Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:4]=[C:5](CCCCCCCCC2C=CC(N)=CC=2)[C:6]2[C:11]([C:12]=1OC)=[CH:10][CH:9]=[CH:8][CH:7]=2.CCN(CC)CC.Cl[C:38]1[C:39]2[C:44]([N:45]=[C:46]3[C:51]=1[CH:50]=[CH:49][CH:48]=[CH:47]3)=[CH:43][CH:42]=[CH:41][CH:40]=2>CO>[C:10]1([C:40]2[C:39]3[C:44](=[N:45][C:46]4[C:51]([CH:38]=3)=[CH:50][CH:49]=[CH:48][CH:47]=4)[CH:43]=[CH:42][CH:41]=2)[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Clc1c2ccccc2nc2ccccc12
Reactant: COc1cc(CCCCCCCCc2ccc(N)cc2)c2ccccc2c1OC
Solvent: CCN(CC)CC
Solvent: CO
Product: c1ccc2nc3cccc(-c4cccc5ccccc45)c3cc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 153 %

Procedure:
To a solution of 99 mg (2.53×10−4 mol) of 1-(3,4-dimethoxy-1-naphthyl)-8-(4-aminophenyl)-octane 37 and 35 mL (2.51×10−4 mol) of Et3N in 4 mL of MeOH were added 54 mg (2.53×10−4 mol) of 9-chloroacridine. The reaction mixture was stirred at room temperature for 20 hr. Evaporation of solvent and column chromatography on silica gel with first 1% MeOH in CH2Cl2 and then 3% MeOH in CH2Cl2 afforded 118.2 mg (82%) of acridine 38: 1H NMR (250 MHz, CDCl3, TMS) δ 8.14 (d, J=8 Hz, 1H), 8.0-7.9 (m, 5H), 7.66 (br t, 2H), 7.46 (t, J=8 Hz, 1H), 7.37 (t, J=8 Hz, 1H), 7.3-7.2 (m, 2H), 7.12 (s, 1H), 7.06 (d, J=8.4 Hz, 2H), 6.82 (d, J=8.4 Hz, 2H), 3.1-3.0 (m, 2H), 2.6-2.5 (m, 2H), 1.8-1.3 (m, 12H).
Reaction SMILES: [H-].[Na+].[N:3]1([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C:10]2=[O:18])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[F:19][C:20]1[CH:25]=[C:24]([CH2:26]Cl)[CH:23]=[CH:22][N:21]=1>O1CCCC1>[F:19][C:20]1[CH:25]=[C:24]([CH2:26][C:11]2([CH2:26][C:24]3[CH:23]=[CH:22][N:21]=[C:20]([F:19])[CH:25]=3)[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([N:3]3[CH2:4][CH2:5][O:6][CH2:7][CH2:8]3)[C:10]2=[O:18])[CH:23]=[CH:22][N:21]=1
Reactant: Fc1cc(CCl)ccn1
Reactant: O=C1Cc2ccccc2N1N1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1N(N2CCOCC2)c2ccccc2C1(Cc1ccnc(F)c1)Cc1ccnc(F)c1
Temperature: 0 °C

Procedure:
Sodium hydride (60% oil dispension 92 mg, 2.3 mmole) was charged to a flame-dried flask and washed with pentane (3×3 ml). The flask was flushed with nitrogen, tetrahydrofuran (10 ml) was added and the slurry was stirred at 0° C. 1,3-dihydro-1-(4-morpholinyl)-2H-indol-2-one (225 mg, 1.0 mmole) was added, the resulting solution was stirred for 15 minutes at room temperature and recooled to 0° C. A solution of 2-Fluoro-4-picolyl chloride (410 mg, 2.3 mmole) in tetrahydrofuran (10 ml) was added and the solution allowed to stir at room temperature overnight. The reaction was quenched into water (40 ml) and extracted with dichloromethane(3×25 ml). The combined organics were washed with brine, dried over magnesium sulfate, filter and concentrated under reduced pressure. The residue was chromatographed on silica gel or directly recrystallized from chloroform/hexane to give the desired product; m.p. 198°-203° C. Anal. (C24H22F2N4O2.0.25H2O): C,H,N,F.
Reaction SMILES: [CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]([CH3:12])=[C:6]([CH3:13])[C:3]=1[CH2:4]Cl.[NH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>C1COCC1>[CH3:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]([CH3:12])=[C:6]([CH3:13])[C:3]=1[CH2:4][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: Cc1c(C)c(C)c(CCl)c(C)c1C
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: Cc1c(C)c(C)c(CN2CCNCC2)c(C)c1C

