Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]#[N:13])(=O)OCC)C.O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:17]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:16]1>C1COCC1>[C:12]([CH:11]=[C:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:17]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:16]1)#[N:13]
Reactant: CCOC(=O)C1CC(=O)CCN1C(=O)OC(C)(C)C
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CC(=CC#N)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 76 %

Procedure:
To a suspension of 0.75 g (0.019 mol, 60% by weight in oil) of sodium hydride (washed three times with hexanes) in 40 ml of THF was added 3.34 g (0.019 mol) of diethylcyanomethylphosphonate. After stirring the reaction mixture for thirty minutes at room temperature, a solution of 4.26 g (0.016 mol) of ethyl 4-oxo-N-t-butoxycarbonyl-2-piperidinecarboxylate in 10 ml of THF was added. The mixture was stirred for 30 minutes at room temperature and 90 minutes at the reflux temperature of the reaction mixture, then cooled to room temperature and quenched with water. The organic layer was separated and the aqueous layer extracted twice with diethyl ether. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. High pressure liquid chromatography of the residue afforded 3.58 g of ethyl 4-cyanomethylidene-N-t-butoxycarbonyl-2-piperidinecarboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:24]([N:25](C)[C:26](=O)C(F)(F)F)=[C:23]([C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]3[C:24]([NH:25][CH3:26])=[C:23]([C:33](=[O:38])[C:34]([CH3:36])([CH3:35])[CH3:37])[O:22][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:6][CH:7]=1
Reactant: CN(C(=O)C(F)(F)F)c1c(C(=O)C(C)(C)C)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CNc1c(C(=O)C(C)(C)C)oc2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C

Procedure:
A solution of the product from Step A (0.0703 mmol) in methanol (2 mL) and water (0.1 mL) was treated with potassium carbonate (0.049 g; 0.351 mmol) at room temperature. The reaction mixture was stirred a room temperature until the reaction was judged complete by TLC analysis. The reaction mixture was then partitioned between ethyl acetate and saturated NaHCO3 solution. The organic layer was washed twice with saturated NaHCO3 solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by MPLC (silica gel; 0% to 20% ethyl acetate:hexane gradient) gave the title compound. HPLC/MS: 487.0 (M+1), 489.0 (M+3); Rt=5.03 min.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([CH2:6][CH2:7][CH2:8][OH:9])[N:3]=[CH:2]1.CCN(CC)CC.[CH3:17][C:18]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C(Cl)Cl>[Si:21]([O:9][CH2:8][CH2:7][CH2:6][C:4]1[N:3]=[CH:2][O:1][CH:5]=1)([C:18]([CH3:20])([CH3:19])[CH3:17])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCc1cocn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCCc1cocn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
To a sol. of 3-oxazol-4-yl-propan-1-ol (1.14 g, 8.96 mmol) in dry CH2Cl2 (25 mL) at 0° C. were added Et3N (3.12 mL, 22.4 mmol) and TBDMS-Cl (2.02 g, 13.4 mmol). The reaction mixture was stirred at rt overnight, and the mixture was concentrated under reduced pressure. The residue was diluted in Et2O, and the mixture was washed with water. The org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane/Et2O; 30:1→1:1) yielded the title compound (1.84 g, 85%). LC-MS: tR=1.06, ES+: 242.28.
Reaction SMILES: [CH:1]([Sn](CCCC)(CCCC)CCCC)=[CH2:2].Br[C:17]1[CH:18]=[C:19]([C:23]2[O:24][C:25]([CH3:46])=[C:26]([CH2:28][CH2:29][O:30][C:31]3[CH:32]=[C:33]4[C:37](=[CH:38][CH:39]=3)[C@H:36]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:35][CH2:34]4)[N:27]=2)[CH:20]=[CH:21][CH:22]=1.ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1>[CH3:46][C:25]1[O:24][C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([CH:1]=[CH2:2])[CH:18]=2)=[N:27][C:26]=1[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[C:33]2[C:37](=[CH:38][CH:39]=1)[C@H:36]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:35][CH2:34]2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(-c4cccc(Br)c4)oc3C)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=Cc1cccc(-c2nc(CCOc3ccc4c(c3)CC[C@H]4CC(=O)OCC)c(C)o2)c1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a mixture of vinyltributyltin (Aldrich, 65.0 mg, 0.21 mmol), ethyl ((1S)-5-{2-[2-(3-bromophenyl)-5-methyl-1,3-oxazol-4-yl]ethoxy}-2,3-dihydro-1H-inden-1-yl)acetate (50 mg, 0.10 mmol), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (4.2 mg, 0.005 mmol) was added toluene (2 mL). The resulting solution was degassed with argon for 30 minutes, and then stirred at 110° C. for 16 h. The reaction mixture was cooled to rt and diluted with 10 mL ethyl acetate. The organic layer was filtered through a silica plug and the filtrate concentrated under reduced pressure. The crude was then redissolved in methanol and filtered through a silica-octyl plug before preparative HPLC purification using 30 to 100% acetonitrile in water (0.1% TFA) gradient to afford the desired product. 1H NMR (CD2Cl2) δ 8.03 (s, 1H), 7.86 (d, 1H), 7.39-7.51 (m, 2H), 7.04 (d, 1H), 6.68-6.84 (m, 3H), 5.88 ( (d, 1H), 5.31-5.35 (m, 1H), 4.10-4.23 (m, 4H), 3.48 (qr, 1H), 2.97 (t, 2H), 2.64-2.89 (m, 3H), 2.29-2.42 (m, 5H), 1.69-1.76 (m, 1H), 1.26 (t, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].O>CO.O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:8]([CH2:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=2)[OH:9])=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccccn1
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc(C(O)Cc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 79 %

