Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:5]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>ClCCl.C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][N:20]([C:32]([NH:31][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])=[O:33])[CH2:19][CH2:18]2)[C:5]2[C:10]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: COc1ccccc1N=C=O
Reactant: Nc1nc(N2CCNCC2)c2c(-c3cccnc3)csc2n1
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccccc1NC(=O)N1CCN(c2nc(N)nc3scc(-c4cccnc4)c23)CC1
Reaction time: 8 h
Yield: 60.7 %

Procedure:
To a solution of Example 10 (50 mg, 0.15 mmol) in dichloromethane (2 mL) and acetonitrile (1 mL) was added 2-methoxyphenyl isocyanate (21 μL, 0.16 mmol). The reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo and the crude residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 0.5% to 3% methanol in dichloromethane), yielding the title compound (42 mg) as a white powder. MS (m/z) 462 [M+H]+.
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C>[OH:1][CH:2]([CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CO1
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC(O)CN1CCCCC1
Temperature: 70 °C
Yield: 64.1 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.27 mmol) and piperidine (79 μl, 0.8 mmol) in DMF (4 ml) was heated at 70° C. for 24 hours. The solvent was removed by evaporation and the residue was recrystallised from acetonitrile. The solid was filtered, washed with diethyl ether and dried to give 7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (80 mg, 65%).
Reaction SMILES: [C:1]([O:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])(OC(C)(C)C)=O.O.Cl.[CH:18]#[C:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1>N1C=CC=CC=1>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([CH:19]=[CH2:18])=[CH:21][CH:22]=1.[C:12]([O:11][C:9]([O:8][C:1]1[CH:22]=[CH:21][C:20]([CH:25]=[CH2:24])=[CH:19][CH:18]=1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C#Cc1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: C=Cc1ccc(O)cc1
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1

Procedure:
In 40 ml of pyridine was dissolved poly(p-hydroxystyrene) (VP-8000, manufactured by Nippon Soda Co., Ltd., weight average molecular weight: 1,1000) and to the solution was added 1.28 g of di-tert-butyl dicarbonate at a room temperature with stirring. The solution was reacted at a room temperature for 3 hours and poured into a solution of one liter of ion exchange water and 20 g of concentrated hydrochloric acid. The powder thus-deposited was collected by filtration, washed with water and dried to obtain 2.1 g of p-hydroxystyrene/p-(tert-butoxycarbonyloxy)-styrene (60/40) copolymer.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[N:3]=1.[OH:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:5]([C:11]#[N:12])=[C:6]([O:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:7]=1
Reactant: OCCc1ccccn1
Reactant: COc1ccccc1-c1nc(N)nc(S(C)=O)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COc1ccccc1-c1nc(N)nc(OCCc2ccccn2)c1C#N

Procedure:
From 2-amino-4-methanesulfinyl-6-(2-methoxy-phenyl)-pyrimidine-5-carbonitrile, 2-(2-hydroxyethyl)pyridine and DBU in DME. ES-MS m/e (%): 348 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([Cl:16])[CH:11]=[C:12]2[Cl:15])=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[C:3]([C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([CH3:17])[CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([Cl:16])[CH:11]=[C:12]2[Cl:15])=[N:7]1)#[N:4]
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)cc2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4,6-dichloro-2H-indazol-2-yl)-2-methylpropionitrile (20 mg, described in Example 145) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (34 mg, 97%). MS (ES): M/Z [M+H]=473. 1H NMR: (400 MHz, CHLOROFORM-d): 1.96 (s, 3H), 4.82 (d, 1H), 4.93 (d, 1H), 7.15 (d, J=0.9 Hz, 1H), 7.60 (s, 1H), 7.79 (d, 2H), 7.88 (d, 2H), 8.22 (s, 1H) and 8.32 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.2 (s, 3F).
Reaction SMILES: [Br:1][C:2]([CH3:12])([CH3:11])[C:3]([NH:5][C:6]([N:8]([CH3:10])C)=[O:7])=[O:4].Br[C:14](C)(C)C(Br)=O.CNC(NC)=O>CS(C)=O>[Br:1][C:2]([CH3:11])([CH3:12])[C:3]([N:5]([CH3:14])[C:6]([NH:8][CH3:10])=[O:7])=[O:4]
Reactant: CN(C)C(=O)NC(=O)C(C)(C)Br
Reactant: CC(C)(Br)C(=O)Br
Agent: CNC(=O)NC
Solvent: CS(C)=O
Product: CNC(=O)N(C)C(=O)C(C)(C)Br
Yield: 38 %

