Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:18]=[CH:17][C:10]3[S:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:34])(=O)=O)=CC=1>C1COCC1>[F:34][C:13]1[C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:18]=[CH:17][C:10]=2[S:11][C:12]=1[C:14]([OH:16])=[O:15]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: O=C(O)c1cc2cc(-c3ccccc3)ccc2s1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1sc2ccc(-c3ccccc3)cc2c1F
Temperature: -70 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a solution of compound 52c (507 mg, 1.99 mmol) in THF (8 mL) at −70° C. was added n-BuLi (1.6 M in hexane, 2.62 mL, 4.19 mmol). The mixture was stirred at −70° C. for 1 h; then a solution of N-fluorobenzenesulfonimide (817.3 mg, 2.59 mmol) in THF (2 mL) was slowly added. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The resulting mixture was partitioned between dilute aqueous HCl and EtOAc. The organic solution was washed with water and brine, dried over Na2SO4, and concentrated. The residue was tritrated from CH2Cl2, filtered and dried the solid to give compound 52d (391.9 mg). MS m/z (M+H+) 273.0.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[C:6]([O:10][C:11]([CH2:13][O:14][N:15]=[C:16]([C:20]1[N:24]=[CH:23][S:22][N:21]=1)[C:17]([OH:19])=O)=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH3:25][N+:26]([CH3:29])=[CH:27][Cl:28].[Cl-].C[Si](C)(C)NC(=O)C.[NH2:39][CH:40]1[C:50](=[O:51])[N:42]2[C:43]([C:47]([OH:49])=[O:48])=[CH:44][CH2:45][S:46][C@H:41]12>C(OCC)(=O)C.O.CN(C)C=O>[CH3:25][N+:26]([CH3:29])=[CH:27][Cl:28].[Cl-:3].[C:6]([O:10][C:11]([CH2:13][O:14][N:15]=[C:16]([C:20]1[N:24]=[CH:23][S:22][N:21]=1)[C:17]([NH:39][CH:40]1[C:50](=[O:51])[N:42]2[C:43]([C:47]([OH:49])=[O:48])=[CH:44][CH2:45][S:46][C@H:41]12)=[O:19])=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)O)c1ncsn1
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: O=P(Cl)(Cl)Cl
Agent: CC(=O)N[Si](C)(C)C
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1ncsn1
Reaction time: 0.5 h

Procedure:
Vilsmeier reagent was prepared from N,N-dimethylformamide (0.31 g) and phosphorus oxychloride (0.64 g) in a usual manner. 2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3-yl)acetic acid (syn isomer) (1.0 g) was added to a stirred suspension of the Vilsmeier reagent prepared above in ethyl acetate (11 ml) under ice-cooling, and the stirring was continued for 30 minutes at the same temperature to produce an activated acid solution. N-Trimethylsilylacetamide (3.2 g) was added to a stirred suspension of 7-amino-3-cephem-4-carboxylic acid (0.7 g) in ethyl acetate (20 ml), and the stirring was continued at 40° to 43° C. for 30 minutes. To this solution was added the above activated acid solution at -10° C., followed by stirring at the same temperature for 30 minutes. Water (10 ml) was added to the resultant solution, and the separated organic layer was washed with water, dried over magnesium sulfate and then evaporated to give 7-[2-tert-butoxycarbonylmethoxyimino-2-(1,2,4-thiadiazol-3 -yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer) (1.4 g).
Reaction SMILES: [Cl:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2C)[C@H:5]([OH:19])[C@@H:4]1[OH:20].[N:21]1C=CC=C[CH:22]=1.O=S(Cl)Cl>CC#N>[Cl:1][CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[NH:21][CH3:22])[C@H:5]([OH:19])[C@@H:4]1[OH:20]
Reactant: c1ccncc1
Reactant: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CNc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O

