Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]1[C:31]2[NH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]=2[CH2:22][CH2:21][NH:20]1>O1CCCC1>[CH2:1]([O:8][C:9]([N:20]1[CH2:21][CH2:22][C:23]2[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[NH:30][C:31]=2[CH2:19]1)=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of N-(benzyloxycarbonyloxy)succinimide (9.61 g, 38.6 mmol) in anhydrous tetrahydrofuran (30 ml) was added to a suspension of 2,3,4,9-tetrahydro-1H-β-carboline (4.43 g, 25.7 mmol) and 4-N,N-dimethylaminopyridine (266 mg) in anhydrous tetrahydrofuran (30 ml), while cooling with ice. The suspension was stirred at room temperature for 16 h and the tetrahydrofuran was then removed i. vac. The residue was dissolved in ethyl acetate (20 ml) and the solution was washed with water (2×20 ml). The organic phase was dried with sodium sulfate and concentrated i. vac. The crude product (11.0 g) was purified by flash chromatography with cyclohexane/ethyl acetate (4:1).
Reaction SMILES: [F:1][C:2]1[CH:51]=[CH:50][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:36]6[CH2:41][CH2:40][N:39](C(OC(C)(C)C)=O)[CH2:38][CH2:37]6)=[O:35])[C:20]5=[N:19][C:18]=4[CH3:49])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[F:1][C:2]1[CH:51]=[CH:50][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34](=[O:35])[N:36]6[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]6)[C:20]5=[N:19][C:18]=4[CH3:49])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCCCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCCCC(=O)N1CCNCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of tert-butyl 4-(6-((3-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)oxy)hexanoyl)piperazine-1-carboxylate, prepared as described in Step A, (408 mg, 0.58 mmol) in dichloromethane (5 mL), under argon, was treated with trifluoroacetic acid (435.62 μL, 5.8 mmol). After stirring for 72 h at room temperature, the reaction mixture was poured into an aqueous saturated sodium bicarbonate solution (5 mL), and the aqueous layer was extracted with dichloromethane (three times 5 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was used in the next step without further purification. (ESI-MS (M+1) 609)
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[CH3:18][CH:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20].N1C=CC=CC=1>ClCCl>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([NH:15][S:21]([CH:19]([CH3:20])[CH3:18])(=[O:23])=[O:22])[C:9]=1[F:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc(N)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1ccc(F)c(NC(=O)OC(C)(C)C)c1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
The tert-butyl-3-amino-2,6-difluorophenylcarbamate (100 mg, 0.41 mmol) prepared at Step 3 was added and dissolved into dichloromethane solvent. 2-propane sulfonyl chloride (50 uL, 0.45 mmol) and pyridine (36 uL, 0.045 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 94 mg of the target compound, tert-butyl-2,6-difluoro-3-(1-methylethylsulfonamido)phenylcarbamate (percentage yield: 65%), was obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][C:7]1[N:8]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][CH:26]=2)[C:9]([S:15][C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)=[C:10]([CH:12]([CH3:14])[CH3:13])[N:11]=1)(=[O:3])[NH2:2].[H][H]>C(OCC)(=O)C.[Pt]>[NH2:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:8]2[C:9]([S:15][C:16]3[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=3)=[C:10]([CH:12]([CH3:13])[CH3:14])[N:11]=[C:7]2[CH2:6][CH2:5][O:4][C:1](=[O:3])[NH2:2])=[CH:30][CH:29]=1
Reactant: CC(C)c1nc(CCOC(N)=O)n(Cc2ccc([N+](=O)[O-])cc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)c1nc(CCOC(N)=O)n(Cc2ccc(N)cc2)c1Sc1cc(Cl)cc(Cl)c1

