Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH3:23])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:24][CH2:25][C:26]#[N:27])=[CH:5][C:4]=2[N:3]=1.[OH-:28].[Na+].OO>CO>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:22][CH3:23])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:24][CH2:25][C:26]([NH2:27])=[O:28])=[CH:5][C:4]=2[N:3]=1
Reactant: CCc1nc2c(N)nc3cc(CCC#N)ccc3c2n1CC1CCOCC1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: CCc1nc2c(N)nc3cc(CCC(N)=O)ccc3c2n1CC1CCOCC1
Temperature: 50 °C
Yield: 27.8 %

Procedure:
3-[4-Amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanenitrile (590 mg, 1.6 mmol), 10% aqueous sodium hydroxide (132 mg, 0.33 mmol), and 30% aqueous hydrogen peroxide (516 mg, 4.55 mmol) were combined in methanol (75 mL) and the reaction was heated at 50° C. for 18 hours. The mixture was concentrated under reduced pressure and then partitioned between chloroform (75 mL) and water (75 mL). The fractions were separated and the aqueous fraction was extracted with chloroform (3×25 mL). The combined organic fractions were sequentially dried (MgSO4), filtered, concentrated to dryness and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 2 L of 10% methanol in dichloromethane). A final recrystallization from acetonitrile provided 35 mg of 3-[4-amino-2-ethyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanamide as an off-white solid, mp 197-199° C.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:24]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([O:16][CH3:24])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
Boc-Asp(OBn)-OH 2.4 g (1 equiv, 7.45 mmol) was dissolved in 17 mL of dry DMF in a 100 mL round-bottom flask. Finely ground K2CO3 (1.5 g, 11 mmol) was added to the solution to form a suspension. The mixture was cooled to 0° C. in an ice-bath over five minutes. MeI (1 mL, 15 mmol) was then added to the mixture over 20 seconds under a positive flow of nitrogen. A yellow color developed within 30 min. The resulting mixture was stirred for 3 hours. The ice-bath was removed and 25 mL of water were added and the mixture left standing at room temperature 2 hours. The mixture was then treated with 30 mL of water and extracted with 3×25 mL AcOEt. The organics were washed with saturated NaHCO3 1×, brine 3×, dried over Na2SO4 filtered and concentrated to yield a yellow oil. This material was passed through a short silica column (eluting w/ AcOEt), after concentration of the pure fractions 2.42 g of Boc-Asp(OBn)-OMe as a yellow oil was obtained (98% yield). 1H NMR (DMSO d6, 500 mHz): δ 7.36 (m, 5H), 5.10 (s, 2H), 4.40 (q, 1H), 3.6 (s, 3H), 2.80 (dd, 1H), 2.72 (dd, 1H), 1.38 (s, 9H). LCMS (C18, 2-98% CH3CN in 0.1% TFA/H2O over 6 min); Calculated mass for C17H23NO6 (M+H)+ 338.23. found by LC-MS 338.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[N:10]1.[Cl:19][C:20]1[CH:27]=[C:26](F)[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[Cl:19][C:20]1[CH:27]=[C:26]([O:15][CH2:14][C:13]2[N:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:10]=[N:11][C:12]=2[CH:16]([CH3:18])[CH3:17])[CH:25]=[CH:24][C:21]=1[CH:22]=[O:23]
Reactant: O=Cc1ccc(F)cc1Cl
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1COc1ccc(C=O)c(Cl)c1
Temperature: 100 °C
Yield: 68.1 %

Procedure:
To solution of [3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol (0.100 g, 1 eq) and 2-chloro-4-fluorobenzaldehyde (0.11 g, 2 eq) in dimethylformamide (3 mL) is added cesium carbonate (0.23 g, 2 eq). The reaction is heated to 100° C. overnight. The reaction is cooled to room temperature and water is added. The mixture is extracted with ethyl acetate and the organic layers are washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified via flash chromatography eluting with 0-10% ethyl acetate:toluene to give 0.101 g of 2-Chloro-4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-benzaldehyde. ES/MS m/e 426.1 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][NH:10][CH3:11])=[CH:6][N:5]=[C:4]2[N:12]([S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:13]=[CH:14][C:3]=12.CCN(C(C)C)C(C)C>C(O)CC>[CH3:11][N:10]1[C:2]2=[C:3]3[CH:14]=[CH:13][N:12]([S:15]([C:18]4[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=4)(=[O:17])=[O:16])[C:4]3=[N:5][CH:6]=[C:7]2[CH2:8][CH2:9]1
Reactant: CNCCc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Solvent: CCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c4c(cnc32)CCN4C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.1 %