Procedure:
Compound 3c was prepared by the same procedure as described for the preparation of 3a using 2c41 (2.9 g, 9.78 mmol), pyridine (1.54 g, 1.57 mL, 19.46 mmol), CH3CN (5 mL), and SOCl2 (5.82 g, 3.56 mL, 48.91 mmol): yield 1.95 g (63%); MS m/z 315 (M+H)+; 1HNMR (DMSO-d6) δ 7.91 (bs, 1H, H-2), 6.78 (q, 1H, 8CH3—NH), 6.50 (bs, 2H, 6-NH2), 5.70 (d, 1H, H-1′, J1′,2′=5.0 Hz), 5.41 (d, 1H, 2′-OH, J2′-2′OH=5.6 Hz), 5.32 (d, 1H, 3′-OH, J3′-3′OH=5.3 Hz), 5.18 (ddd, 1H, H-2′, J1′,2′=5.0 Hz, J2′,3′=5.4 Hz, J2′-2′OH=5.6 Hz), 4.33 (ddd, 1H, H-3′, J2′,3′=5.4 Hz, J3′,4′=4.4 Hz, J3′-3′OH=5.3 Hz), 3.91-4.02 (bm, 2H, H-4′,5′-CH2), 3.76-3.82 (m, 1H, 5′-CH2), 2.88 (d, 3H, 8NH—CH3, J=4.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]([CH:13]=1)[O:8][CH2:9][CH:10]1[CH2:12][O:11]1.[Cl:17][C:18]1[CH:29]=[CH:28][C:21]([O:22][CH:23]2[CH2:27][CH2:26][NH:25][CH2:24]2)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:29]=[CH:28][C:21]([O:22][CH:23]2[CH2:27][CH2:26][N:25]([CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:7]3[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[N+:14]([O-:16])=[O:15])[CH2:24]2)=[CH:20][CH:19]=1
Reactant: COc1ccc([N+](=O)[O-])c(OCC2CO2)c1
Reactant: Clc1ccc(OC2CCNC2)cc1
Product: COc1ccc([N+](=O)[O-])c(OCC(O)CN2CCC(Oc3ccc(Cl)cc3)C2)c1

Procedure:
The subtitle compound was prepared in analogy of Example 253 ii) from 2-[(5-methoxy-2-nitrophenoxy)methyl]oxirane (320 mg, 1.6 mmol) and 3-(4-chlorophenoxy)pyrrolidine (365 mg, 1.6 mmol). The crude product was obtained as a yellow oil (580 mg) and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:13]([C:14](=O)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2F)=[CH:12][C:5]2[CH2:6][CH:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[C:3]=1[Cl:23].Cl.[NH2:25][OH:26].N1[CH:32]=[CH:31]C=CC=1.[OH-].[K+]>C(O)C>[O:26]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:14]([C:13]2[C:2]([Cl:1])=[C:3]([Cl:23])[C:4]3[O:8][CH:7]([C:9]([O:11][CH2:31][CH3:32])=[O:10])[CH2:6][C:5]=3[CH:12]=2)=[N:25]1
Reactant: O=C(c1ccccc1F)c1cc2c(c(Cl)c1Cl)OC(C(=O)O)C2
Reactant: c1ccncc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1Cc2cc(-c3noc4ccccc34)c(Cl)c(Cl)c2O1
Reaction time: 8 h