Procedure:
This compound was prepared similarly to 1-(2-bromo-2-methylpropionyl)-3,3-dimethylurea in Example 7a from 2-bromo-2-methylpropionyl bromide and 1,3-dimethylurea. It was obtained in 38% yield as a yellow oil, νmax (Nujol) 3330 (NH), 1730, 1700 cm-1 (CON. CON). τ(DMSO d6) 6.44 (NMe) 7.13 (d,J 5; NHMe), 7.95 (CMe2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]1([C:16]2[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:16]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=[CH:18][C:19]([CH2:20][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:22][CH:23]=1
Reactant: O=Cc1cccc(O)c1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cccc(OCc2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.1 %

Procedure:
A mixture of 3-hydroxybenzaldehyde (6.02 g, 49 mmol), 4-phenyl-benzylchloride (10 g, 49 mmol) and potassium carbonate (20 g, 148 mmol) in N,N'-dimethylformamide (100 ml) was stirred at room temperature for 16 h. The mixture was poured into water (500 ml) and stirred for 1 h. The solid formed was filtered off, washed with water (2×200 ml) and heptane (2×75 ml) and dried in vacuo at 50° C. for 16 h affording 12.3 g (87%) of 3-(biphenyl-4-ylmetoxy)benzaldehyde as a solid. TLC showed presence of unchanged 4-phenylbenzylchloride.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:26]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[C:18]([NH2:27])[C:17]=2[N:16]=[C:15]1[CH2:28][CH2:29][CH2:30][CH3:31].O.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[NH2:27][C:18]1[C:17]2[N:16]=[C:15]([CH2:28][CH2:29][CH2:30][CH3:31])[N:14]([CH2:13][CH2:12][CH2:11][NH:10][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[S:9])[C:26]=2[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N:19]=1
Reactant: S=C=Nc1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNC(=S)Nc1ccccc1
Yield: 65.4 %

Procedure:
Phenyl isothiocyanate (750 mg, 5.55 mmol) was added dropwise with stirring to a chilled (0° C.) solution of 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.0 g, 3.36 mmol) in 1-methyl-2-pyrrolidinone (50 mL). The reaction mixture was poured into water (500 mL) and the pH adjusted to 10 with solid potassium carbonate. The resulting precipitate was isolated by filtration and then rinsed with water. This material was slurried with hot methanol and then purified by column chromatography (silica gel eluting with 2% methanol in dichloromethane to 7% methanol in dichloromethane). The purified material was recrystallized from isopropanol to provide 950 mg of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylthiourea as a white solid, m.p. 142.8–144.0° C. Analysis: Calculated for C24H28N6S. C3H8O: % C, 65.82; % H, 7.37; % N, 17.06; Found: % C, 65.77; % H, 7.41; % N, 17.11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([O:24][CH:25]([CH3:27])[CH3:26])[C:19]=1[O:20][CH:21]([CH3:23])[CH3:22])[C:5]([NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)=[O:6].[CH:28](Br)(C)C.NC1C=CC(C(OC)=O)=C(C)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([O:24][CH:25]([CH3:27])[CH3:26])[C:19]=1[O:20][CH:21]([CH3:22])[CH3:23])[C:5]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[C:15]([CH3:28])[CH:16]=1)=[O:6]
Reactant: CC(C)Oc1cc(C(=O)Nc2ccc(C(=O)O)cc2)cc(Cl)c1OC(C)C
Reactant: CC(C)Br
Agent: COC(=O)c1ccc(N)cc1C
Product: Cc1cc(NC(=O)c2cc(Cl)c(OC(C)C)c(OC(C)C)c2)ccc1C(=O)O

