was purified on a preparative reverse phase HPLC column using acetonitrile gradient. The fractions containing the pure product were pooled, evaporated to dryness dissolved in 3 mL methanol and treated with 1 mL 4.0M HCl in dioxane. 133 was precipitated with ether as bis-HCl salt, filtered off and dried to yield 44.8 mg (88%). MS: 435.19 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][C:19]=3[N:18]=[CH:17][N:16]=2)[CH2:10]1)(C)(C)C.Cl.O1CCOCC1>CO>[N:18]1[C:19]2[NH:20][C:21]3[C:26]([C:27]=2[C:15]([N:11]2[CH2:12][CH2:13][O:14][CH:9]([CH2:8][NH2:7])[CH2:10]2)=[N:16][CH:17]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ncnc3[nH]c4ccccc4c23)CCO1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCC1CN(c2ncnc3[nH]c4ccccc4c23)CCO1
Yield: 4.6 %

Procedure:
A solution of [4-(9H-pyrimido[4,5-b]indol-4-yl)-morpholin-2-ylmethyl]-carbamic acid tert-butyl ester (0.021 g, 0.548 mmol) and 4M HCl-dioxane (1 mL) in methanol (5 mL) was stirred at room temperature for 2.5 hours. The solution was evaporated to dryness and purified by Ion exchange on SCX-II acidic resin (2 g) eluting with methanol, then 2 M ammonia-methanol. The basic fractions were combined. Preparative silica TLC, eluting with 1% ammonia—9% methanol—90% dichloromethane, gave the title compound (0.007 g, 0.025 mmol, 46%) as a beige powder. 1H NMR (500 MHz, CD3OD) δ 2.75-2.80 (2H, m), 3.00-3.06 (1H, m), 3.35-3.40 (1H, m), 3.75-3.85 (1H, m), 3.90 (1H, dd, J=10.10 Hz), 4.10-4.13 (1H, m), 4.19 (1H, d, J=13 Hz), 4.25 (1H, d, J=13 Hz), 7.35 (1H, dd, J=8.8 Hz), 7.47 (1H, dd, J=8.8 Hz), 7.57 (1H, d, J=8 Hz), 7.79 (1H, d, J=8 Hz), 8.46 (1H, s); LC-MS (3) Rt 1.98 min; m/z (ESI) 284 [MH+].
Reaction SMILES: CC(C)([O-])C.[K+].ClC1C=CC(O[CH2:13][C:14]#[N:15])=CC=1.[CH:18]([O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][N:23]=1)([CH3:20])[CH3:19].Cl>CN(C)C=O>[NH2:28][C:25]1[C:24]([CH2:13][C:14]#[N:15])=[N:23][C:22]([O:21][CH:18]([CH3:20])[CH3:19])=[CH:27][CH:26]=1
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cn1
Reactant: N#CCOc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(N)c(CC#N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 59 %

Procedure:
To a stirred solution of potassium-t-butoxide (12.34 g, 110 mmol) in dry dimethylformamide (DMF) (30 mL) cooled at -10° C. under a nitrogen atmosphere was added dropwise a solution of (4-chlorophenoxy)acetonitrile (9.22 g, 55 mmol) and 2-isopropoxy-5-nitro pyridine (prepared according to the methodology of Friedman, et al., J. Am. Chem. Soc. 69, 1204 (1947)) (9.11 g, 50 mmol) in DMF (30 mL). The resulting purple solution was maintained at 0° to 10° C. for 1 hour. Aqueous hydrochloric acid was added (80 mL, 5% HCl) and the resulting mixture was allowed to warm to room temperature. The mixture was extracted twice with methylene chloride. The combined extracts were dried (MgSO4) and concentrated in vacuo to leave an oil which was passed through a thick pad of silica gel, eluting with 1:1 methylene chloride/hexane. The filtrate was evaporated under reduced pressure and the residual oil containing the desired (6-isopropoxy-3-nitro-2-pyridyl) acetonitrile) was dissolved in a 6:1 mixture of ethanol and acetic acid (10 mL) to which was added 5% palladium/carbon (0.8 g). The mixture was hydrogenated on a Parr shaker at 3 atmospheres pressure for 5 hours. The catalyst was removed by filtration of the mixture through diatomaceous earth (Celite (trademark)) and The filtrate was concentrated in vacuo. The residual oil was taken up in water and the pH was adjusted to 10 by addition of sodium carbonate. The mixture was extracted twice with methylene chloride and the combined extracts were dried (MgSO4) and concentrated. The residue was subjected to flash chromatography on silica gel eluting successively with 1:2 ether/hexane, 1:1 ether/hexane and ethyl acetate. Fractions containing the product eluted with ethyl acetate were combined and evaporated to provide (3-amino-6-isopropoxy-2-pyridyl)acetonitrile as an off-white solid (5.60 g, 59%); m.p. 83°-85° C.
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].CN([CH:12]=[CH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=1)=O)C>C(O)C>[NH2:7][C:6]1[N:8]=[C:14]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:20][CH:21]=2)[CH:13]=[CH:12][N:5]=1
Reactant: N=C(N)N
Reactant: CN(C)C=CC(=O)c1ccc(C(C)(C)C)cc1
Agent: O=C(O)O
Solvent: CCO
Product: CC(C)(C)c1ccc(-c2ccnc(N)n2)cc1
Reaction time: 8 h

