Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([F:21])([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[N:19][OH:20])=[CH:14][CH:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClN1C(=O)CCC1=O.[Cl:30][C:31]1[CH:32]=[C:33]([C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])[CH:34]=[C:35]([Cl:38])[C:36]=1[F:37].C(=O)(O)[O-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:44][C:39]([C:33]4[CH:34]=[C:35]([Cl:38])[C:36]([F:37])=[C:31]([Cl:30])[CH:32]=4)([C:40]([F:43])([F:42])[F:41])[O:20][N:19]=3)=[CH:14][CH:13]=2)([F:21])[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=NO)cc2)C1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)O3)cc2)C1
Temperature: 55 °C
Reaction time: 1 h
Yield: 39.3 %

Procedure:
To a stirred solution of 3-fluoro-3-[4-(hydroxyimino-methyl)-phenyl]-azetidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.7 mmol, 1 eq) in DMF (6.5 mL) was added N-chloro succinimide (0.227 g, 1.7 mmol, 1 eq). Reaction mixture was stirred at 55° C. for 1 hour. After 1 hour (chloro intermediate formation), 1-(3,5-dichloro-4-fluoro-phenyl)-2,2,2-trifluoro-ethanone (0.45 g, 1.73 mmol, 1.02 eq) was added followed by addition of sodium bicarbonate (0.146 g, 1.74 mmol, 1.02 eq) at room temperature. Resulting reaction mixture was stirred at 55° C. for 3 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched by water (10 mL) and extracted with ethyl acetate (3×50 mL). Combined organic phase was washed with brine solution (20 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to get brown thick oil (0.6 g, Crude). Crude was purified by Combiflash using 40 g Redisep column. Desired compound was eluted in 25% ethyl acetate in hexane to afford title compound as colorless thick oil (0.37 g, 39.32%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.16-4.24 (m, 2H), 4.38-4.47 (m, 2H), 7.59 (d, J=8.44 Hz, 2H), 7.66 (d, J=5.88 Hz, 2H), 7.89 (d, J=8.2 Hz, 2H), LC-MS (m/z): No ionization.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[C:17]([S:34][CH3:35])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])[N:18]=[C:17]([S:34][CH3:35])[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(SC)nc1OCCN
Product: CCS(=O)(=O)NCCOc1nc(SC)nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1ccccc1OC
Yield: 29.7 %

Procedure:
According to the procedure described in Example 4a) 2 g of 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamide was reacted with 0.81 g ethanesulfonylchloride to give 0.7 g 4-tert.-butyl-N-[6-(2-ethanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-methylsulfanyl-pyrimidin-4-yl]-benzenesulfonamide. LC-MS: tR=5.85 min, [M+1]+=611.31.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18](=[O:19])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Br:26])[CH:21]=1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: O=C(CBr)c1cccc(Br)c1
Product: CCOC(=O)n1c(C(=O)c2cccc(Br)c2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 2-bromo-3′-bromoacetophenone. 1H-NMR (CDCl3) δ: 8.25 (1H, d, J=1.5 Hz), 7.90 (1H, t, J=1.8 Hz), 7.64-7.59 (2H, m), 7.54 (1H, d, J=8.4 Hz), 7.34-7.26 (2H, m), 5.87 (2H, br s). 3.84 (2H, q, J=7.0 Hz), 0.89 (3H, t, J=7.0 Hz)
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH:29]=[CH:30][CH:31]=[C:32]3[S:37](Cl)(=[O:39])=[O:38])(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl>O1CCCC1>[CH2:8]([NH:15][S:37]([C:32]1[C:33]2[C:28](=[C:27]([O:26][S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:16])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:30][CH:31]=1)(=[O:38])=[O:39])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc3c(S(=O)(=O)Cl)cccc23)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Oc2cccc3c(S(=O)(=O)NCc4ccccc4)cccc23)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Triethylamine (0.17 ml, 1.2 mmol) was added to benzylamine (117.9 mg, 1.1 mmol) dissolved in tetrahydrofuran (5 ml). After the solution was cooled in the ice bath, 5-{[(4-methylphenyl)sulfonyl]oxy}naphthalene-1-sulfonyl chloride (396.9 mg, 1.2 mmol) was added, and the mixture was stirred at room temparature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (eluent; n-hexane : ethyl acetate=2:1) and crystallized (ethyl acetate/hexane) to give the title compound as a white crystal (398.8 mg, 85.3%).
Reaction SMILES: [O:1]1[C:5]([CH:6]=O)=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:19][C:20](=[O:22])[CH3:21])C=CC=CC=1.O>CS(C)=O>[O:1]1[C:5]([CH:6]=[CH:19][C:20](=[O:22])[CH3:21])=[CH:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2
Reactant: O=Cc1cc2ccccc2o1
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)C=Cc1cc2ccccc2o1

