Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:23][CH2:22][C:8]2([CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][C:15]([F:21])([C:18](O)=[O:19])[CH2:14][CH2:13]3)[CH2:9]2)[CH2:7]1)=[O:5])[CH3:2].Cl.[CH3:25][C:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>S(Cl)(Cl)=O>[F:21][C:15]1([C:18](=[O:19])[NH:30][C:26]2([CH3:25])[CH2:29][CH2:28][CH2:27]2)[CH2:16][CH2:17][N:12]([CH:10]2[CH2:11][C:8]3([CH2:22][CH2:23][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7]3)[CH2:9]2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)N1CCC2(CC(N3CCC(F)(C(=O)O)CC3)C2)C1
Reactant: CC1(N)CCC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N1CCC2(CC(N3CCC(F)(C(=O)NC4(C)CCC4)CC3)C2)C1
Temperature: 90 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
Crude 1-[6-(ethoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]-4-fluoropiperidine-4-carboxylic acid was suspended in thionyl chloride (3 mL) and the reaction was stirred at 90° C. for 2 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was dissolved in DCM (5 mL) and (1-methylcyclobutyl)amine hydrochloride (0.196 g, 1.62 mmol) and DIPEA (0.523 g, 0.71 mL, 4.05 mmol) were added, the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 25 g, 40-63 μm, 60 A, 12 mL per min, gradient 0% to 6% MeOH in DCM]) to give ethyl 2-{4-fluoro-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}-6-azaspiro[3.4]octane-6-carboxylate (0.09 g, 28%) as a pale yellow gum as a mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:14]=[C:13]([N+:19]([O-:21])=[O:20])[C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:4]([C:15]([O:17][CH3:18])=[O:16])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)COc1ccc(Cl)cc1C(=O)OC
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1c(C(=O)OC)cc(Cl)cc1[N+](=O)[O-]

Procedure:
A solution of 620 g of ethyl 4-chloro-2-methoxycarbonylphenoxyacetate in 1600 ml of concentrated sulfuric acid is cooled below 0° C, and a mixture of 102 ml of fuming nitric acid (d 1.50) and 102 ml of concentrated sulfuric acid is added dropwise below 5° C. The resultant solution is stirred for 3 hours under ice-cooling and poured into ice-cold water and then extracted with ethyl acetate. The extract is washed with water twice and dried over magnesium sulfate. The solvent is distilled off and the residue is gradually crystallized to give 697 g of ethyl 4-chloro-2-methoxycarbonyl-6-nitrophenoxyacetate, melting at 68°-70° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CC1C=CC(S(O[CH2:16][C@@H:17]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:18][C@H:19]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21][CH2:20]2)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[N:1]([CH2:16][C@@H:17]([NH:26][C:27](=[O:28])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:18][C@@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21][CH2:20]1)=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](C[C@H]2CCCCOC2)NC(=O)OC(C)(C)C)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])C[C@@H]1CCCCOC1
Temperature: 25 °C

Procedure:
The solution of NaN3 (47 mg, 0.72 mmol) and (S)-2-(tert-butoxycarbonylamino)-3-((R)-oxepan-3-yl)propyl 4-methylbenzenesulfonate (103 mmol, 0.24 mmol) in anhydrous DMF was heated to 80° C. for 2 h. After cooling to rt, the reaction was diluted with EtOAc and washed with H2O, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel to give tert-butyl (S)-1-azido-3-((S)-oxepan-3-yl)propan-2-ylcarbamate. MS ESI +ve m/z 321 (M+Na).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]NS(C2C=NC=CC=2)(=O)=O)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].S1C=CN=C1C1C=CC(CNS(C2C=NC=CC=2)(=O)=[O:46])=CC=1.N1C=CC(C2C=CC(CO)=CC=2)=CN=1>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:46])[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2cccnc2)n1
Reactant: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1
Agent: OCc1ccc(-c2ccnnc2)cc1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CO)n1

