Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](O)=[N:6][CH:7]=1.S(Cl)([Cl:14])=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([Cl:14])=[N:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)cnc1Cl
Reaction time: 1 h
Yield: 82 %

Procedure:
N,N′-dimethylformamide (3 mL) was added to a mixture of 5-bromo-2-hydroxy-3-nitropyridine (16.54 g, 80 mmol) and thionyl chloride (43 mL) and the mixture was stirred and heated to reflux. After 1 hour, the solution was cooled and the solvent was evaporated. The mixture was co-evaporated with toluene to give a dark solid. Purification by flash chromatography (10:1 hexanes/ethyl acetate) gave the title compound (14.63 g, 82%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][C:33]=1[O:34][CH:35]([CH3:37])[CH3:36])[C:7]([NH:9][C@H:10]([CH2:28][CH2:29][OH:30])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([C:24](=NO)[CH3:25])[N:21]([CH3:23])[CH:22]=2)=[CH:14][CH:13]=1)=[O:8].Br[CH2:39][CH2:40][O:41][Si](C(C)(C)C)(C)C.CN(C=[O:53])C>CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]([CH:31]=[CH:32][C:33]=1[O:34][CH:35]([CH3:36])[CH3:37])[C:7]([NH:9][C@H:10]([CH2:28][CH2:29][OH:30])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:19]=[C:20]([C:24]3([CH3:25])[O:41][CH2:40][CH2:39][O:53]3)[N:21]([CH3:23])[CH:22]=2)=[CH:14][CH:13]=1)=[O:8]
Reactant: CN(C)C=O
Reactant: CC(=NO)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(-c3cn(C)c(C4(C)OCCO4)n3)cc2)cc1Cl
Reaction time: 1.5 h
Yield: 41 %

Procedure:
To a suspension of NaH (0.39 g, 9.3 mmol) in DMF (15 mL) was added a solution of 3 (1.9 g, 6.5 mmol) in DMF (10 mL) at 0° C. under nitrogen. The reaction was stirred for 1.5 hour, and then (2-bromoethoxy)-tert-butyldimethylsilane (2.09 mL, 9.7 mmol) was added. The reaction mixture was stirred overnight, diluted with EtOAc, quenched with aqueous ammonium chloride solution, and extracted with EtOAc (3×50 mL). The organic layers were combined and dried over Na2SO4. Purification with biotage (EtOAc) gave the product 4 (1.2 g, 41%) as light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12]Cl)=[O:9].[CH2:35]([NH:37][CH2:38][CH3:39])[CH3:36]>C(O)CC.[I-].[Na+]>[CH3:1][C:2]1[NH:3][C:4]([CH:28]([O:32][CH2:33][CH3:34])[O:29][CH2:30][CH3:31])=[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:37]([CH2:38][CH3:39])[CH2:35][CH3:36])=[O:9]
Reactant: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCCl)C1c1cccc([N+](=O)[O-])c1
Reactant: CCNCC
Agent: [I-]
Agent: [Na+]
Solvent: CCCO
Product: CCOC(=O)C1=C(C(OCC)OCC)NC(C)=C(C(=O)OCCN(CC)CC)C1c1cccc([N+](=O)[O-])c1
Yield: 114.5 %

