Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].FC(F)(F)S([O-])(=O)=O.[Br:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]([I+]C1C=CC=CC=1)=[C:22]2[OH:37]>>[Br:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[C:23]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[C:22]2[OH:37]
Reactant: CCNc1ccccc1
Reactant: O=c1[nH]c2ccc(Br)cc2c(O)c1[I+]c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Product: CCN(c1ccccc1)c1c(O)c2cc(Br)ccc2[nH]c1=O

Procedure:
The title compound was prepared using N-ethylaniline in place of aniline according to the procedure of Intermediate 11, step c except the crude solid was purified by flash column chromatography (silica gel, 50% EtOAc-Heptane), affording the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]=1[N+:23]([O-:25])=[O:24].Cl.[CH3:27][O:28][CH2:29][CH:30]([NH2:33])[CH2:31][CH3:32]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH:33][CH:30]([CH2:29][O:28][CH3:27])[CH2:31][CH3:32])[C:10]=1[N+:23]([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1c(-c2ccc(Cl)cc2Cl)ccnc1OS(=O)(=O)C(F)(F)F
Reactant: CCC(N)COC
Agent: Cl
Product: CCC(COC)Nc1nccc(-c2ccc(Cl)cc2Cl)c1[N+](=O)[O-]
Yield: 79.3 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl-ester (3.0 g, 7.19 mmol), prepared substantially as described in Part C of Example 19a, and 1-methoxymethyl-propylamine HCl (2.01 g, 14.4 mmol) were treated substantially as described in Part C of Example 19a to produce 2.11 g (79%) of [4-(2,4-dichloro-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (AP) m/z 370.2 [(M+H)+, 100].
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O=S(Cl)Cl.[NH3:16]>ClCCCl.CN(C=O)C>[F:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:16])=[O:5]
Reactant: N
Reactant: O=C(O)c1ccc(F)nc1F
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)c1ccc(F)nc1F
Temperature: 0 °C
Yield: 77136.1 %

Procedure:
A solution 2,6-difluoronicotinic acid (7.4 g, 0.046 mmol) and SOCl2 (20 mL) in 1,2-dichloroethane (60 mL) containing DMF (1 drop) is heated under reflux for 4 h, then concentrated to dryness under reduced pressure. The residue is dissolved in Et2O (100 mL), cooled to 0° C., and treated dropwise with concentrated ammonia (10.0 mL, 0.17 mmol). After 10 min the solution is washed with aqueous NaHCO3 and worked up to give 2,6-difluoronicotinamide (5.61 g, 76%). 1H NMR (CDCl3) δ 8.70 (1H, dd, J=9.6, 8.3 Hz), 7.00 (1H, ddd, J=8.3, 2.9, 1.1 Hz), 6.71, 6.55 (1H, 1H, 2 brs).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[CH:15]=2)=[O:13])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[CH3:44][C:45]([O:48][C:49]([N:51]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:59]=[C:60](B(O)O)[CH:61]=[CH:62][CH:63]=2)[CH2:53][C@@H:52]1[CH3:67])=[O:50])([CH3:47])[CH3:46].C([O-])([O-])=O.[Na+].[Na+].O>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>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:22][C:20]([C:16]3[CH:15]=[C:14]([C:12]([NH:11][CH2:10][C:4]4[CH:3]=[C:2]([C:60]5[CH:61]=[CH:62][CH:63]=[C:58]([CH2:57][N:54]6[CH2:55][CH2:56][N:51]([C:49]([O:48][C:45]([CH3:47])([CH3:46])[CH3:44])=[O:50])[C@@H:52]([CH3:67])[CH2:53]6)[CH:59]=5)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=4)=[O:13])[CH:19]=[CH:18][CH:17]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: C[C@H]1CN(Cc2cccc(B(O)O)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(Br)cc(OC)c2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cc(OC)cc(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)c3)c2)c1
Temperature: 150 °C
Yield: 65.8 %