Procedure:
In 10 ml of ethyl acetate was dissolved 220 mg (0.43 mmol) of 2-(2-carbamoyloxyethyl)-5-(3,5-dichlorophenylthio)-4-isopropyl-1-(p-nitrobenzyl)-1H-imidazole (128a), and 120 mg of platinum sulfided carbon was added at room temperature. Hydrogen gas was introduced for 7 hours under stirring, and the mixture was worked up. The reaction mixture was filtered through Celite under reduced pressure, and the filtrate was distilled off. The residual oil was treated with ether for crystallization to give Compound I-140 (yield 95%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:9])=[C:6](Cl)[N:7]=1.[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][C:19]=1[O:27][CH3:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(COC)OC.C(Cl)(Cl)Cl>[CH2:10]([O:17][C:18]1[CH:23]=[CH:22][C:21]([C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[N:4][C:5]=2[CH3:9])=[CH:20][C:19]=1[O:27][CH3:28])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1cc(B(O)O)ccc1OCc1ccccc1
Reactant: Cc1nnc(Cl)nc1Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: COc1cc(-c2nc(Cl)nnc2C)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
A degassed solution of 3,5-dichloro-6-methyl-1,2,4-triazine (151 mg, 0.9 mmol), 4-(benzyloxy)-3-methoxybenzene boronic acid (236 g, 0.9 mmol), tetralis(triphenylphosphine)palladium(0) (55 mg, 0.05 mmol) and tripotassium phosphate (249 mg, 1.2 mmol) in dimethoxyethane (5 mL) was heated at reflux for 24 h. Upon cooling to room temperature the solution was diluted with CHCl3 and filtered through Celite®. The filtrate was concentrated in vacuo and the product purified by column chromatography using ethyl acetate-hexane (25:75) as eluent to furnish (75 mg, 22%).
Reaction SMILES: O1C2C(=CC=CC=2)/C(=[N:11]/[OH:12])/CC1.[CH2:13]([CH:15]1[C:23](=O)[C:19]2[CH:20]=[CH:21][O:22][C:18]=2[CH2:17][CH2:16]1)[CH3:14]>>[CH2:13]([CH:15]1[CH2:16][CH2:17][C:18]2[O:22][CH:21]=[CH:20][C:19]=2/[C:23]/1=[N:11]\[OH:12])[CH3:14]
Reactant: O/N=C1\CCOc2ccccc21
Reactant: CCC1CCc2occc2C1=O
Product: CCC1CCc2occc2/C1=N\O

Procedure:
Following the procedure for the preparation of (4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting 5-ethyl-6,7-dihydro-1-benzofuran-4(5H)-one and making non-critical variations provided the title compound as a oil: MS (EI) m/z (rel. intensity) 179 (M+, 21), 162 (50), 151 (43), 135 (99), 134 (99), 107 (86), 106, (83), 84 (34), 79 (35), 52 (47), 51 (48). HRMS (FAB) calcd for C10H13NO2+H 180.1024, found 180.1015.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[C:15]3=[N:16][CH:17]=[C:18]([CH2:21][CH2:22][C:23]#[N:24])[C:19](=[O:20])[N:14]3[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].[N-:31]=[N+:32]=[N-:33].[Na+].Cl>O1CCCC1>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][C:10]2[C:15]3=[N:16][CH:17]=[C:18]([CH2:21][CH2:22][C:23]4[NH:33][N:32]=[N:31][N:24]=4)[C:19](=[O:20])[N:14]3[CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1c(OCc2cccn3c(=O)c(CCC#N)cnc23)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1c(OCc2cccn3c(=O)c(CCc4nnn[nH]4)cnc23)ccc(C(C)=O)c1O
Temperature: 0 °C
Yield: 58.9 %