Procedure:
Synthesized according to General Procedure A: 2,3,4,5,6-pentamethylbenzyl chloride (4{14}, 5 g, 25.4 mmol, 1 equiv.), piperazine (13.1 g, 152.5 mmol, 6 equiv.), THF (55.5 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{14} (5.31 g, 85%) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 3.52 (s, 2H), 2.80 (t, 4H, J=4.8 Hz), 2.45 (br s, 4H), 2.32 (s, 6H), 2.25 (s, 3H), 2.23 (s, 6H), 1.63 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 133.9, 133.7, 132.3, 131.9, 57.2, 54.1, 46.5, 17.0, 16.8, 16.6.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([N:16]([CH3:25])[C:17]3([C:22]([OH:24])=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:26][C:27]([NH2:29])=[NH:28])=[N:5][CH:4]=1.Cl.NC(N)=N.[CH2:35](OC(=O)C1(CCCC1)N(S(C1C=C2C(C(Cl)=CN=C2Cl)=CC=1)(=O)=O)C)[CH3:36].O>CS(C)=O>[CH2:35]([O:23][C:22](=[O:24])[C:17]1([CH2:21][CH2:20][CH2:19][CH2:18]1)[N:16]([S:13]([C:9]1[CH:8]=[C:7]2[C:12]([C:3]([Cl:2])=[CH:4][N:5]=[C:6]2[NH:26][C:27]([NH2:29])=[NH:28])=[CH:11][CH:10]=1)(=[O:14])=[O:15])[CH3:25])[CH3:36]
Reactant: CCOC(=O)C1(N(C)S(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCCC1
Reactant: CN(C1(C(=O)O)CCCC1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Agent: N=C(N)N
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C1(N(C)S(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCCC1
Temperature: 50 °C
Yield: 54.8 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(methyl)cycloleucine hydrochloride ##STR91## NaH (31 mg, 80% dispersion in mineral oil, 1.04 mmol) was added to a solution of guanidine hydrochloride (164 mg, 1.67 mmol) in DMSO (4 ml), and the solution heated at 50° C. for 1 h. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-N-(methyl)cycloleucine ethyl ester (180 mg, 0.42 mmol) in DMSO (2 ml) was added, and the reaction heated at 80° C. for 3 h. The cooled reaction mixture was poured into water, and extracted with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), and evaporated in vacuo. The residual yellow oil was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880 NH3 (90:10:1) as eluant, and recrystallised from EtOAc to afford N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(methyl)cycloleucine ethyl ester (105 mg, 0.23 mmol) as a yellow solid.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][CH2:28][S:29]([C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])(=[O:31])=[O:30]>>[OH:26][CH2:27][CH2:28][S:29]([C:32]1[CH:33]=[C:34]([NH:35][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])[CH:36]=[CH:37][CH:38]=1)(=[O:30])=[O:31]
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)CCO)c1
Product: O=C(Nc1cccc(S(=O)(=O)CCO)c1)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-(2-hydroxy-ethanesulfonyl)-aniline [commercially available] according to general procedure II. Yellow solid. MS (ISP) 541.4 [(M+H)+]; mp 205° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1.[CH:16]1[CH:17]=[CH:18][N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[NH:22][CH2:21][C:20]=12.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH2:25][N:19]4[CH:18]=[CH:17][CH:16]=[C:20]4[CH2:21]3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: Cc1cn(-c2ccc(C(=O)Cl)cc2)cn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.6 %

Procedure:
The 4-(4-methylimidazol-1-yl)benzoyl chloride (0.99 g) was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.64 g) and diisopropylethylamine (0.60 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered through a short column of hydrous sodium magnesium silicate, and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the title compound (0.52 g) was obtained as a solid, m.p. 140-145° C.; MS, m/z: 369 (M+H)+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2C=CC=CC=2N=N1.C1(CC(N2CC3C(=CC=CC=3)C2=O)C(O)=O)CCCC1.NC1SC=CN=1.[CH:54]1([CH2:60][C@@H:61]([N:70]2[CH2:78][C:77]3[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=3)[C:71]2=[O:79])[C:62]([NH:64][C:65]2S[CH:67]=[CH:68][N:69]=2)=[O:63])[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1>>[CH:54]1([CH2:60][C@H:61]([N:70]2[CH2:78][C:77]3[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=3)[C:71]2=[O:79])[C:62]([NH:64][C:65]2[CH:12]=[N:8][CH:67]=[CH:68][N:69]=2)=[O:63])[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: O=C(Nc1nccs1)[C@@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1nccs1
Agent: O=C(O)C(CC1CCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1cnccn1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O