Procedure:
237(a) A mixture of N-{[3-bromo-5-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (150 mg, 0.23 mmol), {3-[((3S)-4-{[(1,1-dimethylethyl)oxy]carbonyl}-3-methyl-1-piperazinyl)methyl]phenyl}boronic acid (100 mg, 0.30 mmol), Na2CO3 (74 mg, 0.69 mmol), Pd(PPh3)4 (13.3 mg, 0.01 mmol), water (0.75 mL) in dioxane (2.25 mL) was degassed for 5 min. and then heated in a microwave for 30 min at 150° C. The reaction was quenched with water and then extracted with ethyl acetate twice. The combined organic layers were washed with water and brine. The organic layer was filtered though a 0.45 μM filter and then concentrated to give a crude residue. It was then purified using Combi Flash chromatography, eluting with 0 to 10% MeOH in DCM. The product fractions were combined and concentrated under vacuum to give 1,1-dimethylethyl (2S)-4-{[3′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]phenyl}carbonyl)amino]methyl}-5′-(methyloxy)-3-biphenylyl]methyl}-2-methyl-1-piperazinecarboxylate as a solid (130 mg, 65%): LC-MS m/z 859 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][CH3:10].Br[CH2:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(O)ccc1Br
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(Br)c(OC)c1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
1.50 g (7.39 mmol) 4-bromo-3-methoxy-phenol are added to 1.36 g (11.1 mmol) 1-bromopropane in 10 mL DMF. 2.04 g (14.8 mmol) K2CO3 are added and the mixture is stirred at 80° C. for 12 h. After that time, the mixture is diluted with water and extracted with DCM. The organic layer is dried over sodium sulphate and the solvent is removed in vacuo.
Reaction SMILES: [C:1]([O-:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[Na+].[Na+].S(=O)(=O)(O)O>>[C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C([O-])c1ccc(C(=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1ccc(C(=O)O)cc1

Procedure:
An aqueous solution of disodium terephthalate, passed through adsorption tower (2), was transferred to neutralization tank (3). Then, the solution was stirred by agitator (3a) in neutralization tank and added slowly with sulfuric acid and incessantly until the pH of reaction solution was 2.0. As a result of monitoring by SEM the particle of terephthalic acid formed from said neutralization process, its particle size (10 to 15 μm) was very small.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][N:29]1[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][C:31]([O:39][Si](C(C)(C)C)(C)C)=[N:30]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1.O>[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][N:29]1[C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][C:31]([OH:39])=[N:30]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)c1cc(O[Si](C)(C)C(C)(C)C)nn1CCNC(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(O)nn1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in THF (20.1 mL, 20.1 mmol) was added to a stirred solution of ethyl 1-{2-[(tert-butoxycarbonyl)amino]ethyl}-3-{[tert-butyl(dimethyl)silyl]oxy}-1H-pyrazole-5-carboxylate (5.54 g, 13.4 mmol) in THF (45 mL). The mixture was stirred at room temperature for 16 hours, diluted with water and extracted with AcOEt. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo to yield ethyl 1-{2-[(tert-butoxycarbonyl)amino]ethyl}-3-hydroxy-1H-pyrazole-5-carboxylate (3.32 g, 83% yield) as a white solid, that was used in the next step without further purification.
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2/[C:7](=[CH:14]\[C:15]2[C:20]([CH2:21][O:22]C3CCCCO3)=[CH:19][C:18]([Cl:29])=[CH:17][N:16]=2)/[C:6]1=[O:30])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[C:20]([CH2:21][OH:22])=[CH:19][C:18]([Cl:29])=[CH:17][N:16]=2)[C:6]1=[O:30])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)/C(=C/c2ncc(Cl)cc2COC2CCCCO2)c2cccnc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)N1C(=O)C(Cc2ncc(Cl)cc2CO)c2cccnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a suspension of 4 (3.0 g, 7.0 mmol) in ethanol (25 mL) was added NaBH4 (0.37 g) in one portion. The resulting suspension was stirred at room temperature for 1 h. The reaction was quenched by adding water (10 mL) followed by 6 N HCl solution in isopropanol (5 mL) slowly. The solution was warmed up to 40° C. and stirred for 3 h. The reaction mixture was mixed with MTBE (50 mL) and saturated aqueous NaCl (50 mL). The organic was separated and washed with water (50 mL). The solution was concentrated under vacuum at 50° C. and residue was triturated with hexane (30 mL). The resulting suspension was stirred at room temperature for 30 min. The precipitates were collected by filtration to give 5 (2.2 g, 86%) as a solid. 1H NMR (CDCl3, 400 MHz): δ 8.34 (s, 1H), 8.15 (d, J=4.9 Hz, 1H), 7.74 (s, 1H), 7.30 (d, J=7.1 Hz, 1H), 6.83 (t, J=5.7 Hz, 1H), 4.73 (dd, J=13.4, 4.9 Hz, 1H), 4.63 (dd, J=13.4, 5.7 Hz, 1H), 4.01 (t, J=6.1 Hz, 1H), 3.44 (dd, J=15.4, 5.2 Hz, 1H), 3.17 (dd, J=15.4, 7.2 Hz, 1H), 2.94 (t, J=5.5 Hz, 1H), 1.79 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 118.72, 159.12, 153.82, 146.45, 145.83 135.72, 135.32, 130.63, 130.27, 124.04, 117.33, 61.40, 58.70, 44.12, 34.01, 28.81.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[C:15]([NH2:17])[C:14](Br)=[CH:13][C:12]=1[Cl:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[C:21](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([C:11]1[CH:16]=[C:15]([NH2:17])[C:14]([CH3:21])=[CH:13][C:12]=1[Cl:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C(C(=O)OCC)c1cc(N)c(Br)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(C(=O)OCC)c1cc(N)c(C)cc1Cl
Temperature: 110 °C
Reaction time: 18 h
Yield: 26.3 %

