Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.Br[CH2:21][CH2:22][CH2:23][CH3:24]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:21]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=2)[CH2:1]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCBr
Reactant: N#Cc1ccc2c(c1)CNCC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCN1CCc2ccc(C#N)cc2C1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To an ice-cold, stirred solution of 1,2,3,4-tetrahydroisoquinoline-7-carbonitrile (J. Med. Chem. 1997, 40, 3997) (485 mg, 3.1 mmol) and triethylamine (0.47 mL, 3.4 mmol) in methylene chloride (5 mL) is added DMAP (37 mg, 0.3 mmol) and bromobutane (0.5 mL, 4.6 mmol). The reaction mixture is stirred for 20 h, diluted with methylene chloride, washed with water, and brine, dried (magnesium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 50% ethyl acetate/hexanes) affords the title compound. ESI MS m/z 215 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.O.[CH3:17]O>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: Cc1ccccc1C(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 40.0 grams (0.29 mole) of 2-methylbenzoic acid in 200 ml of methanol was added dropwise 20 ml of concentrated sulfuric acid. Upon completion of addition the reaction mixture was heated to reflux where it stirred for 18 hours. The reaction mixture was cooled to ambient temperature and poured into 200 ml of water. The mixture was extracted with three 100 ml portions of methylene chloride. The combined extracts were washed with two 50 ml portions of aqueous saturated sodium bicarbonate solution, then with 50 ml of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 42.7 grams of methyl 2-methylbenzoate.
Reaction SMILES: CC([S@]([NH:7][C@@H:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]([CH3:17])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[CH3:10])=O)(C)C.Cl.O1CCOCC1.CO.[OH-].[Na+]>ClCCl.O>[CH3:17][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)([CH3:10])[C@H:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[NH2:7]
Reactant: CC(C)(c1ccccn1)[C@@H](N[S@](=O)C(C)(C)C)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)(c1ccccn1)[C@@H](N)c1ccccc1
Temperature: 32 °C
Reaction time: 1.5 h
Yield: 107.2 %

Procedure:
To a solution of (R)-2-methyl-N-((S)-2-methyl-1-phenyl-2-(pyridin-2-yl)propyl)propane-2-sulfinamide (1200 g, 3.631 moles) dissolved in dichloromethane (12000 mL) was added 4N hydrogen chloride/dioxane solution (3000 mL, 12.00 moles) in a steady stream over a period of 1 hour at room temperature. A thick suspension formed, which was continued stirring for 1.5 hours at 32° C.; at which point Methanol (1000 mL) was added to improve stirring. After 30 minutes additional stirring, all of the solids dissolved, giving a clear amber solution and indicating complete reaction. The solvents were removed under reduced pressure leaving a gummy amber residue. The residue was taken up in distilled water (5000 mL), and the resulting solution washed with diethyl ether (2×1000 mL) to remove neutral impurities. The acidic solution was treated with solid Sodium hydroxide (400 g, 10.00 moles) until strongly basic (pH=11). The resulting aqueous mixture was extracted with dichloromethane (2×1000 mL, then 2×500 mL). The combined organic extracts were dried (anhydrous magnesium sulfate). Filtration, followed by removal of the solvent under reduced pressure, left a thick amber syrup. This residue was further dried under high vacuum to yield the crude de-protected amine (880.9 g, 107.2% of theory). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.64 (d, J=3.79 Hz, 1 H) 7.57 (td, J=7.69, 1.90 Hz, 1 H) 7.05-7.30 (m, 7 H) 4.48 (s, 1 H) 1.47 (br.s., 2H) 1.36 (s, 3 H) 1.25 (s, 3 H). MS: m/z 227.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](OC)=[O:19])=[CH:14][CH:13]=2)=[C:8]([CH3:22])[CH:7]=1)(=[O:3])[CH3:2].[CH3:23][N:24]([CH3:40])[CH2:25][CH2:26][CH2:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33][NH:34]2)=[CH:30][C:29]=1[O:37][CH2:38][CH3:39]>>[C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([N:34]3[C:35]4[C:31](=[CH:30][C:29]([O:37][CH2:38][CH3:39])=[C:28]([CH2:27][CH2:26][CH2:25][N:24]([CH3:40])[CH3:23])[CH:36]=4)[CH2:32][CH2:33]3)=[O:19])=[CH:16][CH:17]=2)=[C:8]([CH3:22])[CH:7]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc(CNC(C)=O)cc2C)cc1
Reactant: CCOc1cc2c(cc1CCCN(C)C)NCC2
Product: CCOc1cc2c(cc1CCCN(C)C)N(C(=O)c1ccc(-c3ccc(CNC(C)=O)cc3C)cc1)CC2