Procedure:
A mixture of 1.07 g (2.65 mmoles) of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl ]-3-(2-cyanoethyl)-4H-pyrido[1,2-a]pyrimidin-4-one, 1.76 g 2.57 g (39.53 mmoles) of sodium azide and 45 ml of tetrahydrofuran was heated under reflux for 23 hours. After cooling, the resulting reaction solution was poured into ice water and then acidified with dilute hydrochloric acid. The precipitate so formed was separated by filtration and recrystallized from acetonitrile to obtain 0.70 g (59% yield) of 9-[(4-acetyl-3-hydroxy-2-n-propylphenoxy)methyl]-3-[2-(1H-tetrazol-5-yl)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one in the form of white crystals. These crystals had a melting point of 238°-239° C. (dec.).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][C:6]([C:9]1[C:14]([OH:15])=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:12]=[C:11]([C:20](=[O:24])[CH:21](Br)[CH3:22])[N:10]=1)([CH3:8])[CH3:7]>O.CC(C)=O>[N:1]([CH:21]([CH3:22])[C:20]([C:11]1[N:10]=[C:9]([C:6]([CH3:5])([CH3:8])[CH3:7])[C:14]([OH:15])=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[N:12]=1)=[O:24])=[N+:2]=[N-:3]
Reactant: CC(Br)C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(N=[N+]=[N-])C(=O)c1nc(C(C)(C)C)c(O)c(C(C)(C)C)n1
Reaction time: 2 h
Yield: 96.2 %

Procedure:
A solution of 1.2 g (18 mmol) of sodium azide in 9.0 mL of water was added dropwise to a solution of 5.5 g (16 mmol) of 1-[4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidinyl]-2-bromo-1-propanone in 35 mL of acetone. The mixture was stirred for 2 hours then added to 100 mL of water and extracted with ethyl acetate. The organic layers were washed with brine, dried (anhydrous sodium sulfate), and evaporated to yield 4.7 g (96%) of the azide product, mp 91° C.-92° C., suitable for further synthesis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:19]([CH3:20])[CH2:18][CH2:17][C@@:14]4([C:15]=2[CH:16]=1)[C@H:9]3[C@@H:10]([CH2:22][CH2:23][CH3:24])[CH2:11][C:12](=[O:21])[CH2:13]4.[N:25]#CBr>>[C:20]([N:19]1[CH2:18][CH2:17][C@@:14]23[C:15]4[CH:16]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=4[CH2:7][C@@H:8]1[C@@H:9]2[C@@H:10]([CH2:22][CH2:23][CH3:24])[CH2:11][C:12](=[O:21])[CH2:13]3)#[N:25]
Reactant: N#CBr
Reactant: CCC[C@H]1CC(=O)C[C@]23CCN(C)[C@H](Cc4ccc(OC)cc42)[C@H]13
Product: CCC[C@H]1CC(=O)C[C@]23CCN(C#N)[C@H](Cc4ccc(OC)cc42)[C@H]13
Yield: 97 %

Procedure:
To a rapidly stirred solution of 3-methoxy-17-methyl-8β-n-propylmorphinan-6-one (prepared in Part A) was added cyanogen bromide as in Example 1B. The product was obtained as a syrup, 97% yield, and was used without further purification.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1.Br[C:17]1[C:26]([Cl:27])=[C:25]([Cl:28])[C:24]([O:29][CH3:30])=[C:23]2[C:18]=1[CH:19]=[C:20]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH:21]([C:31]([F:34])([F:33])[F:32])[O:22]2>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:27][C:26]1[C:17]([CH3:1])=[C:18]2[C:23](=[C:24]([O:29][CH3:30])[C:25]=1[Cl:28])[O:22][CH:21]([C:31]([F:34])([F:33])[F:32])[C:20]([C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:19]2
Reactant: CCOC(=O)C1=Cc2c(Br)c(Cl)c(Cl)c(OC)c2OC1C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)C1=Cc2c(C)c(Cl)c(Cl)c(OC)c2OC1C(F)(F)F
Temperature: 25 °C
Yield: 55 %