Procedure:
A mixture of 6,7-dichloro-2,3-dihydro-5-(2-fluorobenzoyl)benzofuran-2-carboxylic acid (15 g.) hydroxylamine hydrochloride (20 g.) and pyridine (80 ml.) was heated at reflux for 5 hours. The pyridine was evaporated under reduced pressure and the residue poured slowly into cold, 5% HCl. The resulting solid was filtered and dried to give 12 g. of the corresponding oxime. The oxime was dissolved in 100 ml. of absolute ethanol and mixed with a solution of 9.4 g. of potassium hydroxide in 150 ml. of ethanol. After refluxing for 2 hours, the solution was allowed to cool and the precipitated potassium carboxylate salt was filtered. This salt was converted to the free acid as described in Example 42 and then esterified by stirring overnight in 150 ml. of ethanol containing 0.5 ml. of concentrated H2SO4. Partial evaporation of the ethanol was followed by distribution of the residue between methylene chloride and saturated aqueous HCl. The organic phase was dried and evaporated to give a mixture of ethyl esters. The mixture was subjected to preparative high pressure liquid chromatography to afford pure samples of ethyl 8-chloro-3-(2-fluorophenyl)-5,6-dihydrofuro[3,2-f]-1,2-benzizisoxazole-6-carboxylate, m.p. 135°-136° C. and ethyl 5-(1,2-benzisoxazole-3-yl)-6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylate, m.p 114°-116° C. The corresponding carboxylic acids were obtained by hydrolysis with potassium hydroxide. Thus, a 1 g. sample of each ester was dissolved in 25 ml. of 80% aqueous methanol containing 2 molar equivalents of KOH. After 2 hours at room temperature, the methanol was partially evaporated and the residue diluted with water. Acidification with hydrochloric acid furnished the acids: 8-chloro-3-(2-fluorophenyl)-5,6-dihydrofuro[3,2-f]-1,2-benzisoxazole-6-carboxylic acid, m.p. 197.5°-199° C.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[CH2:9]([O:16][C:17]1[C:18]([O:26][CH3:27])=[CH:19][C:20]([CH2:24]Br)=[C:21]([Br:23])[CH:22]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCCCCC.O1CCCC1>[CH2:9]([O:16][C:17]1[C:18]([O:26][CH3:27])=[CH:19][C:20]([CH2:24][CH2:7][C:6]#[N:8])=[C:21]([Br:23])[CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC#N
Reactant: COc1cc(CBr)c(Br)cc1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(CCC#N)c(Br)cc1OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a solution of n-butyllithium (1.8 mL of a 2.5 M solution in hexane, 4.5 mmol) in 5 mL of tetrahydrofuran is added a solution of acetonitrile (1.0 mL, 19.1 mmol) in 5 mL of tetrahydrofuran. The reaction mixture is stirred at −78° C. for 15 min. A solution of 5-(benzyloxy)-1-bromo-2-(bromomethyl)-4-methoxybenzene (0.7 g, 1.8 mmol) in 3 mL of tetrahydrofuran is added and stirring is continued for 1 hour at −78° C. The reaction is quenched by the addition of 15 mL of water and the mixture is allowed to warm to room temperature. The mixture is extracted with ethyl acetate and the organic layers combined, then dried with sodium sulfate. After reducing in vacuo, the crude product is purified by flash chromatography using a gradient of 95:5 to 4:1 hexanes/ethyl acetate as an eluent. The clean fractions are combined, reduced in vacuo and dried to yield 0.343 g of 3-(4-benzyloxy-2-bromo-5-methoxyphenyl)-propionitrile as a white solid, mp 52–53° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1[C:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=[C:7]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])[CH:6]=1.[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][NH2:29]>ClCCl>[CH3:24][N:25]([CH3:30])[CH2:26][CH2:27][CH2:28][NH:29][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C:10]1[CH:5]=[CH:6][C:7]([N:17]([CH2:21][CH2:22][Cl:23])[CH2:18][CH2:19][Cl:20])=[CH:8][CH:9]=1
Reactant: CN(C)CCCN
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CN(C)CCCNC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 4 °C
Reaction time: 16 h

Procedure:
1.25 ml of thionyl chloride is added at 0° C., under an inert atmosphere, to a solution of 1.61 mmol of chlorambucil in 5 ml of dichloromethane The reaction mixture is stirred at 4° C. for 16 hours and then excess SOCl2 is evaporated off under reduced pressure. The residue obtained is taken up in 10 ml of dichloromethane. 1.61 mmol of 3-(dimethylamino)propylamine dissolved in 10 ml of dichloromethane are added to the resulting solution at 0° C. under an inert atmosphere. The mixture is then stirred at ambient temperature for 1 hour. At the end of that time, a second addition of 1.61 mmol of diamine is carried out. After 4 hours+ stirring, the reaction mixture is evaporated under reduced pressure. Following neutralisation with a 1N NaHCO3 solution, the aqueous phase is extracted several times with dichloromethane. The different organic phases are combined, washed with water until neutral, dried, filtered and evaporated under reduced pressure. The residue obtained is purified by chromatography on silica gel (eluant: gradient of ethanol in dichloromethane starting from 0 and going up to 50% and then, to finish, the eluant: dichloromethane/ethanol/ammonia, 50/49/1, is used). The expected product is obtained in the form of an oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:9]=[CH:8][NH:7][CH:6]=1)=[O:4].[H-].[Na+].[CH3:12][C:13]([C:17]1[N:21]([CH2:22][CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:20]2[CH:29]=[CH:30][C:31]([S:33](Cl)(=[O:35])=[O:34])=[CH:32][C:19]=2[N:18]=1)([CH3:16])[CH2:14][CH3:15]>C1COCC1>[CH3:16][C:13]([C:17]1[N:21]([CH2:22][CH:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[C:20]2[CH:29]=[CH:30][C:31]([S:33]([N:7]3[CH:8]=[CH:9][C:5]([C:3]([NH:2][CH3:1])=[O:4])=[CH:6]3)(=[O:35])=[O:34])=[CH:32][C:19]=2[N:18]=1)([CH3:12])[CH2:14][CH3:15]
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Reactant: CNC(=O)c1cc[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NC)c3)ccc2n1CC1CCOCC1
Yield: 61.6 %