Procedure:
A stainless steel bomb containing p-nitrobenzaldehyde (300 g, 1.99 moles), α-picoline (650 ml, 6.59 moles) and distilled water (100 ml, 5.56 moles) was sealed and held in an oil bath at 140°-160° C. for 19 hours. It was cooled to room temperature and opened to the atmosphere. The contents of the reactor, a mass of crystals and some dark liquid, were added to one liter of a 60:40 methanol-water mixture and the resulting mixture stirred for two hours. The solid was recovered by filtration, washed with one liter of the same solvent mixture and dried under vacuum at 50° C. to give 383-396 g (79%-82% yield) of ##STR29## 4-nitrophenyl-(α-picolyl)carbinol.
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:11][CH3:12]>>[CH2:11]([S:8][C:1](=[NH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:12]
Reactant: CCI
Reactant: NC(=S)c1ccccc1
Product: CCSC(=N)c1ccccc1

Procedure:
As depicted in Scheme 4, cyclic aridines of the invention can be prepared by reacting 2-substituted benzonitrile with hydrogen sulfide to form a thiobenzamide. The resulting thiobenzamide is then treated with iodoethane to give a thiobenzimidic acid ethyl ester. In the presence of hydrochloric acid, the thiobenzimidic acid ethyl ester is suspended in tetrahydrofuran and treated with hydrogen sulfide. The resulting dithiobenzoic acid ethyl ester is then heated with various diamines, in the presence or absence of an added catalyst such as silver trifluoroacetate, to give cyclic amidines.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)=[CH:6][C:3]=1[C:4]#[N:5].C([OH:21])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:21])[NH:14]3)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCO
Reactant: N#Cc1cc(-c2cccc3[nH]ccc23)ccc1F
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: N#Cc1cc(-c2cccc3c2CC(=O)N3)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 68 %

Procedure:
To the suspension of 2-fluoro-5-(1H-indol-4-yl)-benzonitrile (2.68 g, 11.34 mmol) in t-BuOH:ethanol:acetic acid (72 mL:43 mL:23 mL) was added pyridinium tribromide (10.91 g, 34.1 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (55 mL). Zinc dust (4 g, 61.2 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 1.93 g (68%) of 2-fluoro-5-(2-oxo-2,3-dihydro-1H-indol-4-yl)-benzonitrile.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](Cl)=O)=[CH:6][CH:5]=1)[CH3:2].[NH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[NH:23][CH2:24][CH:25]1[CH2:27][CH2:26]1)[C:18]#[N:19]>C(O)(=O)C>[CH:25]1([CH2:24][N:23]2[C:22]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=3[N:14]=[C:11]2[CH2:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=2)[CH2:26][CH2:27]1
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Reactant: N#Cc1ccc(NCC2CC2)c(N)c1
Solvent: CC(=O)O
Product: CCOc1ccc(Cc2nc3cc(C#N)ccc3n2CC2CC2)cc1
Yield: 78.3 %