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(a) except for using tert-butyl(tert-butoxycarbonyl{6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetate (158 mg, 0.330 mmol) obtained in Reference Example 12-(d) in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide, and using 4-(pyridazin-4-yl)benzyl alcohol (60.2 mg, 0.323 mmol) obtained in Reference Example 13 in place of tert-butyl[tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate to afford the title compound (152 mg) as a white foam. (Yield: 73%)
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([O:17]S(C4C=CC(C)=CC=4)(=O)=O)[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4](S(C2C=CC(C)=CC=2)(=O)=O)[CH:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[CH:67]([C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][N:70]=1)=[CH2:68]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[N:70]1[CH:71]=[CH:72][CH:73]=[CH:74][C:69]=1[CH:67]=[CH:68][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][CH:3]=1
Reactant: C=Cc1ccccn1
Reactant: Cc1ccc(S(=O)(=O)Oc2cccc(-c3cnc4c(c3)c(I)cn4S(=O)(=O)c3ccc(C)cc3)c2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Oc1cccc(-c2cnc3[nH]cc(C=Cc4ccccn4)c3c2)c1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
To toluene-4-sulfonic acid 3-[3-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenyl ester (50 mg, 0.077 mmol), tri-ortho-tolylphosphine (10 mg, 0.031 mmol), palladium (II) acetate (2 mg, 0.0077 mmol) was added DMF (0.5 mL), triethylamine (32 uL, 0.232 mmol), and 2-vinylpyridine (42 uL, 0.388 mmol). The vial was flushed with nitrogen, and the reaction was run in a Personal Chemistry® microwave reactor at 150° C. for 900 s. Water was added and the mixture was neutralized to pH 6 with 1N aqueous HCl, then extracted with EtOAc three times. The extracts were combined and concentrated in vacuo. The crude was treated with 1 mL of EtOH and 1 mL of aqueous KOH (50 wt %). The reaction mixture was stirred at 80° C. for 15 h. The mixture was neutralized to pH 7 with 1N aqueous HO, and the resulting precipitate was filtered, washed with water, dried in vacuo, and adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 3-[3-(2-pyridin-2-yl-vinyl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-phenol us a yellow solid (17 mg, 35% yield), 1H NMR (500 MHz, DMSO-d6) δ 6.78 (dd, J=2.0, 8.0 Hz, 1H), 7.13 (s, 1H), 7.15-7.20 (m, 2H), 7.26 (d, J=16.0 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.73 (dt, J=2.0, 8.0 Hz, 1H), 7.90 (d, J=16.0 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 8.50 (d, J=2.0 Hz, 1H), 8.52 (d, J=5.0 Hz, 1H), 8.54 (d, J=2.5 Hz, 1H), 9.56 (s, 1H), 12.1 (s, 1H). MS: m/z 314 (M+H+).
Reaction SMILES: [H-].[Na+].[CH3:3]N(C)C=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[O:18])[O:16][C:15](=[O:19])[NH:14][C:13]=2[CH:20]=1.IC>O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[C:17](=[O:18])[O:16][C:15](=[O:19])[N:14]([CH3:3])[C:13]=2[CH:20]=1
Reactant: O=c1[nH]c2cc(Br)ccc2c(=O)o1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cn1c(=O)oc(=O)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
Sodium hydride (0.47 g, 12 mmol) was added to a 3 neck 250 mL RBF under nitrogen and then washed with hexanes. Once the hexanes were decanted, N,N-dimethylformamide (20.0 mL, 11 mmol) was added. The resulting mixture was cooled to 0° C. using an ice-water bath, and then 7-bromo-1H-benzo[d][1,3]oxazine-2,4-dione (2.7 g, 11 mmol) was added in one batch. After stirring at room temperature for 1 hour, iodomethane (0.70 mL, 11 mmol) was added dropwise to the yellow solution, and the reaction mixture was stirred for 16 hours. Water (50 mL) was added, and the resulting precipitate that formed was collected via filtration. The solid was washed with additional water (100 mL), followed by ether (100 mL). Drying in a vacuum oven overnight at 50° C. afforded the desired product as an off-white solid (2.1 g, 74% yield).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]1=[S:12].C[Si](C)(C)Cl.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[NH4+].[OH-]>N1C=CC=CC=1.CO>[C:23]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:3]2[O:4][C@H:5]([CH2:8][OH:9])[C@@H:6]([OH:7])[C@H:2]2[CH3:1])[C:11](=[S:12])[N:13]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=S
Reactant: O=C(Cl)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Product: C[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(NC(=O)c2ccccc2)nc1=S
Reaction time: 0.25 h
Yield: 48.3 %

Procedure:
To a stirred solution of 2'-deoxy-2'-methylthiocytidine (0.86 g, 3.15 mmol) in dry pyridine (20 ml) was added trimethylchlorosilane (2.0 ml, 15.75 mmol), and stirring continued for 15 min. Benzoyl chloride (2.18 ml, 18.9 mmol) was added to the solution followed by stirring for 2 hr. The mixture was then cooled in an ice-bath and MeOH (10 ml) was added. After 5 mins., NH4OH (20 ml, 30% aq.) was added and the mixture stirred for 30 min. The reaction mixture was then concentrated under vacuum and the residue purified by short silica gel (70 g) column chromatography. Elution with CH2Cl2 :MeOH (9:1, v/v), pooling of appropriate fractions and evaporation furnished the title compound (0.55 g, 46.6%) which crystallized from EtOH as needles, m.p. 193°-194° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([O:15][CH3:16])=[O:14].C(O)(C)(C)C.N.[K].[CH2:24](I)[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27]>O1CCCC1>[CH3:27][C:26]([CH3:29])([CH3:28])[CH2:25][CH2:24][C:4]1([C:13]([O:15][CH3:16])=[O:14])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1]
Reactant: COC(=O)c1c(OC)ccc2ccccc12
Reactant: CC(C)(C)CCI
Agent: N
Agent: [K]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COC(=O)C1(CCC(C)(C)C)C(OC)=CCc2ccccc21
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 44.8 %

Procedure:
To a solution of methyl 2-methoxy-naphthoate (1.00 g, 4.6 mmol) and tert-butyl alcohol (0.43 mL, 4.6 mmol) in anhydrous tetrahydrofuran (10 mL) at −78° C. under N2 was added anhydrous ammonia (˜20 mL), followed by the portionwise addition of potassium metal until a dark blue solution was maintained for >15 min. To the resulting mixture was added neohexyl iodide (0.5 g, 2.36 mmol), the mixture was stirred at −78° C. for 20 min, and then allowed to slowly warm to rt while evaporating the ammonia with a dry N2 stream. To the resulting suspension was added anhydrous tetrahydrofuran (10 mL), and the mixture was heated at 50° C. under N2 for 16 h. The reaction mixture was partitioned between saturated aq. NaHCO3 (20 mL) and ethyl acetate (3×20 mL), and the combined organic layers were dried over Na2SO4. The crude product was purified by column chromatography on silica gel using 19:1 hexanes:ethyl acetate to provide the title compound as a colorless gum (0.32 g, 23%). 1H NMR (300 MHz, CDCl3) δ ppm 7.11-7.23 (m, 4H), 5.06 (t, J=3.9 Hz, 1H), 3.61 (s, 3H), 3.60 (s, 3H), 3.54-3.57 (m, 2H), 2.20-2.31 (m, 1H), 2.00-2.11 (m, 1H), 0.82-0.94 (m, 1H), 0.75 (s, 9H), 0.45-0.57 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[O:21])=[CH:16][CH:15]=1>O1CCCC1>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[OH:21])=[CH:16][CH:15]=1
Reactant: Brc1ccncc1
Reactant: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1ccncc1)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of 4-bromopyridine (0.78 g, 5.0 mmol) in tetrahydrofuran (5 mL) was added isopropylmagnesium chloride (2.0 Min tetrahydrofuran, 2.5 mL, 5.0 mmol) via syringe under nitrogen at room temperature. The reaction mixture was stirred for one hour. To the reaction mixture was then added bis(4-fluorophenyl)methanone (0.98 g, 4.5 mmol) dissolved in tetrahydrofuran (7 mL) via syringe. The reaction mixture was stirred overnight, quenched with a saturated aqueous solution of ammonium chloride (10 mL), and extracted with diethyl ether. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with 5% methanol/dichloromethane gave bis(4-fluorophenyl)(pyridin-4-yl)methanol on (0.73 g, 2.45 mmol).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:37]3[CH:42]=[CH:41]C(C#N)=[CH:39][CH:38]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=O)C.Cl.[OH-].[Na+].[C:48]([OH:51])(=[O:50])[CH3:49]>>[C@@H:6]1([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]3[S:33][C:34]([C:37]4[CH:42]=[CH:41][C:49]([C:48]([OH:51])=[O:50])=[CH:39][CH:38]=4)=[CH:35][CH:36]=3)[CH:25]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C#N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1ccc(-c2ccc(Cc3cc([C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)ccc3Cl)s2)cc1

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene (128 mg) obtained in Example 191-(1) was dissolved in acetic acid (2 ml) and added thereto was a concentrated hydrochloric acid aqueous solution (2 ml). The mixture was refluxed for 6.5 hours. To the mixture was added a 10% aqueous sodium hydroxide solution at 0° C., and the mixture was washed with ethyl acetate. The aqueous layer was acidified by adding concentrated hydrochloric acid, and extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by washing with a mixture of ethyl acetate and diethyl ether to give the desired 1-(β-D-glucopyranosyl)-3-(5-(4-carboxyphenyl)-2-thienylmethyl)-4-chlorobenzene (49 mg) as pale brown powder. ESI-Mass m/Z 489/491 (M−H).
Reaction SMILES: [CH3:1][O:2][C@:3]12[CH2:17][C@@H:16]([CH2:18][OH:19])[CH2:15][N:14]([CH3:20])[C@@H:13]1[CH2:12][C:11]1[C:21]3[C:8]([N:9]([CH3:22])[CH:10]=1)=[CH:7][CH:6]=[CH:5][C:4]2=3.C(N(CC)CC)C.[S:30](Cl)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>C(Cl)Cl>[S:30]([O:19][CH2:18][C@@H:16]1[CH2:17][C@@:3]2([O:2][CH3:1])[C@@H:13]([CH2:12][C:11]3[C:21]4[C:8](=[CH:7][CH:6]=[CH:5][C:4]2=4)[N:9]([CH3:22])[CH:10]=3)[N:14]([CH3:20])[CH2:15]1)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CO[C@]12C[C@@H](CO)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CO[C@]12C[C@@H](COS(=O)(=O)c3ccc(C)cc3)CN(C)[C@@H]1Cc1cn(C)c3cccc2c13
Yield: 72.7 %

Procedure:
A mixture of 10 g of 10-methoxy-1,6-dimethylergoline-8β-methanol, 12.4 ml of triethylamine, and 12.6 g of tosyl chloride in 200 ml of methylene chloride is refluxed 5 hr. The solution is washed first with 10% Na2CO3 and then with water, the solvent is evaporated in vacuo, and the residue is crystallized from methanol to give 11 g of 10-methoxy-1,6-dimethylergoline-8β-methanol tosylate; m.p. 169° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[C:19]([C:27]5[CH:28]=[C:29]([NH:33][C:34](=[O:41])[C:35]6[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=6)[CH:30]=[CH:31][CH:32]=5)=[N:20][N:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=45)[CH:15]=[CH:14][N:13]=3)[CH:9]=2)[CH2:4][CH2:3][NH:2]1.[CH2:42](Cl)Cl.CO.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH3:42][N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][C:8]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[C:19]([C:27]5[CH:28]=[C:29]([NH:33][C:34](=[O:41])[C:35]6[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=6)[CH:30]=[CH:31][CH:32]=5)=[N:20][N:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=45)[CH:15]=[CH:14][N:13]=3)=[CH:7][CH:6]=2)[CH2:1]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1
Reactant: ClCCl
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)c6ccccc6)c5)nn5ccccc45)n3)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-(3-{3-[2-(1,2,3,4-tetrahydro-7-isoquinolinylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenyl)benzamide (107 mg, 0.199 mmol) in 2:1 DCM/MeOH (1.5 mL) was added 37% aq. formaldehyde (50 μL, 0.67 mmol), glacial acetic acid (13 μL) and sodium triacetoxyborohydride (64 mg, 0.30 mmol). The mixture was stirred at rt for 1 h. The mixture was worked up by removal of solvent with a totary evaporator and partitioning the residue between saturated aq. NaHCO3 and 5:1 CHCl3/isopropanol. The organic layer was separated, dried and concentrated to give 67 mg of crude material. Purification by silica gel chromatography (0 to 30% methanol in DCM) afforded 60.4 mg of the title compound as a cream-colored solid. LCMS (ES)+ 552.3. 1H NMR (400 MHz, DMSO-d6) δ 2.47 (s, 3H), 2.57 (bs, 2H), 2.72 (m, 2H), 3.39 (s, 2H), 6.49 (d, 1H, J=5.6), 6.95 (d, 1H, J=8.0, 7.10 (t, 1H, J=6.8), 7.28 (d, 1H, J=8.0), 7.37 (d, 1H, J=8.0), 7.42-7.56 (m, 5H), 7.93 (d, 2H, J=7.2), 8.11 (s, 1H), 8.22 (d, 1H, J=5.6), 8.45 (d, 1H, J=8.8), 8.81 (d, 1H, J=7.2, 9.41 (s, 1H), 10.37 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]([F:29])([F:28])[C:15]1[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=1)[C:18]([NH:20][CH2:21][C:22](O)=[O:23])=[O:19].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([NH:12][C:22](=[O:23])[CH2:21][NH:20][C:18](=[O:19])[C:17]2[CH:25]=[CH:26][CH:27]=[C:15]([C:14]([F:13])([F:29])[F:28])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1

Procedure:
A solution of 3-amino-azetidine-1-carboxylic acid tert-butyl ester (BetaPharma, 1.2 g, 6.97 mmol) and (3-trifluoromethyl-benzoylamino)-acetic acid (Bionet, 1.57 g, 6.36 mmol) in DCM (10 mL) was treated with EDCI (Aldrich, 1.57 g, 6.36 mmol) and HOBT (Aldrich, 1.22 g, 6.36 mmol) at room temperature for 4 hours. The reaction solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give a yellow oil, which was then purified by silica gel column on a CombiFlash® system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:7]2[CH2:8][CH2:9][CH:4]([CH:5]([CH2:10][CH2:11]O)[CH2:6]2)[C:3]1=[O:13].S(Cl)([Cl:17])=O.O>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[CH:7]2[CH2:8][CH2:9][CH:4]([CH:5]([CH2:10][CH2:11][Cl:17])[CH2:6]2)[C:3]1=[O:13]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)C(=O)C2CCC1CC2CCO
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)C(=O)C2CCC1CC2CCCl
Temperature: 50 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a stirred solution of 50 g of 3,3-dimethyl-6-(2-hydroxyethyl)-bicyclo(2.2.2)-octan-2-one (produced according to Example II) in 200 ml of dry pyridine is added 30 g of thionyl chloride. The mixture is stirred at 50° C. for 2 hours and then poured into 50 g of water. The resulting aqueous solution is extracted with three 200 ml portions of ether. The combined ether layers are washed with two 100 ml portions of 5% aqueous HCl and dried over anhydrous sodium sulfate. The ether is stripped and the residue is vacuum distilled, yielding about 42 g of 3,3-dimethyl-6-(2-chloroethyl)-bicyclo(2.2.2)-octan-2-one, having the structure: ##STR28##
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([C:20]([NH:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[O:21])=[CH:23][CH:24]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Reactant: Nc1ccc2cccnc2c1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccc3cccnc3c2)cc1

Procedure:
Using the procedure outlined in Example 45, the title compound was prepared from 7-aminoquinoline (D55) (30 mg, 21 mmol) and 4-tert -butylbenzoic acid (45 mg, 0.25 mmol) as a yellow solid. MS(ES): MH+ 305, M-H+ 303
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])=[CH:22][C:16]2[N:17]=[C:18]([S:20][CH3:21])[NH:19][C:15]=2[CH:14]=1.S(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:12][C:13]1[C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])=[CH:22][C:16]2[N:17]=[C:18]([S:20]([CH3:21])=[O:9])[NH:19][C:15]=2[CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc2cc(Oc3ccc(Cl)cc3Cl)c(Cl)cc2[nH]1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nc2cc(Oc3ccc(Cl)cc3Cl)c(Cl)cc2[nH]1
Reaction time: 15 h
Yield: 71.1 %

Procedure:
A solution of 19.5 g of 90% pure m-chloroperbenzoic acid in 450 ml of chloroform is added dropwise in the course of 30 minutes to a solution, which has been cooled to 0° to 5° C., of 35 g of 5-chloro-6-(2',4'-dichlorophenoxy)-2-methylthio-benzimidazole in 1,750 ml of chloroform, with stirring. The mixture is stirred for a further 3 hours at 0° to 5° C. and then for 15 hours at room temperature and then is freed from the small amount of precipitate which arises. The filtrate, which still contains residues of m-chloroperbenzoic acid, is treated with sodium bisulphite solution, washed with water, dried over calcium chloride, filtered and concentrated in vacuo. After recrystallising the residue from 500 ml of ethyl acetate, and at the same time clarifying the hot solution with active charcoal, and then drying the white crystals at 50° C., 26 g of 5-chloro-6-(2',4'-dichlorophenoxy)-2-methylsulphinyl-benzimidazole with a melting point of 206°-208° C. are obtained, which corresponds to a yield of 69%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH2:33][CH2:34][OH:35]>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH2:33][CH2:34][OH:35])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(C)cccc1C
Reactant: NCCO
Product: Cc1cc(F)ccc1-c1nc(NCCO)nc2c1ccc(=O)n2-c1c(C)cccc1C

Procedure:
Prepared as described above in Example 60 starting from 8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one and 2-aminoethanol to give the title compound 8-(2,6-dimethyl-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3): δ 1.92 (s, 6H), 2.12 (s, 3H), 2.95 (br s, 2H), 3.30 (br s, 2H), 3.45 (br s, 1H), 6.31 (d, 1H, J=9.7 Hz), 6.92 (m, 2H), 7.17 (m, 5H). LC MS (m/e)=419.4 (MH+). Rt=1.84 min