Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=1[CH3:26])[C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)[CH:6]=[CH:5][C:4]=1[CH3:14].[CH3:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C@@H:38]([CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:39](Cl)=[O:40])(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClC(Cl)C.N1C=CC=CC=1>[N:9]1([C:7]2[CH:6]=[CH:5][C:4]([CH3:14])=[C:3]([CH:8]=2)[CH:2]([C:15]2[C:16]([CH3:26])=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][C:24]=2[CH3:25])[O:1][C:39](=[O:40])[C@@H:38]([NH:37][S:34]([C:31]2[CH:30]=[CH:29][C:28]([CH3:27])=[CH:33][CH:32]=2)(=[O:36])=[O:35])[CH2:42][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: COC(=O)c1cc(C)c(C(O)c2cc(-n3ccnc3)ccc2C)c(C)c1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2ccccc2)C(=O)Cl)cc1
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cc(C)c(C(OC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2ccc(C)cc2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Yield: 100.5 %

Procedure:
Methyl (±)-4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoate (46 g) was suspended in dichloroethane (550 ml) and pyridine (15.8 ml), and a solution of (S)-2-(4-methylbenzenesulfonylamino)-3-phenylpropionyl chloride (53.2 g) in dichloroethane (125 ml) was added dropwise to the suspension over 10 minutes with stirring under ice-cooling. The mixture was stirred at room temperature for 4 hours, and the reaction mixture was washed successively with water, 5% citric acid, 5% potassium carbonate and water. The organic layer was separated and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 86 g of methyl (±)-4-[5-(1-imidazolyl)-2-methyl-α-{(S)-2-(4-methylbenzenesulfonylamino)-3-phenylpropionyloxy}-benzyl]-3,5-dimethylbenzoate as a pale-yellow oil. This was crystallized from ethyl acetate (150 mil) and isopropyl ether (600 ml) and the obtained crystals were recrystallized from ethyl acetate (75 ml) and isopropyl ether (150 ml) to give 29.8 g of methyl (S)-4-[5-(1-imidazolyl)-2-methyl-α-{(S)-2-(4-methylbenzenesulfonylamino)-3-phenylpropionyloxy}benzyl]-3,5-dimethylbenzoate as white crystals, melting point 111-112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[N+:14]([O-])[C:13]=2[C:19]([O:21][CH3:22])=[O:20])[N:4]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+].[CH3:34][N:35]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)C(Cl)=O>C(#N)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[C:13]([C:19]([O:21][CH3:22])=[O:20])=[N:14][C:15]([N:35]([CH3:34])[CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:16][CH:17]=2)[N:4]=1
Reactant: CN(Cc1ccccc1)C(=O)Cl
Reactant: COC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc[n+]1[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1nc(N(C)Cc2ccccc2)ccc1Oc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32 %

Procedure:
20 g (77.1 mmol) of methyl 3-[(4,6-dimethoxypyrimidin-2-yl)oxy]picolinate N-oxide, 15 g (116 mmol) of diisopropylethylamine and 46.2 g (308.2 mmol) of sodium iodide were suspended in 200 ml of acetonitrile and stirred at room temperature for 15 minutes. To this mixture, 21.2 g (115.4 mmol) of N-methyl-N-benzylcarbamoyl chloride dissolved in 20 ml of acetonitrile was added at room temperature. The mixture was refluxed. Foaming started at a temperature slightly lower than the boiling point, and such foaming terminated in about 30 minutes. The reaction was continued for further 10 minutes. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried, concentrated and then purified by silica gel column chromatography to obtain the desired product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1.[CH:73]([O:76][CH2:77][CH2:78]O)([CH3:75])[CH3:74]>C1COCC1>[CH:73]([O:76][CH2:77][CH2:78][O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])([CH3:75])[CH3:74]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: CC(C)OCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)OCCOc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 55.9 %