Procedure:
Following the same procedure in Example 29, using N-methyl-1H-pyrrole-3-carboxamide (57 mg, 0.46 mmol) (see following step B for preparation), sodium hydride (110 mg, 60%, 2.76 mmol), 2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (352 mg, 0.92 mmol) in THF (10 mL). The crude product was purified by MPLC using EtOAc on silica gel to give 134 mg (62%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.77 (t, J=7.42 Hz, 3 H), 1.40-1.56 (m, 4 H), 1.59 (s, 6 H), 1.94 (q, J=7.42 Hz, 2 H), 2.19-2.37 (m, 1 H), 2.79 (s, 3 H), 3.24-3.36 (m, 2 H), 3.84-3.94 (m, 2 H), 4.41 (d, J=7.62 Hz, 2 H), 6.63 (dd, J=3.32, 1.56 Hz, 1 H), 7.29 (dd, J=3.32, 2.34 Hz, 1 H), 7.78 (dd, J=2.15, 1.76 Hz, 1 H), 7.88-7.92 (m, 1 H), 7.92-7.98 (m, 1 H), 8.26 (dd, J=1.56, 0.59 Hz, 1 H); MS (ESI) (M+H)+=473.0; Anal. Calcd for C24H32N4O4S+1.0 TFA (586.63): C, 53.23; H, 5.67; N, 9.55. Found: C, 53.28; H, 5.77; N, 9.42.
Reaction SMILES: C([O:3][C:4](=[O:12])[C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=[O:6])C.[BH4-].[Na+]>CCO.O>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[CH:5]([OH:6])[C:4]([OH:12])=[O:3]
Reactant: CCOC(=O)C(=O)c1ccco1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)C(O)c1ccco1
Yield: 70 %

Procedure:
A solution of the product from step a.) (25 g, 135 mmol) in EtOH (250 ml) was cooled to 0° C. and treated with a solution of NaBH4 (2.5 g, 66 mmol) in H2O (27 ml) for 5 minutes. Next, the reaction mixture was quenched with AcOH (17 ml) and H2O (271 ml) and concentrated to dryness. The crude oil was dissolved in CH2Cl2 (300 ml), washed with brine (2×100 ml), dried (MgSO4) and concentrated providing 17.5 g (70%) of the above subtitle compound, which was carried forward without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:35]=[CH:34][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:19]4([CH:32]=[CH:31][C:30](=[O:33])[CH:29]=[CH:28]4)[N:18]=3)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]>ClC1C=CC(Cl)=CC=1Cl.C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[N:18]4[CH:32]=[CH:31][C:30](=[O:33])[CH:29]=[CH:28][C:19]4=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:21]=3)[CH2:13][CH2:12]2)=[CH:34][CH:35]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc(CN2CCN(C3=NC4(C=CC(=O)C=C4)C(c4ccccc4)=C3)CC2)cc1
Solvent: ClCCl
Solvent: Clc1ccc(Cl)c(Cl)c1
Product: CCOC(=O)c1ccc(CN2CCN(c3cc(-c4ccccc4)c4ccc(=O)ccn34)CC2)cc1
Yield: 46 %