Procedure:
BOP coupling of (3-Cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Step A; 273 mg; 1.00 mmol) and 2-aminothiazole (100 mg; 1.00 mmol) in a manner similar to that used for the preparation of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Merck Silica gel 60, 230-400 mesh, eluent: 40% ethyl acetate/hexanes) 132 mg (37%) of 3-Cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide as a white solid: ES-HRMS m/e calcd for C19H21N3O2SNa (M++Na+) 378.1247, found 378.1250.
Reaction SMILES: C([O:5][C:6](=[O:32])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([Cl:29])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]2[CH3:30])=[CH:9][C:8]=1[CH3:31])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:29][C:24]1[CH:23]=[C:22]([C:16]2([C:18]([F:20])([F:19])[F:21])[O:15][N:14]([CH3:30])[CH:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:32])=[O:5])=[C:8]([CH3:31])[CH:9]=3)[CH2:17]2)[CH:27]=[C:26]([Cl:28])[CH:25]=1
Reactant: Cc1cc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C2CC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)ON2C)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-[5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-isoxazolidin-3-yl]-2-methyl-benzoic acid tert-butyl ester (Example 4.4) (0.67 g) in dichloromethane (15 ml) was added trifluoroacetic acid (“TFA”) (1.05 ml). The reaction mixture was stirred at ambient temperature for 16 hours. The dichloromethane was evaporated and ethyl acetate was added. The mixture was washed with water, dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to give 4-[5-(3,5-dichloro-phenyl)-2-methyl-5-trifluoromethyl-isoxazolidin-3-yl]-2-methyl-benzoic acid as a mixture of diastereoisomers (0.56 g). 1H-NMR (CDCl3, 400 MHz): 8.05 (m, 1H), 7.45-7.15 (m, 5H), 3.90-3.60 (m, 1H), 3.35-2.60 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH2:8][CH2:9][CH2:10]O)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:10][CH2:9][CH2:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[F:12]
Reactant: OCCCc1cc(Cl)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Fc1ccc(Cl)cc1CCCBr
Yield: 88.8 %

Procedure:
Compound 64-2 (2.28 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.50 g) and N-bromosuccinimide (2.37 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.70 g) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[CH:8]=O.[C:10]1([C:16]2[S:17][C:18]3[C:26]([N:27]=2)=[CH:25][CH:24]=[C:23]2[C:19]=3[CH2:20][C:21](=[O:28])[NH:22]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCCCC1.Cl>CC(O)C.O>[CH3:1][O:2][C:3]1[CH:7]=[CH:6][NH:5][C:4]=1/[CH:8]=[C:20]1\[C:21](=[O:28])[NH:22][C:23]2[CH:24]=[CH:25][C:26]3[N:27]=[C:16]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[S:17][C:18]=3[C:19]\1=2
Reactant: COc1cc[nH]c1C=O
Reactant: O=C1Cc2c(ccc3nc(-c4ccccc4)sc23)N1
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc3nc(-c4ccccc4)sc3c21

Procedure:
3-Methoxypyrrole-2-carboxaldehyde (13 mg, 0.105 mmol) (Bellamy, supra) and 2-phenyl-6,8-dihydro-thiazolo[5,4-e]indol-7-one (20 mg, 0.075 mmol) (from Example 5) were suspended in a solution of 10% piperidine in 2-propanol (1 mL). The mixture was heated at reflux for 3 h. The mixture was cooled, poured into water, and the aqueous mixture was made acidic with concentrated hydrochloric acid. The aqueous layer was extracted with ethyl acetate, and the combined organic extracts were washed with water, brine, and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the crude product was purified by reverse phase HPLC using acetonitrile-water as solvent. (Yield 10 mg, 36%).
Reaction SMILES: Cl[CH2:2][C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[C:6]=2[CH:7]=1.[NH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH3:17][O:16][C:8]1[C:6]2[CH:7]=[C:3]([CH2:2][N:18]3[CH2:23][CH2:22][N:21]([CH2:2][C:3]4[S:4][C:5]5[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][CH3:15])=[C:8]([O:16][CH3:17])[C:6]=5[CH:7]=4)[CH2:20][CH2:19]3)[S:4][C:5]=2[CH:11]=[C:10]([O:12][CH3:13])[C:9]=1[O:14][CH3:15]
Reactant: C1CNCCN1
Reactant: COc1cc2sc(CCl)cc2c(OC)c1OC
Product: COc1cc2sc(CN3CCN(Cc4cc5c(OC)c(OC)c(OC)cc5s4)CC3)cc2c(OC)c1OC