Procedure:
The title compound was prepared from methyl 4'-acetamidomethyl-2'-methylbiphenyl-4-carboxylate (D2) and 2,3-dihydro-6-(3-dimethylamino propyl)-5-ethoxy-1H-indole (D29) using a similar procedure to Example 1 (18%). The hydrochloride salt was obtained as a cream coloured solid mp 120°-123° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][C@@H:11]2[C@:20]3([CH3:21])[C@H:15]([C:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][CH2:19]3)[CH2:14][CH2:13][C@@:12]2([CH3:25])O)[CH:6]=[CH:7][CH:8]=1.Cl[Sn](Cl)(Cl)Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C@@:12]3([CH3:25])[C@H:11]([CH2:10][S:9]2)[C@:20]2([CH3:21])[C@H:15]([C:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][CH2:19]2)[CH2:14][CH2:13]3)=[CH:7][CH:8]=1
Reactant: COc1cccc(SC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)SC[C@@H]1[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]21C
Temperature: -78 °C
Reaction time: 4 h
Yield: 46.3 %

Procedure:
To a solution of (1R,2R,4aS,8aS)-1-{[(3-methoxyphenyl)sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (12b) (2.5 g, 6.9 mmol) in CH2Cl2 (70 mL), cooled to −78° C., a solution of SnCl4 (3.22 mL, 27.6 mmol) in CH2Cl2 (30 mL) was added dropwise. The mixture was stirred at −78° C. for 4 h. The reaction was quenched with water (100 mL), and the organic layer was separated, dried (Na2SO4), and concentrated. Purification by column chromatography on silica gel (Hexanes/toluene, 2:1) gave (1R,10R,11S,16S)-5-methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 51) (1.10 g, 46%) as a white solid. 1H NMR (CDCl3): δ 7.19 (d, 1H), 6.58 (m, 2H), 3.72 (s, 3H), 2.95 (q, 2H), 2.40 (m, 1H), 1.84-1.35 (m, 9H), 1.20 (s, 3H), 1.18-0.99 (m, 2H), 0.95 (s, 3H), 0.85 (s, 3H), 0.82 (s, 3H). (1R,10R,11S,16S)-3-Methoxy-1,11,15,15-tetramethyl-8-thiatetracyclo[8.8.0.02,7.011,16]octadeca-2,4,6-triene (Compound No. 52) (0.44 g, 19%) was also isolated as a white solid. 1H NMR (CDCl3): δ 6.96 (t, 1H), 6.67 (d, 1H), 6.56 (d, 1H), 3.78 (s, 3H), 3.32 (m, 1H), 2.82 (q, 2H), 1.82-1.40 (m, 7H), 1.38 (s, 3H), 1.35-0.98 (m, 3H), 0.92 (s, 3H), 0.95 (m, 1H), 0.87 (s, 3H), 0.83 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH2:27]>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([NH:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1)=[CH:5]2
Reactant: Nc1ccccn1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Nc3ccccn3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and pyridin-2-ylamine to give 6-Methoxy-N3-(5-methyl-1H-pyrazol-3-yl)-N1-pyridin-2-yl-isoquinoline-1,3-diamine. LC-MS m/e 347(MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.ClCCCOC1C=C(C2C3SC=CC=3ON=2)C=CC=1.[NH2:39][CH2:40][C:41]1[CH:42]=[N:43][CH:44]=[CH:45][CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>>[N:43]1[CH:44]=[CH:45][CH:46]=[C:41]([CH2:40][NH:39][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[C:16]4[S:17][CH:18]=[CH:19][C:15]=4[O:14][N:13]=3)[CH:7]=2)[CH:42]=1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1cccnc1
Agent: ClCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1cncc(CNCCCOc2cccc(-c3noc4ccsc34)c2)c1
Yield: 77 %