Procedure:
In a similar manner to Step 1 of Example 149, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.102 g, 0.221 mmol) was dissolved in THF (5.1 mL), and the solution was treated with triphenylphosphine (0.116 g, 0.442 mmol), 40% DEAD-toluene solution (0.201 mL, 0.442 mmol) and 2-isopropoxyethanol (0.126 mL, 1.10 mmol), followed by purification by flash column chromatography (chloroform/methanol=4/1) to obtain 4-(2-isopropoxyethoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0677 g, yield 59%).
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14]([CH2:17]P(=O)(OCC)OCC)=[N:15][N:16]=3)[N:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[Br:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH:35]=O.O>C1COCC1>[N:1]1([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14](/[CH:17]=[CH:35]/[C:34]4[CH:37]=[CH:38][CH:39]=[CH:40][C:33]=4[Br:32])=[N:15][N:16]=3)[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CCOP(=O)(Cc1nnc2ccc(N3CCCCCC3)nn12)OCC
Reactant: O=Cc1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccccc1/C=C/c1nnc2ccc(N3CCCCCC3)nn12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of diethyl [(6-azepan-1-yl-1,2,4-triazolo[4,3-b]pyridazin-3-yl)methyl]phosphonate (367 mg) in THF (10 ml), potassium tert-butoxide (127 mg) was added with cooling in an ice bath, and the mixture was stirred at room temperature for 40 minutes. The resultant red solution was combined with 2-bromobenzaldehyde (0.128 ml), and stirred at room temperature for further 1 hour. The reaction solution was combined with water, and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resultant white solids were recrystallized from methanol to obtain 6-azepan-1-yl-3-[(E)-2-(2-bromophenyl)vinyl]-1,2,4-triazolo[4,3-b]pyridazine (152 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([NH:9][C:10]([C@@H:12]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCNC(=O)[C@@H]1CCCCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCNC(=O)[C@@H]1CCCCCN1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
(S)-(−)-1-(tert-Butoxycarbonyl)-2-azepanecarboxylic acid n-octyl amide (2) (1.00 g; 2.82 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added and the solution is stirred for 7 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3 times, 50 mL each). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product (3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.C1(C)C=CC=CC=1.S(Cl)([Cl:36])=O>>[Cl:36][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH:20]=[N:19][CH:18]=[N:17]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCn1cncn1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCn1cncn1
Yield: 65 %

Procedure:
A solution of 6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (1.11 g, 3.86 mmol) and DMF (0.6 ml) in thionyl chloride (15 ml) was heated at reflux for 1 hour. The mixture was allowed to cool, toluene was added and the volatiles were removed by evaporation. The residue was partitioned between methylene chloride and water and the aqueous layer was adjusted to pH8.5 with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried (MgSO4), and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5). The purified solid was triturated with ether, collected by filtration, washed with water and then ether, and dried under vacuum to give 4-chloro-6-methoxy-7-(2-(1,2,4-triazol-1-yl)ethoxy)quinazoline (756 mg, 65%).
Reaction SMILES: [S:1]1(=[O:7])(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1)=[O:14]>O1CCCC1.CCCCCC>[O:6]=[S:1]1(=[O:7])[CH2:5][CH2:4][CH2:3][CH:2]1[CH:13]([OH:14])[C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(C)c1ccc(C=O)cc1
Reactant: O=S1(=O)CCCC1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)c1ccc(C(O)C2CCCS2(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
Tetrahydrothiophene-1,1-dioxide (1.5 g) was dissolved in tetrahydrofuran (10 ml), and to the solution was added dropwise a 1.6 M solution of n-butyllithium in hexane (6.0 ml) at −60° C. The reaction mixture was gradually warmed to 0° C., stirred at the same temperature for 30 minutes, then a solution of ethyl 2-(4-formylphenyl)propionate (1.5 g) in tetrahydrofuran (2.0 ml) was added dropwise at 0° C., and the mixture was stirred at room temperature for 2 days. The reaction mixture was quenched with 10% aqueous citric acid, and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over sodium sulfate. The solvent was evaporated under reduced pressure, and then the residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give the title compound (800 mg, 39%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:11].O.[N+:13]([O-])([OH:15])=[O:14].S([O-])([O-])=O.[Na+].[Na+]>C(O)(=O)C>[I:1][C:2]1[CH:10]=[C:9]([N+:13]([O-:15])=[O:14])[C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:11]
Reactant: O=[N+]([O-])O
Reactant: Oc1c(I)ccc2c1CCC2
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(I)c(O)c2c1CCC2