Procedure:
Following the general procedure 2D, the freshly prepared (4-ethoxyphenyl)acetyl chloride (from 793 mg of acid, 4.4 mmol) and crude 3-amino-4-[(cyclopropylmethyl)amino]benzonitrile (750 mg, 4.01 mmol) were heated in acetic acid (HOAc) overnight. After work-up, the crude residue was purified by silica gel column chromatography to afford pure product (1.04 g, 78%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 8.08 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.38 (d, J=8.4 Hz, 1H), 7.14 (d, J=8.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 4.29 (s, 2H), 4.01 (d, J=7.6 Hz, 2H), 3.96 (q, J=7.6 Hz, 2H), 1.39 (t, J=7.6 Hz, 3H), 1.04–1.00 (m, 1H), 0.58–0.53 (m, 2H), 0.29–0.25 (m, 2H). MS (ESI) (M+H)+=332. Anal. Calcd for C21H21N3O.0.1H2O: C, 75.50; H, 6.41; N, 12.61. Found: C, 75.76; H, 6.72; N, 12.45.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Cl:13][C:14]1[S:15][C:16]([Cl:49])=[C:17]([CH:34]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=2)[O:35]C2CCCCO2)[C:18]=1[C:19]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:20]>CO>[Cl:13][C:14]1[S:15][C:16]([Cl:49])=[C:17]([CH:34]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=2)[OH:35])[C:18]=1[C:19]([NH:21][C@H:22]([C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=1)[CH3:23])=[O:20]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2c(Cl)sc(Cl)c2C(OC2CCCCO2)c2cccc(Cl)c2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2c(Cl)sc(Cl)c2C(O)c2cccc(Cl)c2)cc1
Reaction time: 1.5 h

Procedure:
p-Toluenesulfonic acid monohydrate (6.00 mg, 0.0338 mmol) was added to methyl 4-{(1S)-1-[({2,5-dichloro-4-[(3-chlorophenyl)(tetrahydro-2H-pyran-2-yloxy)methyl]-3-thienyl}carbonyl)amino]ethyl}benzoate from Example 8, Step 4 (197 mg, 0.338 mmol) in MeOH (2 mL). After 1.5 h, the reaction mixture was quenched with 5% aq. NaHCO3 and extracted with EtOAc. The combined organics were washed with 5% aq. NaHCO3, water and brine, dried (Na2SO4) and concentrated. The crude product was purified by Combi Flash chromatography system (2-8% EtOAc/toluene in 20 min.) to afford the desired product as a colorless gum.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[CH:13][C:12]([N+:18]([O-:20])=[O:19])=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N+:18]([C:12]1[CH:13]=[N:14][C:15]2[CH2:16][CH2:17][NH:8][CH2:9][C:10]=2[CH:11]=1)([O-:20])=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCc2ncc([N+](=O)[O-])cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1cnc2c(c1)CNCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To the solution of 3-nitro-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid tert-butyl ester (6.14 g, 22 mmol) in CH2Cl2 (60 mL) was added TFA (7 mL). The reaction was stirred for 18 h at RT. After evaporation of the solvent, the residue was taken into water and neutralized with saturated NaHCO3 aqueous solution. The solid was filtered and washed with cold water and dried. The solid was recrystallized from CH3CN to give desired title compound as pale white solid. MS (ES+): 180.1 (M+H)+. Calc'd for C8H9N3O2—179.07.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([O:19]CC)=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29].[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>>[CH2:30]([N:32]([CH2:33][CH3:34])[C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[C:3]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH:4]=2)[N:9]=[C:8]([N:12]2[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]2)[N:7]=1)[CH3:31]
Reactant: CCNCC
Reactant: CCOC(=O)c1cnn(-c2nc3cc(F)c(-c4ccccc4C)cc3c(=O)[nH]2)c1
Product: CCN(CC)c1nc(-n2cc(C(=O)O)cn2)nc2cc(F)c(-c3ccccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(7-fluoro-4-oxo-6-(o-tolyl)-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and diethylamine in step E. MS (ESI): predicted mass calcd. for C23H22FN5O2, 419.2
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH3:25])[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:32]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:32])=[N:4][CH:5]=1)[CH3:25]
Reactant: CC(=O)O
Reactant: C[C@@H](Nc1cnc(C#N)c(Nc2ccc3ncccc3c2)n1)C(N)=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: C[C@@H](Nc1cnc(C(N)=O)c(Nc2ccc3ncccc3c2)n1)C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)propanamide (97 mg, 0.430 mmol), 6-aminoquinoline (62 mg, 0.430 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)propanamide (15 mg). The compound (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)propanamide (15 mg, 0.045 mmol) was dissolved in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 90 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (14 mg). MS 352.58 (M+H); UV 202.9, 265.2, 297.2, 357.9 nm; t 0.335 min.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])(=[O:5])=[O:4].[CH2:19]([O:21][C:22]([C:24]1[O:25][C:26]2[C:32]([CH:33]=[O:34])=[CH:31][C:30]([CH3:35])=[CH:29][C:27]=2[CH:28]=1)=[O:23])[CH3:20]>C1COCC1.CCCCCCC>[CH2:19]([O:21][C:22]([C:24]1[O:25][C:26]2[C:32]([CH:33]([C:9]3[N:8]=[C:7]([Si:11]([C:14]([CH3:15])([CH3:17])[CH3:16])([CH3:13])[CH3:12])[N:6]([S:3](=[O:4])(=[O:5])[N:2]([CH3:18])[CH3:1])[CH:10]=3)[OH:34])=[CH:31][C:30]([CH3:35])=[CH:29][C:27]=2[CH:28]=1)=[O:23])[CH3:20]
Reactant: CN(C)S(=O)(=O)n1ccnc1[Si](C)(C)C(C)(C)C
Reactant: CCOC(=O)c1cc2cc(C)cc(C=O)c2o1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: CCOC(=O)c1cc2cc(C)cc(C(O)c3cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n3)c2o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-(tert-butyl-dimethyl-silanyl)-imidazole-1-sulfonic acid dimethylamide (1.0 g) in THF (10 ml) was cooled under an Argon atmosphere to −78° C. n-Buthyllithium solution (1.6 M in heptane, 2.37 ml) were added dropwise. After stirring for 1 hr at −78° C. a solution of 7-formyl-5-methyl-benzofuran-2-carboxylic acid ethyl ester (963 mg) in THF (10 ml) was added dropwise. Stirring was continued for 15 min at −78° C., then the reaction mixture was warmed up to r.t. overnight. After quenching with water, the mixture was extracted with EtOAc. The organics were dried over MgSO4, filtrated and concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 1:1) to give rac-7-{[2-(tert-butyl-dimethyl-silanyl)-1-dimethylsulfamoyl-1H-imidazol-4-yl]-hydroxy-methyl}-5-methyl-benzofuran-2-carboxylic acid ethyl ester as light yellow amorphous solid; MS (ISP): 522.3 ((M+H)+.).
Reaction SMILES: [CH:1]([N:4]1[C:8](=[O:9])[C:7](=[O:10])[N:6]=[C:5]1SC)([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]([NH2:24])=[NH:23])[CH:17]=[CH:18][C:19]=1[Cl:20]>C(Cl)(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]([N:24]=[C:5]2[NH:6][C:7](=[O:10])[C:8](=[O:9])[N:4]2[CH:1]([CH3:3])[CH3:2])=[NH:23])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: CSC1=NC(=O)C(=O)N1C(C)C
Reactant: N=C(N)Nc1ccc(Cl)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(C)N1C(=O)C(=O)NC1=NC(=N)Nc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Yield: 39.9 %

