Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:13]([OH:15])=O)=[N:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([Cl:9])[C:7]=1[Cl:8].Cl.Cl.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[S:26][C:27]([CH2:30][N:31]2[CH2:36][CH2:35][CH:34]([CH2:37][NH2:38])[CH2:33][CH2:32]2)=[CH:28][N:29]=1>>[NH2:1][C:2]1[C:3]([C:13]([NH:38][CH2:37][CH:34]2[CH2:35][CH2:36][N:31]([CH2:30][C:27]3[S:26][C:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=4)=[N:29][CH:28]=3)[CH2:32][CH2:33]2)=[O:15])=[N:4][C:5]([O:10][CH2:11][CH3:12])=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: NCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Reactant: CCOc1nc(C(=O)O)c(N)c(Cl)c1Cl
Agent: Cl
Product: CCOc1nc(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)c(N)c(Cl)c1Cl

Procedure:
According to the same procedure described in Example 16, using the compound prepared in Example 431 instead of 4-chloro-3-methoxybenzoic acid and the compound prepared in Example 214 instead of the compound prepared in Example 9, the title compound having the following physical data was obtained.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:3]([NH2:5])=[O:4].N1C=CN=C1.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[NH2:1][C@H:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][Si:25]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27])=[CH:13][CH:14]=1)[C:3]([NH2:5])=[O:4]
Reactant: NC(=O)[C@H](N)CCCc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CCC[C@@H](N)C(N)=O)cc1
Temperature: 70 °C

Procedure:
To a stirred solution of (R)-2-Amino-5-(4-hydroxy-phenyl)-pentanoic acid amide (5 g, 24.01 mmol) in THF (250 ml) is added imidazole (4.90 g, 72 mmol), followed by tert-butyldimethylchlorosilane (3.98 g, 26.4 mmol). The resulting solution is heated at 70° C. for 4 hours and then allowed to cool to room temperature. Dilution with Et2O (200 ml) washing with water (2×100 ml) and brine (100 ml), drying MgSO4, and concentration in vacuo yields (R)-2-Amino-5-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-pentanoic acid amide; [M+H]+ 323
Reaction SMILES: [CH3:1][CH:2]([CH3:25])[CH:3]([NH:8][C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[CH:14][N:15]=1)=[O:10])[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1.O>CC(C)=O>[F:40][C:37]1[CH:38]=[CH:39][C:34]([CH2:33][NH:22][C:19]2[CH:20]=[CH:21][C:16]([C:13]3[S:12][C:11]([C:9]([NH:8][CH:3]([CH:2]([CH3:25])[CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[O:10])=[N:15][CH:14]=3)=[CH:17][CH:18]=2)=[CH:35][CH:36]=1
Reactant: COC(=O)C(NC(=O)c1ncc(-c2ccc([N+](=O)[O-])cc2)s1)C(C)C
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C(NC(=O)c1ncc(-c2ccc(NCc3ccc(F)cc3)cc2)s1)C(C)C
Temperature: 62.5 °C
Reaction time: 8 h

