Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][CH:5]([C:8]2[S:33][C:11]3[N:12]=[C:13]([CH3:32])[N:14]=[C:15]([CH2:16][N:17]4[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C:18]4([CH3:31])[CH3:30])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1.Cl.CCOC(C)=O>O1CCOCC1>[CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][CH:5]([C:8]2[S:33][C:11]3[N:12]=[C:13]([CH3:32])[N:14]=[C:15]([CH2:16][N:17]4[CH2:22][CH2:21][NH:20][CH2:19][C:18]4([CH3:30])[CH3:31])[C:10]=3[CH:9]=2)[CH2:4][CH2:3]1
Reactant: Cc1nc(CN2CCN(C(=O)OC(C)(C)C)CC2(C)C)c2cc(C3CCC(C)(C)CC3)sc2n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1nc(CN2CCNCC2(C)C)c2cc(C3CCC(C)(C)CC3)sc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
To tert-butyl 4-{[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]methyl}-3,3-dimethylpiperazine-1-carboxylate (645 mg) and dioxane (6.45 mL) was added 4 M HCl/EtOAc (1.66 mL), followed by stirring at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue was added EtOAc, followed by stirring. The precipitate was filtered and dried under reduced pressure to obtain 6-(4,4-dimethylcyclohexyl)-4-[(2,2-dimethylpiperazin-1-yl)methyl]-2-methylthieno[2,3-d]pyrimidine (422 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[C:9]1[CH:10]=[CH:11][C:12]([N+:24]([O-:26])=[O:25])=[C:13]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=1.[H-].[Na+]>CN(C)C=O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][C:9]1[CH:10]=[CH:11][C:12]([N+:24]([O-:26])=[O:25])=[C:13]([N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[CH:14]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccn2)ccc1[N+](=O)[O-]
Yield: 13.1 %

Procedure:
By using 0.76 g of 2-hydroxypyridine, 2.29 g of t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate, 0.35 g of sodium hydride (55% by weight) and 10 ml of anhydrous N,N-dimethylformamide, reaction and purification were carried out in a similar manner to that described in Reference Example 6, whereby 0.36 g of the title compound were obtained.
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)C.[NH:23]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:31]([N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:21])=[N:15][C:16]=3[Cl:20])[CH:8]=[CH:7]1)([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32]
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (2.5 g, 7.29 mmol), di-t-butyl iminodicarboxylate (1.74 g, 8.02 mmol), tris(dibenzylideneacetone)-dipalladium(0) (0.33 g, 0.36 mmol) and triphenylphosphine (0.29 g, 1.09 mmol) are placed ira an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (30 ml) is added and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 3 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica, ethyl acetate/isohexane 4:1) 1H nmr (CDCl3, 400 MHz); 8.70(s, 1H), 6.20(m, 1H), 5.85(m, 1H), 5.80(m, 1H), 5.40(m, 1H), 3.20(m, 1H), 2.15(m, 1H), 1.55(s, 18H), MS (ES+) m/e 470 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[C:5]([F:17])[CH:4]=1.[NH4+:18].[OH-]>C1COCC1.CO>[NH2:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])=[O:10])=[C:5]([F:17])[CH:4]=1
Reactant: [NH4+]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(CBr)cc1F
