Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9][CH2:8][N:7]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO.O>[C:37]([O:36][C:34]([N:7]1[CH2:8][CH2:9][CH:10]([NH:11][S:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:19][CH:20]=2)(=[O:13])=[O:14])[CH:5]([C:3]([OH:4])=[O:2])[CH2:6]1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3CCN(C(=O)OC(C)(C)C)CC3C(=O)O)cc2)c2ccccc2n1

Procedure:
A solution of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (0.3 g, 0.525 mmol) and lithium hydroxide (0.1 g, 4.2 mmol) in THF:methanol:water (2.5: 1.5:1.5 mL) was stirred at 25° C. for 19 h. The solution was concentrated in vacuo to provide 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester as a crude solid (0.170 g, 58%). MS: 557 (M+H)+
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[Cl-].CS(O[CH2:21][CH2:22][NH+:23]([CH3:25])[CH3:24])(=O)=O.C(O)(=O)C>COCCOC>[CH3:24][N:23]([CH3:25])[CH2:22][CH2:21][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: C[NH+](C)CCOS(C)(=O)=O
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: COCCOC
Product: CCOC(=O)c1ccc(OCCN(C)C)cc1
Temperature: 25 °C
Yield: 92 %

Procedure:
20 g (0.12 mol) of ethyl 4-hydroxybenzoate were dissolved in 300 mL of ethylene glycol dimethyl ether in a nitrogen atmosphere. 11.6 g (0.29 mol) of 60% sodium hydroxide were added in portions over the course of 25 minutes while stirring at room temperature followed by heating to 50° C. and stirring for 1 hour. Moreover, 29.4 g (0.14 mol) of [2-(methanesulfonyloxy)ethyl]dimethylammonium chloride were added in portions over the course of 1 hour at the same temperature followed by additionally stirring for 2 hours. After adding 4 mL of acetic acid while cooling with ice, the precipitate that formed was filtered out. The filtrate was concentrated and ethyl acetate was added to the residue followed by extraction with 3% sulfuric acid. After washing the aqueous phase with ethyl acetate, potassium hydrogen carbonate was added to bring to pH8 followed by extraction with ethyl acetate. The organic layer was dried with magnesium sulfate followed by distilling off the solvent to obtain 26.3 g of the target substance (yield: 92%).
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:7][CH2:8]Cl)[CH2:4][CH2:5]Cl.[N+:10]([C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16])([O-:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:2][N:3]1[CH2:7][CH2:8][N:16]([C:15]2[CH:14]=[C:13]([N+:10]([O-:12])=[O:11])[CH:19]=[CH:18][CH:17]=2)[CH2:5][CH2:4]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: CN1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Yield: 50.3 %

Procedure:
A mixture of N-methylbis (2-chloroethyl)amine hydrochloride (9.8 g) and 3-nitroaniline (7.0 g) in 1-butanol (100 ml) was heated at reflux for 60 h then cooled to room temperature. Sodium carbonate (2.8 g) was then added and the mixture heated at reflux for a further 18 h, then cooled to 0° C. and filtered. The solid was collected, washed with anhydrous ether then partitioned between dichloromethane (200 ml) and sodium hydroxide solution (1M, 150 ml). The organic layer was separated and the aqueous phase washed once more with dichloromethane (200 ml). The combined organic layers were dried (K2CO3) and evaporated in vacuo. The resultant residue was chromatographed on silica gel, using dichloromethane:methanol (96:4) as the eluant, to afford an orange oil. The oil crystallised on standing and the resultant solid was triturated with petrol (60/80) to give the desired piperazine (5.64 g). 1H NMR (360 MHz, CDCl3) δ2.37 (3H, s), 2.58 (4H, t, J=5 Hz), 3.30 (4H, t, J=5 Hz), 7.18 (1H, dd, J=9 and 3 Hz), 7.35 (1H, t, J=8 Hz), 7.64 (1H, dd, J=9 and 2 Hz), 7.71 (1H, d, J=2 Hz). MS (CI, NH3) 222 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH2:8].[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].C(N(CC)CC)C>C(O)C>[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[N:8][CH2:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: NCCc1cccs1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(C=NCCc2cccs2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76 %