Procedure:
To a solution of the methyl 2-(5-(4-aminophenyl)thiazole-2-carboxamido)-3-methylbutanoate (Intermediate 2, 250 mg) in acetone (8 ml) was added potassium carbonate (155 mg, 1.5 eq) and 1-(bromomethyl)-4-fluorobenzene (0.112 ml, 1.2 eq). The reaction mixture was stirred for 8 hours at 60-65° C. Water was added after the completion of the reaction, and the reaction mixture was extracted with ethyl acetate. Organic layer was washed with water and concentrated. The compound was purified by column chromatography using 10-15% ethylacetate in petroleum ether to give the title compound. Yield: 130 mg (39%). 1H NMR (CDCl3; 300 MHz): δ 7.87 (s, 1H), 7.66 (d, 1H), 7.44 (d, 2H), 7.37 (m, 2H), 7.08 (t, 2H), 6.68 (d, 2H), 4.74 (m, 1H), 4.37 (s, 2H), 3.79 (s, 3H), 2.37 (m, 1H), 1.05 (t, 6H); MS (ESI) m/z 442.1 [M+H]+, 464.1 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[CH:13]=[N:12][CH:11]=2)[N:5]=[C:4]([OH:18])[CH:3]=1.[Li]CCCC.[Cl:24]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1.CO>[Cl:24][C:13]1[N:14]([CH:15]([CH3:16])[CH3:17])[C:10]([CH2:9][S:8][C:6]2[N:5]=[C:4]([OH:18])[CH:3]=[C:2]([CH3:1])[N:7]=2)=[CH:11][N:12]=1
Reactant: Cc1cc(O)nc(SCc2cncn2C(C)C)n1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(O)nc(SCc2cnc(Cl)n2C(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
In a 250 mL round bottom flask, 6-methyl-2-({[1-(propan-2-yl)-1H-imidazol-5-yl]methyl}sulfanyl)pyrimidin-4-ol (260 mg, 1.0 mmol) was dissolved in THF (20 mL) at −78° C. BuLi (0.88 mL, 2.2 mmol) was added dropwise. After 1 hour, hexachloroethane (360 mg, 1.5 mmol) was added. The resulting mixture was stirred at 0° C. for 2 hours. A few drops of methanol were added to quench the reaction. Then, the solvent as removed under vacuum, and the crude was purified by column chromatography to provide the title compound as a white solid (200 mg, 87% yield); 1H NMR (400 MHz, CD3OD): δ 1.45 (d, 6H), 2.20 (s, 3H), 4.46 (s, 2H), 4.62 (m, 1H), 6.02 (bs, 1H), 6.84 (s, 1H); M+ 299.
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:16]=[CH:15][N:14]=[CH:13][C:9]=3[CH2:10][C:11](=[O:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>C1COCC1>[CH3:19][N:20]([CH:22]=[C:10]1[C:9]2[CH:13]=[N:14][CH:15]=[CH:16][C:8]=2[NH:7][C:6]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:11]1=[O:12])[CH3:21]
Reactant: COC(OC)N(C)C
Reactant: O=C1Cc2cnccc2Nc2ncccc21
Solvent: C1CCOC1
Product: CN(C)C=C1C(=O)c2cccnc2Nc2ccncc21

Procedure:
A solution of 6,11-dihydro-5H-dipyrido[2,3-b:3′,4′-f]azepin-5-one (0.440 g, 2.08 mmol, Intermediate D-6) and 1,1-dimethoxy-N,N-dimethylmethanamine (2.49 mL, 18.7 mmol) in THF (30 mL) was stirred for three days under an atmosphere of nitrogen. The mixture was concentrated in vacuo to give the desired product as an orange solid which was used directly for the next step. LC/MS: 267 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7])[NH2:2].CN(C)/[CH:13]=[CH:14]/[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>C(O)C.CC(O)=O>[C:17]1([C:15]2[N:1]([C:3]3[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=3)[C:6]#[N:7])[N:2]=[CH:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1ccccc1
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1ccnc(-n2nccc2-c2ccccc2)c1
Reaction time: 12 h
Yield: 81.2 %

Procedure:
To a solution of 2-hydrazinylisonicotinonitrile (100 mg, 0.75 mmol, 1.0 eq., PREPARATION 2) and (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (132 mg, 0.75 mmol, 1.0 eq.) in ethanol (10 mL) was added 2-5 drops of AcOH. The reaction mixture was under reflux conditions for 12 h. After reaction completion, volatiles were removed under reduced pressure, and the resultant crude material was purified by flash column chromatography (20% EtOAc/hexane) to obtain the title compound as a yellow oil (150 mg, 81% yield). [M+H] Calc'd for C15H10N4, 247.09. Found 247.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:34])[CH2:15][CH2:16][CH2:17][N:18]1[C:24](=[O:25])[CH2:23][C:22]3[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:21]=3[CH:20]=[CH:19]1)[CH2:6]2.C(O)C>[OH-].[OH-].[Pd+2].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:34])[CH2:15][CH2:16][CH2:17][N:18]1[C:24](=[O:25])[CH2:23][C:22]3[CH:26]=[C:27]([O:32][CH3:33])[C:28]([O:30][CH3:31])=[CH:29][C:21]=3[CH2:20][CH2:19]1)[CH2:6]2
Reactant: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)C=C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)CC2
Reaction time: 5 h