Procedure:
A solution of benzo[b]furan-2-carboxaldehyde (3.3 g) and 1-triphenylphosphoranylidene-2-propanone (1.2 equivalents) in dimethyl sulfoxide (180 ml) was stirred at a temperature of 35° C. for a period of 30 minutes. The cooled mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The solvent was evaporated from the dried (MgSO4) fraction and the residue was purified by column chromatography over silica gel (dichloromethane elution) to give 1-(benzo[b]furan-2-yl)but-1-en-3-one (3.0 g) as an orange solid, mp 100°-101° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][CH2:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[C:36]([F:44])[CH:35]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:41][O:40][C:38](=[O:39])[C:37]1[CH:42]=[CH:43][C:34]([CH2:33][NH:32][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[CH:35][C:36]=1[F:44]
Reactant: COC(=O)c1ccc(CN)cc1F
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Yield: 98 %

Procedure:
In a manner similar to the method described in Example 379, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (66.1 mg, 0.141 mmol) and methyl 4-(aminomethyl)-2-fluorobenzoate (51.0 mg, 0.278 mmol in N,N-dimethyl formamide (5 mL) were reacted with DIPEA (111 mg, 0.857 mmol), HOBt (37.6 mg, 0.277 mmol) and HBTU (104.9 mg, 0.275 mmol) at room temperature to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid methyl ester (88.5 mg, 98%). HRMS (ES+) m/z Calcd C32H30Cl2F3N3O3+H [(M+H):632.1689. Found: 632.1692.
Reaction SMILES: [OH-].[Li+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([O:16]C)=[O:15])=[N:8][CH:9]=1.Cl>CO.O>[NH2:3][C:4]1[N:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][C@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([OH:16])=[O:15])=[N:8][CH:9]=1
Reactant: COC(=O)[C@H](CCCc1cnc(N)cn1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CCCc1cnc(N)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
Lithium hydroxide (1.2 g, 28.6 mmol) is added, at 0° C., to a solution of methyl (S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoate (7.75 g, 23.9 mmol) in methanol (60 ml) and water (20 ml). The mixture is allowed to warm to room temperature and stirring is continued for 18 hours. The methanol is evaporated off under reduced pressure and the residue obtained is cooled to 0° C., acidified to pH 3-4 with 1N hydrochloric acid (30 ml), extracted with ethyl acetate (2×200 ml), washed with brine (50 ml), dried over sodium sulphate, filtered and concentrated under reduced pressure. 7.17 g of (S)-5-(5-amino-2-pyrazinyl)-2-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoic acid are obtained in the form of a white powder, which is used without further purification in the following step.
Reaction SMILES: [C:1]([S:7][CH2:8]/[C:9](=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)/[C:10]([OH:12])=O)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]>>[O:12]=[C:10]([NH:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])/[C:9](/[CH2:8][S:7][C:1](=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5])=[CH:13]\[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)C(=O)SC/C(=C/c1ccccc1)C(=O)O
Reactant: COC(=O)CCN
Product: COC(=O)CCNC(=O)/C(=C\c1ccccc1)CSC(=O)C(C)(C)C
Yield: 69 %