Procedure:
2-(2-Thienyl)-ethylamine (5 g, 39.4 mmol), 4-nitrobenzaldehyde and triethylamine (10 ml) were dissolved in ethanol (100 ml). The reaction mixture was stirred at room temperature for 48 hours. The solid formed was filtered and dried to afford 7.75 g (76%) (4-nitrobenzylidene)-(2-thiophen-2-yl-ethyl)-amine.
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[H-].[Na+].[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:23]=1)[N:20]([CH2:28]C=O)[CH:19]=[C:18]2[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[Cl:14][C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:23]=1)[N:20]([CH2:28][NH:3][C@H:4]1[CH:9]3[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]3)[CH2:5]1)[CH:19]=[C:18]2[CH3:31]
Reactant: COC(=O)c1cc(Cl)cc2c(C)cn(CC=O)c12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [H-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)cc2c(C)cn(CN[C@@H]3CN4CCC3CC4)c12
Reaction time: 1 h
Yield: 106.3 %

Procedure:
To a stirred suspension of (S)-(−)-3-aminoquinuclidine dihydrochloride (621 mg, 3.1 mmol) in methylene chloride (20 mL) was added sodium hydride (250 mg, 6.2 mmol) in portions and the mixture was stirred for 1 h. Acetic acid (0.6 mL) was added dropwise and then methyl 5-chloro-3-methyl-1-(2-oxoethyl)-1H-indole-7-carboxylate (690 mg, 2.6 mmol) from Step D above was added and the mixture continued to stir at room temperature for 2 h. Sodium triacetoxyborohydride (2.2 g, 10.4 mmol) was added in one portion and stirring was continued overnight at room temperature. The solvent was removed under reduced pressure and the crude material was purified by column chromatography (silica gel, 90:10:1 methylene chloride/methanol/concentrated ammonium hydroxide) to afford (S)-methyl 5-chloro-3-methyl-1-((quinuclidin-3-ylamino)methyl)-1H-indole-7-carboxylate (1.0 g, quantitative yield) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 7.69 (d, J=1.0 Hz, 1H), 7.56 (d, J=1.0 Hz, 1H), 7.14 (s, 1H), 3.02-2.97 (m, 1H), 2.84-2.62 (m, 8H), 3.00-2.97 (m, 1H), 2.85-2.58 (m, 7H), 2.32 (s, 3H), 2.23-2.19 (dq, J=10.0, 2.0 Hz, 1H), 1.72-1.61 (m, 3H), 1.47-1.45 (m, 1H), 1.47-1.45 (m, 1H); MS (ESI+) m/z 362 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([NH:12][C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][C@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]3)[CH:16]=[CH:15][C:14]=2[N+:27]([O-])=O)=[O:11])=[N:2]1>C(O)C.[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([NH:12][C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][C@H:23]([CH3:25])[O:22][C@H:21]([CH3:26])[CH2:20]3)[CH:16]=[CH:15][C:14]=2[NH2:27])=[O:11])=[N:2]1
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])c(NC(=O)c3n[nH]c4ccccc34)c2)C[C@H](C)O1
Agent: [Pd]
Solvent: CCO
Product: C[C@@H]1CN(c2ccc(N)c(NC(=O)c3n[nH]c4ccccc34)c2)C[C@H](C)O1
Reaction time: 18 h