Procedure:
A mixture of 2-chloroethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate (2.0 g), diethylamine (1.75 g) and sodium iodide (60.3 mg) in n-propylalcohol (4 ml) was refluxed for 17 hours. After removal of the solvent from the reaction mixture, water and ethyl acetate were added to the residue. The ethyl acetate layer was washed twice with water, dried over magnesium sulfate, and concentrated to give a brown oil (2.46 g) of 2-(N,N-diethylamino)ethyl 2-methyl-4-(3-nitrophenyl)-5-ethoxycarbonyl-6-diethoxymethyl-1,4-dihydropyridine-3-carboxylate, which was identified by converting to the corresponding 6-formyl compound (oil) and then to the corresponding 6-cyano compound, m.p. 150° to 152° C.
Reaction SMILES: CO[C:3](=[O:20])[C:4]1[C:9]([NH2:10])=[CH:8][N:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[CH:5]=1.[NH2:21][C:22](N)=[O:23]>O>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[O:11][C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:22](=[O:23])[NH:21][C:3](=[O:20])[C:4]=2[CH:5]=1
Reactant: NC(N)=O
Reactant: COC(=O)c1cc(Oc2ccc(F)cc2F)ncc1N
Solvent: O
Product: O=c1[nH]c(=O)c2cc(Oc3ccc(F)cc3F)ncc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Compound (1C) (4.2 g, 15.0 mmol) and urea (9.0 g, 10 eq) were heated to a melt at 160° C. with stirring. After 2 hours, the melt solidified and by TLC the reaction was complete. The reaction mixture was cooled to room temperature, water (250 mL) was added, and the resulting mixture was left to stand for 1 hour. Then the solids were broken up with a spatula and the mixture was stirred vigorously for 1 hour. After suction filtration, a tan powder was collected which was air-dried in the frit for two days. Drying under high vacuum at 56° C. gave the title compound (1D) as a tan powder (4.307 g, (M−H)−=290, M.P.>300° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[F:24][C:25]1[CH:26]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[C:29]([F:31])[CH:30]=1>>[F:31][C:29]1[CH:28]=[C:27]([S:32]([NH:23][C:22]2[C:16]3[CH2:15][O:14][C:13]([NH:12][CH:9]4[C:8]5[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=5[O:11][CH2:10]4)=[N:18][C:17]=3[CH:19]=[CH:20][CH:21]=2)(=[O:33])=[O:34])[CH:26]=[C:25]([F:24])[CH:30]=1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: COc1cccc2c1C(NC1=Nc3cccc(N)c3CO1)CO2
Product: COc1cccc2c1C(NC1=Nc3cccc(NS(=O)(=O)c4cc(F)cc(F)c4)c3CO1)CO2

Procedure:
The title compound, MS (ISP) m/e=488.0 [(M+H)+], was prepared from N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-4H-benzo[d][1,3]oxazine-2,5-diamine (example 3) and 3,5-difluoro-benzenesulfonyl chloride according to the procedure described for example 5.
Reaction SMILES: [C:1]1([NH:11][C:12]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([C@@H:20]([NH:22][C:23]3[N:28]=[C:27]([N:29]4[C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=5[N:31]=[CH:30]4)[CH:26]=[CH:25][N:24]=3)[CH3:21])[CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N:38]1[CH:43]=[CH:42][C:41]([CH:44]=O)=[CH:40][CH:39]=1.C([BH3-])#N.[Na+]>>[N:38]1[CH:43]=[CH:42][C:41]([CH2:44][N:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[NH:11][C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[CH2:15][C@H:16]2[C@@H:20]([NH:22][C:23]2[N:28]=[C:27]([N:29]3[C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=4[N:31]=[CH:30]3)[CH:26]=[CH:25][N:24]=2)[CH3:21])=[CH:40][CH:39]=1
Reactant: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1
Reactant: O=Cc1ccncc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](Nc1nccc(-n2cnc3ccccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1Cc1ccncc1