Procedure:
4-(3-Chloro-4,5-diisopropoxybenzamido)benzoic acid (AAA-051) (103 mg, 48% for final step) was prepared in essentially the same manner as AAA-044 except isopropyl bromide was used instead of cyclopentyl iodide and the reaction performed at 80° C. in step (iii) and that methyl 4-amino-2-methylbenzoate was used instead of methyl 4-aminobenzoate in step (v): m/z 404 [M−H]− (ES−); 1H NMR (400 MHz, DMSO-d6) δ: 12.62 (1H, br s), 10.34 (1H, s), 7.87 (1H, d), 7.73 (1H, dd), 7.68 (2H, d), 7.54 (1H, d), 4.76 (1H, m), 4.59 (1H, m), 2.54 (3H, s), 1.33 (6H, d), 1.28 (6H, d).
Reaction SMILES: C(OC([N:8]([N+:36]([O-:38])=[O:37])[C@H:9]([C:17]([CH:19]([NH2:35])[CH2:20][CH2:21][CH2:22][C@@H:23]([C:25]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30])=[O:26])[NH2:24])=[O:18])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:16])[NH2:15])=O)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([O-:43])=[O:42].[N+:36]([NH:8][C@H:9]([C:17]([CH:19]([NH2:35])[CH2:20][CH2:21][CH2:22][C@@H:23]([C:25]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30])=[O:26])[NH2:24])=[O:18])[CH2:10][CH2:11][CH2:12][NH:13][C:14](=[NH:15])[NH2:16])([O-:38])=[O:37]
Reactant: CC(C)(C)OC(=O)N([C@@H](CCCNC(=N)N)C(=O)C(N)CCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)O)[N+](=O)[O-]
Reactant: O=C(O)C(F)(F)F
Product: N=C(N)NCCC[C@H](N[N+](=O)[O-])C(=O)C(N)CCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Product: O=C([O-])C(F)(F)F

Procedure:
the product of stage (d) is treated with trifluoroacetic acid to obtain trifluoroacetate of α-benzyloxycarbonyl, ε-(nitroarginyl) lysylproline;
Reaction SMILES: [C:1]1([C:7]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[SH:17][CH2:18][CH2:19]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CCC>[C:11]1([C:9]2[S:17][CH2:18][CH2:19][O:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCCS
Reactant: O=C(c1ccccc1)C(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: c1ccc(C2=C(c3ccccc3)SCCO2)cc1