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)NS(=O)(=O)c1ccc(CN)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(bromomethyl)-N-tert-butyl-2-fluorobenzenesulfonamide (500 mg) in THF/MeOH (1:1, 15 ml) was added NH4OH (4.5 ml). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated and partitioned between EtOAc/H2O and the aq phase was extracted by EtOAc (3×). The organic phase was then combined, washed with brine, dried over Na2SO4 and concentrated to give 4-(aminomethyl)-N-tert-butyl-2-fluorobenzenesulfonamide as a viscous oil, which was used in the next step without further purification.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH:8]([C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:31])[C@H:9]([C:11]([NH:13][C@@H:14]([C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:15][CH2:16][C:17](=[O:19])[OH:18])=[O:12])[CH3:10]>>[NH:8]([C:30]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])=[O:31])[C@H:9]([C:11]([NH:13][C@@H:14]([C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21])[CH2:15][CH2:16][C:17](=[O:18])[O:19][N:13]1[C:3](=[O:5])[CH2:2][CH2:9][C:11]1=[O:12])=[O:12])[CH3:10]
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)O)C(=O)OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](C)C(=O)N[C@H](CCC(=O)ON1C(=O)CCC1=O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Trifluoroacetic acid (15 ml) was added to Boc-L-Ala-D-Glu-(OH)OBzl (1)(3.26 g) and the mixture was stirred for 20 minutes at room temperature, concentrated in vacuo and washed with diisopropylether. The oil was dissolved in a mixture of water (15 ml) and sodium bicarbonate was added until the pH of the solution became 8-9. The mixture of water (6 ml) and acetone (20 ml) was added to the solution and palmitoyl chloride (2.20 g) was added in one portion. After stirring for 30 minutes at room temperature, the pH of the solution was adjusted to 3 with 1N-hydrochloric acid and the reaction mixture was concentrated. To the residue was added water (30 ml) and the precipitates was collected and dried to give a crude product, which was purified by column chromatography of Silicagel (90 g) with chloroform-methanol (30:1, v/v) as an eluent to give palmitoyl-L-Ala-D-Glu(OH)OBzl (2)(2.00 g). mp. 131°-132° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([NH:10]C(=O)OCC)=S.Cl.NO.CC[N:21](C(C)C)C(C)C.C(O)C>CO>[N:7]1[C:8]([NH2:10])=[N:21][N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=12
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1cnccn1
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Nc1nc2cnccn2n1
Temperature: 65 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 270a (6.00 g, 26.43 mmol, 1.0 eq.), hydroxylamine hydrochloride (3.32 g, 47.52 mmol, 1.8 eq.), DIPEA (12 mL), ethanol (40 mL), and methanol (40 mL). The reaction mixture was stirred at 65° C. for 16 hours. After the reaction was complete, it was cooled to room temperature and concentrated to a volume of around 20 mL under reduced pressure. The resulting suspension was collected by filtration and the solid was washed with 60:1 dichloromethane/ethanol (50 mL) to afford 270b (3.3 g, 92%) as a white solid. MS-ESI:[M+H]+ 136.3. 1H NMR (500 MHz, DMSO-d6) δ 8.84 (d, J=1.0 Hz, 1H), 8.70 (dd, J=1.0, 4.0 Hz, 1H), 7.98 (d, J=5.0 Hz, 1H), 6.47 (s, 2H).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:9]=1[C:10]([NH:12][CH3:13])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[CH:25](OCC)=[O:26]>C1COCC1>[CH3:19][O:18][C:16]1[CH:15]=[CH:14][C:9]([C:10]([NH:12][CH3:13])=[O:11])=[C:8]([CH:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:25]=[O:26])[CH:17]=1
Reactant: CNC(=O)c1ccc(OC)cc1Cc1ccccc1
Reactant: CCOC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(OC)cc1C(C=O)c1ccccc1
Reaction time: 0.33 h

Procedure:
A solution of 2-benzyl-4-methoxy-N-methylbenzamide (125 mg) in 5 mL THF was cooled to −78 C. n-BuLi (0.400 mL, 2.5 M in hexanes) was added, and the reaction was stirred at −78 C for 20 min. A solution of ethyl formate (0.160 mL) in 1 mL THF was added via cannula. The reaction was quenched at −78 C by addition of saturated aqueous ammonium acetate. The mixture was extracted with EtOAc and concentrated to give 4-methoxy-N-methyl-2-(2-oxo-1-phenylethyl)benzamide, which was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50](Br)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:54]([C:56]1[CH:57]=[C:58](B(O)O)[CH:59]=[CH:60][CH:61]=1)#[N:55].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[CH:44][C:43]([Cl:46])=[C:42]([CH2:47][C:48]2[S:49][C:50]([C:60]3[CH:59]=[CH:58][CH:57]=[C:56]([C:54]#[N:55])[CH:61]=3)=[CH:51][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)s1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: N#Cc1cccc(-c2ccc(Cc3cc([C@@H]4O[C@H](COCc5ccccc5)[C@@H](OCc5ccccc5)[C@H](OCc5ccccc5)[C@H]4OCc4ccccc4)ccc3Cl)s2)c1

Procedure:
A mixed solution of 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene 53 (1.24 g) obtained in Example 119-(6), 3-cyanophenylboronic acid (270 ml), bis(triphenylphosphine)palladium (II)dichloride (54 mg) and 2M aqueous sodium carbonate solution (2.3 ml) in 1,2-dimethoxyethane (12 ml) was heated under reflux for 4 hours. The mixture was diluted with ethyl acetate and washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine. The mixture was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:1-5:1) to give 1-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-4-chloro-3-(5-(3-cyanophenyl)-2-thienylmethyl)benzene (1.12 g) as colorless oil. APCI-Mass m/Z 849/851 (M+NH4).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([CH:26]1[NH:30][C:29](=[O:31])[N:28]([CH3:32])[C:27]1=[O:33])[CH3:25]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:30]4[CH:26]([CH2:24][CH3:25])[C:27](=[O:33])[N:28]([CH3:32])[C:29]4=[O:31])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CCC1NC(=O)N(C)C1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Product: CCC1C(=O)N(C)C(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cn1
Yield: 54.4 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 127 and 5-ethyl-3-methylimidazolidine-2,4-dione (63 mg) described in Preparation Example 215 and by the reaction and treatment in the same manner as in Example 536, the title compound (95 mg) was obtained.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[NH:29]N>>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[N:29]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: NNc1cc(Cl)ccc1Cl
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1cc(Cl)ccc1Cl
Yield: 23 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 2,5-dichlorophenylhydrazine according to the method described for Example 1 in 23% yield. MS: M=383.0 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:5]=1)([O-])=O.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=3[CH3:17])[CH2:26][CH2:27]2)=[O:10])=[C:6]([C:13]([F:16])([F:15])[F:14])[CH:5]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N)cc3C(F)(F)F)CC2)c(C)c1
Yield: 106.3 %

Procedure:
Using 4-nitro-2-trifluoromethylbenzoic acid (500 mg) and 1-(2,4-dimethylphenyl)piperazine (403 mg) and by the reaction and treatment in the same manner as in Preparation Example 148, the title compound (850 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:18])[C:4]2[C:9]([C:10](=[O:17])[C:11]=1[NH:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH2:19]([OH:21])[CH3:20].C(OCC)(=O)C>S(=O)(=O)(O)O.C(OC(=O)C)(=O)C>[Cl:1][C:2]1[C:3](=[O:18])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:17])[C:11]=1[N:12]([CH2:13][CH2:14][O:15][CH3:16])[C:19](=[O:21])[CH3:20]
Reactant: CCO
Reactant: COCCNC1=C(Cl)C(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: COCCN(C(C)=O)C1=C(Cl)C(=O)c2ccccc2C1=O
Temperature: 45 °C
Reaction time: 1 h

Procedure:
A few drops of concentrated sulfuric acid was added to a solution of 2-chloro-3-[(2-methoxyethyl)amino]-1,4-naphthoquinone (33 g) in acetic anhydride (100 ml) and the mixture was stirred at 45° C. for 1 hour. By adding ethanol (100 ml) to the reaction solution, excess acetic anhydride was esterified. After cooling, ethyl acetate was added to the reaction solution and the mixture was washed with water and brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was crystallized from diethyl ether to give N-(3-chloro-1,4-dihydro-1,4-dioxo-2-naphthalenyl)-N-(2-methoxyethyl)acetamide (29 g) as a yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].Cl>CN(C)C=O>[CH2:27]([O:21][CH:17]1[CH2:18][CH2:19][CH2:20][CH:15]([O:14][CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH3:22])[CH2:16]1)[CH:26]=[CH2:25]
Reactant: Cc1oc(-c2ccc(F)cc2)nc1COC1CCCC(O)C1
Reactant: C=CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC1CCCC(OCc2nc(-c3ccc(F)cc3)oc2C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2 g of the 3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy)cyclohexanol are dissolved in 15 ml of dimethylformamide, and 0.3 g of sodium hydride is added. After 30 minutes, 2.4 g of allyl bromide are added dropwise. The mixture is stirred at room temperature for 5 hours. 15 ml of 1N HCl are then added to the reaction mixture, and the mixture is washed three times with 15 ml of ethyl acetate. The organic phase is dried over magnesium sulfate and the solvent is then removed under reduced pressure. The residue is purified by RP-HPLC. This gives 2.4 g of 4-(3-allyloxycyclohexyloxymethyl)-2-(4-fluorophenyl)-5-methyloxazole as a yellowish oil. C20H24FNO3 (345.42) MS (ESI): 346 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[N:19][CH:18]=[CH:17][CH:16]=3)([NH2:11])[CH2:9][NH2:10])=[CH:4][CH:3]=1.CO[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#N)[CH:27]=1)=[NH:25].C(Cl)(Cl)Cl>CO>[C:24]([C:26]1[CH:27]=[C:28]([C:32]2[NH:10][CH2:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)([C:12]3[CH:13]=[N:14][C:15]4[C:20]([CH:21]=3)=[N:19][CH:18]=[CH:17][CH:16]=4)[N:11]=2)[CH:29]=[CH:30][CH:31]=1)#[N:25]
Reactant: NCC(N)(c1ccc(F)cc1)c1cnc2cccnc2c1
Reactant: COC(=N)c1cccc(C#N)c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: N#Cc1cccc(C2=NC(c3ccc(F)cc3)(c3cnc4cccnc4c3)CN2)c1
Temperature: 25 °C
Reaction time: 19 h
Yield: 33.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-1-(1,5-naphthyridin-3-yl)-1,2-ethanediamine (17 mg) in methanol (1 mL) was added 3-cyanobenzeneimidic acid methyl ester (23 mg), and the mixture was stirred at room temperature for 19 hrs. To the reaction mixture was added chloroform and insolubles were removed by filtration, followed by concentration of the filtrate in vacuo. The residue was purified by preparative thin-layer chromatography (100% ethyl acetate) to give the objective compound (8.0 mg).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[O:49]CC1C=CC=CC=1)(=[O:42])=[O:41])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CCO.[Pd]>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:36]=[CH:35][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:37][CH2:38][NH:39][S:40]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[OH:49])(=[O:41])=[O:42])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccccc3OCc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccccc3O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 104.9 %

Procedure:
Methyl 4-(2-{1-benzhydryl-2-[2-(2-benzyloxy-benzenesulfonylamino)-ethyl ]-5-chloro-1H-indol-3-yl}-ethoxy)-benzoate (0.55 g, 0.70 mmol), (Step 1, Example 184) and 10% Pd/C (55 mg) in MeOH (30 ml) and EtOH (20 ml) was hydrogenated. The resulting mixture was filtered through Celite and concentrated. The residue was chromatographed with 35-40% EtOAC/hexane to give the desired product (0.50 g, 95%).