Procedure:
The title compound is prepared from a mixture of 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-[3-(3-chloro-propoxy)-phenyl]-thieno[2,3-d]isoxazole, 3-(aminomethyl)pyridine and potassium carbonate essentially as described above in example 4. Combine the appropriate fractions and concentrate to give the title compound (0.28 g, 77% Yield) as and oil. Purity by LC/MS (APCI)=98% area, [M+H]+=366 m/e.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20](I)[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2].N1C=CC=CC=1C1C=CC=CN=1.[CH2:36]([S:38]SCC)[CH3:37]>CN(C)C=O.[Zn].[Ni](Br)Br>[C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([S:38][CH2:36][CH3:37])[C:21]=1[OH:22])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10](=[O:18])(=[O:17])[CH2:9]1)=[O:7])#[N:2]
Reactant: CCSSCC
Reactant: N#Cc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(I)c1O
Agent: Br[Ni]Br
Agent: [Zn]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CN(C)C=O
Product: CCSc1cc(C(=O)N2CS(=O)(=O)c3ccccc32)cc(C#N)c1O
Temperature: 110 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
3-(3-cyano-4-hydroxy-5-iodobenzoyl)-1,1-dioxo-2,3-dihydro-1,3-benzothiazole (500 mg) was dissolved in N,N-dimethylformamide (5 mL), and 2,2′-bipyridine (18 mg), zinc powder (149 mg), nickel bromide (25 mg) and diethyl disulfide (70 mg) were added to the solution, and then the mixture was stirred at 110° C. for 1 hour. After the reaction solution was filtered, 1N hydrochloric acid was added and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) and then crystallized from diethylether-ethyl acetate to obtain the title compound (63 mg) as a colorless crystal.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[K+].[K+].[O:21]=[CH:22][C:23]1[CH:31]=[CH:30][C:28]([OH:29])=[C:25]([O:26][CH3:27])[CH:24]=1.CN(C)C=O>O>[CH3:27][O:26][C:25]1[CH:24]=[C:23]([CH:31]=[CH:30][C:28]=1[O:29][CH2:2][C:3]1[N:4]=[C:5]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[S:6][C:7]=1[CH3:8])[CH:22]=[O:21]
Reactant: Cc1sc(N2CCCCC2)nc1CCl
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OCc1nc(N2CCCCC2)sc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
A mixture of 1-(4-chloromethyl-5-methyl-1,3-thiazol-2-yl)piperidine (0.57 g), potassium carbonate (0.35 g), vanillin (0.38 g) and N,N-dimethylformamide (20 mL) was stirred at 80° C. for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 3-methoxy-4-[(5-methyl-2-piperidin-1-yl-1,3-thiazol-4-yl)methoxy]benzaldehyde as colorless crystals (0.61 g, yield 70%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 80-81° C.
Reaction SMILES: N[C@H](C(O)=O)C[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.CC1C(O)=C(C=O)C(COP(O)(O)=O)=CN=1.OP([O-])([O-])=O.[K+].[K+].OP([O-])(O)=O.[K+].ClC(Cl)(Cl)C(O)=O>>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=C(O)C(Cl)(Cl)Cl
Agent: O=P([O-])(O)O
Product: c1ccc2[nH]ccc2c1
Reaction time: 0.17 h

Procedure:
Measured in accordance with the method of Yamada et al. as follows. In 4.0ml of a reaction mixture containing 10 micromoles of L-tryptophan, 0.4 micromole of pyridoxalphosphate (PLP)), 200 micromoles of K2HPO4 -KH2PO4 (pH 8.0), the enzyme is incubated at 65° C. for 10 minutes. Then, 1.0 ml of a 30% aqueous solution of trichloroacetic acid (TCA) is added to stop the reaction. Indole formed in the reaction system is quantitatively determined by the method of E. McEvoy-Bowe [The ANALYST, vol. 88, pages 893-894 (1963)]. The activity is expressed in units in which 1 U is the amount in micromoles of indole formed during 1 minute.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)Cl.[CH2:22]=[C:23]([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][C:23]([CH3:25])([CH3:24])[CH3:22])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C=C(C)C
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 98 %