Procedure:
To a solution of 2-(5-amino-4-bromo-2-chloro-phenyl)-malonic acid diethyl ester (1.25 g, 3.43 mmol) in dioxane (20 ml) and water (2 ml) was added potassium carbonate (1.42 g, 10.28 mmol), PdCl2(dppf) (0.28 g, 0.342 mmol) and trimethyl boroxine (0501 ml, 3.42 mmol). The mixture was stirred at 110° C. for 18 hours, then cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. Purification of the crude product by flash chromatography (hexanes:EtOAc 8:2) gave 0.270 g (71%) of 2-(5-amino-2-chloro-4-methyl-phenyl)-malonic acid diethyl ester as a yellow 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[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>C(#N)C.ClCCl>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:33]([C:30]3[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=3)(=[O:35])=[O:34])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CC#N
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNS(=O)(=O)c1ccc(F)cc1
Temperature: 4 °C
Yield: 40.9 %

Procedure:
1-(4-Aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.331 g, 1.0 mmol) was dissolved in anhydrous acetonitrile (35 mL) and the solution was cooled to 4° C. A solution of 4-fluorobenzenesulfonyl chloride (0.194 g, 1.0 mmol) in anhydrous dichloromethane (10 mL) was slowly added. The reaction was allowed to slowly warm to ambient temperature over the weekend. The reaction was quenched by the addition of aqueous saturated sodium bicarbonate solution. The layers were separated and the organic layer was concentrated to provide a pale yellow solid. This material was recrystallized from isopropyl alcohol and then further purified by flash chromatography (silica gel eluting with 10% methanol in dichloromethane). The pure fractions were combined and concentrated. The residue was recrystallized from isopropyl alcohol to provide 0.2 g of N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-4-fluoro-1-benzenesulfonamide as a pale yellow solid, m.p. 214-216° C. Analysis: Calculated for C26H24FN5O2S: % C, 63.79; % H, 4.94; % N, 14.30; Found: % C, 63.19; % H, 4.85; % N, 13.90. Mass spec M+1=490.2
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CCO>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(CC(C)C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Cc1ccc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a solution of methyl 3-fluoro-4-isobutylbenzoate (243 mg, 1.16 mmol) in 10 mL of EtOH was added sodium hydroxide (2.3 mL, 5.0 N). The mixture was stirred at rt for 1 hr and then concentrated. The residue was partitioned in a mixture of diluted HCl (10 mL) and Et2O (10 mL). The aqueous layer was separated and further extracted with Et2O (2×10 mL). The organic layers were combined, dried over MgSO4, and concentrated to give 212 mg (93%) of the title compound: 1H NMR δ 0.93 (d, J=6.6, 6H), 1.95 (m, 1H), 2.58 (d, J=7.4, 2H), 7.26 (m, 1H), 7.74 (dd, J=1.4, 10.1, 11H), 7.82 (dd, J=1.5, 7.9, 11H), 11.2 (br. s, 1H).
Reaction SMILES: [C:1]1([CH:7]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([C:28]([CH3:33])([CH3:32])[C:29]([OH:31])=[O:30])[N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:41]>CO.CC(O)C>[C:34]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([C:28]([CH3:33])([CH3:32])[C:29]([O-:31])=[O:30])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Na+:41]
