Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[N:8]/[CH2:9][CH2:10][OH:11])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CCO>[CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC/N=C/c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 71.1 %

Procedure:
To a solution of Compound 1 (2.62 g, 17.3 mmol) in anhydrous EtOH (55 mL) was portionwise added NaBH4 (0.67 g, 17.7 mmol) at 0° C. over 1 h period. The resulting mixture was gradually warmed to room temperature and was stirred for 20 h. The resulting mixture was filtered to eliminate excess NaBH4, and the solvent was evaporated. The residue was dissolved in CH2Cl2 (50 mL) and filtered, and the filtrate was concentrated in vacuo to afford Compound 2 (1.86 g, 61.3%). 1H NMR (CDCl3) δ 2.60 to 2.70 (m, 2H), 3.60 to 3.73 (m, 2H), 7.24 to 7.27 (m, 5H); 13C NMR (CDCl3) δ 50.62, 53.44, 60.45, 126.98, 128.11, 128.36, 139.73. HRMS (Positive ion FAB) Calcd for C9H13NO [M+H]+ m/z 152.2163. Found: [M+H]+ m/z 152.1075.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[C:4]2[CH:3]=[CH:2]1>C(O)(=O)C.[Pd]>[O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[C:4]2[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2occc12
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)c1cccc2c1CCO2
Yield: 83 %

Procedure:
Benzofuran-4-carboxylic acid ##STR37## [Eissenstat, et al, J. Medicinal Chemistry, 38 (16) 3094-3105 (1995)] (10.0 g, 61.7 mmol) was hydrogenated (60 psi) in acetic acid (100 mL) over 10% Pd/C (2 g) for 12 hr. The mixture was filtered and the filtrate was diluted with water (500 mL) to give 2,3-dihydrobenzofuran-4-carboxylic acid as a white powder (8.4 g, 83%). A sample was recrystallized from isopropanol to give fine white needles (mp: 185.5-185.5° C.).
Reaction SMILES: [Br:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Br:14]P(Br)Br>O>[Br:1][C:2]1[C:3]([Br:14])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)c1cnc(O)c(Br)c1
Solvent: O
Product: CCOC(=O)c1cnc(Br)c(Br)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 86.3 %

Procedure:
A mixture of ethyl 5-bromo-6-hydroxynicotinate (preparation 47a, 6.35 g, 25.8 mmol), tribromophosphine (2.50 mL, 26 mmol) and phosphorus oxytribromide (7.50 g, 26.2 mmol) was stirred at 120° C. After 3 hours, the mixture was cooled, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4) and evaporated to yield the title compound (6.88 g, 86%) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[C@@H:19]([O:20][CH3:21])[C@H:18]([O:22][CH3:23])[C@H:17]([C:24]3[CH:29]=[CH:28][C:27]([O:30]CC4C=CC=CC=4)=[CH:26][CH:25]=3)[N:16]2[C:38]2[CH:43]=[CH:42][C:41]([C:44]([CH3:47])([CH3:46])[CH3:45])=[CH:40][CH:39]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[C:44]([C:41]1[CH:40]=[CH:39][C:38]([N:16]2[C@@H:17]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C@@H:18]([O:22][CH3:23])[C@H:19]([O:20][CH3:21])[C@@H:15]2[C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)=[CH:43][CH:42]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CO[C@H]1[C@H](OC)[C@H](c2ccc(OCc3ccccc3)cc2)N(c2ccc(C(C)(C)C)cc2)[C@H]1c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CO[C@H]1[C@H](OC)[C@H](c2ccc(O)cc2)N(c2ccc(C(C)(C)C)cc2)[C@H]1c1ccc(O)cc1
Reaction time: 20 h
Yield: 100 %

Procedure:
To a solution of the product from Example 48B (168 mg, 0.268 mmol) in ethyl acetate (3 ml) was added 10% palladium on carbon (17 mg) and the flask was evacuated and back-filled with H2 gas. The solution was stirred under a balloon of H2 gas for 20 h, filtered through Celite, and washed with ethyl acetate and methanol. The filtrate was concentrated and the residue was azeotroped with ether to give title compound (120 mg, 100%) as a white solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[N+:4]([O-])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].CS([Cl:21])(=O)=O.COCCOC>ClCCl>[Cl:21][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2oc(C)c(C)[n+]2[O-])cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: COCCOC
Solvent: ClCCl
Product: Cc1ccc(-c2nc(CCl)c(C)o2)cc1
Temperature: 15 °C

Procedure:
32.8 g (137 mmol) of 4,5-dimethyl-2-p-tolyloxazole 3-oxide hydrochloride were suspended in 165 ml of dichloromethane. 17.5 g (151 mmol) of methanesulfonyl chloride were added. The reaction was stirred at reflux up to full conversion (HPLC). Subsequently, 200 ml of ethylene glycol dimethyl ether were added, and the dichloromethane was distilled off under reduced pressure. The reaction mixture was cooled to 15° C. and 250 ml of water were added. The mixture was stirred at 15° C. for 1 hour. The precipitated product was isolated by filtration with suction, washed with water and dried at elevated temperature under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[CH2:10][CH2:9][CH:8]2[NH:19]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.Cl>ClCCl.C(O)(C)C>[ClH:1].[NH2:19][CH:8]1[CH:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:28][CH:27]=2)[C:16]2[CH:15]=[C:14]([C:17]#[N:18])[CH:13]=[CH:12][C:11]=2[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(C#N)cc2C1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)O
Product: N#Cc1ccc2c(c1)C(Cc1ccc(Cl)cc1)C(N)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyl [1-(4-chlorobenzyl)-7-cyano-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (15 mg, 0.038 mmol) was dissolved in dichloromethane (1.5 mL) and 5 M hydrochloric acid in isopropanol (0.3 mL) was added. The reaction mixture was stirred for 3 h at room temperature. The solvent and the excess hydrochloric acid were evaporated in vacuo. Yield: 11 mg (0.033 mmol, 87%, colorless solid).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](Cl)=[O:32]>N1C=CC=CC=1>[ClH:27].[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]4)[CH2:20]3)=[O:18])=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)=[O:32]
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1)c1cccc(Cl)c1

Procedure:
A solution of 50 mg (0.13 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 44.4 mg (0.25 mmol) of 3-chlorobenzoyl chloride in 1.0 ml of pyridine is stirred at room temperature for 3 h. The reaction mixture is concentrated in vacuo, and the residue is purified by preparative HPLC. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 62 mg (98.5% of theory) of the title compound are obtained.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([CH:10]([NH:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH2:32])[CH:27]=3)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)=[O:15])[CH2:11][CH3:12])[CH3:9].Cl[C:34]([O:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:35]>O1CCCC1>[CH2:8]([CH:10]([NH:13][C:14]([N:16]1[C:24]2[C:19](=[CH:20][C:21]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([NH:32][C:34](=[O:35])[O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH:27]=3)=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)=[O:15])[CH2:11][CH3:12])[CH3:9]
Reactant: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)ccc21
Temperature: 0 °C
Yield: 91.5 %

Procedure:
Tetrahydrofuran (20 ml) and triethylamine (1.73 ml, 12.4 mmol) were added to N1-(1-ethylpropyl)-5-(2-amino-4-pyridyl)oxy-1H-1-indolecarboxamide (1.45 g, 4.29 mmol); phenyl chloroformate (1.15 ml, 9.1 mmol) was added thereto at 0° C. while stirring; and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was concentrated and subjected to silica gel column chromatography to yield a mixture (1.8 g) of phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)oxy-2-pyridyl)carbamate and phenyl N-(4-(1-((1-ethylpropyl)amino)carbonyl-1H-5-indolyl)-oxy-2-pyridyl)-N-(phenoxycarbonyl)carbamate. A portion of 0.6 g of the mixture was dissolved in N,N-dimethylformamide (5 ml); 4-tetrahydro-1H-1-pyrrolylpiperidine (0.7 g, 4.7 mmol) and stirred for 2 hours; the reaction mixture was partitioned between ethyl acetate and water; the organic layer was concentrated; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate:methanol=10:1) to yield as white crystals (202 mg, 0.391 mmol).
Reaction SMILES: C([O:4][CH:5]([CH3:18])[CH2:6][CH2:7][C:8]1[CH:13]=[C:12](Cl)[N:11]2[N:15]=[CH:16][CH:17]=[C:10]2[N:9]=1)(=O)C.[NH3:19]>>[NH2:19][C:12]1[N:11]2[N:15]=[CH:16][CH:17]=[C:10]2[N:9]=[C:8]([CH2:7][CH2:6][CH:5]([OH:4])[CH3:18])[CH:13]=1
Reactant: N
Reactant: CC(=O)OC(C)CCc1cc(Cl)n2nccc2n1
Product: CC(O)CCc1cc(N)n2nccc2n1
Temperature: 105 °C

Procedure:
The compound prepared in step (5) (4.3 g) and 25% aqueous ammonia (50 ml) were enclosed in a stainless steel sealed tube, heated at 105° C. for 14 hours and allowed to cool. The crystals precipitated were collected by filtration, washed with water and dried to provide 3.2 g of 7-amino-5-(3-hydroxybutyl)pyrazolo[1,5-a]pyrimidine as light yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH:9][C:10](=[O:38])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:14][CH:13]2[CH3:37])=[C:4]([Cl:39])[CH:3]=1.C(O)(=O)C.[O-:44][C:45]#[N:46].[K+]>O>[NH2:46][C:45]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([NH:9][C:10](=[O:38])[CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH:22]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH2:14][CH:13]2[CH3:37])=[C:4]([Cl:39])[CH:3]=1)=[O:44]
Reactant: CC1CN(CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1CC(=O)Nc1c(Cl)cc(N)cc1Cl
Reactant: N#C[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC1CN(CCCCC(c2ccc(F)cc2)c2ccc(F)cc2)CCN1CC(=O)Nc1c(Cl)cc(NC(N)=O)cc1Cl
Reaction time: 8 h
Yield: 51.9 %

Procedure:
To a stirred solution of 4.5 parts of N-(4-amino-2,6-dichlorophenyl)-4-[5,5-bis(4-fluorophenyl)pentyl]-2-methyl-1-piperazineacetamide in 60 parts of acetic acid was added dropwise a solution of 1.02 parts of potassium cyanate in 17 parts of water. Upon completion, stirring was continued overnight at room temperature. The reaction mixture was evaporated and the residue was taken up in water. The whole was treated with an ammonium hydroxide solution and the product was extracted twice with dichloromethane. The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The second fraction was collected and the eluent was evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.49 parts (51.9%) of N-[4-[(aminocarbonyl)amino]-2,6-dichlorophenyl]-4-[5,5-bis(4-fluorophenyl)pentyl]-2-methyl-1-piperazineacetamide; mp. 119.9° C. (compound 76).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>ClCCl>[C:25]([N:15]1[CH2:16][CH2:17][N:12]([C:5]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:13][CH2:14]1)(=[O:27])[CH3:26]
Reactant: COc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(N2CCN(C(C)=O)CC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.9 %

Procedure:
To a solution of 1-[3-(methyloxy)-4-nitrophenyl]piperazine (0.5 g, 2.11 mmol) and triethylamine (1.27 g, 12.63 mmol, Aldrich) in dichloromethane (25 mL) was added acetic anhydride (0.64 g, 6.35 mmol, Aldrich). After stirring 3 hrs at rt, the reaction was washed with water (25 mL), organic layer adsorbed to silica gel and purified by column chromatography (dichloromethane to 10% methanol/dichloromethane) to give 1-acetyl-4-[3-(methyloxy)-4-nitrophenyl]piperazine (0.4 g, 68%). ESIMS (M+H)+=280.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15][C:16](=[O:18])[CH3:17])[C:12]([CH3:14])=[CH2:13])=[CH:7][C:6]=1[O:19][CH3:20])(=[O:3])[CH3:2]>CCO.O=[Pt]=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([O:15][C:16](=[O:18])[CH3:17])[CH:12]([CH3:14])[CH3:13])=[CH:7][C:6]=1[O:19][CH3:20])(=[O:3])[CH3:2]
Reactant: C=C(C)C(OC(C)=O)c1ccc(OC(C)=O)c(OC)c1
Agent: O=[Pt]=O
Solvent: CCO
Product: COc1cc(C(OC(C)=O)C(C)C)ccc1OC(C)=O

Procedure:
1.0 g (3.6 mmol) diacetate 13 is dissolved in 17 ml EtOH and hydrogenated over PtO2. The catalyst is removed by filtration over Celite and the solvent is evaporated. Flash chromatography of the crude product gave 0.83 g (82% by weight) of compound 14 in the form of a yellowish oil having the following: 1H NMR (CDCl3) values: 0.81 (d, J=7.0 CH3); 0.98 (d, J=7.0, CH3); 1.98-2.15 (m, 1H, CH); 2.08 (s, CH3); 2.30 (s, CH3); 3.82 (s, OCH3); 5.46 (d, J=7.0, CH); 6.84-7.02 (m, 3 aromatic H). MS: 280 (8, [M+]), 238 (38), 195 (56), 153 (100), 43 (68).
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC>[CH2:20]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: O=Cc1ccccc1O
Reactant: CCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCOc1ccccc1C=O
Temperature: 100 °C

Procedure:
A mixture of salicylaldehyde (10.15 mmoles), undecylbromide (10.3 mmoles) and potassium carbonate (11.7 mmoles) in dimethylformamide (10 ml) is heated to 100° C. for 1 hour and then is cooled. The reaction mixture is taken up in hexane and is washed with 5 percent sodium hydroxide and brine. After treatment with anhydrous magnesium sulfate and charcoal, the volatiles are removed under vacuum and the residue is purified by flash chromatography to give the desired product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][CH:37]([C@@H:39]1[N:44]([CH2:45][CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH2:43][CH2:42][N:41]([C:51]2[CH:57]=[CH:56][C:54]([NH2:55])=[C:53]([O:58][CH3:59])[CH:52]=2)[CH2:40]1)[CH3:38].Cl.N>C(O)C(F)(F)F.CO>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:55][C:54]3[CH:56]=[CH:57][C:51]([N:41]4[CH2:42][CH2:43][N:44]([CH2:45][CH2:46][S:47]([CH3:50])(=[O:49])=[O:48])[C@@H:39]([CH:37]([CH3:38])[CH3:36])[CH2:40]4)=[CH:52][C:53]=3[O:58][CH3:59])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)[C@@H](C(C)C)C2)ccc1N
Agent: Cl
Agent: N
Solvent: OCC(F)(F)F
Solvent: CO
Product: COc1cc(N2CCN(CCS(C)(=O)=O)[C@@H](C(C)C)C2)ccc1Nc1nccc(-c2c(-c3ccc(OC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 80 °C
Yield: 48.3 %

Procedure:
To 5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (0.241 g, 0.490 mmol) and 4-{(3S)-3-(1-methylethyl)-4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}-2-(methyloxy)aniline (0.174 g, 0.489 mmol) were dissolved in 5 mL of trifluoroethanol with stirring in a pressure vessel. Hydrogen chloride (0.49 mL, 4N in dioxane, 2.0 mmol) was added, and the vessel was sealed. The reaction was heated to 80° C. for 3 days and subsequently cooled to rt. The reaction was poured into 10 mL of 7N NH3 in MeOH and concentrated onto silica gel. The compound was purified by flash chromatography, and the fractions containing the desired compound were concentrated in vacuo. The material was triturated with diethyl ether, filtered, and washed with diethyl ether. The solid was collected to afford the title compound (0.191 g, 0.236 mmol, 48%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H), 9.33 (br. s., 1H), 8.42 (s, 1H), 8.17 (d, J=5.1 Hz, 1H), 8.03-8.09 (m, 1H), 7.70-7.78 (m, 1H), 7.66 (d, J=9.0 Hz, 1H), 7.29-7.43 (m, 3H), 7.25 (d, J=8.8 Hz, 1H), 7.10-7.19 (m, 2H), 6.87-6.95 (m, 1H), 6.61 (s, 1H), 6.43-6.52 (m, 2H), 3.95 (s, 3H), 3.77 (s, 3H), 3.43-3.51 (m, 1H), 3.30-3.41 (m, 2H), 3.27 (s, 3H), 2.99 (s, 3H), 2.91-2.98 (m, 1H), 2.68-2.85 (m, 2H), 2.51-2.60 (m, 1H), 2.22-2.30 (m, 1H), 2.05-2.16 (m, 1H), 0.96 (d, J=6.8 Hz, 3H), 0.87 (d, J=7.0 Hz, 3H). MS (M+H, ES+) 811.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]([OH:14])=[O:13].[CH3:15][Si](Cl)(C)C>CO>[CH3:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]([O:14][CH3:15])=[O:13]
Reactant: Cc1cccc2c1CCOC2C(=O)O
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)C1OCCc2c(C)cccc21
Reaction time: 1.5 h

Procedure:
The mixture of 5-methylisochroman-1-carboxylic acid (1 g), methanol (20 ml) and trimethylsilylchloride (2 ml) was stirred for 1.5 hrs and volatiles evaporated. Separation method E yielded the title compound (0.5 g) as yellowish oil. Alternatively sulphuric acid can be used instead of trimethylsilylchloride.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7](C(OC(C)(C)C)=O)[CH2:8][C@H:9]([O:10][S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C@H:5]2[O:4][CH2:3]1.[H][H]>[Pd].C(O)C>[CH3:18][C:17]1[CH:19]=[CH:20][C:14]([S:11]([O:10][C@H:9]2[CH2:8][NH:7][C@@H:6]3[C@@H:2]([OH:1])[CH2:3][O:4][C@H:5]23)(=[O:13])=[O:12])=[CH:15][CH:16]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)O[C@H]2CN[C@H]3[C@@H]2OC[C@@H]3O)cc1
Reaction time: 1.5 h

Procedure:
Preparation (3R,3aR,6S,6aS)-tert-Butyl 3-hydroxy-6-(tosyloxy)tetrahydro-2H-furo[3,2-b]pyrrole-4(5H)-carboxylate (35). Ethanol (20 mL) was added dropwise to a mixture of 10% palladium on charcoal (50 mg) and anti-(33) (578 mg, 1.33 mmol) under an atmosphere of argon. The argon was replaced by hydrogen then the suspension was stirred for 1.5 hours before filtering the mixture through celite in vacuo. The filter cake was washed with ethanol then the solvents removed in vacuo from the filtrate to obtain (3R,3aR,6S,6aS)-3-hydroxyhexahydro-2H-furo[3,2-b]pyrrol-6-yl 4-methylbenzenesulfonate which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.O.[N+:10]([O-])([OH:12])=[O:11]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)ccc1O
Reaction time: 5 h

Procedure:
0.125 mol (16 g) of 4-chlorophenol, 25 ml of water and 35 ml of acetic acid are introduced into a 125 ml three-necked flask equipped with a stirring system and a thermometer; the mixture is brought to 40° C. and 14.2 ml of nitric acid (d=1.38) are then added drop by drop; the reactants are left in contact for 5 hours. The product is separated by filtration and is crystallized in the minimum of absolute alcohol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[C:13]([S:18]([NH:21][C:22]2[O:26][N:25]=[C:24]([CH3:27])[C:23]=2[CH3:28])(=[O:20])=[O:19])=[CH:14][CH:15]=[CH:16][CH:17]=1.[CH:29](=O)[CH2:30][CH3:31]>>[CH3:27][C:24]1[C:23]([CH3:28])=[C:22]([NH:21][S:18]([C:13]2[C:12]([C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:7][C:2]=3[NH:1][CH2:29][CH2:30][CH3:31])=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:20])=[O:19])[O:26][N:25]=1
Reactant: CCC=O
Reactant: Cc1noc(NS(=O)(=O)c2ccccc2-c2ccc(CC(C)C)cc2N)c1C
Product: CCCNc1cc(CC(C)C)ccc1-c1ccccc1S(=O)(=O)Nc1onc(C)c1C
Temperature: 2.5 °C
Reaction time: 2 h

Procedure:
The title compound was prepared from the compound of Example 32 and propionaldehyde as described for Example 58, with stirring at 0-5° C. for 2 hours. Following workup, chromatography on silica gel with 4:1 hexanes/ethyl acetate afforded the title compound as a light yellow gum.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].Cl.[NH2:21][CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>>[C:1]([C:3]1[CH:11]=[C:7]([C:8]([NH:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:31][CH:32]=2)=[O:10])[C:6]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:5][CH:4]=1)#[N:2]
Reactant: N#Cc1cnc(Oc2ccc(F)cc2)c(C(=O)O)c1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Product: COC(=O)c1ccc(CNC(=O)c2cc(C#N)cnc2Oc2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 5-cyano-2-(4-fluorophenoxy)nicotinic acid (step 3) and methyl 4-(aminomethyl)benzoate hydrochloride: 1H-NMR (CDCl3) δ 8.91 (1H, d, J=1.8 Hz), 8.48 (1H, d, J=1.8 Hz), 8.03 (2H, d, J=8.1 Hz), 7.43 (2H, d, J=8.1 Hz), 7.17–7.12 (4H, m), 4.78 (2H, d, J=5.4 Hz), 3.91 (3H, s); MS (ESI) m/z 406 (M+H)+, 404 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=[O:3])[CH3:2].[CH3:33][C@@H:34]1[CH2:38][O:37][C:36](=[O:39])[NH:35]1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[C:13]([N:35]3[C@H:34]([CH3:33])[CH2:38][O:37][C:36]3=[O:39])[CH:12]=[CH:11][C:10]=2[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])[C:5]1=[O:32])(=[O:3])[CH3:2]
Reactant: C[C@@H]1COC(=O)N1
Reactant: CC(=O)N1CCN(c2cc(Cl)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Product: CC(=O)N1CCN(c2cc(N3C(=O)OC[C@H]3C)ccc2C(=O)N2CCN(c3ncc(C)cc3C)CC2)C1=O
Yield: 11.8 %

Procedure:
By reaction and treatment in the same manner as in Example 201 and using 1-acetyl-3-{5-chloro-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one (519 mg) described in Preparation Example 126 and (R)-4-methyloxazolidin-2-one (115 mg) described in Preparation Example 25, the title compound (69.9 mg) was obtained.