Procedure:
Benzoin (106 g, 0.5 mole), 2-mercaptoethanol (43 g, 0.55 mole), and p-toluenesulfonic acid (pTSA) (5 g) are charged into a 2-liter 3-neck flask. n-Butanol (1200 mL) is added and the mixture stirred with a mechanical stirrer. The reaction is heated to reflux and the distillate passed through a vacuum-jacketed column (18 in by 3/4 in) packed with porcelain saddles. A Dean-Stark trap is placed at the top of the column to assist in the separation of the aqueous layer from the butanol/water azeotrope. After water ceases to separate, distillate is slowly removed until the vapor temperature at the top of the column reaches 117°-118°, the boiling point of dry n-butanol. The reaction mixture is cooled and seeded, and the crystalline product separated by filtration. The filtrate is returned to the reactor along with further amounts of benzoin, 2-mercaptoethanol, and pTSA as specified above. Sufficient n-butanol is added to make up for that removed in the prior reaction. When the procedure is repeated five times, the overall isolated yield of 2,3 -dihydro-5,6-diphenyl-1,4-oxathiin is 76% of theoretical.
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15]CC)=O)[CH:5]=[N:4][C:3]1=2.[NH2:18][CH2:19][CH2:20][CH2:21][NH2:22].CCOCC.C(#N)C>CO>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([NH:18][CH2:19][CH2:20][CH2:21][NH2:22])=[O:15])[CH:5]=[N:4][C:3]1=2
Reactant: NCCCN
Reactant: CCOC(=O)CCn1cnc2c(=O)[nH]cnc21
Solvent: CC#N
Solvent: CO
Solvent: CCOCC
Product: NCCCNC(=O)CCn1cnc2c(=O)[nH]cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
0.250 g (1.06 mmol) of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propionic acid, ethyl ester (AIT-0027) was added to 1.85 g (25.0 mmol) of 1,3-diaminopropane in a 10 ml round bottom flask equipped with a magnetic stirring bar. The solution was stirred at room temperature for two hours. 10 ml ether was added and the solution was stirred for a few minutes. The ether solution was decanted, leaving an oil residue. 5 ml of acetonitrile and 4 ml of ether were added and the solution was stirred. Methanol was added dropwise until a precipitate had formed. The solution was filtered and washed with acetonitrile and ether, to yield 205 mg of 3-(1,6-dihydro-6-oxo-9H-purin-9-yl)-N-(3-aminopropyl)propanamide (AIT-0074). m.p. 172°-175° C. Yield: 73%
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:20]=[CH:19][C:12]2[S:13][C:14]([C:16](O)=[O:17])=[CH:15][C:11]=2[CH:10]=1)[CH3:2].[NH3:23].C(OCC)(=O)C>O1CCCC1>[CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][O:6][CH2:7][CH2:8][C:9]1[CH:20]=[CH:19][C:12]2[S:13][C:14]([C:16]([NH2:23])=[O:17])=[CH:15][C:11]=2[CH:10]=1)[CH3:2]
Reactant: CCN(CC)CCOCCc1ccc2sc(C(=O)O)cc2c1
Reactant: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCN(CC)CCOCCc1ccc2sc(C(N)=O)cc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 30 mL of tetrahydrofuran is dissolved 2.18 g of 5-{2-[2-(diethylamino)ethoxy]ethyl}benzo[b]-thiophene-2-carboxylic acid, to which is added 1.98 g of N,N′-carbonyldiimidazole. The resulting mixture is stirred at ambient temperature for one hour. Then, 50 mL of 25% aqueous ammonia is added to the mixture and the resulting mixture is stirred at ambient temperature for one hour. Ethyl acetate is added to the mixture, the organic layer is separated, washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent:chloroform:methanol to chloroform:methanol:ammonia=5:1 to 100:10:1). Thus, 2.00 g of 5-{2-[2-(diethylamino)ethoxy]ethyl}benzo[b]-thiophene-2-carboxamide is obtained as a colorless crystalline product.
Reaction SMILES: C1(PC2C=CC=CC=2)C=CC=CC=1.CO[CH:16]1[C@@H:21]2[C:22]3[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=3[O:24][CH2:25][C@@H:20]2[CH2:19][CH2:18][N:17]1[CH2:30][CH2:31][CH3:32].Cl.C1C[O:37]CC1>CCCCCC>[OH:37][C:29]1[C:22]2[C@@H:21]3[C@H:20]([CH2:25][O:24][C:23]=2[CH:26]=[CH:27][CH:28]=1)[CH2:19][CH2:18][N:17]([CH2:30][CH2:31][CH3:32])[CH2:16]3
Reactant: CCCN1CC[C@H]2COc3ccccc3[C@H]2C1OC
Reactant: C1CCOC1
Agent: Cl
Agent: c1ccc(Pc2ccccc2)cc1
Solvent: CCCCCC
Product: CCCN1CC[C@H]2COc3cccc(O)c3[C@H]2C1
Reaction time: 0.05 h