Procedure:
To a solution of 5-iodoindan-4-ol (358 mg) in acetic acid (3 mL) was added water (0.5 mL). To the solution was added nitric acid (60%, 0.105 mL) in small portions under ice-cooling, and the mixture was stirred under ice-cooling for 20 min. After adding water (10 mL) and aqueous sodium sulfite (1.5 g/10 mL) successively, the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was crystallized from a small amount of dichloromethane and hexane to give the title compound (70 mg).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([N:11]([C:22](=[O:31])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=2)[S:9][CH:10]=1)=[O:5])C.C(O)(=O)C.Cl>O1CCOCC1>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:22]([N:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=1)[C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1)=[O:31]
Reactant: CCOC(=O)c1csc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(OC)c(OC)c2)n1
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)O)cs2)cc1OC
Temperature: 60 °C

Procedure:
A mixture of 2.25 g (4.68 mmol) 2-[(2,4-Dichloro-benzoyl)-(3,4-dimethoxy-phenyl)-amino]-thiazole-4-carboxylic acid ethyl ester, 2.5 ml acetic acid and 7.5 ml HCl conc. in 10 ml dioxane was heated to 60° C. for 2 h. The precipitate was filtered off and washed with dioxane to yield after drying 0.566 g (22%) of the title compound. MS (m/e): 453.0 (MH+, 100%)
Reaction SMILES: Cl[CH2:2][C:3]1[C:7]([CH3:8])=[CH:6][N:5]([CH3:9])[N:4]=1.[CH2:10]([NH2:12])[CH3:11]>C1COCC1>[CH3:9][N:5]1[CH:6]=[C:7]([CH3:8])[C:3]([CH2:2][NH:12][CH2:10][CH3:11])=[N:4]1
Reactant: Cc1cn(C)nc1CCl
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1nn(C)cc1C

Procedure:
prepared by reaction of 3-chloromethyl-1,4-dimethyl-1H-pyrazole (Calderwood E. F. et al Synth. Commun. 2004, 34, 19, 3455-3464) with 2M ethylamine in THF.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C.[CH3:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.C(Cl)Cl>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH3:34])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: Cc1ccccc1CBr
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccccc1CN1C(=O)C(=O)c2cc(Br)ccc21
Yield: 53 %

Procedure:
Combine 5-bromoisatin (90 mg, 0.4 mmol), 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine on polysteyrene (270-290 mg, 0.60-0.64 mmol, 2.2 mmol/g, Fluka) and 2-methylbenzyl bromide (0.054 mL, 0.4 mmol) in acetonitrile (4 mL) in a 20 dram scintillation vial and shake on a rotator for 2.5 days. Dilute with and a small amount of CH2Cl2 as needed to soluabilize solids. Filter off beads, washing with MeOH, and concentrate in vacuo. Triturate the resulting solid with diethyl ether (about 4 mL) and pipet off the liquid. Dry the solid to obtain approximately 70 mg of the title compound as crude material and use without further purification.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:31]([NH2:33])=[O:32])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][NH:29][CH3:30])=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].CN.O1CC[CH2:38][CH2:37]1>>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:31]([NH2:33])=[O:32])[CH:17]=[C:18]([C:21]4[CH:22]=[CH:23][C:24]([CH2:27][CH2:28][NH:29][CH2:30][CH2:37][CH3:38])=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CCNC)cc4)cc23)CC1
Reactant: C1CCOC1
Agent: CN
Product: CCCNCCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cc1
Yield: 27.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[2-(methylamino)ethyl]phenyl}-indole-7-carboxamide, substituting 2 M propylamine in tetrahydrofuran (0.4 mL) for methylamine to afford 15 mg of the title compound (27.5%).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13]Br)=[CH:5][CH:4]=1.C[O:16][P:17]([O:20][CH3:21])[O:18][CH3:19]>C1(C)C=CC=CC=1>[CH3:19][O:18][P:17]([CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][P:17](=[O:16])([O:20][CH3:21])[O:18][CH3:19])=[CH:5][CH:4]=1)(=[O:16])[O:20][CH3:21]
Reactant: COP(OC)OC
Reactant: BrCc1ccc(CBr)c2ccccc12
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccc(CP(=O)(OC)OC)c2ccccc12)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.1 %