Procedure:
2-(4-Chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-N-methylethanamine (0.670 g, 1.84 mmol) in PrOH (20 mL) was heated to about 105° C. for about 44 h. DIEA (0.39 mL, 2.2 mmol) was added and heating was continued at about 105° C. for about 24 h. The mixture was cooled to rt and the solvent was evaporated under reduced pressure. The material was treated with saturated NaHCO3 (15 mL) and water (10 mL) then extracted with DCM (25 mL then 10 mL). The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The material was purified by flash chromatography on 10 g of silica with EtOAc as an eluent to give 1-methyl-6-tosyl-1,2,3,6-tetrahydrodipyrrolo[2,3-b:2′,3′-d]pyridine (0.308 g, 51%): LC/MS (Table 2, Method a) Rt=2.53 min; MS m/z 328 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.Br[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][C:16]2[CH:15]=[CH:14][CH:19]=[CH:18][C:17]=2[CH2:20][CH2:21][OH:22])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1C
Reactant: OCCc1ccc(Br)cc1
Product: Cc1cc(Nc2ccccc2CCO)c([N+](=O)[O-])cc1C

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 45 from 4,5-dimethyl-2-nitroaniline and 4-bromophenylethyl alcohol.
Reaction SMILES: [C:1]([O:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)=[C:14]([Cl:29])[C:13]=1[CH2:30][CH3:31])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OC(=O)C)C>C(O)C>[C:1]([O:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([O:19][C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)=[C:14]([Cl:29])[C:13]=1[CH2:30][CH3:31])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCc1c(OC(=O)C=Cc2ccccc2)cc(Cl)c(Oc2ccc([N+](=O)[O-])cc2)c1Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCc1c(OC(=O)C=Cc2ccccc2)cc(Cl)c(Oc2ccc(N)cc2)c1Cl
Yield: 85.6 %

Procedure:
A mixture of ethyl(3,5-dichloro-4-[4-nitrophenoxy]phenyl) cinnamate (0.65 g), tindichloride dihydrate (1.0 g), ethylacetate (25 mL) and ethanol (25 mL) was heated at reflux for one hour. The reaction mixture was concentrated and the residue partioned beetween diethyl ether and sodium hydroxide (1 N). After purification on column (silica gel, ethyl acetate/petrolium ether, 3:7), 0.52 g of ethyl(3,5-dichloro-4-[4-aminophenoxy]phenyl) cinnamate was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][CH2:16][C:17]([OH:19])=[O:18]>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([N:15]([CH2:16][C:17]([OH:19])=[O:18])[C:10](=[O:11])[C:5]=12)=[O:9])([O-:3])=[O:2]
Reactant: NCC(=O)O
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Product: O=C(O)CN1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Yield: 79.9 %

Procedure:
3-nitrophthalic anhydride (0.5 g, 0.0026 mol) and glycine (0.19 g, 0.0026 mol) were refluxed as above overnight. The clear solution was concentrated under vacuum with a rotary evaporator and the crude material triturated with hot 1,4-dioxane. Undissolved material was filtered through a Buchner funnel and washed twice with 1 ml hot 1,4-dioxane. The filtrate was diluted with water. A white solid appeared which was filtered through a Buchner and washed three times with 3–5 ml water. The product was dried in air for a short time and then in vacuo for 48–72 hours to afford 0.52 g (81%) 120 as off white crystals: mp=200–202° C.; Rf 0.73 (A): Rf 0.77 (C): Rf 0.23 (D): IR (cm−1): 2800–3200 (OH), 3096 (C═CH), 2652 (C—H), 1779 (C═O), 1724 (C═O), 1690 (C═O), 1648 (C═C), 1544 (N═O), 1470 (C═C), 1448 (C═C), 1412 (C—O), 1368 (N═O), 1260 (C—O), 722 (C═CH); MS m/z (rel intensity) 250 (15), 249 (100), 205 (89).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[Si]([N:27]1[CH2:32][CH2:31][N:30](C)[CH2:29][CH2:28]1)(C(C)(C)C)(C)C>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: CN1CCN([Si](C)(C)C(C)(C)C)CC1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O