Procedure:
The (E)-2-pivaloylthiomethyl-3-phenylpropenoic acid described in Example 8 (step B) is coupled with methyl β-alaninate according to the experimental procedure described in Example 1 (step D). Yield: 69% (after flash chromatography, eluent: ether/petroleum ether 55/45) oil IR: 3300, 1730, 1660, 1630 cm-1 1H NMR (CDCl3): 7.20 (s, 5H); 6.75 (s, 1H); 5.90 (broad t, 1H); 3.80 (s, 2H); 3.50 (s, 3H); 3.60 to 3.25 (m, 2H); 2.40 (t, 2H, J=6.5 Hz); 1.20 (s, 9H) Microanalysis: C19H25NO4S Calc. % C=62.79 H=6.93 N=3.85 Found. % C=63.20 H=7.10 N=3.92
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.Cl.[Cl:28][C:29]1[C:30]([CH2:35][NH2:36])=[N:31][CH:32]=[CH:33][N:34]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:28][C:29]1[C:30]([CH2:35][NH:36][C:11]([C@H:8]2[CH2:7][CH2:6][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)=[O:13])=[N:31][CH:32]=[CH:33][N:34]=1
Reactant: COC(=O)C1CCC(C(=O)O)CC1
Reactant: NCc1nccnc1Cl
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC[C@H](C(=O)NCc2nccnc2Cl)CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A THF (370 mL) solution of 4-(methoxycarbonyl)cyclohexanecarboxylic acid (15.14 g, 81.30 mmol) and CDI (13.18 g, 81.30 mmol) was placed under a nitrogen atmosphere and stirred at 60° C. for 4 h. The reaction mixture was cooled to r.t., then, (3-chloropyrazin-2-yl)methylamine bis-hydrochloride salt (16.00 g, 73.91 mmol) and DIPEA (31.52 g, 244.00 mmol, 42.5 mL) was added. After stirring at 60° C. for 20 h, the reaction was concentrated in vacuo. The crude reaction mixture was purified by a silica gel glass column chromatography (eluted with 3:2 DCM/EtOAc) to obtain the pure desired product as a slightly yellowish creamy white powder; 1H NMR (CDCl3, 400 MHz) δ 1.43-1.65 (m, 4H), 2.01-2.14 (m, 4H), 2.25 (tt, J=12.0, 3.6 Hz, 1H), 2.34 (tt, J=11.6, 3.2 Hz, 1H), 3.68 (s, 3H), 4.70 (d, J=4.4 Hz, 2H), 6.81 (s, br, -NH), 8.32-8.36 (m, 1H), 8.46 (d, J=2.4 Hz, 1H); MS (ES+): m/z 312.17/314.12 (84/32) [MH+]; HPLC: tR=2.44 min (OpenLynx, polar—5 min).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[B-](F)(F)F.[O:18]=[N+:19]=[O:20].S1(CCCC1)(=O)=O>COCCOC>[N+:19]([C:6]1[CH:5]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:9]=[CH:8][C:7]=1[OH:10])([O-:20])=[O:18]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: COCCOC
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1cc(OC(F)(F)F)ccc1O
Temperature: -50 °C
Reaction time: 6 h