Procedure:
To the solution of dione 11 (0.712 g, 3.83 mmol) in 80 ml of dry CHCl3 was added guanidine 14 (0.74 g, 3.64 mmol) and the reaction mixture was heated in an oil-bath at 50° C. for 16 hours. The solid precipitates were collected, washed sequentially with H2O, CH3OH and CHCl3 to afford the compound 3 as a light yellow solid (0.497 g, 40%). mp 233° C. 1H NMR (600 MHz, DMSO-d6): δ 7.77 (d, J=2.2 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.31 (dd, J=8.6 and 2.2 Hz, 1H), 4.38 (m, 1H), 1.33 (d, J=6.7 Hz, 6H). 13C NMR: δ 172.24, 170.65, 162.14, 160.08, 132.13, 131.76, 126.96, 125.00, 44.44, 20.54. IR: 3277, 3140, 1752, 1725, 1553, 1464, 1317, 996, 808, 754 cm−1. Anal. (C13H13Cl2N5O2): C, 45.63; H, 3.83; N, 19.94. Found: C, 45.40; H, 3.71; N, 19.94.
Reaction SMILES: [NH:1](/[C:8](/NC(C)C)=[CH:9]\[C:10]([C:12]1[C:13](Cl)=[N:14][C:15](Cl)=[C:16](F)[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+]>CN(C=O)C.O>[C:2]1([N:1]2[C:13]3[C:12](=[CH:17][CH:16]=[CH:15][N:14]=3)[C:10](=[O:11])[CH:9]=[CH:8]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N/C(=C/C(=O)c1cc(F)c(Cl)nc1Cl)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=c1ccn(-c2ccccc2)c2ncccc12
Temperature: 85 °C
Yield: 86.7 %

Procedure:
(2Z)-3-Anilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2-propen-1-one (40.0 mg, 0.109 mmol) was dissolved in 4 mL of DMF. NaH (8.70 mg, 0.217 mmol, 60% dispersion in oil) was added and the reaction was heated to 85° C. under argon for 2 h. The reaction mixture was cooled to room temperature and diluted with water and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 100% EtOAc to 95:5 EtOAc:MeOH provided 7-chloro-6-fluoro-2-isopropylamino)-1-phenyl-1,8-naphthyridin-4(1H)-one (21 mg, 64%) as a white solid: LCMS RT: 2.57 min, MH+: 332.2.
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[N:16]1([CH2:21][CH2:22][CH2:23][C:24]2[N:25]=[N+:26]([O-:37])[C:27]3[CH:36]=[C:35]4[C:31]([CH2:32][CH2:33][CH2:34]4)=[CH:30][C:28]=3[N:29]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[N:16]1([CH2:21][CH2:22][CH2:23][C:24]2[N:25]=[N+:26]([O-:37])[C:27]3[CH:36]=[C:35]4[C:31]([CH2:32][CH2:33][CH2:34]4)=[CH:30][C:28]=3[N+:29]=2[O-:4])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: [O-][n+]1nc(CCCN2CCCC2)nc2cc3c(cc21)CCC3
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [O-][n+]1nc(CCCN2CCCC2)[n+]([O-])c2cc3c(cc21)CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 58.5 %

Procedure:
H2O2 (70%, 2.0 mL, 39 mmol) was added dropwise to a stirred solution of TFAA (5.4 mL, 39 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 84 (1.50 g, 4.6 mmol) and TFA (1.5 mL, 19.5 mmol) in DCM (50 mL) at 0° C. The solution was stirred at 20° C. for 6 h, diluted with dilute aqueous NH3 solution (30 mL) and extracted with DCM (3×150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 85 (846 mg, 35%) as a red gum: 1H NMR δ 8.25 (s, 1H, H-9), 8.20 (s, 1H, H-5), 3.22-3.22 (m, 6H, 3×CH2), 3.11-3.20 (m, 4H, H-6, H-8), 2.80-3.05 (m, 2H, CH2), 2.33-2.43 (m, 2H, CH2), 2.21-2.30 (m, 2H, H-7), 2.13 (br s, 4H, 2×CH2); 13C NMR δ 155.4, 152.4, 151.0, 139.0, 133.9, 115.7, 113.7, 54.2, 53.5 (2), 33.3, 32.8, 27.1, 25.4, 23.8, 23.2 (2); HRMS (FAB+) calcd for C17H23N4O2 (MH+) m/z 315.1821, found 315.1820.
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[C:18]([C:19](Cl)=[O:20])=[C:17]([Cl:22])[N:16]([CH3:23])[N:15]=1.CC(C)([O-])C.[K+].O>O1CCCC1>[C:1]1([C:7](=[C:19]([C:18]2[C:14]([Cl:13])=[N:15][N:16]([CH3:23])[C:17]=2[Cl:22])[OH:20])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Cc1ccccc1
Reactant: Cn1nc(Cl)c(C(=O)Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=C(O)c1c(Cl)nn(C)c1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
8.2 g (50 mmols) of ethyl phenylacetate and 10.7 g (50 mmols) of 3,5-dichloro-1-methylpyrazole-4-carboxylic acid chloride were dissolved in 100 ml of dry tetrahydrofuran, and 14 g (125 mmols) of potassium tert-butoxide at room temperature. The reaction mixture was stirred at room temperature for 1 hour, and 300 ml of water was added thereto, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 17 g of the intended ethyl 2-phenyl-3-(3,5-dichloro-1-methylpyrazol-4-yl)-3-hydroxyacrylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C@H:12]([NH2:19])[CH2:11][C@@H:10]2[CH3:20])=[O:8])=[CH:5][CH:4]=1.[C:23]1(=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>CO>[CH:23]1([NH:19][C@H:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]([C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:22][CH:21]=3)[C@@H:10]([CH3:20])[CH2:11]2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N)C[C@@H]2C)cc1
Reactant: O=C1CCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](NC3CCCC3)C[C@@H]2C)cc1
Temperature: 25 °C

Procedure:
To (2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine (200 mg, 0.67 mmol) in MeOH was added cyclopentanone (0.073 mL, 0.74 mmol) followed Na(OAc)3BH (284 mg, 1.34 mmol) and catalytic amount of HOAc. The reaction mixture was stirred at room temperature over night. The reaction wash quenched by adding water. And the mixture was extracted with EtOAc 3 times. The organic layers were combined then dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (hexanes-ethyl acetate system) to afford (2S,4R)-N-cyclopentyl-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-amine in decent yield.