Procedure:
The title compound was prepared from (S,S)-2-[1-(4-(N-naphth-1-yl-carbamoyl)-piperazin-2-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 36, Step C; 12.5 mg), 4-pyridinecarboxaldehyde (16.4 mg), and sodium cyanoborohydride (3.1 mg) according to the procedure described in Example 14, Step G. Mass spectrum (ESI) 585.0 (M+2).
Reaction SMILES: [CH:1](=[N:8][OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCl.[C-:12]#[N:13].[Na+].[OH-].[Na+]>C(Cl)(Cl)(Cl)Cl.O>[N:8](=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:12]#[N:13])[OH:9]
Reactant: [C-]#N
Reactant: ON=Cc1ccccc1
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CC(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 9.07 g (75 mmol) of benzaldoxime in 25 ml of carbon tetrachloride is added dropwise, at 5°, a solution of 45 ml of carbon tetrachloride saturated with 5.6 g (79 mmol) of chlorine gas. The mixture is stirred for 1 hour in an ice bath and then excess HCl is removed by vacuum. A saturated solution of 7.35 g (150 mmol) of sodium cyanide in water is added dropwise, at 0°. The mixture is stirred for 2 hours as it is allowed to warm to RT. An excess of aqueous sodium hydroxide is added and then the carbon tetrachloride layer is discarded. The aqueous layer is acidified and filtered, and the resulting solid is washed with water and dried to give α-oximinophenylacetonitrile, m.p.=120°-125°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([F:22])[CH:14]=2)=[CH:5][C:4]=1[N+:24]([O-])=O>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:23])/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([F:22])[CH:14]=2)=[CH:5][C:4]=1[NH2:24]
Reactant: COc1ccc(NC(=O)/C=C/c2ccc([N+](=O)[O-])c(F)c2)cc1[N+](=O)[O-]
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(NC(=O)/C=C/c2ccc(N)c(F)c2)cc1N
Yield: 47 %

Procedure:
A solution of N-(4-methoxy-3-nitrophenyl)-3-(3-fluoro-4-nitropheny)-2-propenamide (Example 8) (1.3 mmol) in acetone-water (10:5) was reacted according to the procedure as described in the Example 6. The title compound, melting point 170-172° C., was thereby obtained in 47% yield.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][N:16]2[CH:24]=1.[CH2:25]([NH2:28])[C:26]#[CH:27]>>[CH2:25]([NH:28][C:21]([C:19]1[CH:18]=[CH:17][N:16]2[CH:24]=[C:13]([C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)=[N:5][O:6][C:2]=3[CH3:1])[N:14]=[C:15]2[CH:20]=1)=[O:22])[C:26]#[CH:27]
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Reactant: C#CCN
Product: C#CCNC(=O)c1ccn2cc(-c3c(-c4ccccc4)noc3C)nc2c1
Yield: 63 %

Procedure:
As described for Example 11b, 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (64 mg, 0.2 mmol) was converted, using propargylamine instead of aminomethylcyclopropane, to the title compound (45 mg, 63%) which was obtained as a white solid. MS: m/e=357.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]3[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=3)[C:18]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)=[O:19])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1>N1C=CC=CC=1>[CH:34]1([C:37]([NH:1][C:2]2[S:3][C:4]3[C:10]([N+:11]([O-:13])=[O:12])=[C:9]([O:14][C:15]4[CH:16]=[C:17]([CH:31]=[CH:32][CH:33]=4)[C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=4)=[O:19])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[O:38])[CH2:36][CH2:35]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1nc2ccc(Oc3cccc(C(=O)Nc4cccc(C(F)(F)F)c4)c3)c([N+](=O)[O-])c2s1
Solvent: c1ccncc1
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.5 %

