Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:17][C:18]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:19]([OH:21])=O)=[O:16])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[CH3:26][NH:27][CH2:28][CH3:29]>>[CH2:24]([C:18]([NH:17][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[N:8]=1)=[O:16])([C:19](=[O:21])[N:27]([CH2:28][CH3:29])[CH3:26])[CH2:22][CH3:23])[CH3:25]
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)O
Reactant: CCNC
Product: CCN(C)C(=O)C(CC)(CC)NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid (Example 274 a) and N-methylethanamine (CAN 624-78-2) as starting materials. MS (EI): m/e=388.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:25][C@H:24]([CH2:26][O:27]C(C3C=CC(C)=CC=3)=O)[C@@H:13]([O:14]C(C3C=CC(C)=CC=3)=O)[CH2:12]2)=[C:4]([N:37]2C=CN=C2CCCCC)[N:3]=1>N>[NH2:37][C:4]1[N:3]=[C:2]([Cl:1])[N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[C@@H:11]1[O:25][C@H:24]([CH2:26][OH:27])[C@@H:13]([OH:14])[CH2:12]1
Reactant: CCCCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1
Agent: N
Product: Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
A solution of 2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]-6-(2-pentylimidazol-1-yl)purine (0.35 g, 0.55 mmol) in methanolic ammonia (14%) was stirred at 80° C. for 13 h. Volatiles were evaporated, and the oily residue was extracted with CH2Cl2 (10 mL) to remove lipophilic by-products. The semi-solid residue was dissolved in acetone (with additions of small amounts of MeOH—if necessary), volatiles were evaporated, and the semi-solid was allowed to crystallize (˜1 h). This material was extracted with CH2Cl2 (10 mL) and dried. The resulting 2-chloro-2′-deoxyadenosine (white powder; 113 mg, 70%) was pure by 1H NMR analysis. Additional amounts of cladribine (˜24 mg, 15%; containing traces of the α-anomer) were recovered from the concentrated extracts by chromatography (EtOAc→EtOAc/MeOH, 10:1) followed by a similar extraction sequence.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[CH:10](=O)[C:11]1[CH:21]=[C:18]([O:19][CH3:20])[C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=1>CN(C=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9][C:10]([C:11]3[CH:21]=[C:18]([O:19][CH3:20])[C:16]([OH:17])=[C:13]([O:14][CH3:15])[CH:12]=3)=[N:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1S
Reactant: COc1cc(C=O)cc(OC)c1O
Solvent: CN(C)C=O
Product: COc1cc(-c2nc3cc(Cl)ccc3s2)cc(OC)c1O
Temperature: 80 °C
Yield: 47.2 %

Procedure:
In a DMF (3 mL) solvent in the presence of Na2S2O5 (120.3 mg, 0.63 mmol), a solution including 2-amino-4-chlorobenzenethiol (100 mg, 0.63 mmol) and syringaldehyde (115.3 mg, 0.63 mmol) was heated at a temperature of 80° C. for 22 hours. After DMF was evaporated, water was added thereto. The produced precipitate was filtered, and washed with water to obtain Compound 126.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[C:13]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)=[C:20]([CH3:30])[S:19][C:14]=3[NH:15][C:16](=O)[CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C1(P(Cl)([Cl:39])=O)C=CC=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([Cl:39])[N:15]=[C:14]3[S:19][C:20]([CH3:30])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C:13]=23)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccc(-c2c(C)sc3[nH]c(=O)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reactant: O=P(Cl)(Cl)c1ccccc1
Product: COc1cccc(-c2c(C)sc3nc(Cl)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.7 %

Procedure:
A solution of 3-chloro-N-{2-methyl-3-[3-(methyloxy)phenyl]-6-oxo-6,7-dihydrothieno[2,3-b]pyridin-4-yl}benzenesulfonamide (Example 116) (150 mg, 0.325 mmol) in phenylphosphonic dichloride (1.5 mL, 10.72 mmol) was heated to 200° C. under a nitrogen atmosphere. The reaction mixture was cooled to RT, poured dropwise onto ice and left for ca. 30 min. The aqueous layer was extracted with DCM (ca. 25 mL×2), the combined organics passed through phase separator and the solvent removed in vacuo. The residue was then purified by normal phase chromatography, eluting with a gradient of 0-50% ethyl acetate in cyclohexane and then further purified by MDAP (acidic conditions), to afford the title compound (37 mg). LCMS (A) m/z: 479 [M+1]+, Rt 1.62 min (acidic).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]#[N:8].C([O-])([O-])=O.[Cs+].[Cs+].C([O:17][CH:18]=[CH:19][C:20](OCC)=O)C.Cl>CN(C=O)C.O>[OH:17][C:18]1[CH:19]=[CH:20][N:6]2[N:5]=[CH:4][C:3]([C:7]#[N:8])=[C:2]2[N:1]=1
Reactant: CCOC=CC(=O)OCC
Reactant: N#Cc1cn[nH]c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cnn2ccc(O)nc12
Temperature: 100 °C
Yield: 96.7 %

Procedure:
To a mixture of 5-amino-1H-pyrazole-4-carbonitrile (2.70 g, 25.0 mmol) and Cs2CO3 (16.3 g, 50.0 mmol) in dry DMF (70 mL) was added ethyl 3-ethoxyacrylate (5.41 g, 37.5 mmol) and the mixture was heated at 100° C. for 4 hours. The mixture was cooled to ambient temperature and the resultant slurry was poured into deionized H2O (150 mL). The resulting aqueous solution was cooled on an ice bath and concentrated HCl was added slowly with mixing to pH=3.5. The resulting precipitate was collected, washed with H2O followed by Et2O. The solid was dried in vacuum to afford the product as a light beige powder (3.87 g, 97%). MS (apci) m/z=159.0 (M−1).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([OH:9])=[CH:4][CH:3]=1.CI.[C:12](=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[N:7]=[C:6]([I:8])[C:5]([O:9][CH3:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)nc1I
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COc1ccc(F)nc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.2 %

Procedure:
6-Fluoro-2-iodo-pyridin-3-ol (50 mg) was dissolved in acetonitrile (2 ml) to prepare a solution. Methyl iodide (148 mg) and potassium carbonate (87 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous magnesium sulfate, the solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform to give 6-fluoro-2-iodo-3-methoxypyridine (52 mg, yield 100%).
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:22])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C([O-])(O)=O.[Na+]>C1COCC1.O>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[C:3]([OH:23])=[O:2])=[O:22])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.6 %

Procedure:
N-tert-butoxycarbonyl L-prolyl L-proline methyl ester 1 (1.10 g, 3.37 mmol) was dissolved in THF (23 mL) and the solution cooled to 0° C. (icebath). LiOH monohydrate (0.156 g, 3.72 mmol) was dissolved in de-ionized H2O (11.5 mL) and the solution cooled to 0° C. before being added dropwise to the solution of 1 over 5 min. The icebath was removed and stirring continued for an additional 3 h 30 min before solid NaHCO3 (0.566 g, 6.74 mmol) was added. Stirring was continued for 20 minutes and the THF evaporated. The solution was diluted with H2O (11.5 mL), washed with Et2O (2×11.5 mL) and acidified to pH 2 by addition of 2M aqueous H2SO4. The resulting solution was extracted with CH2Cl2 (70 mL+4×23 mL). The combined organic extracts were dried with anhydrous MgSO4 and the solvent evaporated affording the title compound as a white solid (0.933 g, 89%) with spectral characteristics in accordance with literature data1; δH(300 MHz; d6-DMSO) 12.41 (1H, br s, COOH), 4.45-4.21 (2H, m, CαH(Pro1)/CαH(Pro2)), 3.73-3.13 (4H, m, CδH2(Pro1)/CδH2(Pro2)), 2.29-1.61 (8H, m, CH2), 1.37/1.30/1.16 (9H, s, (CH3)3, all rotomers); δC (75 MHz; CDCl3) 173.8, 173.5, 173.3, 173.0, 154.6, 153.6, 79.9, 59.6, 59.5, 57.7, 57.6, 47.1, 47.0, 46.9, 46.7, 30.0, 29.2, 28.4, 28.3, 27.7, 27.5, 25.0, 24.2, 23.6; m/z (ESI) 335.1595 ([M+Na]+; C15H24N2O5Na requires 335.1582)
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=O)=O.Cl>O>[CH3:16][N:2]([CH2:3][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH2:6]1)[CH3:1]
Reactant: CN(C)C(=O)C1Cc2ccccc2NC1=O
Agent: Cl
Solvent: O
Product: CN(C)CC1CNc2ccccc2C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.3 %

Procedure:
N,N-Dimethyl-2-oxo-1,2,3,4-tetrahydro-3-quinolinecarboxamide (9.486 g) was added to 1M Borane-THF complex (200 ml). The reaction mixture was heated under reflux for 45 minutes, and left standing for cooling. The reaction mixture was ice-cooled, to which were added water (20 ml) and 6N hydrochloric acid (50 ml). The mixture was stirred at room temperature for 15 hours, and concentrated. A methanol solution (200 ml) of the residue was heated under reflux for 6 hours, and concentrated. 3N aqueous sodium hydroxide solution was added to the residue to become basic, which was extracted with ethyl acetate. The residue was purified by alumina column chromatography (eluent: ethyl acetate/hexane=1/10). The obtained crude crystals were washed with hexane to give the entitled compound (5.569 g)
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:13]NOC.C[Mg]Br>>[Br:1][C:2]1[CH:10]=[C:6]([C:7](=[O:9])[CH3:13])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: CNOC
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Agent: C[Mg]Br
Agent: Cl
Product: CC(=O)c1cnc(Cl)c(Br)c1

Procedure:
5-Bromo-6-chloronicotinic acid and N,O-dimethylhydroxyamine hydrochloride were treated in the similar manner to Reference Example 7(5), and then the resulting compound and methylmagnesium bromide were treated in the similar manner to Reference Example 7(6) to give 1-(5-bromo-6-chloropyridin-3-yl)ethanone [REx(113-1)] as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([NH2:12])=[N:8][NH:9]2)=[CH:5][CH:4]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:8]([CH:14]=[C:15]([C:17]4[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=4)[N:12]=3)[NH:9][C:10]=2[CH:11]=1
Reactant: O=C(CBr)c1cccc(O)c1
Reactant: COc1ccc2c(N)n[nH]c2c1
Product: COc1ccc2c(c1)[nH]n1cc(-c3cccc(O)c3)nc21

Procedure:
Compound 3-(7-methoxy-5H-imidazo[1,2-b]indazol-2-yl)phenol (W298) was prepared using the general procedure for cyclization between 6-methoxy-1H-indazol-3-amine (80 mg, 0.5 mmol) and 2-bromo-1-(3-hydroxyphenyl)ethanone (107 mg, 0.55 mmol), as a white solid (40 mg, 22%). 1H NMR (400 MHz, DMSO-d6) δ 9.84 (brs, 1 H), 8.63 (s, 1 H), 7.85 (d, J=9.2 Hz, 1 H), 7.36 (t, J=8.0 Hz, 1 H), 7.31-7.29 (m, 1 H), 7.24 (t, J=2.0 Hz, 1 H), 7.13 (d, J=2.0 Hz, 1 H), 6.99 (dd, J=9.2, 2.0 Hz, 1 H), 6.88 (m, 1 H), 3.90 (s, 3 H); MS (ESI) m/z 280 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH3:36])[C:3](=[O:35])[CH2:4][C:5]1[C:32]([F:33])=[CH:31][C:8]([O:9][CH2:10][CH2:11][C@@H:12]2[CH2:14][C@@H:13]2[CH:15]2[CH2:20][CH2:19][N:18](C(OCC3C=CC=CC=3)=O)[CH2:17][CH2:16]2)=[C:7]([F:34])[CH:6]=1>CO.[Pd]>[F:33][C:32]1[CH:31]=[C:8]([O:9][CH2:10][CH2:11][C@@H:12]2[CH2:14][C@@H:13]2[CH:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[C:7]([F:34])=[CH:6][C:5]=1[CH2:4][C:3]([N:2]([CH3:36])[CH3:1])=[O:35]
Reactant: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCN(C(=O)OCc3ccccc3)CC2)cc1F
Agent: [Pd]
Solvent: CO
Product: CN(C)C(=O)Cc1cc(F)c(OCC[C@@H]2C[C@@H]2C2CCNCC2)cc1F
Reaction time: 2 h

Procedure:
To a solution of benzyl 4-[(1R,2S)-2-(2-{4-[2-(dimethylamino)-2-oxoethyl]-2,5-difluorophenoxy}ethyl)cyclopropyl]piperidine-1-carboxylate (226 mg, 0.451 mmol) in 2 ml anhydrous methanol at RT was added 10% palladium on carbon (25.0 mg). The reaction mixture was stirred under a hydrogen atmosphere for 2 hours. The slurry was filtered through celite, and the filtrate concentrated to afford the title compound. LC/MS (m/z): 368.4 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[N:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.CO.C([O-])=O.[NH4+]>[Pd].C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]([C:10]2[CH:19]=[N:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccncc1-c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccncc1-c1cccc(N)c1
Reaction time: 2 h

Procedure:
Into an RBF was placed methyl 3-(3-nitrophenyl)isonicotinate (1.85 g, 7.16 mmol) and to this was added methanol (50 ml), ammonium formate (6.0 g, 35.8 mmol) and 5 wt % Pd/C (Degussa type). No initial exotherm was noticed (to the touch) and no bubbling or gas evolution was observed. After 2 h, some SM was observed to be undissolved and THF (25 ml) was added to aid in solubility. The reaction was slow at room temperature. The reaction mixture was then placed on the Buchi hydrogenator overnight. The mixture was then filtered through a pad of Celite and washed with ethyl acetate. This solution was washed with water, separated and the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The orange oil was purified by silica gel flash chromatography using 30% ethyl acetate/Hexanes as eluent to yield 1.15 g (71% th) of an orange oil.
Reaction SMILES: C(OC([C:6]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=2[F:25])[O:8][N:7]=1)=O)C.[Li+].[OH-].Cl>C1COCC1.O.O>[F:25][C:19]1[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:9]1[O:8][N:7]=[CH:6][N:10]=1
Reactant: CCOC(=O)c1noc(-c2ccncc2Nc2ccc(I)cc2F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cc(I)ccc1Nc1cnccc1-c1ncno1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of 5-[3-(2-Fluoro-4-iodo-phenylamino)-pyridin-4-yl]-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester (1.8 g, 3.96 mmol) in THF-H2O (1:1)(20 mL) LiOH (0.19 g, 7.93 mmL) was added. The reaction mixture was stirred for 2 hrs at RT. The pH was adjusted to 5 with 1N HCl and the mixture was diluted with water. A solid precipitated and was filtered to give the product (1.4 g). LC/MS (Method A) [4.39 min; 383(M+1)]
Reaction SMILES: [NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH:24][C:25]3[NH:26][CH:27]=[CH:28][C:29](=[O:31])[N:30]=3)[CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:32].ClC1N=C(O)[C:41]2[C:36](=[CH:37][CH:38]=CC=2)N=1.[O-2].[Ca+2]>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]2[O:8][CH2:9][CH2:10][O:11][C:6]=2[C:5]([C:12]([O:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][NH:24][C:25]3[NH:26][C:27]4[C:28]([C:29](=[O:31])[N:30]=3)=[CH:38][CH:37]=[CH:36][CH:41]=4)[CH2:18][CH2:17]2)=[O:13])=[CH:4][C:3]=1[Cl:32]
Reactant: Nc1c(Cl)cc(C(=O)OCC2CCN(CCNc3nc(=O)cc[nH]3)CC2)c2c1OCCO2
Reactant: Oc1nc(Cl)nc2ccccc12
Agent: [Ca+2]
Agent: [O-2]
Solvent: CC(=O)N(C)C
Product: Nc1c(Cl)cc(C(=O)OCC2CCN(CCNc3nc(=O)c4ccccc4[nH]3)CC2)c2c1OCCO2
Temperature: 140 °C
Reaction time: 1 h
Yield: 63.2 %

Procedure:
A mixture of intermediate 15 (2 g), 2-chloro-4-hydroxyquinazoline (1.9 g), N,N-dimethylacetamide (0.3 ml) and calciumoxide (0.4 g) was stirred for 1 hour at 140° C., then cooled and partitioned between water and DCM (+methanol). The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/(CH3OH/NH3) 95/5). The desired fractions were collected and the solvent was evaporated. The residue was suspended in DIPE, filtered off, then dried (vacuum, 60° C.), yielding 1.4 g (50%) [1-[2-[(1,4-dihydro-4-oxo-2-quinazolinyl)amino]ethyl]-4-piperidinyl]methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate (compound 19).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15]Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[Na+].[F:19][C:20]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:21]=1[CH2:22][OH:23].[H-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][CH2:15][O:23][CH2:22][C:21]2[CH:24]=[C:25]([Br:28])[CH:26]=[CH:27][C:20]=2[F:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(CCBr)C1
Reactant: OCc1cc(Br)ccc1F
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(CCOCc2cc(Br)ccc2F)C1
Temperature: 25 °C

Procedure:
In a 25 ml round bottom flask, 2-[1-(t-butoxycarbonyl)piperidin-3-yl]ethyl bromide (1.011 g, 3.46 mmol) was dissolved in N,N-dimethylformamide (9 ml). Sodium iodide (1.037 g, 6.92 mmol) was added and the resulting mixture was stirred at ambient temperature for ten minutes. The 2-fluoro-5-bromobenzyl alcohol (0.852 g, 4.15 mmol) and sodium hydride (60%, 208 mg, 5.19 mmol) were then added and the resulting mixture began to froth and exotherm. After thirty minutes, the solution cooled and solidified. Three milliliters of N,N-dimethylformamide was added and the mass was slurried and stirred for three more hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between brine and diethyl ether. The organic fraction was washed six times with brine, and then dried over sodium sulfate. The desired title product was further purified by liquid chromatography.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:18])[O:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[O:11]1>>[CH:1](=[C:13]1[C:14](=[O:16])[O:15][C:10]([CH3:18])([CH3:9])[O:11][C:12]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Product: CC1(C)OC(=O)C(=Cc2ccccc2)C(=O)O1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 120, Step 1 starting from benzaldehyde and 2,2-dimethyl-1,3-dioxane-4,6-dione.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[C:19](OC(=O)C)(=[O:21])C.S(=O)(=O)(O)O>>[CH3:19][O:21][C:7]1[CH:8]=[CH:3][C:4]2[S:9][C:10]3[C:11](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:12](=[O:14])[C:5]=2[CH:6]=1
Reactant: COc1ccccc1Sc1ccccc1C(=O)O
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Product: COc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 80 °C

Procedure:
Finally, 2-methoxythioxanthen-9-one (S-17) was prepared. To a mixture of 2-(2-methoxyphenylthio)benzoic acid (11.0 g, 42 mmol) and 43.1 g (423 mmol) of acetic anhydride was added dropwise 4.14 g (42 mmol) of concentrated sulfuric acid. The mixture was heated at 80° C. for 4 h, cooled to ambient, and poured very slowly onto 500 g of ice. The precipitate was extracted with dichloromethane, and the extract was washed with 10% aqueous NaHCO3 and then with brine. The solution was dried (MgSO4), passed through a short column of silica gel, and concentrated to deposit an orange solid. The product was purified by successive recrystallizations from isopropanol and from toluene/heptane. 1H NMR (CDCl3): δ 3.95 (s, 3H), 7.27 (dd, 1H), 7.5 (m, 2H), 7.6 (m, 2H), 8.09 (d, 1H), 8.64 (d 1H).
Reaction SMILES: O=[C:2]([CH3:20])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1.[NH2:21][CH2:22][CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)[OH:24].C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:19][O:18][C:16]([CH:11]([C:12]([O:14][CH3:15])=[O:13])[C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH:2]([NH:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=2)[OH:24])[CH3:20])=[CH:10][CH:9]=1)=[O:17]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: COC(=O)C(C(=O)OC)c1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)C(C(=O)OC)c1ccc(OCC(C)NCC(O)c2cccc(Cl)c2)cc1
Yield: 61.2 %

Procedure:
Following a procedure similar to that described in Example 6, but using 0.42 g of dimethyl 4-(2-oxopropoxy)phenylmalonate (prepared as described in Preparation 38), 0.26 g of 2-amino-1-(3-chlorophenyl)ethanol (prepared as described in Preparation 8), 50 ml of dry benzene, 50 ml of absolute methanol and 0.9 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 0.4 g of the title compound was obtained, having an Rf=0.28 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [C:1](Cl)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[CH:21][N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:15][CH:14]=1>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([C:1]([O:3][CH2:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[O:2])[N:22]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)=[CH:15][CH:14]=1
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: O=C(Cl)OCc1ccccc1
Product: C[Si](C)(C)CCOCn1c(C(=O)OCc2ccccc2)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1

Procedure:
Using essentially the same procedure as Example 25, Step B, but using CBZ-Cl (0.030 mL, 1.2 mmol) in Step B, 4,5-di-(4-chlorophenyl)-1-(2-(trimethylsilyl)ethoxymethyl)imidazole (31 mg, 0.074 mmol) from Example 25, Step A was converted to the title compound. HPLC/MS: 553 (M+1), 555 (M+3); Rt=5.2 min.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[C:27](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26]3[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=3[CH2:24][O:23][C:22]=2[CH:38]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH2:12][CH3:13])[N:7]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]4[C:27](=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:26]5[CH:34]=[CH:35][CH:36]=[CH:37][C:25]=5[CH2:24][O:23][C:22]=4[CH:38]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1nc2c(C)cccc2[nH]1
Reactant: CCOC(=O)C=C1c2ccccc2COc2cc(CCl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCc1nc2c(C)cccc2n1Cc1ccc2c(c1)OCc1ccccc1C2=CC(=O)OCC
Reaction time: 0.5 h
Yield: 60.6 %

Procedure:
4-Methyl-2-propyl-1H-benzimidazole (464 mg) was dissolved in a mixture of 50 ml of DMF and 80 ml of toluene, and 106.4 mg of sodium hydride (60% oily) was added to the solution under ice cooling, followed by stirring for 30 minutes. To the mixture was added 732 mg of Compound 1-c, and the mixture was heated under reflux for 3 hours. After the solvent was distilled off under reduced pressure, the residue was diluted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: hexane/ethyl acetate/triethylamine (20/5/1)] to give 629 mg (61%) of the product.