Procedure:
To a solution of 1H-indazol-3-yl-N-[5-((6S,2R)-2,6-dimethyl-morpholin-4-yl)-2-nitrophenyl]carboxamide (1.0 equivalent) in ethanol was added 10% Pd/C (0.5 equivalents). The reaction vessel was repeatedly purged with nitrogen, and then the reaction was stirred under a hydrogen atmosphere (1 atm) for 18 hours. The product was filtered through Celite with ethanol. The solvent was removed to provide a brown solid which was used without purification. LC/MS (m/z) 366.2 (MH+), Rt 2.19 minutes.
Reaction SMILES: C[O:2][C:3](=[O:29])[C@H:4]([CH2:8][O:9][C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:5]([CH3:7])[CH3:6].[OH-].[Na+]>CO>[CH3:6][N:5]([CH3:7])[C@H:4]([C:3]([OH:29])=[O:2])[CH2:8][O:9][C:10]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: COC(=O)[C@H](COC1(c2ccccc2)c2ccccc2-c2ccccc21)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)[C@@H](COC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.1 %

Procedure:
To a solution of 0.39 g (1 mmol) N,N-Dimethyl--O--(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester from Step 1 in methanol (4 mL) was added 20% sodium hydroxide (2 mL) and the mixture stirred at room temperature for 1 h. Most of the methanol was evaporated in vacuo, the residue suspended in water (10 mL) and extracted with diethyl ether (2×2 mL). The alkaline aqueous phase was acidified with 20% acetic acid by cooling with an ice bath, the white precipitate was filtered, washed with water and dried in vacuo over P2O5 to give 0.314 g (yield 84%) N,N-dimethyl-O-(9-phenyl-9H-fluoren-9-yl)-L-serine as a white powder. 1H NMR (CD3OD, 300 MHz) δ: 7.87 (br s, 2H), 7.70-7.10 (m, 11H), 3.70-3.45 (m, 3H), 2.95 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:13]=3[N:14]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>C(O)CC.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:13]=3[N:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(-c2nc3cc([N+](=O)[O-])ccc3o2)c1
Agent: [Pd]
Solvent: CCCO
Product: Nc1cccc(-c2nc3cc(N)ccc3o2)c1
Temperature: 70 °C

Procedure:
A 11.1-gram portion of the 2-(m-nitrophenyl)-5-nitrobenzoxazole is dissolved in 200 milliliters of n-propanol. A 10% palladium-on-carbon catalyst (2.0 grams) is added, and the mixture stirred under nitrogen. The mixture is heated to 70° C., and hydrogen gas is bubbled into the mixture until substantially all the nitro groups have been reduced to primary amine groups, as indicated by liquid chromatography. The catalyst is then filtered off and the remaining solution added to water. The solvent and water are then evaporated off to yield 2-(m-aminophenyl)-5-aminobenzoxazole.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][N:20]([Si](C)(C)C)[Si](C)(C)C>>[NH2:20][CH2:19][CH2:18][CH2:17][N:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9]1=[O:13]
Reactant: C[Si](C)(C)N(CCCBr)[Si](C)(C)C
Reactant: O=C1NCCN1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: NCCCN1CCN(Cc2ccccc2)C1=O

Procedure:
As shown in FIG. 9B (Scheme 4), the synthesis of 1-(3-aminopropyl)-3-benzylimidazolidin-2-one (35) will be performed by treating the starting material N1-benzylethane-1,2-diamine with diethoxymethoxyethane to form 1-benzyl-4,5-dihydro-1H-imidazole. The imidazole intermediate will be treated with BuLi (forming a lithiate) followed by quenching with water to form the final intermediate 1-benzylimidazolidin-2-one. Treating the imidazolidinone with NaH followed by Br—(CH2)3—N(SiMe3)2 under reducing conditions will afford the intermediate 35.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][O:17][CH:18]([O:24][CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22]Br>>[CH3:16][O:17][CH:18]([O:24][CH3:25])[CH2:19][CH2:20][CH2:21][CH2:22][N:13]1[CH2:12][CH2:11][CH:10]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH3:9])[CH2:15][CH2:14]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: COC(CCCCBr)OC
Product: COC(CCCCN1CCC(N(C)C(=O)OC(C)(C)C)CC1)OC