Procedure:
In a manner similar to that of Example 1, 1-cyclopropyl-6-fluoro-7-chloro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (II, R1 : cyclopropyl; X: chloro) is reacted with 1-(t-butylmethylsilyl)piperazine (III, R2 : hydrogen; R3 and R4 : methyl; R5 : t-butyl) to afford a solid compound.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[F:19][C:20]1[C:40]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)=[CH:39][C:23]2[NH:24][C:25]([C:27]3[C:31]([NH2:32])=[CH:30][N:29]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[N:28]=3)=[N:26][C:22]=2[CH:21]=1>C1COCC1>[F:19][C:20]1[C:40]([N:41]2[CH2:42][CH2:43][O:44][CH2:45][CH2:46]2)=[CH:39][C:23]2[NH:24][C:25]([C:27]3[C:31]([NH:32][C:7]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[O:8])=[CH:30][N:29]([CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][O:34]4)[N:28]=3)=[N:26][C:22]=2[CH:21]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCOCC3)cc2[nH]1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCOCC3)cc2[nH]1)N1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
10 mL of piperidinecarbonyl chloride and 13.55 mL of N,N-diisopropylethylamine are added to a solution of 10 g of 3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-ylamine in 200 mL of THF. The reaction mixture is refluxed for 3 hours and then left stirring at ambient temperature for 48 hours. After concentration of the medium vacuum in a rotary evaporator, the reaction crude is purified by flash chromatography on 1200 g of 40-63 μM silica, elution being carried out with a 90:10 mixture of dichloromethane/acetone. 10.4 g of piperidine-1-carboxylic acid [3-(5-fluoro-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]amide are isolated. 1H NMR (300 MHz, (CD3)2S, δ in ppm): 1.50-1.79 (m: 10H); 1.91-2.04 (m: 2H); 3.00 (m: 4H); 3.50 (m: 4H); 3.66 (m: 1H); 3.77 (m: 4H); 3.96 (broad d J=11 Hz: 1H); 5.46 (dd, J=10 and 2 Hz: 1H); 7.10 (very broad s: 1H); 7.40 (very broad s: 1H); 8.13 (s: 1H); 9.96 (broad s: 1H); 13.00 (very broad s: 1H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:35])[NH:15][CH:16]([CH2:26][CH2:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][CH:9]1C)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:20]1([CH2:19][CH2:18][CH2:17][CH:16]([NH:15][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]2)=[O:35])[CH2:26][CH2:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC1CC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
4-[4-Phenyl-1-(3-phenyl-propyl)-butylcarbamoyl]-methylpiperidine-1-carboxylic acid tert-butyl ester (56) (1.62 g; 3.29 mmol) is dissolved in methylene chloride (50 mL) at ambient temperature. Trifluoroacetic acid (50 mL) is added in a slow stream, and the solution is stirred for 90 minutes at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is slurried in a mixture of methylene chloride (30 mL) and water (200 mL), then potassium carbonate is added until the slurry is alkaline. The slurry is diluted with water (200 mL) then extracted with methylene chloride (3×100 mL). The organic extracts are dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (1.23 g) as a white solid.
Reaction SMILES: [C:1]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]1[C:20]#[N:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-:23].[Na+].[OH-].[Na+].OO>CC(C)=O.C(OCC)(=O)C>[C:1]([N:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]1[C:20]([NH2:21])=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: N#CC1C=Cc2cc(Cl)ccc2N1C(=O)c1ccccc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: NC(=O)C1C=Cc2cc(Cl)ccc2N1C(=O)c1ccccc1
Reaction time: 4 h
Yield: 17.7 %

Procedure:
A solution of 1-(Benzoyl)-6-chloro-1,2-dihydro-quinoline-2-carbonitrile (8.0 g), sodium bicarbonate (4.0 g), and 0.1N aqueous sodium hydroxide (20 mL) in acetone (125 mL) was treated with slow addition of 30% hydrogen peroxide (120 mL). The pH of the reaction was kept near 8 by the addition of 0.1N sodium hydroxide. After 4 hours, the mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium thiosulfate. The organic phase was subsequently washed with water and brine. The organic phase was dried over magnesium sulfate and evaporated to dryness. The residue was chromatographed on silica gel using ethyl acetate/hexane (2:8) followed by ethyl acetate/methylene chloride/hexane (3:1:6) and finally 100% ethyl acetate to yield 1.5 g of the desired compound as a white solid, m.p. 230-234° C.
Reaction SMILES: [CH3:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:5]([CH2:6][OH:7])=[C:4]([F:12])[C:3]=1[F:13].[Cl:14]/[C:15](=[CH:20]\[C@@H:21]1[C@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27])/[C:16]([F:19])([F:18])[F:17]>>[CH3:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:5]([CH2:6][O:7][C:24]([C@H:23]2[C:22]([CH3:28])([CH3:27])[C@H:21]2/[CH:20]=[C:15](\[Cl:14])/[C:16]([F:19])([F:18])[F:17])=[O:25])=[C:4]([F:12])[C:3]=1[F:13]
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: Cc1c(F)c(F)c(CO)c(F)c1F
Product: Cc1c(F)c(F)c(COC(=O)[C@@H]2[C@H](/C=C(\Cl)C(F)(F)F)C2(C)C)c(F)c1F

