Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([CH:14]3[CH2:17][N:16]([C:18]([NH:20][CH2:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[O:19])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:30]I>CN(C=O)C>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([CH:14]3[CH2:15][N:16]([C:18]([N:20]([CH2:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH3:30])=[O:19])[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CI
Reactant: O=C(NCC1CCCCC1)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC1CCCCC1)C(=O)N1CC(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
To a stirred solution of 3-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]-N-(cyclohexylmethyl)azetidine-1-carboxamide (26 mg, 0.069 mmol) in dry DMF (1 ml) at 0° C. under a nitrogen atmosphere was added sodium hydride (4.1 mg of a 60% dispersion in mineral oil, 0.103 mmol). The resulting suspension was stirred at 0° C. for 30 min. Methyl iodide (4.3 μl, 0.069 mmol) was added and the reaction mixture allowed to warm to RT and was stirred for 16 hrs. The reaction mixture was poured onto ice-water, extracted with EtOAc (3×5 ml), the combined organics washed with brine (5 ml), dried (MgSO4), filtered and concentrated at reduced pressure. Purification by preparative HPLC provided the title compound (5.6 mg, 21% yield) as colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH3:17][O:18][C:19]([C:21]1(Br)[CH2:24][CH2:23][CH2:22]1)=[O:20]>CN(C=O)C.COC(C1(Br)CCC1)=O>[CH3:17][O:18][C:19]([C:21]1([O:10][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=2[CH:7]=[O:8])[CH2:24][CH2:23][CH2:22]1)=[O:20]
Reactant: COC(=O)C1(Br)CCC1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1(Oc2ccc(Cl)cc2C=O)CCC1
Temperature: 140 °C
Yield: 104.7 %

Procedure:
To a mixture of 5-chloro-2-hydroxy-benzaldehyde (10 g, 64 mmol), KI (3 g) and K2CO3 (13 g, 94 mmol) in DMF (100 mL) was added 1-bromo-cyclobutanecarboxylic acid methyl ester (15 g, 77 mmol). The mixture was heated at 140° C. for 1.5 h. Then additional 1-bromo-cyclobutanecarboxylic acid methyl ester (0.5 g, 2.6 mmol) was added and the mixture was heated at 140° C. for additional 10 min, cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with water, dried over anhydrous Na2SO4, concentrated to give the title compound as dark oil (18 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[C:26](O)=[O:27])=[CH:4][N:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:24]=[CH:25]/[C:26]([N:32]2[CH2:33][CH2:34][NH:29][C:30](=[O:35])[CH2:31]2)=[O:27])=[CH:4][N:3]=1
Reactant: Nc1ncc(/C=C/C(=O)O)c2scc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: O=C1CNCCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Nc1ncc(/C=C/C(=O)N2CCNC(=O)C2)c2scc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
A mixture of Example 11B (0.09 g, 0.23 mmol), 2-piperazinone (0.069 g, 0.69 mmol), HOBT (0.095 g, 0.7 mmol), N-methylmorpholine (0.22 mL, 0.92 mmol), and EDCI (0.136 g, 0.71 mmol) in DMF (1 mL) was stirred at room temperature overnight, treated with water (20 mL), and filtered. The filter cake was dried to provide 110 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 3.20-3.36 (br m, 2H), 3.71-3.91 (br m, 2H), 4.03-4.35 (m, 2H), 5.94 (br s, 2H), 6.92-7.15 (br m, 1H), 7.11-7.16 (m, 4H), 7.21 (t, J=7.3 Hz, 1H), 7.42-7.52 (m, 4H), 7.63 (s, 1H), 7.71 (d, J=14.9 Hz, 1H), 8.13 (br s, 1H), 8.33 (s, 1H); MS (ESI(−)) m/e 469.3 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=1[O:34][CH3:35].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:33])[C:29]([F:30])([F:31])[F:32])=[CH:24][C:23]=4[O:34][CH3:35])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(=O)C(F)(F)F)ccc1OCCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(=O)C(F)(F)F)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Yield: 55.9 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (1.5 g, 6.7 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]-2,2,2-trifluoroethanone (2.0 g, 6.7 mmol), K2CO3 (0.88 g), KI (0.1 g) and acetonitrile (50 ml) was stirred and refluxed for 16 hours. After cooling, the reaction was poured into water and the aqueous mixture extracted with ethyl acetate. The extract was washed (H2O), dried (MgSO4), and the solvent was concentrated to an oil, which upon evacuation at high vacuum afforded 3.2 g of a waxy solid. The solid was chromatographed on a Waters preparative LC (silica columns, eluting with 3% methanol-dichloromethane). Concentration of the appropriate fractions gave 1.8 g (56%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-propoxy]-3-methoxyphenyl]-2,2,2-trifluoro-ethanone solid, m.p.=94°-96° C.
Reaction SMILES: Br[N:2]1[C:6]2[N:7]=[CH:8][CH2:9][NH:10][C:5]=2[CH:4]=[CH:3]1.[C:11]([C:13]1[CH:14]=[C:15]([NH:20][C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)=[C:26]([C:38]([F:41])([F:40])[F:39])[CH:25]=2)=[O:22])[CH:16]=[CH:17][C:18]=1[CH3:19])#[CH:12]>>[NH:10]1[CH2:9][CH:8]=[N:7][C:6]2[N:2]([C:12]#[C:11][C:13]3[CH:14]=[C:15]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([CH2:30][N:31]5[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]5)=[C:26]([C:38]([F:41])([F:39])[F:40])[CH:25]=4)=[O:22])[CH:16]=[CH:17][C:18]=3[CH3:19])[CH:3]=[CH:4][C:5]1=2
Reactant: C#Cc1cc(NC(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)ccc1C
Reactant: Brn1ccc2c1N=CCN2
Product: Cc1ccc(NC(=O)Nc2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1C#Cn1ccc2c1N=CCN2

Procedure:
The title compound was prepared using 5-bromo-1H-pyrrolo[2,3-b]pyrazine and N-(3-ethynyl-4-methylphenyl)-N′-[4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethylphenyl]urea as raw materials, according to the method described in Step 4 of Example 1.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[S:11][CH:12]=[C:13]([NH:19][C:20]([C:22]2[CH:31]=[C:25]3[C:26]([F:30])=[CH:27][CH:28]=[CH:29][N:24]3[N:23]=2)=[O:21])[C:14]=1[C:15]([O:17]C)=[O:16].[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[S:11][CH:12]=[C:13]([NH:19][C:20]([C:22]2[CH:31]=[C:25]3[C:26]([F:30])=[CH:27][CH:28]=[CH:29][N:24]3[N:23]=2)=[O:21])[C:14]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1c(NC(=O)c2cc3c(F)cccn3n2)csc1-c1ccc(C)c(F)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2scc(NC(=O)c3cc4c(F)cccn4n3)c2C(=O)O)c(F)c1F
Yield: 98.3 %

Procedure:
Ester 379 (1.45 g, 3.3 mmol) and lithium hydroxide (467 mg, 19.5 mmol) in tetrahydrofuran:methanol:water (3:2:1, 16 mL) was stirred at 50° C. for 1 h. The mixture was cooled in an ice bath and quenched with 2 M HCl (16 mL). The precipitate that formed was filtered off to provide 368 (1.40 g, 100%) as a solid: LRESIMS m/z 432.0 [M+H]+, calcd. for C20H13F3N3O3S1 432.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][C@@H:30](O)[CH2:31][C@H:32]([OH:34])[CH3:33].COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C@@H:30]([CH3:29])[CH2:31][C@H:32]([OH:34])[CH3:33])=[CH:5][CH:4]=1.[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: COc1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(O[C@@H](C)C[C@@H](C)O)cc1
Reaction time: 14 h

Procedure:
After 4-methoxyphenol (300 mg, 2.41 mmol), triphenylphosphine (761 mg, 2.89 mmol), (2R,4R)-2,4-pentanediol (302 mg, 2.89 mmol), and THF (12 mL) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (680 mg, 2.89 mmol) dissolved in THF (6 ml) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 14 hours. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 mL,×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 30% ethyl acetate-hexane solution) to give (4S,2R)-4-(4-methoxyphenoxy)pentane-2-ol as a colorless oily substance (418 mg, yield: 82%/4-methoxyphenol).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:18][C@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[C@@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=O)[CH3:2].ClCCCl.C(O)[C:40]1[CH:45]=[CH:44]C=[CH:42][CH:41]=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>CCCCCC.C(OCC)(=O)C>[C:9]([O:8][C@H:7]1[C@H:12]([O:13][C:14](=[O:16])[CH3:15])[C@@H:17]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:18][C@@H:5]([O:4][CH2:1][C:2]2[CH:44]=[CH:45][CH:40]=[CH:41][CH:42]=2)[C@@H:6]1[N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34])(=[O:11])[CH3:10]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: OCc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](N2C(=O)c3ccccc3C2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
Under anhydrous conditions, 1,3,4,6-tetra-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranose (5) (47.7 g, 100 mM), molecular sieves (4 Å) powder (20 g) and 250 ml of 1,2-dichloroethane and benzyl alcohol (12.5 ml, 120 mM) were placed in a dry 1 liter round bottom flask equipped with magnetic stirring bar, septum inlet and bent tube adapter. During a 5 minute period, trimethylsilyl trifluoromethane sulfonate (19.3 ml, 100 mM) was then added to the stirred mixture. The contents were stirred at room temperature for 16 hours. The reaction was found to be complete as evidenced by the products present on thin layer chromtography (TLC, 2:3 ethyl acetate:hexane). The reaction mixture was cooled in an ice-bath, quenched with saturated sodium bicarbonate and extracted with dichloromethane in the manner well known to those skilled in the art. The combined extract was washed with water, brine and dried over anhydrous magnesium sulfate. The residue after removal of solvent was purified by "flash chromatography" (silica gel, 500 g, solvent 1:3 ethyl acetate:hexane) to provide 40.6 g (85% yield) of benzyl 3,4,6-tri-O-acetyl-2-deoxy-2-phthalimido-β-D-glucopyranoside (6).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([NH2:6])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.[C:20](OC(=O)C)(=[O:22])[CH3:21].O>C(O)(=O)C.S(=O)(=O)(O)O>[Br:1][C:2]1[CH:8]=[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]([NH:6][C:20](=[O:22])[CH3:21])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1c(OCc2ccccc2)cc(Br)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a solution of 4-bromo-2-nitro-6-[(phenylmethyl)oxy]aniline (33.0 g, 102 mmol, WO 2004054984) and acetic anhydride (14.5 mL, 153 mmol) in acetic acid (90 mL) was added concentrated sulfuric acid (2 drops) at 70° C. The mixture was stirred at 70° C. for 20 minutes. After cooling to room temperature, water (800 mL) was added, and the formed precipitate was collected by filtration, and washed with diisopropyl ether to give the title compound as a brown solid (30.9 g, 83%).
Reaction SMILES: Br[CH:2]([CH2:7][CH2:8][CH2:9]Br)[C:3]([O:5][CH3:6])=[O:4].C1(C)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][C@H:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O>[CH3:6][O:5][C:3](=[O:4])[CH:2]1[CH2:7][CH2:8][CH2:9][N:32]1[C@@H:25]([CH3:24])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C(Br)CCCBr
Reactant: C[C@H](N)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1CCCN1[C@@H](C)c1ccccc1
Reaction time: 9.5 h
Yield: 78.1 %

Procedure:
Methyl (RS)-2,5-dibromovalerate (24.5 g) and toluene (19.8 g) were added to a 49% aqueous potassium carbonate solution (53.3 g), and heated to 80° C. (S)-α-methylbenzylamine (12.0 g) was added dropwise to the mixture obtained above at that temperature, and was stirred at that temperature for 9.5 hours. Water (33.9 g) was added to the reaction mixture, and then the organic layer was separated from the resulting mixture. Separated organic layer was washed with water, a 1% aqueous hydrochloric acid solution and water in this order, and concentrated under reduced pressure. Thus, N-[(S)-α-methylbenzyl]-(RS)-proline methyl ester (16.3 g) was obtained in a yield of 77.8%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]#[N:11].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]#[N:11]
Reactant: [H][H]
Reactant: N#CC=Cc1ccccc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: N#CCCc1ccccc1F
Yield: 96 %

Procedure:
A solution of the cis/trans mixture of 3-(2-fluorophenyl)acrylonitrile (9.36 g) in ethanol (100 mL) was treated with Pearlman's catalyst (palladium hydroxide, 1 g, 20% Pd by wt. dry) and the mixture shook vigorously under 60 p.s.i. hydrogen for 30 minutes. The mixture was filtered and the filtrate concentrated to afford 3-(2-fluorophenyl) propionitrile (9.11 g). GC/MS gave: m/z (rel.int.) 149 (M+, 19), 109 (100) and 83 (15).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][O:12][CH2:11][C:10]([NH2:15])=[N:9]1.[N+:20]([O-])([O-:22])=[O:21].[K+].CC(OC)(C)C>S(=O)(=O)(O)O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:20]([O-:22])=[O:21])=[CH:4][C:3]=1[C:8]1([C:16]([F:19])([F:17])[F:18])[CH2:14][CH2:13][O:12][CH2:11][C:10]([NH2:15])=[N:9]1
Reactant: NC1=NC(c2ccccc2F)(C(F)(F)F)CCOC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: COC(C)(C)C
Product: NC1=NC(c2cc([N+](=O)[O-])ccc2F)(C(F)(F)F)CCOC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of 5-(2-fluoro-phenyl)-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine (1.12 g, 4.05 mmol) in 12 mL concentrated sulfuric acid (95%) was added potassium nitrate (533 mg, 5.27 mmol) in two portions. The reaction mixture was stirred at rt for 30 minutes, it was then poured onto ice water and TBME was added. The layers were separated, washed with water and TBME. The combined aqueous layers were basified with solid Na2CO3 and extracted with EtOAc. The EtOAc layers were dried over MgSO4.H2O and evaporated to give 1.29 g of the title compound was a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9](OCC)=[O:10])[N:5]=[N:4][N:3]=1.[O-]CC.[K+]>CN(C)C=O.O>[N:5]1[N:6]2[C:7]3[C:8]([C:9]([OH:10])=[CH:1][C:2]2=[N:3][N:4]=1)=[CH:14][CH:15]=[CH:16][CH:17]=3
Reactant: CCOC(=O)c1ccccc1-n1nnnc1C
Agent: CC[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cc2nnnn2c2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Under a nitrogen atmosphere, ethyl 2-(5-methyl-1H-tetrazol-1-yl)benzoate (92.7 g, 0.34 mol) was dissolved in N,N-dimethylformamide (600 ml) and the solution was chilled in an ice water bath. Potassium ethoxide (67.2 g, 0.80 mol) was added slowly to the solution. After a few minutes, the ice water bath was removed and the reaction was stirred at room temperature for 3 hours. The reaction was treated with 100 ml of water and approximately 300-400 ml of solvent was removed in vacuo. The remainder of the reaction was poured over a solution of glacial acetic acid (125 ml) in ice water (2 L). A precipitate formed and the mixture was diluted with additional water (3 L). The solid was collected by vacuum filtration to yield 63.25 g of tetrazolo[1,5-a]quinolin-5-ol as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:14][CH3:15])[C:5]([O:10][CH:11]([F:13])[F:12])=[C:6]([O:8][CH3:9])[CH:7]=1.[O:16]1[CH:20]=[CH:19][CH:18]=[C:17]1B(O)O>>[F:12][CH:11]([F:13])[O:10][C:5]1[C:4]([O:14][CH3:15])=[CH:3][C:2]([C:17]2[O:16][CH:20]=[CH:19][CH:18]=2)=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: COc1cc(Br)cc(OC)c1OC(F)F
Reactant: OB(O)c1ccco1
Product: COc1cc(-c2ccco2)cc(OC)c1OC(F)F

Procedure:
5-Bromo-2-(difluoromethoxy)-1,3-dimethoxybenzene was coupled with 2-furylboronic acid following the procedure for the synthesis of Example 21. Purification by chromatography (0-30% EtOAc-hexanes) provided 2-(4-(difluoromethoxy)-3,5-dimethoxyphenyl)furan as a white crystalline material (0.555 g, 67% yield).
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=[CH:26][C:27]([O-:29])=[O:28])=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]>O1CCCC1.O>[CH3:3][N:4]([C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1)[C:5]([NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:6]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2cnc(C=CC(=O)[O-])nc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCNC(=O)N(C)c1cccc(-c2cnc(C=CC(=O)O)nc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
10 mg (242.5 μmol, 2.5 eq) of sodium hydroxide pellets are added to a solution of 37.6 mg (97 μmol, 1 eq) of 3-{5-[3-(1-methyl-3-pentylureido)phenyl]pyrimidine-2-acrylate in 2 ml of tetrahydrofuran and 4 drops of water. The reaction mixture is stirred for 8 hours at room temperature. The reaction medium is concentrated and then diluted with 10 ml of water and washed with twice 10 ml of dichloromethane. The aqueous phase is acidified with 1 N hydrochloric acid and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on a preparative silica plate (95/5/0.5% dichloromethane/methanol/aqueous ammonia). 7.9 mg of 3-{5-[3-(1-methyl-3-pentylureido)phenyl]pyrimidin-2-yl}acrylic acid are obtained in the form of beige-colored crystals. Yield=22%.
Reaction SMILES: C(OCC1C2C(=CN=C(C([NH:21][OH:22])=O)C=2)N(CC2C=CC(F)=CC=2F)C=1)C1C=CC=CC=1.[F:32][C:33]1[CH:56]=[CH:55][C:36]([O:37][CH2:38][C:39]2[C:43]3[CH:44]=[N:45][C:46]([C:48]([O:50]CC)=O)=[CH:47][C:42]=3[N:41]([CH2:53][CH3:54])[CH:40]=2)=[CH:35][CH:34]=1.FC1C=CC(O)=C(C=1)CC1C2C=NC(C(OCC)=O)=CC=2N(CC)C=1>>[F:32][C:33]1[CH:56]=[CH:55][C:36]([O:37][CH2:38][C:39]2[C:43]3[CH:44]=[N:45][C:46]([C:48]([NH:21][OH:22])=[O:50])=[CH:47][C:42]=3[N:41]([CH2:53][CH3:54])[CH:40]=2)=[CH:35][CH:34]=1
Reactant: O=C(NO)c1cc2c(COCc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Reactant: CCOC(=O)c1cc2c(cn1)c(COc1ccc(F)cc1)cn2CC
Agent: CCOC(=O)c1cc2c(cn1)c(Cc1cc(F)ccc1O)cn2CC
Product: CCn1cc(COc2ccc(F)cc2)c2cnc(C(=O)NO)cc21

Procedure:
Ethyl 3-(4-fluoro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate. The title compound can be prepared from ethyl 3-hydroxymethyl-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and 4-fluorophenol using a methods similar to step (e) of Example 54. (b) 3-(4-Fluoro-phenoxymethyl)-1-ethyl-N-hydroxy-1H-pyrrolo[3,2-c]pyridine-6-carboxamide. The title compound can be prepared from the mixture of ethyl 3-(4-fluoro-phenoxymethyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate and ethyl 3-(5-fluoro-2-hydroxy-benzyl)-1-ethyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate in a manner similar to step (e) of Example 11. Purification by HPLC can provide the pure title compound.
Reaction SMILES: CCO[C:4]([C:6]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1)=[O:5].Cl.[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23].[OH-].[Na+]>C(OCC)C>[CH2:20]([NH:24][C:4]([C:6]1([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7][CH2:8][N:9]([CH3:12])[CH2:10][CH2:11]1)=[O:5])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: CCOC(=O)C1(c2ccccc2)CCN(C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCNC(=O)C1(c2ccccc2)CCN(C)CC1

Procedure:
Pethidine hydrochloride (2.56 g, 9 mmol) and butylamine (5 ml) were heated in an autoclave at 180° C. for 3 days. The reaction mixture was shaken between 10 ml of 1N NaOH and diethyl ether and the ether extracts dried (MgSO4). The solvent was evaporated and the residue chromatographed on aluminium oxide with ethyl acetate as eluent. The crystalline product (1.0 g) was recrystallized from n-hexane yielding 0.59 g with m.p. 73°-76.5° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[CH:15]3)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>CC(O)C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:21][C:22]1[CH:27]=[C:26]([C:2]2[N:3]=[C:4]([NH:11][C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[NH:17][N:16]=[CH:15]4)[C:5]3[S:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: Clc1nc(Nc2ccc3[nH]ncc3c2)c2sccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(O)C(C)O
Product: Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3sccc3n2)c1
Temperature: 100 °C
Yield: 56.9 %

Procedure:
2-Chloro-N-(1H-indazol-5-yl)thieno[3,2-d]pyrimidin-4-amine (10 mmol, 1 equivalent) was suspended in dimethyl ethylene glycol (60 mL) and Na2CO3 solution (2M, 10 mL) and flushed with argon for 20 min. To this suspension 3-aminophenyl boronic acid (25 mmol, 2.5 eq) and Pd(PPh3)4 (2.5 mmol, 0.25 eq) were added. The reaction mixture was refluxed under AR at 100° C. for 48 h. The solvent was evaporated off in vacuo. The residue was taken into THF (100 mL) plus EtOAc/water. (100 mL, 1:1). The organic layer was evaporated to dryness. The residue was separated by silica gel column chromatography (0-5% MeOH in CH2Cl2). The product was obtained as yellow powder (2.04 g, 57%). (M+H)+=359, RT (LC-MS)=1.93.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([O:15][CH3:16])[CH:6]=[CH:5][C:4]=1/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20].ClC1C(OC)=C(CCC(O)=O)C=CC=1OC>>[CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([O:15][CH3:16])[CH:6]=[CH:5][C:4]=1[CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: COc1ccc(/C=C/C(=O)O)c(OC)c1-c1ccccc1
Agent: COc1ccc(CCC(=O)O)c(OC)c1Cl
Product: COc1ccc(CCC(=O)O)c(OC)c1-c1ccccc1
Yield: 98 %

Procedure:
Compound 4c was synthesized from 3c in 98% yield using the procedure described for 4a. 1H NMR (DMSO-d6): δ 12.0 (br s, 1H), 7.39 (m, 2H), 7.29 (m, 3H), 7.18 (d, J=8.5 Hz, 1H), 6.80 (d, J=8.5 Hz, 1H), 3.64 (s, 3H), 3.18 (s, 3H), 2.78 (t, J=7.5 Hz, 2H), 2.50 (t, J=7.5 Hz, 2H).