Procedure:
A 100-ml flask was charged with 5 ml of toluene and 2.12 g (10 mmol) of 4′-methyl-2-biphenylcarboxylic acid, and they were vigorously stirred. To this mixture was added dropwise 0.18 ml (2 mmol) of phosphorus oxytrichloride, and isobutene gas (98 mmol) was introduced to the mixture at a flow rate of 1.2 liter/min for 2 minutes. The resulting mixture was stirred at room temperature for 6 hours. After having confirmed that almost all of the peaks ascribed to 4′-methyl-2-biphenylcarboxylic acid disappeared by HPLC, the reaction solution was washed with a 1.5 M aqueous sodium hydroxide. The reaction solution was dried over anhydrous magnesium sulfate, and then the mixture was concentrated by distilling off toluene by using a rotary evaporator, to give 2.63 g of tert-butyl 4′-methyl-2-biphenylcarboxylate as crystals (yield: 98% based on 4′-methyl-2-biphenylcarboxylic acid, purity by HPLC: 99.9%). Incidentally, the obtained compound had the same physical properties as those of the compound obtained in Example II-1.
Reaction SMILES: [NH2:1][C@H:2]1[C:15]2[CH:14]=[C:13]3[C:8]([N:9]=[CH:10][CH:11]=[N:12]3)=[CH:7][C:6]=2[O:5][C:4]([CH3:17])([CH3:16])[C@@H:3]1[OH:18].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO>[CH:15]1([CH2:2][CH2:3][NH:1][C@H:2]2[C:15]3[CH:14]=[C:13]4[C:8]([N:9]=[CH:10][CH:11]=[N:12]4)=[CH:7][C:6]=3[O:5][C:4]([CH3:16])([CH3:17])[C@@H:3]2[OH:18])[CH2:14][CH2:13][CH2:8][CH2:7][CH2:6]1
Reactant: CC1(C)Oc2cc3nccnc3cc2[C@H](N)[C@H]1O
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC1(C)Oc2cc3nccnc3cc2[C@H](NCCC2CCCCC2)[C@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 48 %

Procedure:
To a solution of (8R*,9S*)-9-amino-7,7-dimethyl-8,9-dihydro-7H-pyrano[2,3-g]quinoxalin-8-ol (100 mg, 0.408 mmol) in methanol (2 mL), cyclohexylmethyl aldehyde (103 mg, 0.816 mmol) was added, and the resulting mixture was stirred at room temperature for 20 minutes. Sodium cyanoborohydride (51 mg, 0.816 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. Upon the completion of the reaction, saturated sodium hydrogencarbonate aqueous solution was added thereto, the resulting solution was extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over magnesium sulfate and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=2/1) to obtain the aimed product (yield: 48%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]([CH3:24])=[CH2:23])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].C([NH+](CC)CC)C.O>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]([CH3:24])=[CH2:23])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]2[NH:27][N:26]=[N:25][N:18]=2)=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: [N-]=[N+]=[N-]
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C#N)nn1
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(-c2nnn[nH]2)nn1
Temperature: 120 °C
Reaction time: 7 h
Yield: 47.7 %

Procedure:
6-[N-(5-Bromo-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]-3-cyanopyridazine (reference example 13) (0.52 g, 1.34 mmol) in N-methylpyrrolidone (13 ml) was treated with sodium azide (403 mg, 6.1 mmol) followed by triethylammonium chloride (537 mg, 3.9 mmol) and the mixture stirred under argon for 7 hours at 120° C. The mixture was then poured into water and acidified to around pH2. It was then extracted twice with ethyl acetate and the combined organic extracts washed twice with water, dried and evaporated to give a solid. The solid was purified by MPLC, and triturated with a 1:1 mixture of diethyl ether/ethyl acetate to give the title compound as an off-white solid (275 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:15]([CH3:18])([O-:17])=[O:16].[OH-].[K+]>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:18][N+:15]([O-:17])=[O:16])[CH:7]=[CH:8][CH:9]=1
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1cccc(Cl)c1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1cccc(Cl)c1

Procedure:
A mixture of 28.11 g (200 mmol) of 3-chlorobenzaldehyde, 15.4 g of ammonium acetate and 32.5 mL of nitromethane in 230 mL of glacial acetic acid was heated at reflux temperature for 3 h and then poured onto ice. The resultant aqueous mixture was made basic by the addition of 45% aqueous potassium hydroxide. The precipitate was filtered and crystallized from ethyl acetate/hexane to give 5 g of the title compound. The filtrate was concentrated to afford an additional 13.5 g of product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](O)[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][OH:23]>C(O)CC>[OH:23][CH2:22][CH2:21][CH2:20][NH:19][C:6]1[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=[CH:2][CH:7]=1
Reactant: NCCCO
Reactant: CCCOc1ccccc1-c1nc(O)cc(Cl)n1
Solvent: CCCO
Product: CCCOc1ccccc1-c1nccc(NCCCO)n1