Procedure:
In a 250-ml autoclave, 4 g of the product obtained in Example 1 and 2 g of Pd(OH)2 (20%, 50% moist) are added to a solution of ethanol (90 mL) and acetic acid (10 mL). After remaining in contact for 5 hours at ambient temperature under a hydrogen pressure of 5 bar, the reaction mixture is filtered over Celite®. The residue obtained after concentrating under reduced pressure is taken up in dichloromethane (100 mL) and then washed with saturated aqueous sodium bicarbonate solution. The oil obtained after drying the organic phase over MgSO4 and then concentrating under reduced pressure is purified by chromatography over silica (dichloromethane/ethanol/NH4OH 28%: 95/5/0.5), and 2.6 g of the title product are obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:18])=[CH:4][C:5]([Cl:17])=[C:6]([N:8]([S:12]([CH2:15][Cl:16])(=[O:14])=[O:13])C(=O)C)[CH:7]=1.Cl>C(O)C.[OH-].[Na+]>[NH2:1][C:2]1[C:3]([F:18])=[CH:4][C:5]([Cl:17])=[C:6]([NH:8][S:12]([CH2:15][Cl:16])(=[O:14])=[O:13])[CH:7]=1
Reactant: CC(=O)N(c1cc(N)c(F)cc1Cl)S(=O)(=O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cc(NS(=O)(=O)CCl)c(Cl)cc1F
Temperature: 50 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
3 g (0.0095 mol) of N-(5-amino-2-chloro-4-fluorophenyl)-N-[(chloromethyl)sulfonyl]acetamide were dissolved in 30 mL of ethanol and 30 mL of 25% sodium hydroxide solution. The mixture was stirred for 3 hours at 50° C. and then cooled to room temperature. 6 N hydrochloric acid was added with stirring and cooling until the solution had a pH of 5-6. The suspension was further cooled to 0-5° C., filtered, washed with water and dried to yield 2.4 g (92%) of the title compound as a solid melting at 103.5-105.5° C. Recrystallization from toluene raised the melting point to 105-106° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.BrBr.O.[OH-].[NH4+]>C(O)(=O)C>[CH2:11]([NH:10][C:8]1[S:9][C:6]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]=2[N:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C(NCc1ccccc1)Nc1ccccc1
Agent: BrBr
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: c1ccc(CNc2nc3ccccc3s2)cc1

Procedure:
To a stirred solution of 12.1 g (0.05 mol) of N-phenyl-N'-benzylthiourea in 150 ml of glacial acetic acid was added dropwise 8.0 g (0.05 mol) of bromine in 60 mL of glacial acetic acid. The reaction was poured into 10 volumes of water and made basic with concentrated ammonium hydroxide. A solid precipitated from the aqueous solution and was filtered. The solid could be recrystallized from an appropriate solvent to yield N-benzyl-2-benzothiazolamine.
Reaction SMILES: [O:1]1CCCC1.BrBr.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]([OH:15])[CH3:14]>O>[CH3:14][C:13]1[O:15][CH:12]=[CH:11][C:10](=[O:1])[C:9]=1[OH:8]
Reactant: C1CCOC1
Reactant: CC(O)c1ccco1
Agent: BrBr
Solvent: O
Product: Cc1occc(=O)c1O
Temperature: 10 °C
Yield: 53 %