Procedure:
Pd(PPh3)4 (0.13 g, 0.85 mmol), K2CO3 (0.34 g, 0.85 mmol) and trimethylboroxine (0.14 g, 0.85 mmol) was added to a stirring solution of ethyl 5-bromo-6,7-dichloro-8-methoxy-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.38 g, 0.85 mmol) dissolved in 1,4-dioxane and heated to reflux for 24 hrs. Allowed to cool to R.T., filtered through celite and washed with EtOAc. The resulting solution was condensed in vacuo and purified by flash chromatography (silica gel) and eluted with 10% EtOAc/ hexanes to yield 0.18 g (56%) of the title compound as an amorphous solid: GCMS m/z 384.0 (M+). 1H NMR (CDCl3/300 MHz) 7.92 (s, 1H), 5.80 (q, 1H, J=7.0 Hz), 4.35 (m, 2H), 3.89 (s, 3H), 2.47 (s, 3H), 1.36 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH3:13])[C:9]([OH:11])=O)=[C:4]([F:14])[CH:3]=1.[NH2:15][CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:12][CH3:13])[C:9]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:17]([C:16]#[N:15])=[CH:18][CH:19]=2)=[O:11])=[C:4]([F:14])[CH:3]=1
Reactant: COC(C(=O)O)c1ccc(Br)cc1F
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(Br)cc1F

Procedure:
(RS)-(4-Bromo-2-fluoro-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-2-(4-bromo-2-fluoro-phenyl)-N-(4-cyano-benzyl)-2-methoxy-acetamide. Light yellow gum.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:3]1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O.O>[CH3:1][C:2]1([CH3:12])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13](=[O:15])[CH3:14])[CH:8]=2)[O:3]1
Reactant: CC1(C)CCc2ccccc2O1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Product: CC(=O)c1ccc2c(c1)CCC(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 5.0 g (30.82 mmol) of 2,2-dimethylchroman (Compound 56) in 50 ml of nitromethane was treated, under nitrogen, with 2.53 g (32.35 mmol) of acetyl chloride followed by 4.4 g (33 mmol) of aluminum chloride. The reaction mixture was stirred at room temperature for 3 hours and then cooled in an ice-bath and treated slowly with 50 ml of 6M HC1. The mixture was diluted with water and extracted with ether. The ether extracts were washed successively with saturated NaHCO3 solution, water and saturated NaCl solution and then dried (MgSO4). The solvent was removed in-vacuo and the resultant residue was purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a white solid. PMR (CDCl3) : & 1.36 (6H, s), 1.84 (2H, t, J~6.8 Hz), 2.54 (3H, s), 2.82 (2H, t, J~6.8 Hz), 6.80 (1H, d, J~8.4 Hz), 7.69-7.76 (2H, m). MS exact mass, m/e 204.1140 (calcd. for C13H16O2, 204.1150).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@H:12]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][CH:28]=[N:29][C:30]=3[NH2:34])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][O:36][C:37]1[CH:56]=[CH:55][C:40]([C:41](Cl)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:39][CH:38]=1.CO>N1C=CC=CC=1>[CH3:35][O:36][C:37]1[CH:56]=[CH:55][C:40]([C:41]([NH:34][C:30]2[N:29]=[CH:28][N:27]=[C:26]3[C:31]=2[N:32]=[CH:33][N:25]3[C@H:12]2[O:13][C@@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C@@H:10]([O:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:11]2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[CH:39][CH:38]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1ncnc2c1ncn2[C@@H]1C[C@H](OC(=O)c2ccccc2)[C@H](COC(=O)c2ccccc2)O1
Solvent: c1ccncc1
Solvent: CO
Product: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@H](OC(=O)c3ccccc3)[C@H](COC(=O)c3ccccc3)O2)(c2ccccc2)c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
To a solution of compound 4 (0.88 g, 1.92 mmol) in dry pyridine (40 mL) was added 4-monomethoxytrityl chloride (1.18 g, 3.84 mmol). The mixture was stirred at 60° C. for 24 h. After addition of methanol (5 mL), the solution was concentrated to dryness, the residue was dissolved in dichloromethane (50 mL) and washed successively with water (30 mL), aqueous saturated NaHCO3 (30 mL) and water (30 mL). The organic layer was dried, filtered, concentrated and co-evaporated with toluene to give pure 5 (1.01 g, 72%) as a foam: 1H NMR (CDCl3): δ 2.9-3.0 (m, 2H, H-2′ and H-2″), 3.62 (s, 3H, OCH3), 4.6-4.8 (m, 3H, H-4′, H-5′ and H-5″), 5.85 (pt, 1H, H-3′), 6.44 (dd, 1H, H-1′, J1′,2′=3.1 Hz, J1′,2″=7.3 Hz), 6.9 (br s, 1H, NH-6), 6.7-6.8 and 7.2-7.4 (2m, 24H, 2 benzoyls and MMTr), 7.97 and 8.13 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+) m/z 732 [M+H]+, (FAB−) m/z 730 [M−H]−; UV (95% ethanol): λmax 274 nm (ε 12100), 225 nm (ε 24200), λmin 250 nm (ε 5900); [α]D20=−16 (c 1.12, DMSO).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[NH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=[C:15]([NH2:22])[C:14]=2[N:13]=[C:12]1[CH3:23].NCCN1C2C(C)=C(C)N=C(N)C=2N=C1C.C(N(CC)CC)C>ClCCl>[NH2:22][C:15]1[C:14]2[N:13]=[C:12]([CH3:23])[N:11]([CH2:10][CH2:9][NH:8][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:19]=2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=1
Reactant: Cc1nc(N)c2nc(C)n(CCN)c2c1C
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(N)c2nc(C)n(CCNC(=O)C(C)C)c2c1C
Reaction time: 0.25 h
Yield: 74.5 %