Procedure:
A 200 mL round bottom flask is charged with 1,4-bis(bromomethyl)naphthalene (Example 26(b), 2.07 g, 6.6 mmol) and toluene (75 mL). The flask is equipped with a Dean-Stark trap, condenser, and nitrogen inlet. The mixture is heated to reflux temperature to dry the toluene and starting material. A total of 25 mL of toluene is collected in the Dean-Stark trap and then discarded. The mixture is cooled to room temperature and then trimethyl-phosphite (4 mL, 34 mmol) is added and the reaction is heated at a gentle reflux overnight. The reaction is checked by TLC after 24 hours and found to be complete. The toluene and excess trimethylphosphite are removed at a reduced pressure to yield an oil. The product is chromatographed on 400 g of 40-63 μm silica gel. The sample is applied in ethyl acetate and elution is with 10% methanol-ethyl acetate. Fractions which contained 50 mL each are collected. The desired product (2.01 g, 0.00542 mole, 81%) is eluted in fractions 60-80 and is a viscous oil.
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][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH3:21].C(N(CC)CC)C.[CH:29]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)(Cl)Cl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH3:21])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:34]([CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:35])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCc1nc2c(N)nc3ccccc3c2n1CCCCN
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)C1CCCC1
Reaction time: 0.17 h
Yield: 76 %

Procedure:
A solution of 1-(4-aminobutyl)-2-ethyl-1H-imidazo[4,5-c]quinolin-4-amine (1.00 g, 3.5 mmol) and triethylamine (0.64 mL, 4.6 mmol) in chloroform (100 mL) was cooled with an acetone/ice bath. Cyclopentanecarbonyl chloride (0.47 mL, 3.9 mmol) was slowly added. The reaction was complete within 10 minutes. The reaction mixture was washed with water (1×100 mL) and brine (1×100 mL). The organic layer was dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was slurried with acetonitrile. The resulting solid was isolated by filtration and dried in an oven overnight to provide 1.01 g of N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]cyclopentanecarboxamide as a light brown solid, m.p. 178.6-179.5° C. Analysis: Calculated for C22H29N5O-0.25H2O: % C, 68.81; % H, 7.74; % N, 18.24; Found: % C, 68.77; % H, 7.87; % N, 18.19.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:30](I)[CH3:31]>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH2:30][CH3:31])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.6 %