Procedure:
To a solution of 0.48 g of diphenylphospine in 4 ml THF under nitrogen at 0° is added 1.38 ml n-butylithium (2.24M in hexane). After 3 min., 0.238 g (±)-[4aR*,10bS*]-1,3,4,4a,5,10b-hexahydro-1-methoxy-2-propyl-2 H-[1]benzopyrano[4,3-c]pyridine in 1 ml THF is added. The mixture is refluxed 2.5 hours. After cooling 8 ml 2N HCl is added and the THF evaporated under reduced pressure. The aqueous phase is extracted with two 10 ml portions of ether, basified with solid NaHCO3 and extracted with six 20 ml portions of CH2Cl2. The CH2Cl2 extracts are dried over Na2SO4, filtered, concentrated under reduced pressure and flash chromatographed with CH2Cl2 /ammonia saturated methanol (20:1) to yield the title compound; m.p. of HCl salt 264°-265° dec.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH3:8].[N+](=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])=[N-]>CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cu]>[CH2:3]([C:4]1[C:11]([C:16]([O:18][CH3:19])=[O:17])([C:12]([O:14][CH3:15])=[O:13])[C:5]=1[CH2:6][CH2:7][CH3:8])[CH2:2][CH3:1]
Reactant: CCCC#CCCC
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Agent: [Cu]
Solvent: CC(=O)CC(C)=O
Product: CCCC1=C(CCC)C1(C(=O)OC)C(=O)OC

Procedure:
4-Octyne and dimethyl diazomalonate were reacted in the presence of cupric acetylacetonate in a manner similar to that described in Example XCVII Part A to give dimethyl 2,3-di-n-propyl-2-cyclopropene-1,1-dicarboxylate which was saponified to give mono-methyl 2,3-di-n-propyl-2-cyclopropene-1,1-dicarboxylate and worked up by the general procedure of Example XCVII Part B. Reaction of the latter mono-methyl ester in sequence with ethyl chloroformate and 4-bromo-2-methylaniline, in the presence of potassium carbonate and 18-crown-6, in a manner similar to that described in Example XCIX Part B to give methyl 1-(4-bromo-2-methylphenyl-aminocarbonyl)-2,3-di-n-propyl-2-cyclopropenecarboxylate having a melting point of 52° C.-54° C. Elemental analysis of the product indicated the following:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)#[CH:17]>C(O)(C)C>[C:16]([C:18]1[CH:19]=[C:20]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:21]=[CH:22][CH:23]=1)#[CH:17]
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Reactant: C#Cc1cccc(N)c1
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(F)c([N+](=O)[O-])cc23)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
4-Chloro-7-fluoro-6-nitroquinazoline and 3-ethynylbenzenamine (234 mg, 2 mmol) was dissolved into isopropanol (5 mL) and refluxed for 3 h. After cooled to room temperature, the precipitate was filtered out and washed with water to give 0.59 g of N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazolin-4-amine (95%).
Reaction SMILES: Cl.CO[C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6].[CH3:16][NH2:17].CO.[CH3:20][C:21]([CH3:23])=O>>[OH:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@@H:5]2[NH:6][C:21]([CH3:23])([CH3:20])[N:17]([CH3:16])[C:4]2=[O:15])=[CH:13][CH:12]=1
Reactant: CN
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CC(C)=O
Agent: Cl
Solvent: CO
Product: CN1C(=O)[C@H](Cc2ccc(O)cc2)NC1(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(S)-tyrosine methyl ester hydrochloride (23 g, 100 mmol) was added to an ethanolic solution of MeNH2 (60 mL, 8 M), and the resulting mixture was stirred at room temperature for 24 h. The excess MeNH2 was removed by distillation or by washing with THF several times until the N-methyl amide product was obtained as a white solid. Dry MeOH (200 mL) and dry acetone (40 mL) were added to this residue. The resulting solution was stirred at 60° C. for 24 h, cooled to room temperature, and then concentrated in vacuo. Compound 2 was obtained as a white solid in 82% overall yield (19.2 g, 82 mmol) after silica gel chromatography (1:1 of EtOAc:Hex). 1H NMR (CDCl3): δ 7.09 (d, 2H), 6.74 (d, 2H), 3.82 (t, 1H), 3.06 (m, 2H), 2.78 (s, 3H), 1.32 (s, 3H), 1.22 (s, 3H). Elemental analysis for C13H18N2O2 (2)—calculated: C 66.64, H 7.74, N 11.96%; observed: C 66.24, H 7.70, N 12.10%.
Reaction SMILES: [CH3:1][C:2](=O)[CH:3]([S:7][C:8]1[N:12]=[CH:11][NH:10][N:9]=1)[C:4](=[O:6])[CH3:5].Cl.NO.C([N:19](CC)CC)C>C(O)C>[CH3:1][C:2]1[C:3]([S:7][C:8]2[N:12]=[CH:11][NH:10][N:9]=2)=[C:4]([CH3:5])[O:6][N:19]=1
Reactant: CCN(CC)CC
Reactant: CC(=O)C(Sc1nc[nH]n1)C(C)=O
Agent: Cl
Agent: NO
Solvent: CCO
Product: Cc1noc(C)c1Sc1nc[nH]n1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 3-(2,4-pentanedion-3-yl)thio-1H-1,2,4-triazole (2 g), hydroxylamine hydrochloride (0.7 g), triethylamine (1.4 ml) and ethanol (10 ml) was heated and stirred for 5 hours on an oil bath at 100° C. The reaction solution was concentrated under reduced pressure, and then extracted with ethyl acetate-water. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to a silica-gel column chromatography with 10 to 30% (20% 2-propanol/ethyl acetate)/hexane, followed by recrystallization in ethyl acetate-hexane to yield the title compound (440 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[CH2:10](Br)[C:11]#[CH:12].C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[F:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:9][CH2:12][C:11]#[CH:10])[C:2]=1[F:1]
Reactant: C#CCBr
Reactant: Oc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C#CCOc1cccc(F)c1F