Procedure:
To a solution of 3-[(2-amino-7-nitro-1,3-benzothiazol-6-yl)oxy]-N-[3-(trifluoromethyl)phenyl]benzamide (200 mg, 0.421 mmol) in pyridine (4 mL) was added cyclopropanecarbonyl chloride (76 μL, 0.842 mmol), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was concentrated under reduced pressure. The obtained residue was diluted with ethyl acetate (50 ml), washed successively with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (97 mg, 42%) as a pale-yellow powder.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])(=O)=O.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C@H:24]([NH2:26])[CH3:25])=[CH:15]1.C(N(C(C)C)C(C)C)C>O1CCOCC1.CCOC(C)=O>[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C@H:24]([NH:26][CH2:7][C@H:8]([CH3:11])[CH2:9][F:10])[CH3:25])=[CH:15]1
Reactant: C[C@H](CF)COS(=O)(=O)C(F)(F)F
Reactant: C[C@@H](N)Cc1c[nH]c2ccccc12
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](CF)CN[C@H](C)Cc1c[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
(S)-3-Fluoro-2-methylpropyl trifluoromethanesulfonate (666 mg, 2.97 mmol) was added to a solution of (R)-1-(1H-indol-3-yl)propan-2-amine (470 mg, 2.7 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.700 ml, 4.05 mmol) in 1,4-dioxane (6.05 ml). The reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (20 ml) and washed with water (20 ml). The aqueous was extracted with EtOAc (2×20 ml), then the combined organics were dried (MgSO4) and concentrated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% methanol in DCM. Pure fractions were evaporated to dryness to afford (S)—N—((R)-1-(1H-indol-3-yl)propan-2-yl)-3-fluoro-2-methylpropan-1-amine (590 mg, 88%) as a, brown oil. 1H NMR (400 MHz, CDCl3, 30° C.) δ 0.86 (3H, dd), 1.20 (3H, d), 1.94-2.11 (1H, min), 2.64-2.74 (2H, m), 2.85-2.98 (2H, m), 3.05-3.15 (1H, m), 4.13-4.39 (2H, m), 7.09 (1H, d), 7.12 (2H, ddd), 7.20 (1H, ddd), 7.33-7.41 (1H, m), 7.56-7.65 (1H, m), 8.10 (1H, s). m/z: ES+ [M+H]+ 249
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1.[CH3:16]O.S(Cl)([Cl:20])=O>N1C=CC=CC=1>[ClH:20].[CH3:16][O:12][C:11](=[O:13])[C@@H:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:15][CH:14]=1)[NH2:10]
Reactant: CO
Reactant: COc1ccc(C[C@@H](N)C(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H](N)Cc1ccc(OC)cc1
Reaction time: 1 h

Procedure:
O-Methyl-D-tyrosine hydrochloride, 10.0 g., in 100 ml. of methanol is cooled in an ice bath and treated slowly with 3.4 ml. of thionyl chloride. The reaction is stirred for one hour with cooling and then overnight at room temperature. The solution is evaporated to dryness and the residue crystallized from methanol-ether to give 5.2 g. of the above named compound mp. 189°-190° C., [α]D23 -68° (c 1.04, pyridine).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=3[N:11]=[C:10]([NH2:20])[C:9]=2[N:8]=[C:7]1[CH2:21][CH2:22][CH3:23].C(N(CC)CC)C.[CH:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>C(Cl)(Cl)Cl>[NH2:20][C:10]1[C:9]2[N:8]=[C:7]([CH2:21][CH2:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:36]([CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:37])[C:18]=2[C:17]2[CH:16]=[CH:15][C:14]([Br:19])=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNC(=O)C1CCCC1
Temperature: 0 °C
Yield: 49.9 %

Procedure:
A suspension of 1-(4-aminobutyl)-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (2.42 g, 6.4 mmol) and triethylamine (0.99 mL, 7.1 mmol) in chloroform (240 mL) was cooled to 0° C., and cyclopentanecarbonyl chloride (0.78 mL, 6.4 mmol) was added dropwise over a period of five minutes. The reaction was stirred for ten minutes, washed sequentially with water (50 mL) and 1% aqueous sodium carbonate (100 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was triturated with isopropanol:water (10 mL/g and 1.7 mL/g) and isolated by filtration. The filtrate was concentrated under reduced pressure and recrystallized from isopropanol (5 mL/g). The two solids were combined and dried overnight in a vacuum oven to provide 1.51 g of N-{4-[4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}cyclopentanecarboxamide as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH2:11])=[S:10])[CH:5]=[CH:6][CH:7]=1.[CH3:12][I:13]>C(O)C>[IH:13].[CH3:12][S:10][C:9](=[NH:11])[NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: CI
Reactant: NC(=S)Nc1cccc(F)c1
Solvent: CCO
Product: CSC(=N)Nc1cccc(F)c1
Product: I
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 3-fluorophenylthiourea (20.0 g, 166.7 mmol) and methyl iodide (24.8 g, 175.0 mmol) in 300 ml of ethanol is stirred at RT for 2 days. It is then heated to reflux for 30 min., cooled and stripped of solvent to give S-methyl-3-fluorophenylisothiourea hydroiodide, an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.Cl[C:30]1[N:35]=[N:34][C:33]([C:36]([O:38][CH3:39])=[O:37])=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[C:14]([NH:13][C:11]1[CH:10]=[CH:9][C:3]2[C:4](=[O:6])[N:35]3[N:34]=[C:33]([C:36]([O:38][CH3:39])=[O:37])[CH:32]=[CH:31][C:30]3=[N:1][C:2]=2[CH:12]=1)(=[O:16])[CH3:15]
Reactant: CCOC(=O)c1ccc(NC(C)=O)cc1N
Reactant: COC(=O)c1ccc(Cl)nn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc2nc3cc(NC(C)=O)ccc3c(=O)n2n1