Procedure:
In a further aspect of the invention the 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol is reacted with cis-Z 3-(2-chloro-1,1,1-trifluoro-2-propenyl)-2,2-dimethylcyclopropane carbonyl chloride to give tefluthrin.
Reaction SMILES: CO[C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.Br.[NH:18]([C:20]1[S:21][CH2:22][CH2:23][N:24]=1)[NH2:19]>C(O)C>[S:21]1[CH2:22][CH2:23][NH:24][C:20]1=[N:18][N:19]=[C:3]1[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=2[NH:10][C:11]2[C:16]1=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: NNC1=NCCS1
Reactant: COc1c2ccccc2nc2ccccc12
Agent: Br
Solvent: CCO
Product: c1ccc2c(=NN=C3NCCS3)c3ccccc3[nH]c2c1

Procedure:
2.09 g of 9-methoxyacridine are dissolved in 50 ml of dry ethanol, treated with a solution of 1.98 g of 2-hydrazino-2-thiazoline hydrobromide in 50 ml of dry ethanol, heated to boiling under reflux for 1 hour and the solvent is removed in vacuo. The residue is treated with aqueous ammonia (1:5) and extracted with ethyl acetate. After drying the extract over sodium sulfate and evaporation, the material obtained is crystallized by the addition of pentane. There is obtained 9-acridanone (2-thiazolidinylidene)hydrazone of melting point 214°-215° (decomposition).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:18][C:19]([CH3:23])([CH3:22])[CH:20]=O)[CH2:15][CH:16]=[CH2:17].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:14]([S:18][C:19]([CH3:23])([CH3:22])[CH2:20][NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:11])[CH3:12])[CH2:15][CH:16]=[CH2:17]
Reactant: CC(C)(S)CNc1ccccc1N
Reactant: C=CCCSC(C)(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C=CCCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Reaction time: 17 h
Yield: 83 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (3.5 g, 1.78×10-2 mol, 100 M%) and 2-(3-butenylthio)-2-methylpropanal (4.23 g, 2.67×10-2 mol, 150 M%) were dissolved in 200 ml methanol. Glacial acetic acid (2.05 ml, 3.56×10-2 mol, 200 M%) and sodium cyanoborohydride (3.36 g, 5.35×10-2 mol, 300 M%) were then added. After 17 hours, the reaction was quenched by the addition of 100 ml 0.5 N HCl. The acidic solution was then extracted with 2×100 ml diethyl ether. The combined organic extracts were washed with 100 ml saturated NaHCO3, followed by 100 ml saturated NaCl. The ether layer was then dried over anhydrous Na2SO4. The solvent was removed on the rotary evaporator, and the residue was purified by filtration through a 600 ml sintered-glass funnel silica bed, using 90% hexane/diethyl ether as the eluting solvent, to give 5 g (84% yield) 1-[2-(3-butenylthio)-2-methylpropylamino]-2-(2-mercapto-2-methylpropylamino)-benzene as a yellow oil.
Reaction SMILES: [ClH:1].CO[C:4](=O)[CH:5]([NH2:9])[CH2:6][C:7]#[CH:8].[N:11]#[C:12][NH2:13]>>[ClH:1].[CH2:6]([C:5]1[N:9]=[C:12]([NH2:13])[NH:11][CH:4]=1)[C:7]#[CH:8]
Reactant: N#CN
Reactant: C#CCC(N)C(=O)OC
Agent: Cl
Product: C#CCc1c[nH]c(N)n1
Yield: 59 %