Procedure:
Isobutyryl chloride (1.3 mL, 12.2 mmol) was added dropwise to a mixture of 1-(2-aminoethyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine hydrochloride (4.0 g of material from Example 24, 12.2 mmol), triethylamine (85 mL, 610 mmol) and dichloromethane (400 mL). After 15 minutes analysis by high performance liquid chromatography indicated that the reaction was complete. The solvents were removed under reduced pressure. The residue was partitioned between chloroform (250 mL) and water (250 mL) containing 10 g of sodium carbonate (pH 12). This mixture was placed in a continuous extractor and extracted with chloroform for 24 hours. The extract was dried over magnesium sulfate and then concentrated under reduced pressure to provide a light yellow oil. The oil was purified by chromatography (silica gel eluting with 85/15 dichloromethane/methanol) to provide 2.63 g of N-[2-(4-amino-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-1-yl)ethyl]-2-methylpropanamide as a white powder, m.p. 220-222° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]1[CH:14]=[C:13](F)[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:8][C:9]1[CH:14]=[C:13]([N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]2=[O:1])[CH:12]=[CH:11][C:10]=1[N+:16]([O-:18])=[O:17]
Reactant: Oc1ccccn1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1ccccn1-c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2.5 g (26.3 mmol) 2-hydroxypyridine, 2.9 ml (26.3 mmol) 2,4-difluoronitrobenzene, are dissolved in 100 ml acetone, combined with 4.0 g (28.9 mmol) potassium carbonate and stirred for one day at ambient temperature. The undissolved matter is filtered off and the salt residues are rinsed with acetone. The combined organic phases are evaporated to dryness. The residue is purified by chromatography (silica gel; eluant: cyclohexane-ethyl acetate gradient).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([C:12](=[O:15])[NH:13][CH3:14])[C:6](=[O:16])[C:5]2=[O:17].[NH2:18][C:19]([NH2:21])=[S:20].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:12](=[O:15])[N:13]([CH3:14])[C:5]2([OH:17])[C:6]([NH:18][C:19]([NH2:21])=[S:20])=[O:16]
Reactant: CNC(=O)N1C(=O)C(=O)c2cc(Cl)c(Cl)cc21
Reactant: NC(N)=S
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN1C(=O)Nc2cc(Cl)c(Cl)cc2C1(O)C(=O)NC(N)=S
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.4 %