Procedure:
A solution of ethyl 2-amino-4-(acetylamino)benzoate (4.03 g, 18.13 mmol, Example 4, Step A), p-toluenesulfonic acid, monohydrate (0.5 g, 2.63 mmol) and methyl 6-chloro-3-pyridazinecarboxylate [3.13 g, 18.14 mmol, prepared according to the procedure of Barlin, G. B. and Yap, C. Y. (Aust. J. Chem. 1977, 30, 2319-2322)] in 500 mL of toluene was refluxed under Dean-Stark conditions for 12 h. The mixture was concentrated, dissolved into chloroform, washed with saturated sodium bicarbonate solution, dried (MgSO4), filtered and concentrated. Medium pressure chromatography (silica gel, 5% methanol in chloroform) afforded methyl 7-acetylamino-10-oxo-10H-pyridazino[6,1-b]-quinazoline-2-carboxylate as a yellow solid, mp 281°-285° C., dec.
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2](C=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[H][H].C[CH:18]([OH:20])C>>[C:9]1([CH2:18][OH:20])([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: [H][H]
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: CC(C)O
Product: OCC1(C2CCCCC2)CCCCC1
Temperature: 150 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a 5000 ml autoclave, 910 g of 2-propanol (IPA, Wako Pure Chemical Industries, special grade), 364 g of biphenyl aldehyde made by Mitsubishi Gas Chemical (2.0 mol), 7.3 g of 5% Ru/Al2O3 (made by N. E. CHEMCAT) and 10 MPa of hydrogen were charged, and stirred at 150° C. for 8 h. After cooling, a catalyst was filtered under an inert gas atmosphere. After a solvent was removed, distillation was conducted under reduced pressure to obtain bicyclohexyl methanol (BCHM) (80% yield, 99% purity).
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:14].[C:15](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[CH3:15][O:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:14]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(I)c2c(c1O)CNC2=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(I)c2c(c1OC)CNC2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.1 %

Procedure:
4-Hydroxy-5-methoxy-7-iodoisoindolinone (30.0 mg, 0.0983 mmol) was dissolved in DMF (2 mL), and the solution was treated with potassium carbonate (26.0 mg, 0.188 mmol) and methyl iodide (0.020 mL, 0.32 mmol), followed by stirring at room temperature for 1.5 hours. The reaction mixture was added with water and the precipitated solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4,5-dimethoxy-7-iodoisoindolinone (22.0 mg, yield 70%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](OC)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20]>CO>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:21][CH2:17][CH2:18][CH2:19][CH3:20])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: CCCCN
Reactant: COc1c([N+](=O)[O-])cc(Br)c2ccccc12
Solvent: CO
Product: CCCCNc1c([N+](=O)[O-])cc(Br)c2ccccc12
Yield: 66.8 %