Procedure:
To a 4-neck round bottom flask equipped with a thermometer, a condensor and two addition funnels was charged 50 ml of tetrahydrofuran and 50 ml of water and the solution was cooled to 10° C. To this well stirred solution was added together in the two addition funnels bromine (0.20 mole) and 1(2-furyl)-1-ethanol (0.09 mole). The temperature of the reaction was maintained at 15° C. throughout the double addition. The reaction mixture was then heated to 75° C. for 10 hours. Maltol was isolated by the procedure of Example 1 (53% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:20])[CH:23]([CH3:25])[CH3:24]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CC(C)COC(=O)Cl
Product: CC(C)COC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.053 mMol) isobutyl chloroformate, the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:21])[CH:11]([NH:18][CH2:19][CH3:20])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.C=O.[C:26](=O)([O-])[O-].[K+].[K+]>CCCCCC.C(OCC)(=O)C>[CH2:19]([N:18]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:21])[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:22])([F:23])[F:1])[CH:4]=2)[CH2:26]1)[CH3:20]
Reactant: O=C([O-])[O-]
Reactant: CCNC(C(=O)Nc1cccc(C(F)(F)F)c1)c1ccccc1
Agent: C=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCN1CN(c2cccc(C(F)(F)F)c2)C(=O)C1c1ccccc1
Yield: 203.4 %

Procedure:
An ethanolic (50 mL) solution of the above N-aryl-2-ethylamino-2-phenylacetamide prepared in Example II (6.8 grams, 0.02 mol) and paraformaldehyde (0.65 grams, 0.02 mol) and potassium carbonate (1.5 grams, 0.01 mol) was heated under reflux for 2 hours. The reaction was followed by thin layer chromatography (3:1 hexane-ethyl acetate). The mixture was concentrated in a rotary evaporator. The product was extracted into ethyl acetate and washed with water and isolated to give the desired 1-ethyl-5-phenyl-3-(3-trifluoromethylphenyl) imidazolidine-4-one (6.8 grams, 97% yield) whose structure was confirmed by nuclear magnetic resonance, infra-red spectroscopy, and mass spectroscopy analysis.
Reaction SMILES: [CH2:1]([C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[C:11]1([CH3:33])[CH:16]=[CH:15][C:14]([S:17]([N:20]=C2CCCCI2C2C=CC=CC=2)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].C(#N)C>[S:17]([N:20]1[CH2:3][CH:2]1[CH2:1][C:4]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([C:14]1[CH:15]=[CH:16][C:11]([CH3:33])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: C=CCC1(O)CCCCC1
Reactant: Cc1ccc(S(=O)(=O)N=C2CCCCI2c2ccccc2)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2CC2CC2(O)CCCCC2)cc1
Temperature: 25 °C
Yield: 13.3 %

Procedure:
A flame-dried 100 mL three-necked flask was purged with N2, and charged with Cu(OTf)2 (95 mg, 0.26 mmol), 1-allylcyclohexanol (960 mg, 9.86 mmol) and acetonitrile (HPLC grade). Solid [N-(p-Toluenesulfonyl)imino]phenyliodinane (PhINTs, prepared as described in Inorgania Chimica Acta 2003, 342, 301-304, 1.97 g, 5.28 mmol) was added in a single portion and the mixture was stirred at rt until all PhINTs had dissolved (within 5 to 30 min). The solvent was removed and the residue was chromatographied on silica gel eluted with hexane/EtOAc to give 1-((1-tosylaziridin-2-yl)methyl)cyclohexanol (217 mg, 13%). MS m/z 310 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C:16]4=[O:21])=[CH:11][C:8]=3[O:9][CH2:10][C@H:5]2[C@H:4]([C:22]([OH:24])=O)[O:3]1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([NH2:32])=[N:30][CH:31]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([NH:32][C:22]([C@H:4]2[C@H:5]3[N:6]([C:7]4[CH:14]=[CH:13][C:12]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][C:16]5=[O:21])=[CH:11][C:8]=4[O:9][CH2:10]3)[C:2](=[O:1])[O:3]2)=[O:24])=[N:30][CH:31]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ccc(Cl)cn1)[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Yield: 52.65 %