Procedure:
2-Hydroxymethyl-4,5,6-trimethoxbenzothiophene (374 mg) was treated in the same manner as in Preparation Example 4, and 2-chloromethyl-4,5,6-trimethoxy-benzothiophene thus obtained was immediately reacted with piperazine (63 mg) in the same manner as in Example 1 without isolating it to obtain the title compound as a free base.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][NH:6][C:7](=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH3:2].CN1C=CN=C1.[C:33](Cl)(=[O:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48].C(N(CCCC)CCCC)CCC>[Ti](Cl)(Cl)(Cl)Cl.O.C(Cl)Cl>[C:7]([NH:6][CH:5]([C:33](=[O:49])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[C:4]([O:3][CH2:1][CH3:2])=[O:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCC(=O)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: O
Solvent: ClCCl
Solvent: CCCCN(CCCC)CCCC
Product: CCCCCCCCCCCCCCCCCC(=O)NC(C(=O)CCCCCCCCCCCCCCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 0.1 %

Procedure:
A methylene chloride solution (100 ml) of N-octadecanoylglycine ethyl ester (3.70 g, 10 mmol) and N-methylimidazole (985.4 mg, 12 mmol) was cooled to −45° C., and a methylene chloride solution (10 ml) of palmitoyl chloride (2.76 mg, 9.74 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 20 minutes at the same temperature, a methylene chloride solution (10 ml) of titanium tetrachloride (6.81 mg, 35 mmol) and a methylene chloride solution (10 ml) of tributylamine (7.42 g, 40 mmol) were added thereto. The resulting mixture was stirred for 2 hours at −45° C. After 100 ml of water was added thereto and the mixture was heated to room temperature, the organic layer was separated. Further, the water layer was extracted twice with methylene chloride (100 ml), and the organic layers were combined and dried with magnesium sulfate. After the solvent was removed in reduced pressure, the obtained crude product was purified by silica gel chromatography (Kieselgel 60 manufactured by Merck, hexane:ethyl acetate=4:1) to obtain the title compound (3.20 mg, yield: 54%).
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:10]2=[C:11]3[C:18]([CH3:19])=[N:17][N:16]([C:20]4[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[C:12]3=[N:13][C:14]([CH3:15])=[C:9]2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH2:1]([CH:3]([N:6]1[C:10]2=[C:11]3[C:18]([CH3:19])=[N:17][N:16]([C:20]4[C:25]([Cl:26])=[CH:24][C:23]([Cl:27])=[CH:22][C:21]=4[Cl:28])[C:12]3=[N:13][C:14]([CH3:15])=[C:9]2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCc2c(C)nc3c(c(C)nn3-c3c(Cl)cc(Cl)cc3Cl)c21
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCC(CC)n1ccc2c(C)nc3c(c(C)nn3-c3c(Cl)cc(Cl)cc3Cl)c21
Temperature: 40 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
1-(1-Ethylpropyl)-4,8-dimethyl-6-(2,4,6-trichlorophenyl)-1,2,3,6-tetrahydropyrazolo[3,4-b]pyrrolo[2,3-d]pyridine (70 mg, 0.160 mmol) was dissolved in toluene (7 mL). Manganese dioxide (700 mg) was added thereto, followed by stirring at 40° C. overnight. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was evaporated, and the residue was purified by silica gel column chromatogrpahy (5% ethyl acetate/hexane), to give the title compound (48 mg, 0.110 mmol) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][OH:17])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:18])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][O:17][CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Br:19])=[CH:21][CH:22]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CO)cs1
Reactant: BrCc1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(COCc2ccc(Br)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
2-{[4-(Hydroxymethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (5.0 g) synthesized in Example 10 and 4-bromobenzylbromide (4.75 g) were dissolved in N,N-dimethylformamide (50 mL), potassium tert-butoxide (2.33 g) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=7:1) to give the title compound (4.5 g) as a colorless oil.
Reaction SMILES: CC1(C)OC(C(=O)C)(C)CO1.C(O[CH:15](OCC)[CH2:16][C:17]([C:19]1([CH3:26])[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[O:20]1)=O)C.S(O)(O)(=O)=O.[NH2:35][C:36]1[NH:37][CH:38]=[CH:39][N:40]=1>>[CH3:25][C:21]1([CH3:24])[O:20][C:19]([C:17]2[CH:16]=[CH:15][N:37]3[CH:38]=[CH:39][N:40]=[C:36]3[N:35]=2)([CH3:26])[CH2:23][O:22]1
Reactant: CCOC(CC(=O)C1(C)COC(C)(C)O1)OCC
Reactant: Nc1ncc[nH]1
Agent: CC(=O)C1(C)COC(C)(C)O1
Agent: O=S(=O)(O)O
Product: CC1(C)OCC(C)(c2ccn3ccnc3n2)O1
Yield: 96 %