Procedure:
115.0 g (0.88 mol) of 2,3-difluorophenol are refluxed for 3 h in 1.6 l of ethyl methyl ketone together with 118.2 ml (17.7 mol) of propargyl bromide (80% soln. in toluene) and 146.6 g (138.2 mol) of potassium carbonate. The batch is filtered, and the filter residue is washed with MTBE. The filtrate is evaporated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:MTBE=3:1).
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH:24]([NH:23][S:21]([C:17]([CH3:18])([CH3:20])[CH3:19])=[O:22])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)CCCCC=NS(=O)C(C)(C)C
Reactant: COc1cccc(OC)c1I
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CCCCC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A cooled (−78° C.) yellow solution of 2-iodo-1,3-dimethoxybenzene (6.337 g; 24.00 mmol) in anh. THF (130 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (15.0 ml; 24.00 mmol). The resulting yellow solution was further stirred at −78° C. for 15 min. A yellow solution of ethyl 6-((tert-butylsulfinyl)imino)hexanoate (5.018 g; 19.20 mmol) in anh. THF (12 ml) was then added dropwise to the cooled reaction mixture, and stirring at −78° C. was continued for 50 min. The resulting orange reaction mixture was treated successively with aq. sat. NH4Cl (65 ml), Et2O (200 ml) and water (60 ml). The separated yellow organic layer was then washed with brine (60 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded ethyl 6-(2,6-dimethoxyphenyl)-6-(1,1-dimethylethylsulfinamido)hexanoate as a yellow oil. LC-MS (conditions B): tR=0.91 min.; [M+H]+: 400.05 g/mol.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[ClH:14].[H][H]>C(O)C.[Pd]>[ClH:14].[NH2:2][CH2:1][C:3]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)c1cccnc1C#N
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cccnc1CN
Reaction time: 12 h

Procedure:
To a solution of ethyl 2-cyano-3-pyridinecarboxylate (2.5 g) and conc. HCl (5 mL) in 150 mL ethanol was added 10% Pd/C (wet, 250 mg) and the reaction mixture was hydrogenated using a hydrogen balloon and stirred for 12 h. The reaction was filtered through celite and ethanol was evaporated to give ethyl 2-(aminomethyl)-3-pyridinecarboxylate HCl as a white solid which was used in the next step without further purification.