Reactant: CC(C)(C(=O)O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Product: CC(C)(C(=O)[O-])c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionic acid (528 mg) in methanol (2 ml), a 2N aqueous solution of sodium hydroxide (0.47 ml) was added, followed by stirring at room temperature for 5 minutes. This solution was diluted with 2-propanol and concentrated under reduced pressure. The residue was dissolved in 2-propanol and again concentrated under reduced pressure. To this residue, 2-propanol and ethyl ether were added; the resulting powder was collected by filtration to yield the title compound (474 mg).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH:19]1([O:24][C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([O:24][C:25]2[CH:26]=[C:27]([NH:28][C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)[CH:29]=[CH:30][CH:31]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1cccc(OC2CCCC2)c1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(OC2CCCC2)c1
Yield: 67.8 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 354 mg of 3-(cyclopentyloxy)aniline in place of the 2,4-difluoroaniline. 269 mg of N-[3-(cyclopentyloxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.[C-:18]#[N:19].[K+]>C1COCC1.CS(C)=O.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][C:18]#[N:19])=[CH:12][CH:11]=1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 72 h

Procedure:
To a solution of 4-(benzoxazol-2-yl)benzyl bromide (0.5 g; 1.7 mmol) in THF (3 ml) and DMSO (3 ml) is added potassium cyanide (0.22 g; 3.4 mmol) and the reaction is stirred for 72 hours. The reaction is diluted with CH2Cl2, washed with H2O 3×, dried (MgSO4) and concentrated to dryness. The residue is purified by column chromatography using methylene chloride to yield 4-(benzoxazol-2-yl)-benzyl cyanide which is used directly in Step D.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:10][C:11]([CH3:13])=[O:12]>>[C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:1]([O:6][CH2:10][CH:11]1[O:12][CH2:13]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(C)=O
Agent: C=C(C)C(=O)OCCO
Product: C=C(C)C(=O)OCC1CO1

Procedure:
A copolymer of 2-hydroxyethyl methacrylate (HEMA; the extra pure grade reagent, Wako Pure Chemical Industries, Ltd., Japan) and glycidyl methacrylate (GMA; Nacalai tesque, Ltd., Japan) was prepared as a polymer for coating as follows. First of all, those reagents were distilled under reduced pressure to remove the polymerization inhibitor (hydroxy monomethyl ether). Then, 12 mL of HEMA and 60 μL of GMA in 50 mL of ethanol were polymerized at 60° C. for ten hours in the presence of 400 mg of α,α′-azobisisobutyronitrile (polymerization initiator; Nacalai tesque, Ltd., Japan). The obtained GMA-HEMA copolymer was added dropwise into acetone to give spherical beads and collected by filtration. Then, the obtained beads were dried under reduced pressure and crushed using mill to prepare a powder of GMA-HEMA copolymer.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][CH:33]=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:43])[NH:19][C@:18]2([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:44][C@H:17]2[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:50]1CCCC1.B.[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:23](=[O:24])[N:22]2[CH2:25][C@H:26]([O:28][C:29]3[N:30]=[C:31]4[C:36](=[C:37]5[C:42]=3[CH:41]=[CH:40][CH:39]=[CH:38]5)[CH:35]=[CH:34][CH:33]=[CH:32]4)[CH2:27][C@H:21]2[C:20](=[O:43])[NH:19][C@:18]2([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:44][C@H:17]2[CH2:16][CH:15]([OH:50])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@]12C[C@H]1C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Reactant: C1CCOC1
Agent: B
Agent: CCOC(=O)[C@@]12C[C@H]1/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Agent: OO
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@@]12C[C@H]1CC(O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](Oc3nc4ccccc4c4ccccc34)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.3 %