Procedure:
1-(2,2,4-Trimethyl-[1,3]dioxolan-4-yl)ethanone was converted to 3,3-diethoxy-1-(2,2,4-trimethyl-[1,3]dioxolan-4-yl)propan-1-one as described in Example 3 then condensed with 2-aminoimidazole sulfate as in Example 2 to give 7-(2,2,4-trimethyl-[1,3]dioxolan-4-yl)imidazo[1,2-α]pyrimidine as a pale orange solid (7.10 g, 96%): δH (360 MHz, d6-DMSO) 1.31 (3H, s), 1.47 (3H, s), 1.57 (3H, s), 4.05 (1H, d, J 9), 4.49 (1H, d, J 9), 7.27 (1H, d, J 7), 7.71 (1H, d, J 1), 7.92 (1H, d, J 1), 8.98 (1H, d, J 7).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[CH:35]12[O:41][CH:40]1[CH2:39][CH2:38][CH2:37][CH2:36]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C>[CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C@@H:39]3[CH2:38][CH2:37][CH2:36][CH2:35][C@H:40]3[OH:41])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: C1CCC2OC2C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CCCc1nc(CC)n(-c2ccc(O[C@@H]3CCCC[C@H]3O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 120 °C
Reaction time: 24 h
Yield: 62.4 %

Procedure:
To a solution of 4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) in N,N-dimethylacetamide (20 mL) were added 7-oxabicyclo[4.1.0]heptane (0.66 g) and cesium carbonate (1.5 g), and the mixture was stirred at 120° C. for 24 hr. The mixture was allowed to cool to room temperature. The insoluble material was filtered off, diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (0.76 g, 62%) as a pale-yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH2:20])=[S:19])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3]1.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)=O>C(O)C>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:20]=[C:18]([NH:17][C:14]3[CH:13]=[CH:12][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[C:10]5[C:5]=4[CH2:4][NH:3][C:2]5=[O:1])=[CH:16][CH:15]=3)[S:19][CH:22]=2)=[CH:26][CH:27]=1
Reactant: NC(=S)Nc1ccc(-c2cccc3c2CNC3=O)cc1
Reactant: COc1ccc(C(=O)CBr)cc1
Solvent: CCO
Product: COc1ccc(-c2csc(Nc3ccc(-c4cccc5c4CNC5=O)cc3)n2)cc1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A suspension of Example 125A (90 mg, 0.32 mmol) and 2-bromo-1-(4-methoxy-phenyl)ethanone (73 mg, 0.32 mmol) in ethanol (3 mL) was stirred at reflux for 2 hours, cooled to room temperature, and filtered. The filter cake was washed with ethanol and dichloromethane and dried to give 118 mg (90% yield) of the desired product as the hydrobromide salt. 1H NMR (300 MHz, DMSO-d6) δ 3.80 (s, 3H); 4.55 (s, 2H); 7.01 (d, J=8.81 Hz, 2H); 7.21 (s, 1H); 7.58–7.64 (m, 3H); 7.66–7.69 (m, 2H); 7.86 (dd, J=8.81, 7.12 Hz, 4H); 8.67 (s, 1H); 10.43 (s, 1H); MS (ESI(+)) m/e 414 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[O:36][N:35]=[C:34]([CH3:37])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:16][N:14]([CH3:15])[C:12]1[C:11]([C:17]([F:19])([F:20])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:38])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[O:36][N:35]=[C:34]([CH3:37])[CH:33]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)on1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example M18) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (28 mg).