Procedure:
Using compound (3R,3aS)-1-oxo-7-(3-oxomorpholin-4-yl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-carboxylic acid (the product of step (b) in Example 36) (90 mg, 0.24 mmol), 5-chloropyridine-2-amine (37 mg, 0.287 mmol), HATU (137 mg, 0.36 mmol), and TEA (48.4 mg, 0.48 mmol) as starting materials, preparation following the method as described in Example 11 (g) afforded white solid 56 mg, yield: 52.65%.
Reaction SMILES: N[C@H]([C:5](O)=[O:6])C[SeH].[Li]CCCC.[Si]([O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([Cl:28])[CH:22]=1)(C(C)(C)C)(C)C.CN(CCN(C)C)C.CN(C=O)C.Cl>C1COCC1>[OH:20][C:21]1[CH:26]=[C:25]([F:27])[C:24]([CH:5]=[O:6])=[C:23]([Cl:28])[CH:22]=1
Reactant: N[C@@H](C[SeH])C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(Cl)c1
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=Cc1c(F)cc(O)cc1Cl
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Sec-BuLi (1.3M solution in cyclohexane, 42.3 mL, 55 mmol) was added slowly at −78° C. to a solution of intermediate 16, 1-(tert-Butyldimethylsilyl)oxy-3-chloro-5-fluorobenzene (13.1 g, 50 mmol) and TMEDA (8.3 mL, 55 mmol) in THF (200 mL) and the mixture was stirred at the same temperature for 30 min. DMF (4.23 mL, 55 mmol) was added to the mixture at −78° C., and the mixture was stirred at the same temperature for 1.5 h. Then 10% aqueous HCl was added to attain pH˜4-5 (200 mL), and the reaction mixture was stirred at RT for 12 h. Aqueous layer was extracted with EtOAc (200 mL). The organic layer was separated. The organic layer was washed with sat. NaHCO3, then H2O was added, HCl was added to attain pH˜3-4, the organic layer was separated, washed with brine, dried with Na2SO4 and evaporated in vacuo to give the title compound (7.53 g, 86%, 43 mmol) as a white solid. 1H NMR data (dmso-d6): 11.51 (br.s, 1H, OH), 10.15 (s, 1H, CHO), 6.78-6.83 (m, 1H, H—Ar), 6.68 (dd, 1H, J1=2.2 Hz, J2=12.7 Hz, H—Ar).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].S(=O)(=O)(O)O.[CH2:11]=[CH:12][C:13]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])([CH3:15])[OH:14]>>[C:13]([O:14][CH:1]([O:3][CH2:4][CH3:5])[CH3:2])([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])([CH:12]=[CH2:11])[CH3:15]
Reactant: C=COCC
Reactant: C=CC(C)(O)CCC=C(C)C
Agent: O=S(=O)(O)O
Product: C=CC(C)(CCC=C(C)C)OC(C)OCC
Yield: 82.3 %

Procedure:
Into an 1 l reaction flask is placed 216 g vinylethyl ether. Under stirring a solution of 0.2 g concentrated sulfuric acid (s.g. 1.84) in 154 g linalool is added over a 2 hour period at 30°C. Then 100 g of a 10-percent soda solution are added to the reaction mixture and the entire mixture is stirred for half an hour. The organic upper layer is separated and fractionated with 0.5 g soda to obtain 186 g acetaldehyde ethyl linalyl acetal. The acetal has a boiling point of 90°-94°C. at 2 mm Hg; nD20 1,4495-1,4485. The addition of soda to the product to be distilled prevents the formation of 5.9-dimethyl-4.8-decadien-1-al during the fractionation.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([CH2:10][CH2:11][CH2:12][CH:13]=[O:14])=[C:6]([CH:9]=1)[C:7]#[N:8].C1COCC1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]([CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(N)c(Cl)cc1CCCC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(N)c(Cl)cc1CCCCO
Temperature: 0 °C
Reaction time: 2 h
Yield: 47.4 %