Procedure:
To a mixture of 4-(trifluoromethoxy)phenol (4 g, 0.0225 mol) in ethylene glycol dimethyl ether (90 mL) was added a 0.5 M solution of nitronium tetrafluoroborate in sulfolane (46 mL, 0.0229 mol) at −50° C. The mixture was stirred at −50° C. under an atmosphere of nitrogen for 6 hours. The mixture was filtered through silica gel pad, and the pad was washed with 25% ethyl acetate/n-heptane. The solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and brine. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography on silica using 0%-50% ethyl acetate/n-heptane as a mobile phase to give 2-nitro-4-(trifluoromethoxy)phenol (2.5 g, 0.011 mol). TLC (ethyl acetate/n-heptane=25:75) Rf 0.50 MS: MH−: 222.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:35])([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=O)[CH:23]([F:25])[F:24]>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][CH:34]=[C:27]([O:26][C:22]([F:21])([F:35])[CH:23]([F:24])[F:25])[CH:28]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(OC(F)(F)C(F)F)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(OC(F)(F)C(F)F)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 3-(1,1,2,2-tetrafluoroethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 441.98 g/mol.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][O:6][CH2:7][C:8]1[N:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:10]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]=[C:12]([NH2:20])[C:11]=2[N:21]=1>ClCCl.C(N(CC)CC)C>[NH2:20][C:12]1[C:11]2[N:21]=[C:8]([CH2:7][O:6][NH:5][C:1](=[O:3])[CH3:2])[N:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:10]=2[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[N:13]=1
Reactant: CC(=O)Cl
Reactant: CC(C)Cn1c(CON)nc2c(N)nc3c(c21)CCCC3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NOCc1nc2c(N)nc3c(c2n1CC(C)C)CCCC3
Reaction time: 1 h
Yield: 26.1 %

Procedure:
A solution of acetyl chloride (0.232 mL, 3.27 mmol) in dichloromethane (10 mL) was added dropwise to a stirred solution of 2-[(aminooxy)methyl]-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in Example 123, 860 mg, 2.97 mmol) and triethylamine (1.24 mL, 8.92 mmol) in dichloromethane (20 mL) at 0° C. After 1 hour, additional acetyl chloride (0.232 mL) in dichloromethane (10 mL) and triethylamine (1.0 mL) were added. The reaction mixture was stirred for an additional 30 minutes, then was concentrated under reduced pressure. The crude product was purified by chromatography using a HORIZON HPFC system (silica gel, gradient elution with 5-15% 1 M NH3 in methanol/dichloromethane) followed by crystallization from acetonitrile. The crystals were isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to yield 257 mg of N-{[4-amino-1-(2-methylpropyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}acetamide as pale yellow crystals, mp 187-188° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.[NH2:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][O:13][C:14]2=[O:19].S([O-])([O-])(=O)=O.[Mg+2]>C(#N)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1/[CH:7]=[N:9]/[C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][O:13][C:14]2=[O:19]
Reactant: Nc1cccc2c1COC2=O
Reactant: Cn1ccnc1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: Cn1ccnc1/C=N/c1cccc2c1COC2=O
Yield: 99.9 %

Procedure:
A solution of 1-methyl-1H-imidazole-2-carbaldehyde (680 mg, 6.18 mmol), 4-aminoisobenzofuran-1(3H)-one (920.8 mg, 6.18 mmol) and anhydrous magnesium sulfate (7.41 g, 61.8 mmol) in acetonitrile (100 ml) was heated to reflux for two days. The mixture was filtered and the solvents were removed in vacuum. The crude product was re-crystallized from isopropanol to get the title compound (1.49 g, yield 68%). LC-MS (ESI) m/z: 242 (M+1)+. 1H-NMR (400 MHz, DMSO-d6); 4.06 (s, 3H), 5.52 (s, 2H), 7.22 (s, 1H), 7.52 (s, 1H), 7.65-7.67 (m, 1H), 7.72-7.74 (m, 2H), 8.66 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH2:18])=[O:5].[CH3:24][N:25]=[C:26]=[S:27]>C(Cl)CCl>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][NH:18][C:26]([NH:25][CH3:24])=[S:27])=[O:5]
Reactant: CN=C=S
Reactant: NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Solvent: ClCCCl
Product: CNC(=S)NNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A suspension of 8-(2,6-dichlorobenzoylamino)-4-hydrazinoquinoline (200 mg) and methyl isothiocyanate (54.8 mg) in ethylene chloride (4 ml) was stirred for 2 hours at ambient temperature and then gently refluxed for 24 hours. The mixture was concentrated in vacuo, and the residue was recrystallized from ethanol to give 8-(2,6-dichlorobenzoylamino)-4-[4-(methyl)thiosemicarbazido]quinoline (213 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([Cl:28])[CH:3]=1.[CH3:29][C:30]1[O:34][C:33](B(O)O)=[CH:32][CH:31]=1.CC(C)([O-])C.[K+]>COCCOC.O.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:28][C:4]1[CH:3]=[C:2]([C:33]2[O:34][C:30]([CH3:29])=[CH:31][CH:32]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]2)[CH:15]=[CH:14][C:13]=1[O:26][CH3:27])(=[O:10])=[O:9]
Reactant: Cc1ccc(B(O)O)o1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccc(C)o2)cc1Cl
Temperature: 100 °C