Procedure:
To a solution of (2R,6S,13aS,14aR,16aS,Z)-ethyl 6-(tert-butoxycarbonylamino)-5,16-dioxo-2-(phenanthridin-6-yloxy)-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 18a, 3.2 g, 4.77 mmol) in tetrahydrofuran (41.5 ml) at rt with a water bath was added dropwise borane tetrahydrofuran complex (1 M in tetrahydrofuran, 14.3 ml, 14.3 mmol) and stirred at room temperature for 1 h. The mixture was cooled to 0° C. and sodium hydroxide (11.5 ml, 28.6 mmol) was added dropwise followed by hydrogen peroxide (4.0 ml, 43 mmol), and the reaction mixture stirred for 1.5 h at 0° C. The mixture was diluted with ethyl acetate and water, and the organic layer was washed with saturated aqueous sodium chloride solution. The resulting solid was purified via flash chromatography on silica gel (5% methanol in dichloromethane) to provide the title compound (2R,6S,13aS,14aR,16aS)-ethyl 6-(tert-butoxycarbonylamino)-12-hydroxy-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (1.06 g, 1.539 mmol, 32.3% yield). The α-hydroxy analog (2R,6S,13R,13aR,14aR,16aS)-ethyl 6-(tert-butoxycarbonylamino)-13-hydroxy-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (0.7 g, 21% yield) was also isolated.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C(OCC)(=O)C.CC(C)=O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc(Cl)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(Cl)c1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
Acetone (320 ml), 75 g (450 mmol) of ethyl bromoacetate, and 40.0 g (310 mmol) of 3-chlorophenol were mixed together, then 69.8 g (505 mmol) of potassium carbonate was added. The mixture was mechanically stirred and heated to reflux for 4 h, and after cooling to room temperature, was poured into 350 mL of ethyl acetate. To this was then cautiously added 400 mL of 1 M HCl, taking care to avoid excess foaming. The layers were separated and the aqueous layer was extracted with portions of ethyl acetate (3×200 mL). The combined organic layers were dried over MgSO4, filtered, concentrated, and the resulting solid was recrystallized from hexane to afford 58 g (87%) of 10 as a white solid, m.p.=39-40° C. 1 H NMR δ 7.20-7.08 (m, 1 H), 6.95-6.82 (m, 2 H), 6.75-6.70 (m, 1 H), 4.53 (s, 2 H), 4.21 (q, J=7.2 Hz, 2 H), 1.23 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][O:13]C1CCCCO1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH2:11][CH2:12][OH:13]
Reactant: COc1ccccc1SCCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COc1ccccc1SCCCO

Procedure:
A solution of 9.5 g (33.6 mmol) of (RS)-2-[3-(2-methoxy-phenylsulphanyl)-propoxy]-tetrahydro-pyran and 1.0 g (4 mmol) of pyridinium toluene-4-sulphonate in 100 ml of methanol was heated to reflux for 2 hours. For the working-up, the solvent was distilled off under reduced pressure and then the residue was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic phase was subsequently dried over sodium sulphate and evaporated under reduced pressure. The 3-(2-methoxy-phenylsulphanyl)-propane-1-ol was obtained as a yellowish liquid in quantitative yield; MS: 198 (M)+. Reaction with mesyl chloride, effected according to a generally known procedure, yielded 3-(2-methoxy-phenylsulphanyl)-propyl methanesulphonate as a pale yellow liquid; MS: 276 (M)+.