Procedure:
A solution of 2-[4-(4-ethoxycarbonylbenzyl)-1-piperazinyl]-4-phenyl-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (12.4 g) in 1,2,4-trichlorobenzene (250 cc) is heated for 11 hours to a temperature of about 210° C. After evaporation to dryness under reduced pressure (1 mm Hg; 0.13 kPa) at 40° C., the residue obtained is dissolved in methylene chloride (250 cc) and the solution is poured into silica (400 g) contained in a column 6 cm in diameter. Elution is first performed with methylene chloride (2 liters) and the corresponding eluates are rejected. Elution is then performed with a mixture of methylene chloride and methanol (99:1 by volume) (5 liters) and the corresponding eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. After recrystallization of the residue in ethanol (120 cc), 3-[4-(4-ethoxycarbonylbenzyl)-1-piperazinyl]-1-phenyl-7H-pyrrolo[1,2-a]azepin-7-one (5.7 g), m.p. 129° C., is obtained.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].Cl[C:7]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][N:15]=2)[CH:10]=[C:9]([Cl:17])[N:8]=1>CO>[NH2:4][CH2:3][CH2:2][CH2:1][NH:5][C:7]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][N:15]=2)[CH:10]=[C:9]([Cl:17])[N:8]=1
Reactant: Clc1cc2nccnc2c(Cl)n1
Reactant: NCCCN
Solvent: CO
Product: NCCCNc1nc(Cl)cc2nccnc12

Procedure:
A solution of propane-1,3-diamine (890 mg, 12 mmol) and 5,7-dichloropyrido[4,3-b]pyrazine (600 mg, 3 mmol) in methanol (10 mL) was stirred at room temperature for 4 hours. The volatiles were evaporated, and the residue was purified by chromatography to afford the title compound. MS (m/z): 238 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[N:12]NN=2)[CH:5]=1.[Cl:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].N1C(C)=CC(C)=CC=1C.O>C1(OC)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[O:20][C:19]([C:18]3[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=3[Cl:16])=[N:12][N:11]=2)[CH:5]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: COC(=O)c1cccc(-c2nn[nH]n2)c1
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Solvent: COc1ccccc1
Product: COC(=O)c1cccc(-c2nnc(-c3ccccc3Cl)o2)c1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
3-(2H-Tetrazol-5-yl)-benzoic acid methyl ester (204 mg, 1 mmol) (prepared by the method of Tanaka et al, J. Med. Chem., 1998, 41(13), 2406) and 2-chlorobenzoyl chloride (175 mg, 1 mmol) were combined in anisole (10 mL) at room temperature and 2,4,6-collidine (121 mg, 1 mmol) in anisole (1 mL) was added. The reaction mixture was heated at 100° C. for 1 hour followed by 120° C. for 15 minutes, monitoring the evolution of gas by balloon [volume of gas evolved was measured by positive displacement of water, total =22 mL]. Cooled reaction mixture to room temperature, and concentrated to dryness in vacuo. The residue was subjected to flash column chromatography on silica with gradient dilution 5% to 40% ethyl acetate/heptane. 3-[5-(2-Chlorophenyl)-[1,3,4]oxadiazol-2-yl]-benzoic acid methyl ester was isolated as a colorless powder (229 mg, 73%). 1H NMR [CDCl3]: δ 8.79 (s, H); 8.36 (d, H); 8.25 (d, H); 8.14 (d, H); 7.72-7.57 (m, 2H); 7.57-7.41 (m, 2H); 4.00 (s, 3H). MS(Ion spray): 315 and 317 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:5][N:4]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.[Na+].[I-]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:10]2[C:11]3[CH:18]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([CH2:25][N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[CH:21][CH:20]=4)[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(Nc2ncnc3[nH]c(-c4ccc(CCl)cc4)cc23)ccn1
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Product: COc1cc(Nc2ncnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)cc23)ccn1