Procedure:
5,6-Dichloro-1-methylcarbamoylisatin (9.6 g) is suspended in tetrahydrofuran (100 ml) and thereto are added thiourea (3.0 g) and triethylamine (5.6 ml), and the mixture is stirred at room temperature for 5 hours. The resulting precipitates are taken by filtration to give 6,7-dichloro-3-methyl-4-hydroxy-4-thioureidocarbonyl-2-oxo-1,2,3,4-tetrahydroquinazoline (4.1 g). M.p. 225-228° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]([CH2:16][CH2:17][CH2:18][CH:19](OC)[O:20]C)[C:14]([CH2:24][CH2:25][CH3:26])=[N:13][C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1>C1COCC1.O>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:15]([CH2:16][CH2:17][CH2:18][CH:19]=[O:20])[C:14]([CH2:24][CH2:25][CH3:26])=[N:13][C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1
Reactant: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCC(OC)OC
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc2cnc3cc(Br)ccc3c2n1CCCC=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
Concentrated hydrochloric acid (8 mL) was added to a mixture of 7-bromo-1-(4,4-dimethoxybutyl)-2-propyl-1H-imidazo[4,5-c]quinoline (57.0 g, 140.3 mmol) in THF (250 mL) and water (70 mL) and stirred overnight at ambient temperature. Additional concentrated hydrochloric acid (10 mL) was added and the reaction mixture was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water and neutralized with saturated aqueous sodium bicarbonate solution. The mixture was diluted with 10% methanol in dichloromethane, the phases were separated, and the combined organics were dried over magnesium sulfate and concentrated under reduced pressure to afford 50.3 g of 4-(7-bromo-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:7]2[CH:21]=[N:22][C:23]([C:24]#[N:25])=[C:6]12)=[O:4].[Cl:26][C:27]1[CH:45]=[CH:44][C:30]([CH:31]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:29][CH:28]=1.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([CH:31]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:38]2[CH2:39][CH2:40][N:41]([CH2:2][C:3]([N:5]3[CH2:10][CH:9]=[C:8]([C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=4)[N:7]4[CH:21]=[N:22][C:23]([C:24]#[N:25])=[C:6]34)=[O:4])[CH2:42][CH2:43]2)=[CH:44][CH:45]=1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: N#Cc1ncn2c1N(C(=O)CCl)CC=C2c1cccc(C(F)(F)F)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1ncn2c1N(C(=O)CN1CCN(C(c3ccccc3)c3ccc(Cl)cc3)CC1)CC=C2c1cccc(C(F)(F)F)c1
Yield: 77.7 %

Procedure:
A mixture of 1.53 g of 1-(chloroacetyl)-1,2-dihydro-4-[3-(trifluoromethyl)phenyl]imidazo[1,5-a]pyrimidine-8-carbonitrile, 1.32 g of N-(p-chlorobenzhydryl)piperazine and 990 mg of [1,8-bis(dimethylamino)naphthalene, N,N,N',N'-tetramethyl-1,8-naphthalenediamine] in 60 ml of toluene was stirred and heated at reflux for 17 hours. The reaction mixture was filtered hot. The filtrate was cooled, then shaken with 50.0 ml of 1N sodium hydroxide and worked up by the procedure of Example 7 to obtain a viscous oil. The oil in ethyl acetate was passed through a silica column to give a solid upon evaporation of the solvent. The solid was dissolved in 40% ethyl acetate/hexane and again passed through a short silica column. Evaporation of the solvent in vacuo gave 2.00 g of the desired product as a yellow solid, mp 105°-107° C.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.[C:5]([NH:9][NH2:10])([CH3:8])([CH3:7])[CH3:6].[OH-].[K+]>CCOCC>[C:5]([NH:9][N:10]=[C:2]([CH3:4])[CH3:1])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)NN
Reactant: CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(C)=NNC(C)(C)C

Procedure:
To 6.6 g of acetone, cooled in an ice bath, is added 5.0 g of tert-butylhydrazine. The mixture is stirred and then allowed to stand for several minutes. Ether and potassium hydroxide pellets are then added to the mixture. The mixture is stirred, and then the ethereal layer is separated from the mixture. Distillation of the ethereal layer yields the product acetone tert-butylhydrazone b.p. 132°-134° C. ##STR27##