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH2:16][C:17](=[O:23])[C:18]1[CH:22]=[CH:21][NH:20][CH:19]=1)[CH3:12]>ClCCCl>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH2:16][C:17](=[O:23])[C:18]1[CH:22]=[C:21]([CH:4]=[O:5])[NH:20][CH:19]=1)[CH3:12]
Reactant: CN(C)C=O
Reactant: CCOC(=O)CCC(=O)c1cc[nH]c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)CCC(=O)c1c[nH]c(C=O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of DMF (1.2 mL) in 1,2-dichloroethane (25 mL) at 0° C. was treated with POCl3 (1.5 mL). The resulting solution was warmed to ambient temperature and then treated with a solution of γ-oxo-1-H-pyrrole-3-butanoic acid ethyl ester (2.06 g) in 1,2-dichloroethane (10 mL). The reaction mixture was heated to 55° C. After 3.5 hours, the reaction was quenched with the addition of 1N NaOH (16 mL), and then stirred overnight at ambient temperature. The reaction mixture was extracted with ethyl acetate (150 mL), and the organic layer was dried (MgSO4) and concentrated. The resulting oil was chromatographed on SiO2 (100 g) using 4:1 hexane/ethyl actetate to afford 5-formyl-γ-oxo-1-H-pyrrole-3-butanoic acid ethyl ester (0.54 g).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH:4]=[CH:3][CH2:2]1.Cl([O-])=[O:18].[Na+].P([O-])(O)(O)=O.[Na+]>C(O)(C)(C)C.CC(=CC)C>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[C:10]([OH:18])=[O:11])[CH2:2][CH:3]=[CH:4][CH2:5]1
Reactant: COc1ccc(C=O)cc1OC1CC=CC1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: COc1ccc(C(=O)O)cc1OC1CC=CC1
Reaction time: 5 h
Yield: 69.7 %

Procedure:
A stirred solution of 3-cyclopent-3-enyloxy-4-methoxybenzaldehyde (1.75 g) in t-butanol (36.5 mL) and 2-methyl-2-butene (9.0 mL) is treated dropwise with an aqueous solution (34 mL) containing sodium chlorite (80% technical grade; 1.0 g) and sodium dihydrogen phosphate (8.75 g). The resulting mixture is further stirred for 5 hours, the layers are separated and the aqueous layer is extracted with t-butyl methyl ether (3×30 mL). The combined organic layers are washed with water (2×15 mL), dried over sodium sulfate and the solvent removed under reduced pressure. The resulting residue is recrystallized from ethyl acetate to give 3-cyclopent-3-enyloxy-4-methoxybenzoic acid (1.31 g), in the form of a colorless solid, m.p. 171–173° C. [Elemental analysis: C, 66.6; H, 6.0%; calculated: C, 66.7; H, 6.0%].
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.CN(C)C=O>[C:1]1([C:7]2[N:8]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=3)[C:9]3[C:14]([CH:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2c(-c3ccccc3)cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.8 %

Procedure:
A solution of 2-phenylindole (4.2 g, 21.7 mmol) and sodium hydride (60% in oil, 0.96 g, 24 mmol) in tetrahydrofuran (90 mL) and N,N-dimethylformamide (10 mL) was stirred under ice-cooling for 20 min. To the reaction mixture was added methyl 4-bromomethylbenzoate (5.0 g, 21.8 mmol), and the mixture was stirred at room temperature for 18 hr. An aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:10-1:5-1:2) to give the title compound (2.8 g, yield 38%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:12][C:11]([CH2:13]O)=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>C1COCC1>[Br:35][CH2:13][C:11]1[S:12][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:9][CH:10]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(-c2ccccc2Cl)s1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccccc1-c1ccc(CBr)s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
200 mg (0.74 mmol) of the compound from Example 52A and 291 mg (1.11 mmol) of triphenylphosphine were dissolved in 8 ml of THF, and 367 mg (1.11 mmol) of carbon tetrabromide were added at RT. The mixture was then stirred at RT for 16 h. For work-up, the mixture was filtered through 20 g of kieselguhr, the filter residue was rinsed with ethyl acetate and the filtrate was concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1, then 5:1). This gave 113 mg of contaminated target product (32% pure, 17% of theory) which were immediately reacted further.