Procedure:
Sodium metal (10.4 g) was added to absolute ethanol (40 ml). When all the sodium had dissolved, the sodium ethoxide solution so formed was added to a mixture of guanidine carbonate (1.56 g) and (1-(N,N-dimethylamino)-3-(4-(1,1-dimethylethyl) phenyl)prop-1-en-3-one (2.5 g) dissolved in absolute ethanol (40 ml) and the mixture heated under reflux with stirring overnight. The reaction was followed by tlc. On cooling the solid material formed was filtered and washed with water to remove Na2CO3 to give a white crystalline solid, m.p. 186° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[NH:10][C:9](=O)[CH:8]3[CH2:13][CH2:14][CH2:15][CH:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1COCC1>[F:1][C:2]1[C:11]2[NH:10][C:9](=[S:25])[CH:8]3[CH2:13][CH2:14][CH2:15][CH:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2c(F)cccc2C2CCCC12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: Fc1cccc2c1NC(=S)C1CCCC21
Yield: 94.1 %

Procedure:
A solution of 6-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (100 mg, 0.48 mmol) and Lawesson's reagent (512 mg, 1.26 mmol) in THF (20 ml) is refluxed for 1.5 hours and concentrated by evaporation. Column chromatography of the residue with ethyl acetate-hexane yields 100 mg (93%) of product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=C(O)C=CC=1.[C:24]1([CH:30]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](=[O:40])[C:32]2=[O:41])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([C:33]2([OH:40])[C:34]3[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:31]([CH:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:32]2=[O:41])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc(OCc2ccccc2)ccc1O

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 4-(benzyloxy)phenol to replace 3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 3-[5-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one was obtained (76%): 1H NMR (300 MHz, CDCl3) δ 8.63 (s, 1H), 7.46-7.40 (m, 1H), 7.38-7.21 (m, 15H), 7.13-7.06 (m, 2H), 6.97 (d, J=8.8 Hz, 1H), 6.92 (s, 1H), 6.86 (dd, J=8.8, 3.0 Hz, 1H), 6.52-6.45 (m, 2H), 4.85 (s, 2H), 4.53 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[CH2:31]Cl)[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(#N)C>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[C:27]([F:29])[C:26]([F:30])=[CH:25][C:24]=3[CH2:31][N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3cc(F)c(F)cc3CCl)ccc2n1
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CN1CCN(Cc2cc(F)c(F)cc2-c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
200 mg of [2-amino-6-(2-chloromethyl-4,5-difluorophenyl)quinazolin-4-yl]-(1,3-dihydroisoindol-2-yl)methanone are dissolved in 5 ml of acetonitrile. 289 mg of caesium carbonate and 84 μl of methylpiperazine are added, and the mixture is stirred at 80° C. for 16 h. After cooling to 25° C., the mixture is filtered, and the filtrate is evaporated to dryness. The residue is taken up in 5 ml of ethyl acetate, the solution is washed with 5 ml of 2N sodium hydroxide solution, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).