Procedure:
To a mixture of 4-bromo-2-chloro-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E104) (220 mg, 0.45 mmol), (5-methyl-2-furanyl)boronic acid (113 mg, 0.90 mmol) and tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.05 mmol) in DME (3 ml) was added potassium tert-butoxide (454 mg, 4.10 mmol) in water (1 ml), and the reaction heated in the microwave (set at high absorbance) at 100° C. for 30 minutes. The reaction was poured on to the SCX column eluting first with methanol and then 2M ammonia in methanol. The basic fractions were combined and solvent evaporated in vacuo. The product was purified by mass directed autoprep HPLC, the relevant fractions collected and solvent evaporated in vacuo. The product was triturated in ether to give the title compound (E306). MS (ES+) m/e 490/492 [M+H]+.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:6]=1[OH:14])([O-])=O.[H][H]>>[ClH:1].[ClH:1].[NH2:2][C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:6]=1[OH:14]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Agent: Cl
Product: Nc1ccc(O)c(N)c1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Into the reactor described in the foregoing Example 7 there are charged 200 ml of a 4% aqueous solution of hydrochloric acid and 4 g of 2,4-dinitrophenol are added thereto. Hydrogen is continuously introduced inside the chamber under the pressure of 1 atm at the rate of 15 ml/min. The reactor is heated to the temperature of 50° C. and hydrogenation is conducted at this temperature for 1.5 hours. After cooling and precipitation with a 37% hydrochloric acid there are obtained 3.9 g of 2,4-diaminophenol dihydrochloride which corresponds to 91.5% as calculated for the starting 2,4-dinitrophenol.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([N:10]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][C:13](=[O:22])[C:12]([CH3:23])=[C:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:8][CH:9]=1.[CH2:30](Br)[C:31]#[CH:32]>CS(C)=O>[CH3:23][C:12]1[C:13](=[O:22])[CH:14]=[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH2:32][C:31]#[CH:30])[CH:5]=2)[C:11]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C#CCBr
Reactant: Cc1c(-c2ccccc2)n(-c2cccc(O)c2)c(-c2ccccc2)cc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CCOc1cccc(-n2c(-c3ccccc3)cc(=O)c(C)c2-c2ccccc2)c1
Temperature: 0 °C
Yield: 38.3 %

Procedure:
To 50 ml of a suspension of 0.72 g (0.03 mole) of sodium hydride in DMSO, 3.5 g (0.01 mole) of 1-(3-hydroxyphenyl)-3-methyl-2,6-diphenyl-4(1H)-pyridinone was added, followed by further dropwise addition of 1.4 g (0.012 mole) of propargyl bromide. The reaction mixture was thereafter poured into ice water, followed by extraction with chloroform. After washing the organic layer (the extract) with water, it was dried over anhydrous magnesium sulfate. The solvent was distilled off, followed by recrystallization from a 2:1 mixed solvent of acetone and hexane to obtain 1.5 g of 3-methyl-2,6-diphenyl-1-(3-propargyloxyphenyl)-4-(1H)-pyridinone having a melting point of 166°-169° C.