Procedure:
7.05 g (0.025 mole) of 4-bromo-1-methoxy-2-nitronaphthalene is dissolved in 300 cc of methanol by heating the mixture at reflux temperature, then 5 cc (0.05 mole) of butylamine is gradually dripped into the obtained solution and when the addition is terminated the reaction mixture is still refluxed for 30 minutes with stirring. Upon cooling to 0°-5° C. a precipitate forms which is separated by filtration and dried, yielding 5.4 g of 4-bromo-N-butyl-2-nitro-1-naphthylamine. An additional 0.92 g is recovered from the mother liquor and the two crops are combined together and recrystallized from methanol. M.p. 65°-66.5° C. A mixture of 17.6 g (0.0544 mole) of this compound and 7.84 cc (0.0816 mole) of 3-chloropropionyl chloride is stirred at 60° C. for four hours. When the reaction is completed PG,30 the mixture is poured in a separatory funnel and vigorously shaken with methylene chloride and a 5% aqueous NaHCO3 solution. The organic layer is separated, washed with water and dried. The residue which is obtained by evaporating off the methylene chloride is dissolved in 180 cc of EtOH and 22 cc of glacial acetic acid. 10.4 g of powdered iron is added to the obtained solution and the resulting mixture is refluxed with stirring for 20 minutes; then it is poured into 720 cc of water and extracted with methylene chloride. The methylene chloride is evaporated off, the residue is dissolved in a mixture of 125 cc of 95% EtOH and 50 cc of 10% HCl and heated at reflux temperature for 11/2 hour. The solvent is boiled off and the solid residue is triturated with ether, filtered and dried. The yield in 5-bromo-1-butyl-2-(2-chloroethyl)-1H-naphth[1,2-d]imidazole, m.p. 172° C. (dec.), is 19.4 g (90.8%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Ca].[C:11]1(=[O:17])[CH2:16][CH2:15][CH2:14][CH:13]=[CH:12]1>[NH4+].[Cl-]>[CH2:2]([CH:13]1[CH2:14][CH2:15][CH2:16][C:11](=[O:17])[CH2:12]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C1C=CCCC1
Reactant: CCCCCCCCCl
Agent: [Ca]
Agent: [Cl-]
Agent: [NH4+]
Product: CCCCCCCCC1CCCC(=O)C1
Temperature: -35 °C
Yield: 87 %

Procedure:
The following experimental procedure is representative of the reactions set forth below in Table III. The organocalcium reagent (2.66 mmol) was prepared from 1-chlorooctane (395 mg, 2.66 mmol) and highly reactive calcium (3.10 mmol) as described above. An organocalcium cuprate reagent was prepared by adding lithium 2-thienylcyanocuprate (Aldrich Chemical Co., Milwaukee, Wis., 0.25M in THF, 14 mL, 3.50 mmol) to the calcium reagent via a syringe at -50° C. The reaction mixture was gradually warmed to -35° C. over a 30 minute period. The reaction mixture was cooled to -50° C. and 2-cyclohexen-1-one (210 mg, 2.18 mmol) was added via a disposable syringe. The resulting mixture was gradually warmed to room temperature. Saturated aqueous NH4Cl solution (20 mL) was added at room temperature. The reaction mixture was then filtered through a small pad of Celite™ filter agent and was washed with Et2O (50 mL). The aqueous layer was extracted with Et2O (2×30 mL). The combined organic phases were washed with H2O (3×15 mL) and dried over anhydrous MgSO4. Removal of solvent and flash-column chromatography on silica gel (70 g, 230-400 mesh, eluted sequentially with 50:1 hexanes/EtOAc and 10:1 hexanes/EtOAc) gave 3-octylcyclohexanone (401 mg, 87% yield): IR (neat) 2954, 2925, 2854, 1714, 1458, 1225 cm-1 ; 1H NMR (200 MHz, CDCl3) δ 1.10-2.50 (m, 23 H), 0.88 t, J=6.4 Hz, 3 H); 13C NMR (50 MHz, CDCl3) δ 212.0, 48.2, 41.5, 39.1, 36.6, 31.8, 31.3, 29.7, 29.5, 29.2, 26.6, 25.3, 22.6, 14.1.