Procedure:
A stirred solution of 4-chloro-6-hydroxy-2-(2-propoxyphenyl)pyrimidine (0.66 g) and 3-amino-1-propanol (0.56 g) in n-propanol was heated under reflux for 16 hours. The cooled reaction mixture was evaporated under reduced pressure to yield an oil which was partitioned between chloroform (20 ml) and water (20 ml). The chloroform layer was separated from the aqueous layer which was extracted with chloroform (2×10 ml) and the combined chloroform layers were washed with water, dried (magnesium sulphate) and evaporated under reduced pressure. The residue was recrystallised from isopropanol:diethyl ether to yield the title compound, 0.54 g, m.p. 147.5°-148.5° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][OH:5].C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH2:4][O:5][C:20](=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1ccc(F)c(CO)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-fluoro-5-nitrobenzyl alcohol (1 g, 5.84 mmol) in 5 mL dichloromethane and triethylamine (0.81 ml, 5.84 mmol), was added acetyl chloride (0.415 ml, 1 eq) dropwise. The solution was stirred at room temperature for 12 hours, diluted with ethyl acetate and extracted with brine. Combine organic layers was dried over sodium sulfate, concentrated in vacuo to give acetic acid 2-fluoro-5-nitro-benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[S:19][C:18]([CH2:20]Cl)=[CH:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH:34]([OH:38])[CH2:35][NH:36][CH3:37])=[CH:33][C:28]=2[O:27][CH2:26]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH:34]([OH:38])[CH2:35][N:36]([CH2:20][C:18]3[S:19][C:12]4[C:11](=[O:22])[C:10]([C:8]([NH:7][CH2:6][C:5]5[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=5)=[O:9])=[CH:15][N:14]([CH3:16])[C:13]=4[CH:17]=3)[CH3:37])=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2sc(CCl)cc21
Reactant: CNCC(O)c1ccc2c(c1)OCO2
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc2c(s1)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C)CC(O)c1ccc2c(c1)OCO2
Temperature: 60 °C
Reaction time: 5 h
Yield: 65.3 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (80 mg, 0.21 mmol), 1-(1,3-benzodioxol-5-yl)-2-(methylamino)ethanol (Journal of Organometallic Chemistry, 1998, 339, 267-75) (62 mg, 0.32 mmol) and diisopropylethylamine (67 μL, 0.38 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 5 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight in the refrigerator. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile/water (dissolved with warming 3 mL of acetonitrile, then cooled to 0° C. and then diluted with 2 mL of water, left overnight) gave the title compound (74 mg) as a white solid.
Reaction SMILES: [C:1]1(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[CH:2]1.[C:13](O)(=O)[CH2:14]C.S1(CCCC1)(=O)=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(#N)C.O.[N+]([O-])([O-])=O.[Ag+]>[CH2:13]([C:3]1[C:4](=[O:11])[C:5]2[C:10]([C:1](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:14]
Reactant: CCC(=O)O
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: O=S1(=O)CCCC1
Solvent: CC#N
Solvent: O
Product: CCC1=CC(=O)c2ccccc2C1=O
Temperature: 0 °C

Procedure:
A solution of 1,4-naphthoquinone (7.91 g), propanoic acid (3.70 g) and silver nitrate (1.53 g) in a mixture of acetonitrile (11.4 mL), sulfolane (34.1 mL) and water (79.5 mL) was heated at 60°-65° C. for 2 hours. A solution of ammonium persulfate (13.7 g) in water (25 mL) was then added dropwise. The mixture was cooled in ice water and extracted with ether. The organic layer was washed with saturated sodium bicarbonate, water and brine, then dried, filtered and evaporated. Chromatography over silica gel afforded 2-ethyl-1,4-naphthoquinone, m.p. 87°-88° C.
Reaction SMILES: [CH:1]([O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2([O:4][CH:1]([CH3:3])[CH3:2])[CH2:6][CH2:7]2)=[CH:9][CH:10]=1)#[CH:15]
Reactant: CC(C)OC1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(OC(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [4-(1-isopropoxycyclopropyl)-phenylethynyl]-trimethylsilane (Intermediate 65, 260.0 mg, 0.96 mmol) in methanol (10 mL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambient temperature. The crude alkyne (220 mg, 100%) was used directly in the next reaction.