Procedure:
5-amino-4-chloro-2-(4-oxobutyl)benzonitrile (544 mg, 2.443 mmol) was taken up in MeOH (6 mL) and THF (2.000 mL) and cooled to 0° C. NaBH4 (277 mg, 7.33 mmol) was added, and the reaction was stirred at 0° C. for 2 h (reaction followed by TLC until no SM detected). The reaction was quenched with water and extracted 2× with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated. The material was purified by flash column chromatography (0-50% EtOAc/DCM; 40 g column). 5-amino-4-chloro-2-(4-hydroxybutyl)benzonitrile (260 mg) was obtained as a yellow glass.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([O:11]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)[C:15]([O-:17])=[O:16].[O-]CC.[Na+]>C(O)C>[O:11]=[C:9]([CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)CCc1ccccc1
Reactant: CCOC(=O)C(=O)[O-]
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(=O)CCc1ccccc1
Reaction time: 15 h
Yield: 90.9 %

Procedure:
A mixture of 143 g of ethyl 3-phenylpropionate, 234 g of ethyl oxalate and 154 ml of 28% sodium ethoxide solution in ethanol is heated on a water bath at a bath temperature of 60°-70° C. for 1.5 hours, while distilling off the ethanol under reduced pressure. To the resulting red syrupy residue is added 1.3 liters of 15 v/v % sulfuric acid. The mixture is boiled under reflux with stirring for 15 hours, and the oil layer is separated, neutralized with 10% sodium hydroxide and extracted with ethyl acetate. The aqueous layer is made acidic with diluted sulfuric acid. The resulting oil is extracted with ethyl acetate, washed with water and dried. Removal of the ethyl acetate by distillation under reduced pressure gives 130 g of 2-oxo-4-phenylbutyric acid as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].C1(=O)O[CH2:16][CH2:15][O:14]1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[O:12][CH2:16][CH2:15][OH:14]
Reactant: COc1cc([N+](=O)[O-])ccc1O
Reactant: O=C1OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClC(Cl)Cl
Product: COc1cc([N+](=O)[O-])ccc1OCCO
Temperature: 160 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
2-Methoxy-4-nitrophenol (10.2 g), ethylene carbonate (5.66 g) and tetrabutylammonium iodide (2.1 g) were mixed and stirred for 2 hours at 160° C. After being cooled, all solids were dissolved into chloroform (300 ml) and the solution was washed with water (300 ml) two times. The organic layer was dehydrated with anhydrous magnesium sulfate (10 g) and concentrated under vacuum to obtain 2-(2-methoxy-4-nitrophenoxy)ethanol (12.0 g) as yellowish solid.
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15].[C:17]1(C)C=CC(S(O)(=O)=O)=C[CH:18]=1>>[CH3:17][C:18]1[N:4]([CH2:3][CH:2]([CH3:16])[CH3:1])[C:5]2[C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:15]=1
Reactant: CC(C)CNc1c(N)cnc2cccnc12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1nc2cnc3cccnc3c2n1CC(C)C

Procedure:
In one aspect, the invention provides a method for making 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine. The method includes: providing N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in a carrier including toluene; combining the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine in the carrier with a hydrogenation catalyst and isopropanol to form a mixture; subjecting the mixture that includes the N4-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine and the hydrogenation catalyst to a hydrogen atmosphere under conditions effective to form N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine; removing at least a portion of the hydrogenation catalyst from the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine; removing at least a portion of the isopropanol from the mixture of N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in a carrier that includes toluene and isopropanol; heating the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier to a temperature of 20° C. to 55° C.; combining the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine in the carrier with p-toluenesulfonic acid to form a mixture; combining the mixture that includes the N4-(2-methylpropyl)[1,5]naphthyridine-3,4-diamine and p-toluenesulfonic acid with a trialkyl orthoacetate at a temperature of 70° C. to 100° C.; maintaining the temperature at 70° C. to 100° C. for a period of time sufficient to form 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine; cooling the mixture that includes 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine to a temperature of 45° C. to 55° C.; combining the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine in the carrier with an oxidizing agent including peracetic acid to form a mixture; maintaining the mixture that includes the 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine and peracetic acid at a temperature of 45° C. to 55° C. for a time sufficient to form 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine; and isolating at least a portion of the 2-methyl-1-(2-methylpropyl)-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine.