Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:21]=[C:22]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]4)[CH:23]=[CH:24][CH:25]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[CH3:36][C:37]([CH3:51])([CH3:50])[CH2:38][CH2:39][O:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][CH:46]=1>>[Cl:19][C:13]1[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=1[C:10]1[N:11]=[C:7]([CH2:6][C:5]2[CH:34]=[CH:35][C:2]([C:45]3[CH:44]=[CH:43][CH:42]=[C:41]([O:40][CH2:39][CH2:38][C:37]([CH3:51])([CH3:50])[CH3:36])[CH:46]=3)=[CH:3][CH:4]=2)[N:8]([C:20]2[CH:21]=[C:22]([N:26]3[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH2:27]3)[CH:23]=[CH:24][CH:25]=2)[CH:9]=1
Reactant: CC(C)(C)CCOc1cccc(B(O)O)c1
Reactant: O=C1CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(Br)cc3)c2)S(=O)(=O)N1
Product: CC(C)(C)CCOc1cccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3-c3cccc(N4CC(=O)NS4(=O)=O)c3)cc2)c1

Procedure:
5-{3-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,2,5-thiadiazolidine-3-one-1,1-dioxide (59 mg, 0.1 mmol) was treated as described in general procedure G using 3-(3,3-dimethyl-butoxy)phenylboronic acid (45 mg, 0.2 mmol, prepared according to general procedure H) to give 5-(3-{4-(2,4-dichloro-phenyl)-2-[3′-(3,3-dimethyl-butoxy)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: [C:1]([NH:5][NH2:6])(=O)[CH2:2][OH:3].[CH:7]1([N:10]=[C:11]=S)[CH2:9][CH2:8]1.[OH-].[Na+].[N+]([O-])(O)=O.N1C=CN=N1>N([O-])=O.[Na+].O.CO>[CH:7]1([N:10]2[CH:11]=[N:6][N:5]=[C:1]2[CH2:2][OH:3])[CH2:9][CH2:8]1
Reactant: S=C=NC1CC1
Reactant: NNC(=O)CO
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: O=[N+]([O-])O
Product: OCc1nncn1C1CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
To a methanol (50 ml) solution of glycolic acid hydrazide (5.0 g) was added cyclopropyl isothiocyanate (5.5 g) at 20° C. The mixture was stirred for one hour, to which was then added water (30 ml) at 0° C. To the resultant mixture was added dropwise a 5N aqueous solution of NaOH (11 ml), the temperature of which was raised to 20° C., followed by stirring for 3 hours. The reaction mixture was concentrated under reduced pressure to make its volume about 10 ml. The concentrate was diluted with ethanol (100 ml), to which was added dropwise a 5N aqueous solution of HCl (11 ml) under ice-cooling. Insoluble substances were filtered off, and the filtrate was concentrated to dryness under reduced pressure to give crude crystals (6.4 g) of 4-cyclopropyl-5-hydroxymethyl-3-mercapto-4H-1,2,4-triazole. This compound (3.0 g) was added to a mixture of concentrated nitric acid (d=1.38) (4.6 ml), water (12 ml) and sodium nitrite (10 mg) at 60° C. Then, concentrated nitric acid (1.0 ml) was added. When a portion of nitric acid was contacted with small amount of a triazole compound on the inside wall of the reaction vessel, the reaction started and the reaction temperature reached 90° C.~100° C., then the reaction was completed. The reaction mixture was cooled with ice, neutralized with an aqueous solution of NaOH, and concentrated under reduced pressure. The concentrate was subjected to a silica gel chromatography (3×10 cm), eluting with methanol-dichloromethane (1:4). The desired fraction was concentrated to give 4-cyclopropyl-3-hydroxymethyl-4H-1,2,4-triazole (2.0 g). This product (1.0 g) was added to thionyl chloride (10 ml) at 0° C., which was refluxed for 20 minutes. The mixture was cooled, then excess volume of thionyl chloride was distilled off under reduced pressure. To the residue was added diethyl ether, and the resulting powder was collected by filtration. This product was recrystallized from a mixture of ethanol and ethyl acetate to give 4-cyclopropyl-3-chloromethyl-1,2,4-triazole hydrochloride (1.34 g).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.[Cl:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:14]=1[CH2:15][NH:16][NH2:17]>>[NH2:10][C:6]1[NH:17][N:16]([CH2:15][C:14]2[C:13]([Cl:12])=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:22])[C:4](=[O:3])[CH:5]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: NNCc1c(Cl)cccc1Cl
Product: Nc1cc(=O)n(Cc2c(Cl)cccc2Cl)[nH]1

Procedure:
35 g of β-amino-β-ethoxyacrylic acid ethyl ester and 38 g of 2,6-dichlorobenzylhydrazine when reacted as described in Example 45, yield 24 g of the compound identified above as colorless crystals, corresponding to 46% of theory, of melting point 225°.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][NH:9][C:5]2=[N:6][C:7]=1[CH3:8].[H-].[Na+].Cl[CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20]>CN(C)C=O>[Br:1][C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][N:9]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:5]2=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc2[nH]ccc2nc1Br
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c(ccn2COCC[Si](C)(C)C)nc1Br
Reaction time: 0.25 h
Yield: 56.3 %

Procedure:
To a mixture of the crude 2-bromo-3-methyl-5H-pyrrolo[2,3-b]pyrazine (3.83 g, 18 mmol) prepared above and N, N-dimethylformamide (25 mL), under an atmosphere of argon and cooled in an ice bath, was added 95% sodium hydride oil dispersion (0.912 g, 36 mmol) (gas evolution). The mixture was stirred for 15 minutes, and then (2-chloromethoxy-ethyl)-trimethylsilane (3.61 g, 22 mmol) in N, N-dimethylformamide (3 mL) was added dropwise. After 10 minutes, the cooling bath was removed and the mixture stirred for another 3½ hours at room temperature. The mixture was cooled in an ice bath, quenched by the addition of water, and then poured into water and extracted three times with ether. The combined ether extracts were washed twice with water, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by chromatography (silica, 15% ethyl acetate in hexanes) gave 2-bromo-3-methyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (3.47 g, 56%) as an amber solid. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.11 (s, 9H), 0.82 (m, 2H), 2.67 (s, 3H), 3.51 (m, 2H), 5.59 (s, 2H), 6.67 (d, J=3.5 Hz, 1H), 8.01 (d, J=3.5 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:16][C:17]([OH:19])=[O:18])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>>[O:15]=[C:13]1[C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:16][C:17](=[O:18])[O:19]1
Reactant: O=C(O)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1C[C@@H](NC(=O)OCc2ccccc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(benzyloxycarbonylamino)succinic acid (Aldrich, 30 g, 112.26 mmol) and acetic anhydride (65.7 ml, 696.02 mmol) was stirred overnight at room temperature during which time the reaction mixture became clear. The volatiles were removed under reduced pressure (water bath temperature 65° C.) and the concentrate was azeotroped with toluene (3×50 ml) and obtained the title product after drying for ˜48 hours at 60° C. under high vacuum pump (28.0 g, yield: almost quantitative).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:11]=[CH:12][CH3:13]>P(=O)(O)(O)O>[CH:12]([C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)([CH3:13])[CH3:11]
Reactant: c1ccc2ccccc2c1
Reactant: C=CC
Agent: O=P(O)(O)O
Product: CC(C)c1cccc2ccccc12

Procedure:
These and other objects and advantages of the invention by the instant process comprises (1) alkylating naphthalene with propylene in the presence of a phosphoric acid catalyst supported on SiO2, at a temperature of 150°-280° C. and a pressure of 5-30 atm. using a mol ratio of 1/5 to 1/20 mol propylene per 1 mol of starting naphthalene, until in the reaction 45 to 65% of the naphthalene has been isopropylated and then without separating off the unreacted naphthalene, (2) further treating the alkylation mixture by heating it in the presence of a phosphoric acid catalyst supported on SiO2 under an inert gas pressure of 5 to 30 atm. to a temperature of 180° to 280° C. until substantially no more β-isopropylnaphthalene is formed from the α-isopropylnaphthalene. There is thereby obtained an isomeric mixture consisting of 90-95% of the β-isopropylnaphthalene isomer. Pure β-isopropylnaphthalene can be recovered from this isomeric reaction product by distillation and crystallization.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:11])[CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:26][N:27]([CH3:32])[CH2:28][C:29](Cl)=[O:30]>O1CCCC1>[Br:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=[C:2]2[NH:1][C:29](=[O:30])[CH2:28][N:27]([CH3:32])[CH3:26]
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(Br)ccc21
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(C)CC(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of Example 282B (24.43 g, 78 mmol), potassium carbonate (81 g, 587 mmol) and 2-(dimethylamino)acetyl chloride hydrochloride (43.3 g, 274 mmol) was added tetrahydrofuran (200 mL). The reaction mixture was stirred at room temperature for about 2 hours. The reaction mixture was filtered and the filtrate was washed with water (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (3×100 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol in dichloromethane (5%) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.72 (s, 1H), 8.19 (d, 1H, J=1.6), 8.03 (d, 1H, J=9.0), 7.76 (dd, 1H, J=2.0, 9.0), 3.22 (s, 2H), 2.32 (s, 6H), 1.63 (s, 9H).
Reaction SMILES: [CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:2]([CH3:4])[CH3:3].[O:25]([CH2:32][C:33](Cl)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([N:5]([S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])[C@H:6]([C:12]([OH:14])=[O:13])[CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:33](=[O:34])[CH2:32][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCN)C(=O)O)cc1
Reactant: O=C(Cl)COc1ccccc1
Product: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)COc2ccccc2)C(=O)O)cc1
Yield: 77 %

Procedure:
Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine was reacted with phenoxyacetyl chloride under the conditions described in example 2. The crude material was purified by flash chromatography (CH2Cl2:MeOH, 19:1 to 9:1) to yield 77% of the desired product.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)C(N)(CO)C[OH:16].Cl.N1C2C(=NC=CN=2)C(=O)NC=1N>CC1(C)NC2C(N=C(N)NC=2NC1)=O>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:16])=[CH:6][CH:5]=1
Reactant: NC(CO)(CO)CO
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC1(C)CNc2[nH]c(N)nc(=O)c2N1
Agent: Cl
Agent: Nc1nc2nccnc2c(=O)[nH]1
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reaction time: 0.03 h

Procedure:
Absorbance Spectrum of Quinoid-6,6-Me2PH2Generated by Phenylalanine Hydroxylase. Spectra were taken of the q-6,6-Me2PH2 synthesized enzymatically from 6,6-Me2PH4, and a comparison made with the chemically produced compound. The spectrophotometer was baseline corrected with sample and reference cuvettes containing all of the reaction components (0.1M Tris·HCl, pH 7.4, 4 mM phenylalanine, 2500 units catalase, 0.3 unit phenylalanine hydroxylase) except pterin in a total volume of 0.99 ml. 6,6-Me2PH4 (10 μl of 10 mM) was then added to the sample and distilled H2O (10 μl) to the reference cuvette. Scanning was begun immediately and spectra taken at 2 minute intervals. The formation of q-6,6-Me2PH2 was complete within 4 minutes. After correction for tyrosine formed and phenylalanine consumed, the spectrum was within 3% of that produced by Br2 oxidation of 6,6-Me2PH4 (FIGURE).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7](=[O:12])[NH:6][C:5]=2[N:4]=[CH:3]1.[H-].[Na+].[CH2:15](Br)[C:16]1[O:20][CH:19]=[CH:18][CH:17]=1>CS(C)=O>[O:20]1[CH:19]=[CH:18][CH:17]=[C:16]1[CH2:15][N:6]1[C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:10]=2[C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: BrCc1ccco1
Reactant: Cn1cnc2[nH]c(=O)[nH]c(=O)c21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cn1cnc2c1c(=O)[nH]c(=O)n2Cc1ccco1
Reaction time: 0.5 h
Yield: 14.3 %

Procedure:
To a stirring suspension of 7-methylxanthine (2.54 g, 15.3 mmol) in dimethylsulfoxide (80 ml) was added sodium hydride (0.37 mg, 15.3 mmol) in one portion. After stirring for 30 minutes, freshly prepared furfuryl bromide (2.5 g, 15.3 mmol) was added neat. After stirring at room temperature for 18 hours, the reaction was quenched by addition of water (150 ml). Saturated aqueous sodium chloride solution (30 ml) was added and the mixture was extracted with chloroform (4×50 ml). The combined extracts were washed with saturated aqueous sodium bicarbonate solution (3×50 ml), with saturated aqueous sodium chloride solution (2×50 ml) and dried over a mixture of sodium sulfate and activated charcoal. After filtration through a pad of celite, the solvent was evaporated under reduced pressure. The residue was treated with ethyl acetate. The solid was filtered, rinsed with cold ethyl acetate (2×25 ml) and vacuum dried to give 3-(2-furylmethyl)-7-methylxanthine (0.54 g, 14% yield) as a beige solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](CC(=O)C)=[CH:3][CH:2]=1.F[C:12]1[CH:13]=C(C=[CH:18][C:19]=1[O:20]C)C=O.N1CCCCC1>C1(C)C=CC=CC=1>[N:1]1[CH:2]=[CH:3][CH:4]=[C:5]([CH2:18][C:19](=[O:20])[CH:12]=[CH2:13])[CH:6]=1
Reactant: CC(=O)Cc1ccncc1
Reactant: COc1ccc(C=O)cc1F
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: C=CC(=O)Cc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 146.9 %

Procedure:
A solution of 4-pyridylacetone (1.0 g, 7.4 mmol), 3-fluoro-p-anisaldehyde (1.25 g, 8.1 mmol), and piperidine (0.13 g, 1.5 mmol) in toluene (50 ml) was heated to reflux. After 18 hours, the reaction was cooled to room temperature and the solvent was removed under reduced pressure. The crude product (3.0 g) was purified by column chromatography (silica gel, 65:35 ethyl acetate/hexane) to give 4-(3-fluoro-4-methoxy]phenyl)-3-pyridyl-3-butene-2-one as a pale yellow solid (1.60 g, 80%).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[CH:24]=[CH:23][N:22]=[CH:21]1>>[N:20]1([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH2:28][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:24]=[CH:23][N:22]=[CH:21]1
Reactant: O=Cc1cccc(-n2ccnc2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-n2ccnc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with commercially available 3-(1H-imidazol-1-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.57 min.; [M+H]+: 392.38 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.[CH3:28][C:29]([CH3:31])=O>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH:29]([CH3:31])[CH3:28])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:25]=2)[CH2:16][CH2:15]1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ncccn4)CC3)n1-2
Reactant: CC(C)=O
Product: CC(C)N1Cc2cc(Cl)ccc2-n2c(nnc2C2CCN(c3ncccn3)CC2)C1
Yield: 65 %

Procedure:
The title compound was prepared from acetone and the amine of example 12, in 65% yield, using the procedure described in example 13.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[C:5]([CH:14]([CH3:16])[CH3:15])[C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[CH:14]([C:5]1[C:6]([O:12][CH3:13])=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[N:11]=[CH:10]2)([CH3:16])[CH3:15]
Reactant: COc1ccc2cnc(Cl)nc2c1C(C)C
Reactant: Nc1ccccc1
Solvent: CC#N
Product: COc1ccc2cnc(Nc3ccccc3)nc2c1C(C)C
Temperature: 80 °C
Yield: 77.1 %

Procedure:
A mixture of 2-chloro-7-methoxy-8-(2-propyl)quinazoline (100 mg, 0.42 mmol) and aniline (120 mg, 1.29 mmol) in acetonitrile (3 mL), was heated at 80° C. for 18 hours in a sealed tube. The solvent was removed under reduced pressure, to the residue 5% sodium carbonate solution was added. The product was extracted with ethyl acetate (3×25 mL). The combined organic extract was washed with brine, dried (Na2SO4), and concentrated. The product was purified on a column of silica gel to give the title compound as an off-white solid (95 mg, 76.3%), mp 172–173° C.; 1H NMR (CDCl3): δ 1.46 (d, 6H, 2×CH3), 3.97 (s, 3H, OCH3), 4.33 (m, 1H, CH), 7.0–7.1 (m, 2H, Ar-H), 7.38 (t, 2H, Ar-H, 7.58 (d, 1H, Ar-H), 7.85 m, 2H, Ar-H), 8.93 (s, 1H, Ar-H); MS m/z C18H19N3O 294.21 (M++1); Analysis: Calcd.; C, 73.7; H, 6.53; N, 14.32. Found: C, 73.8; H, 6.83; N, 14.59.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[CH3:30][O:31][NH2:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([NH:32][O:31][CH3:30])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Reactant: CON
Product: CONC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and O-methylhydroxylamine gave 189. MS: (ESI+) 443.1
Reaction SMILES: C(O[CH:5]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH:10][C:9](=[O:17])[CH2:8][CH2:7][CH2:6]1)(=O)C>C(O)C.[Pd]>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1=[O:17]
Reactant: CC(=O)OC1CCCC(=O)Nc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: O=C1CCCCc2ccccc2N1

Procedure:
A solution of 6-acetoxy-3,4,5,6-tetrahydro-1-benzazocin-2(1H)-one (7.4 g) in ethanol (250 ml) is hydrogenated at 45 psi at 70° C. using 10% palladium on charcoal (1.5 g) as catalyst. The catalyst is filtered off and the solvent removed under reduced pressure. The residue is recrystallized from methanol/ethyl acetate to give 3,4,5,6-tetrahydro-1-benzazocin-2(1H)-one.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[CH3:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:42](=[O:44])[CH3:43].[Cl-].[NH4+]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:42](=[O:44])[CH3:43])[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:24]=1[CH3:25])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CON(C)C(C)=O
Reactant: Cc1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ncn1COCC[Si](C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
4-(tert-Butyldiphenylsilyloxymethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)-1H-imidazole (24.6 g) was dissolved in THF (300 mL), and cooled to −78° C. while stirring under an argon atmosphere. To the present solution was added dropwise n-butyl lithium (2.66 M hexane solution, 28.9 mL) slowly using a syringe, followed by stirring at the same temperature for 30 minutes. Then, N-methoxy-N-methylacetamide (10.5 mL) was added using a syringe, and stirring was continued for 2 hours while the temperature was raised to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The combined extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=0%→50%) using silica gel column (product name: Hi-Flash Column 5 L, manufactured by Yamazen Corporation) to afford the title compound (11.7 g).
Reaction SMILES: [CH2:1]([C:5]1[S:6][C:7]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14](OCC)=[O:15])[C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]>CCOCC>[CH2:1]([C:5]1[S:6][C:7]2[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[C:8]=2[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(s1)CCCC2C(=O)OCC
Solvent: CCOCC
Product: CCCCc1nc2c(s1)CCCC2CO
Yield: 48 %

Procedure:
The compound is prepared by reduction of the above derivative (III), with AlLiH4 in ether at room temperature. B.p.0.6 =130°-132° C. Yield: 48%.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]>>[CH2:17]([O:16][C:10](=[O:15])[C:11](=[C:4]([NH2:5])[C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])[C:12](=[O:13])[CH3:14])[CH3:18]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1ccccc1F
Product: CCOC(=O)C(C(C)=O)=C(N)c1ccccc1F

Procedure:
The title compound was synthesized in analogy to Example 1 from 2-fluoro-benzonitrile and ethyl acetoacetate: MS (m/z) 252.2 (M+1).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:13]=[C:12]([S:14][CH3:15])[CH:11]=[CH:10][C:6]=1[C:7]([Cl:9])=O)[CH2:2][CH3:3].Cl.C[O:18][C:19]1[C:24]([NH2:25])=[C:23]([NH2:26])[CH:22]=[CH:21][N:20]=1>>[ClH:9].[CH2:1]([O:4][C:5]1[CH:13]=[C:12]([S:14][CH3:15])[CH:11]=[CH:10][C:6]=1[C:7]1[N:25]=[C:24]2[C:19](=[O:18])[NH:20][CH2:21][CH:22]=[C:23]2[N:26]=1)[CH2:2][CH3:3]
Reactant: COc1nccc(N)c1N
Reactant: CCCOc1cc(SC)ccc1C(=O)Cl
Agent: Cl
Product: CCCOc1cc(SC)ccc1C1=NC2=CCNC(=O)C2=N1

Procedure:
This compound was prepared analogous to Example 2 from 2-propoxy-4-methylmercapto-benzoyl chloride and 2-methoxy-3,4-diamino-pyridine hydrochloride. Melting point: above 260° C.