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (138.3 mg, 0.357 mmol) in N,N-dimethylformamide (2.3 mL) was added sodium hydride (21.4 mg, 0.536 mmol) at 0° C. After 30 min, to the mixture was added ethyl iodide (143 μL, 1.785 mmol) at 0° C. The reaction mixture was stirred at room temperature for 17.5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with water (×2) and brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless powder (112.1 mg, 0.270 mmol, 58%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15][C@@H:16]2[O:33][C@H:32]([CH2:34][O:35]C(=O)C)[C@H:27]([O:28]C(=O)C)[C@H:22]([O:23]C(=O)C)[C@H:17]2[O:18][CH2:19][CH:20]=[CH2:21])[C@@H:8]([CH2:39][O:40]C(=O)C)[O:7][C@@H:6]1Cl)(=O)C.[CH3:45][OH:46]>>[CH2:19]([O:18][C@@H:17]1[C@@H:22]([OH:23])[C@@H:27]([OH:28])[C@@H:32]([CH2:34][OH:35])[O:33][C@H:16]1[O:15][C@@H:9]1[C@@H:8]([CH2:39][OH:40])[O:7][C@@H:6]([O:46][CH3:45])[C@H:5]([OH:4])[C@H:10]1[OH:11])[CH:20]=[CH2:21]
Reactant: CO
Reactant: C=CCO[C@H]1[C@H](O[C@H]2[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H](Cl)O[C@@H]2COC(C)=O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Product: C=CCO[C@H]1[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](OC)O[C@@H]2CO)O[C@H](CO)[C@H](O)[C@@H]1O
Reaction time: 48 h
Yield: 67 %

Procedure:
Chloride 3 (4.4 g, 6.74 mmol) was dissolved in dry MeOH and left at room temperature for two days. The mixture was neutralized with Dowex 50W (H+) resin, the suspension was filtered and the filtrate was crystallized from EtOH to give 4 (1.8 g, 67%), [α]D−1.8° (c 0.2, H2O), m.p. 22-223° C.; 1H NMR (D2O) δ 5.99 (m, 1H, Hc), 5.36 (m, 1H, Hb), 5.28 (m, 1H, Ha), 4.49 (d, 1H, J1′,2′=7.9 Hz, H-1′), 4.41 (d, 1H, J1,2=8.0 Hz, H-1), 4.34 (m, 1H, Hd), 4.26 (m, 1H, He), 3.99 (broad d, 1H, H-6a), 3.83-3.62 (m, 8H, H-3, H-4, H-5, H-6b, H-3′, H-5′, H-6′a, H-6′b), 3.58 (s, 3H, Me), 3.4dd, 1H, J2′,3′=10.0 Hz, H-2′), 3.32 (m, H-2). Calc'd for C16H28O11 (396.38) C, 48.48; H, 7.12. Found C, 48.47, H, 7.12.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](Cl)(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CN(C)C=O>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])(=[O:22])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: Cc1ccc(C(=O)O)cc1N
Reactant: CCCCCCCCCC(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCC(=O)Nc1cc(C(=O)O)ccc1C
Yield: 73.8 %

Procedure:
A solution of 3-amino-4-methylbenzoic acid (15.1 g) and n-decanoyl chloride (19.4 g) in dry dimethylformamide (150 ml) was heated on a steam bath for 90 minutes. The solution was poured into water and the solid was collected, and recrystallised from ethanol (600 ml) to give 3-(n-decanamido)-4-methylbenzoic acid (22.5 g), in the form of a white powder, m.p. 246°-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]([CH:12]=[CH:13]Cl)=[O:11].Cl.[NH2:16]O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[O:11][N:16]=[CH:13][CH:12]=1
Reactant: NO
Reactant: O=C(C=CCl)c1cc(F)c(Cl)cc1Cl
Agent: Cl
Solvent: CO
Product: Fc1cc(-c2ccno2)c(Cl)cc1Cl

Procedure:
A mixture of 57.6 g of 2-chlorovinyl 2,4-dichloro5-fluoro-phenyl ketone, 16.4 g of hydroxylamine hydrochloride and 150 ml of methanol is heated at the boiling point under reflux for 6 hours, a precipitate separating out after about one hour. This is filtered off cold with suction, washed with a little methanol and dried at 50° C. in vacuo. 33.3 g (63.2%) of 5-(2,4-dichloro-5-fluorophenyl)-isoxazole of melting point 112°-113° C., which, according to investigations by NMR spectroscopy, contains about 6 mole % of an isomer, are obtained.