Procedure:
The title compound was prepared from the above amine and 5-bromopentanal dimethyl acetal using a similar method to that described for Example 8 (Step 2). δ (360 MHz, CDCl3) 1.34 (1H, m), 1.46-1.73 (19H, m and s), 1.98 (2H, m), 1.33 (2H, m), 2.73 (3H, s), 2.99 (2H, m), 3.31 (6H, s), 4.36 (1H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[C:10](=O)[CH2:9]1.[C:26]([NH:29][NH2:30])([NH2:28])=[NH:27].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:17][C:16]2[N:15]=[N:14][CH:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[C:10](=[N:30][NH:29][C:26]([NH2:28])=[NH:27])[CH2:9]1
Reactant: N=C(N)NN
Reactant: O=C1CC(c2ccccc2Cl)Cc2nncc(-c3ccc(Cl)cc3)c21
Agent: Cl
Solvent: CCO
Solvent: O
Product: N=C(N)NN=C1CC(c2ccccc2Cl)Cc2nncc(-c3ccc(Cl)cc3)c21
Yield: 115.5 %

Procedure:
To a solution of 7-(2-chlorophenyl)-4-(4-chlorophenyl)-5,6,7,8-tetrahydrocinnolin-5-one (0.18 g) and aminoguanidine hydrochloride (65 mg) in ethanol (10 ml) were added concentrated hydrochloric acid (0.12 ml) and water (0.12 ml), and the mixture was refluxed for 6 hours. Under reduced pressure, the solvent was evaporated, and to the residue was added sodium hydrogen carbonate solution to make the solution alkaline. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate-methanol). The resulting crystals were dissolved in 1N hydrochloric acid (1 ml), and the solution was concentrated. The residue was recrystallized from ethanol-ethyl acetate to give 7-(2-chlorophenyl)-4-(4-chlorophenyl)-5-guanidinoimino-5,6,7,8-tetrahydrocinnoline hydrochloride (Compound 145) (0.13 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:3]=1C(O)=O.S(Cl)(Cl)=O.[N-:19]=[N+]=[N-].[Na+]>O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:7][C:3]=1[NH2:19]
Reactant: C[Si](C)(C)c1ccc(F)c(C(=O)O)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Product: C[Si](C)(C)c1ccc(F)c(N)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 2.12 g (10 mmol) of 2-fluoro-5-trimethylsilyl-benzoic acid and 1.78 g (15 mmol) of thionyl chloride is heated 2 hours at 60° C. Then gases and excess of thionyl chloride are removed under reduced pressure. To the crude material dissolved in 10 ml of acetone is added dropwise 6.5 g (10 mmol) of sodium azide in 10 ml of water and the mixture is stirred one hour at 0° C. Acetone is removed under reduced pressure and the acyl azide was extracted with ethyl acetate. The organic phase is dried over MgSO4 and ethyl acetate is removed under reduced pressure. To the acyl azide 20 ml of benzene is added and the reaction mixture is stirred 30 minutes at reflux. Then the solution is cooled to 0° C., 10 ml of concentrated hydrochloric acid is added and the mixture is heated 30 minutes at reflux. Benzene and water are removed under reduced pressure and the hydrochloride salt is recrystallized from isopropanol. To the salt dissolved in 10 ml of water is added 10 ml of 1N sodium hydroxide and the aqueous mixture is extracted with ethyl acetate. The organic layer is washed with brine, dried over MgSO4 and concentrated to obtain pure 2-fluoro-5-trimethylsilyl-aniline.
Reaction SMILES: NC1(C2C=CC(C3C(C4C=CC=CC=4)=CC4N(CCC#N)C(=O)COC=4N=3)=CC=2)CCC1.C(OC(=O)[NH:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:65]4[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=4)=[CH:52][C:53]4[N:58]([CH3:59])[C:57](=[O:60])[CH:56]([CH2:61][CH2:62][OH:63])[O:55][C:54]=4[N:64]=3)=[CH:46][CH:45]=2)[CH2:43][CH2:42][CH2:41]1)(C)(C)C>>[NH2:39][C:40]1([C:44]2[CH:49]=[CH:48][C:47]([C:50]3[C:51]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=4)=[CH:52][C:53]4[N:58]([CH3:59])[C:57](=[O:60])[CH:56]([CH2:61][CH2:62][OH:63])[O:55][C:54]=4[N:64]=3)=[CH:46][CH:45]=2)[CH2:41][CH2:42][CH2:43]1
Reactant: CN1C(=O)C(CCO)Oc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Agent: N#CCCN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Product: CN1C(=O)C(CCO)Oc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc21
Yield: 53.4 %

Procedure:
Following the procedure for 3-(6-(4-(1-aminocyclobutyl)phenyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)propanenitrile, tert-butyl(1-(4-(3-(2-hydroxyethyl)-1-methyl-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (12.5 mg, 0.024 mmol) was reacted to afford the title compound (5.5 mg). 1H NMR (500 MHz, CH3OD) 7.64 (s, 1H), 7.41 (m, 4H), 7.28 (m, 3H), 7.18 (m, 2H), 5.09 (dd, 1H), 3.80-3.92 (m, 2H), 3.41 (s, 1H), 2.72 (m, 2H), 2.54 (m, 2H), 2.24 (m, 2H), 2.13 (m, 1H), 1.94 (m, 1H). LCMS (Method A): RT=3.76 min, M+H+=413.16.
Reaction SMILES: Br[C:2]1[CH:42]=[CH:41][C:5]2[N:6]=[C:7]([N:23]([C:32]3[C:37]([Cl:38])=[CH:36][C:35]([F:39])=[CH:34][C:33]=3[Cl:40])[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:8]3[CH:9]=[CH:10][N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:38][C:37]1[CH:36]=[C:35]([F:39])[CH:34]=[C:33]([Cl:40])[C:32]=1[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:7]1[C:8]2[CH:9]=[CH:10][N:11]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:21])([CH3:22])[CH3:20])[C:12](=[O:14])[C:13]=2[C:4]2[CH:3]=[C:2]([N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[CH:42]=[CH:41][C:5]=2[N:6]=1
Reactant: C1COCCN1
Reactant: C[Si](C)(C)CCOCN(c1c(Cl)cc(F)cc1Cl)c1nc2ccc(Br)cc2c2c(=O)n(COCC[Si](C)(C)C)ccc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCN(c1c(Cl)cc(F)cc1Cl)c1nc2ccc(N3CCOCC3)cc2c2c(=O)n(COCC[Si](C)(C)C)ccc12
Temperature: 100 °C

Procedure:
To a solution of 9-bromo-5((2,6-dichloro-4-fluorophenyl){[2-(trimethylsilyl)ethoxy]methyl}amino)-2-{[2-(trimethylsilyl)ethoxy]methyl}benzo[c]-2,6-naphthyridin-1(2H)-one (58 mg, 0.08 mmol) in dioxane (2 ml) was added morpholine (14.16 mg, 0.16 mmol), xantphos (9.41 mg, 0.02 mmol), cesium carbonate(79 mg, 0.24 mmol) and Pd2(dba)3 (7.44 mg, 8.13 μmol). The solution was degassed by bubbling nitrogen for few minutes and heated to 100° C. in a sealed tube for 16 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was evaporated under vacuum to afford the title compound.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([OH:11])=[CH:6][C:5]=1[CH3:12].Cl[C:14]1[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=1>>[NH2:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([O:11][C:14]2[CH:15]=[CH:16][C:17]([N+:29]([O-:31])=[O:30])=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH:19]=2)=[CH:6][C:5]=1[CH3:12]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Cc1cc(O)cc(C)c1N
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(Oc2ccc([N+](=O)[O-])c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of anhydrous N,N-dimethylformaide (30 ml) containing sodium hydride (0.35 g, 55% (w/w)) was added 4-amino-3,5-dimethylphenol (1.10 g) and the mixture was stirred at room temperature for 15 minutes. To the mixture was added in limited amounts t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (2.29 g) and the mixture was stirred at 120° C. for 1 hour. The reaction mixture was concentrated and partitioned between ethyl acetate and water. The extract was dried over anhydrous sodium sulfate and concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=1:3 as the eluant to afford the desired compound (2.27 g, Rf=0.24: thin layer chromatography on a silica gel plate using ethyl acetate:n-hexane=1:3 as the eluant).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[C:7]([CH3:34])([CH3:33])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24]CC2C=CC=CC=2)=[O:23])=[C:18]([Cl:32])[CH:17]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].[Cl-].[NH4+]>ClCCl.O1CCCC1.O>[C:1]([O:5][C:6](=[O:35])[C:7]([CH3:34])([CH3:33])[CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[C:18]([Cl:32])[CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C)(C)COc1ccccc1-c1ccc(C(=O)OCc2ccccc2)c(Cl)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)COc1ccccc1-c1ccc(C(=O)O)c(Cl)c1
Temperature: 60 °C
Reaction time: 17 h
Yield: 86.1 %

Procedure:
To a tetrahydrofuran (48 ml) and water (24 ml) mixed solvent suspension of benzyl 2′-(3-tert-butoxy-2,2-dimethyl-3-oxopropoxy)-3-chlorobiphenyl-4-carboxylate (2.40 g) was added lithium hydroxide monohydrate (224 mg). After the reaction solution was stirred at 60° C. for 17 hours, lithium hydroxide monohydrate (112 mg) was further added, and stirred at 60° C. for 6 hours. Tetrahydrofuran (40 ml) was further added, and stirred at 60° C. for 1 hour. After the reaction solution was brought back to room temperature, an aqueous ammonium chloride solution and dichloromethane were added, and the solution was separated. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Methanol was added to the resulting residue, and diluted with a large amount of water. The precipitated solid was collected by filtration and dried to afford 2′-(3-tert-butoxy-2,2-dimethyl-3-oxopropoxy)-3-chlorobiphenyl-4-carboxylic acid (1.69 g).
Reaction SMILES: Cl.[NH2:2][C:3]1([CH3:13])[C:8](=[O:9])[N:7]([CH3:10])[C:6](=[O:11])[NH:5][C:4]1=[O:12].[F:14][C:15]1[C:16]([F:28])=[C:17]([F:27])[C:18]([F:26])=[C:19]2C(=O)O[C:21](=[O:22])[C:20]=12.CCN(CC)CC.CS(C)=O>O>[CH3:10][N:7]1[C:8](=[O:9])[C:3]([NH:2][C:21](=[O:22])[C:20]2[CH:19]=[C:18]([F:26])[C:17]([F:27])=[C:16]([F:28])[C:15]=2[F:14])([CH3:13])[C:4](=[O:12])[NH:5][C:6]1=[O:11]
Reactant: CN1C(=O)NC(=O)C(C)(N)C1=O
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CN1C(=O)NC(=O)C(C)(NC(=O)c2cc(F)c(F)c(F)c2F)C1=O
Temperature: 153 °C

Procedure:
A mixture of 5-amino-1,5-dimethylbarbituric acid hydrochloride (0.42 g, 2 mmol), tetrafluorophthalic anhydride (0.44 g, 2 mmol), Et3N (0.28 mL, 0.20 g, 2 mmol) and DMSO (3 mL) was stirred and heated at 153° C. for 5 hours. The reaction mixture was then allowed to cool down to room temperature and poured into water (10 mL). The oil that immediately formed was carefully removed from the solution, from which a solid precipitated after 4 days standing at room temperature. The precipitate was collected by filtration, washed with water and dried under reduced pressure to give 20a as yellow crystals.