Procedure:
330 mg (0.90 mMol) (2-Methoxy-pyridin-4-yl)-[6-(4-chloromethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine, 0.81 ml morpholine and a trace of NaI is stirred for 2 h in 20 ml boiling ethanol. A clear solution is formed from which upon cooling to RT the title compound crystallizes out and can be filtered off; TLC (CH2Cl2/methanol 9:1) Rf=0.33; MS-ES+: (M+H)+=417.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:27][CH2:28][NH:29][CH2:30][CH2:31][OH:32])[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:14]=[CH:15][CH:16]=4)[C:11](=[O:26])[C:10]=1[C:9]=23.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(=O)(O)[O-].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH2:27][CH2:28][N:29]([CH2:30][CH2:31][OH:32])[CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:7]=[C:8]3[C:17]4[C:12](=[C:13]([O:18][CH2:19][C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:14]=[CH:15][CH:16]=4)[C:11](=[O:26])[C:10]=1[C:9]=23
Reactant: O=C1c2c(OCc3ccccc3)cccc2-c2nn(CCNCCO)c3ccc(Cl)c1c23
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2c(OCc3ccccc3)cccc2-c2nn(CCN(CCO)Cc3ccccc3)c3ccc(Cl)c1c23
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 14.5 g (32.3 mmol) of 5-chloro-2-[2-[(2-hydroxyethyl)]amino]-7-(phenylmethoxy)anthra[1,9-cd]pyrazol-6(2H)-one (5) and its 10-phenylmethoxy isomer (4), ~4:1 respectively by HPLC, 3.9 ml of α-bromotoluene, 6.5 g of potassium bicarbonate, and 140 ml of N,N-dimethylformamide was stirred at room temperature for 18 hr. The mixture was diluted with 500 ml of water and extracted with three 200 ml portions of dichloromethane. The combined organic extracts were washed with water, dried, and concentrated to an oil which was purified by chromatography on 600 g of silica gel (230-400 mesh). Elution with ethyl acetate:hexane (3:2) followed by concentration of product fractions gave the faster eluting component as a solid. Crystallization from acetonitrile afforded 3.55 g of pure isomer 9, mp 130°-134° C. Elution with ethyl acetate followed by concentration of product fractions afforded 9.2 g (66%) of slower eluting isomer 8 as a syrup which could not be crystallized.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[CH:13]=[N:12]2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)(Cl)=O.[CH3:23]O>>[CH3:23][O:9][C:8](=[O:10])[CH:7]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[CH:13]=[N:12]1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)C(CC1CCCC1)n1ncc(O)cc1=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C(CC1CCCC1)n1ncc(O)cc1=O
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 3-cyclopentyl-2-(4-hydroxy-6-oxo-6H-pyridazin-1-yl)-propionic acid (12.5 g, 47.6 mmol) in methanol (150 mL) was treated dropwise with thionyl chloride (7.1 g, 59.5 mmol). The mixture was stirred at reflux for 1 h. At this time, the reaction was cooled to 25° C. and concentrated in vacuo. The resulting residue was partitioned between water and ethyl acetate. The combined organics were dried over sodium sulfate and concentrated in vacuo to afford 3-cyclopentyl-2-(4-hydroxy-6-oxo-6H-pyridazin-1-yl)-propionic acid methyl ester as a light yellow oil (10.5 g, 80%).
Reaction SMILES: O.[OH-].[Li+].[Cl:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][C:21]([O:23]C)=[O:22])[N:19]=2)=[CH:11][CH:10]=1>O.O1CCCC1>[Cl:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][CH:17]=[C:18]([CH2:20][C:21]([OH:23])=[O:22])[N:19]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)Cc1coc(-c2ccc(OCCCCl)cc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1coc(-c2ccc(OCCCCl)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of lithium hydroxide hydrate (0.76 g, 18.11 mmol, 2 eq) in water (10 ml) is added to a solution of methyl {2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}acetate ax62 (2.8 g, 9.06 mmol, 1 eq) in tetrahydrofuran (100 ml). The mixture is stirred at room temperature for 1 h. The mixture is then poured into water and extracted with diethyl ether (2×75 ml). The aqueous layer is acidified with 6 N aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated under vacuum to give 2.1 g of {2-[4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}acetic acid ax63 as a brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[CH3:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:22]([C:15]2[C:16]([CH3:21])=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=2[CH3:13])(=[O:24])=[O:23])=[CH:6][CH:7]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Fc1ccc(C2CCCN2)cc1
Product: Cc1cc(C)c(S(=O)(=O)N2CCCC2c2ccc(F)cc2)c(C)c1

Procedure:
The title compound, white solid, m.p. 111° C. and MS: m/e=347 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 2,4,6-trimethyl-benzenesulfonyl chloride.