Procedure:
2-Amino-pent-4-ynoic acid methyl ester hydrochloride (2.91 g, 17.8 mmol) was treated to an Akabori reduction followed by a cyanamide condensation employing conditions previously reported to produce 4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (1.65 g, 59%) as a yellow oil (Olofson et al., Journal of Organic Chemistry 1997, 62, (23), 7918-7919). 1H NMR (300 MHz, CD3OD) δ 6.30 (s, 1H), δ 5.02 (d, 2H), δ 2.26 (t, 1H) ppm; 13C NMR (75 MHz, CD3OD) δ 150.1, 127.2, 109.6, 83.6, 69.8, 15.9 ppm; HRMS (ESI) calcd for C6H7N3 (M+) 122.0712. found 122.0713.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][C:11](=[O:13])[CH3:12].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:21]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:3]([CH2:10][C:11](=[O:13])[CH3:12])[CH:4]=1
Reactant: COc1ccc(I)c(CC(C)=O)c1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ccccc2)c(CC(C)=O)c1
Yield: 112.1 %

Procedure:
A solution of 5.5 g (18.9 mmole) 2-iodo-5-methoxyphenyl-2-propanone (18.9 mmole), 4.15 ml (37.8 mmole) of phenylacetylene, 0.037 g cuprous iodide (1 mole percent) and 0.066 g of bis(triphenylphosphine)palladium (II) chloride (5 mole percent) in 60 ml of triethylamine was stirred for 18 hours under N2 at room temperature. The mixture was partitioned between water and ether. The ether layer was washed successively with cold hydrochloric acid solution, washed and brine. It was dried over MgSO4 and the solvent evaporated in vacuo to give 5.6 g (100% yield) of brown crystals. Recrystallization from methylcyclohexane afforded pure 1-[5-(methoxy)-2-(phenylethynyl)phenyl]-2-propanone, mp 60°-62° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24](F)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[NH:32]1[C:36]2=[N:37][CH:38]=[CH:39][C:40]([CH2:41][NH2:42])=[C:35]2[CH:34]=[CH:33]1.CCN(C(C)C)C(C)C>C(O)(C)(C)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]2[C:10](=[CH:11][C:12]([NH:20][C:21]([C:23]3[C:24]([NH:42][CH2:41][C:40]4[CH:39]=[CH:38][N:37]=[C:36]5[NH:32][CH:33]=[CH:34][C:35]=45)=[N:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccnc2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3F)ccc2C(C)(C)C1
Agent: Cl
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2cc(NC(=O)c3cccnc3NCc3ccnc4[nH]ccc34)ccc2C(C)(C)C1
Reaction time: 0.33 h

Procedure:
A mixture of 7-[(2-fluoro-pyridine-3-carbonyl)-amino]-4,4-dimethyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.99 g, 4.98 mmol) and C-(1H-pyrrolo[2,3-b]pyridin-4-yl)-methylamine, dihydrochloride (1.79 g, 8.14 mmol), DIEA (6 mL), and t-butanol (9 mL) in 3 microwave vials was subjected to 170° C., 1200 s of microwave. The combined mixture was concentrated and purified by column chromatography (Biotage, 0 to 7% MeOH with 10% NH4OH in CH2Cl2) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.C([N:24]=[C:25]=[S:26])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:25]([NH2:24])=[S:26])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (500 mg, 2.46 mmol) in THF (30 ml) at 0° C. was slowly added benzoyl isothiocyanate (0.366 ml, 2.583 mmol) and the reaction mixture was stirred at rt for 2 hours. The solvents were evaporated and the residue was dissolved in methanol (50 ml). A solution of potassium carbonate (1.02 g, 7.38 mmol) in water (23 ml) was added dropwise at rt, the reaction mixture was stirred for 3 h at rt. The methanol was evaporated, water (10 ml) was added and stirred at rt for 1 hour. The solids were filtered off, washed with diethyl ether and dried in vacuo. After trituration with diethyl ether the title compound was obtained as light yellow solid (490 mg, 76%). MS ISP (m/e): 263.1 (100) [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH2:4][OH:5].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([O:1][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[O:14])=[C:3]([CH2:4][OH:5])[CH:6]=1
Reactant: OCc1cc(Br)ccc1O
Reactant: Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)COc2ccc(Br)cc2CO)cc1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
A mixed solution of 2-hydroxy-5-bromobenzyl alcohol (3.00 g) and 2-bromo-4′-methylacetophenone (3.50 g) and potassium carbonate (2.45 g) in acetone (50 ml) was stirred at 80° C. for 4 hours. After cooling to room temperature, a solid material was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to separation and purification using column chromatography (ethyl acetate/hexane 2:3→1:1) to obtain 2-[4-bromo-2-(hydroxymethyl)phenoxy]-1-(4-methylphenyl)-1-ethanone (3.60 g) as colorless crystals.