Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])O[C:14]=2[C:24]([OH:26])=[O:25])=[CH:9][CH:8]=1.Br.[Br:28][CH2:29][CH2:30][CH2:31][NH2:32].C(N(CC)CC)C>CO>[Br:28][CH2:29][CH2:30][CH2:31][N:32]1[C:14]([C:24]([OH:26])=[O:25])=[C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=2)[C:22]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[C:16]1=[O:23]
Reactant: Cc1ccc(-c2c(C(=O)O)oc(=O)c3ncccc23)cc1
Reactant: NCCCBr
Agent: Br
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc(-c2c(C(=O)O)n(CCCBr)c(=O)c3ncccc23)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
A THF (5 ml) solution of 5-(4-methylphenyl)-8-oxo-8H-pyrano[3,4-b]pyridine-6-carboxylic acid (150 mg) was dropwise added to a mixture of 3-bromopropylamine hydrobromide (1.5 g), triethylamine (2.0 ml) and methanol (5 ml), and stirred at room temperature for 2 hours. Then, the solvent was removed by distillation. Hydrochloric acid (10 ml) was added to the residue, stirred for 14 hours at room temperature and then concentrated. The resulting concentrate was adjusted the pH to 1 with 1N-NaOH. The crystals thus precipitated were taken out by filtration and washed with water to obtain 7-(3-bromopropyl)-7,8-dihydro-5-(4-methylphenyl)-8-oxo-6-pyrido[3,4-b]pyridinecarboxylic acid as colorless crystals (131 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.ClCCl>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][Br:17])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)cc(Br)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Clc1cc(Br)cc(CBr)c1
Temperature: 80 °C

Procedure:
Step G2. The mixture of 3-bromo-5-chlorotoluene (9 g, 43.8 mmol), NBS (8.19 g, 46 mmol), and AIBN (200 mg) in carbon tetrachloride (50 mL) was heated at 80° C. for 3 hours. The resulting mixture was run through a silicon gel column with dichloromethane as the eluant. The fraction was collected and solvent was removed by rotovap, crude 1-bromo-3-(bromomethyl)-5-chlorobenzene (3) was obtained as a brown residue and used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc2c(-c3ccncc3)cnn12
Yield: 23 %

Procedure:
Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (285 mg, 1.0 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (160 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (94 mg, 46%). MS (ISP) 409.2 [(M+H)+]; mp 260° C.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=O)[S:12][CH:13]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:19])=O>>[Cl:19][C:11]1[S:12][CH:13]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:16])([F:15])[F:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)cs1
Product: FC(F)(F)c1ccc(-c2csc(Cl)n2)cc1
Yield: 64.1 %

Procedure:
A mixture of 28.05 g (114.4 mmole) of 4-(4-trifluoromethyl-phenyl)-3H-thiazol-2-one and 85 mL (0.92 mole) of phosphorus oxychloride was heated at reflux for 5 hours. The mixture was cooled and the excess phosphorus oxychloride was removed under reduced pressure. The residue was diluted with ethyl acetate and the slurry was poured onto ice. The mixture was made basic by the addition of saturated aqueous sodium carbonate solution. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexanes (gradient 10:90-20:80) to give 19.34 g of 2-chloro-4-(4-trifluoromethyl-phenyl)-thiazole as a light brown solid.
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)C.[OH-].[Na+]>CO.O>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:6]([CH2:5][C:4]([OH:25])=[O:3])=[C:7]([C:16](=[O:24])[C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[NH:8]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2cc(Cl)ccc12
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of [6-chloro-2-(4-chloro-benzoyl)-1H-indol-3-yl]-acetic acid ethyl ester (200 mg, 0.532 mmol) in methanol (2 ml) and water (0.8 ml) was added sodium hydroxide (137 mg, 3.43 mmol). The reaction mixture was stirred 24 hours, and was concentrated to a low volume. Water (4 ml) was added, the material was transferred to a separatory fumnel and was washed with dichloromethane (5 ml). The aqueous layer was acidified to pH 1 with 1N hydrochloric acid and was extracted with ethyl acetate (15 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrate to afford [6-chloro-2-(4-chloro-benzoyl)-1H-indol-3-yl]-acetic acid (150 mg, 81%). The 1H NMR spectrum was identical with the one obtained for the compound prepared by the method described in example 2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2CCC(=O)CC2)cc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc([C@H]2CC[C@@H](O)CC2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a −78° C. solution of 4-(4-methoxyphenyl)cyclohexanone (456.7 mg, 2.24 mmol) (prepared as described above in INTERMEDIATE 34) in THF (22 mL) was added L-Selectride (6.71 ml of a 1M solution in THF, 6.71 mmol). The reaction was allowed to warm to 0° C. over 3 hours. The reaction was then quenched with 3 mL of acetone added dropwise and 7.5 mL of H2O at 0° C. Next 3 mL of 30% H2O2 was added in a slow, dropwise manner. This mixture was stirred at 0° C. for 5 min and then diluted with EtOAc (50 mL). The organic layer was washed with water (2×25 mL) and brine (25 mL), dried (Na2SO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0 to 70% EtOAc/hexanes) to afford cis-4-(4-methoxyphenyl)cyclohexanol. 1H NMR (500 MHz, CDCl3): δ 7.16 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 4.12 (bs, 1H), 3.79 (s, 3H), 2.50 (m, 1H), 1.62-1.90 (m, 8H).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[CH:16]=3)[CH:9]=2)[N:4]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1.[F:34][C:35]1[CH:57]=[CH:56][C:55]([F:58])=[CH:54][C:36]=1[CH2:37][N:38]1[C:42]([CH3:43])=[C:41](B2OC(C)(C)C(C)(C)O2)[C:40]([CH3:53])=[N:39]1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1.C(O)C.O>[F:34][C:35]1[CH:57]=[CH:56][C:55]([F:58])=[CH:54][C:36]=1[CH2:37][N:38]1[C:42]([CH3:43])=[C:41]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:12]=[CH:13][C:14]([O:22][CH3:23])=[C:15]([S:17]([NH:20][CH3:21])(=[O:19])=[O:18])[CH:16]=4)[CH:9]=3)[N:4]([S:24]([C:27]3[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=3)(=[O:26])=[O:25])[CH:3]=2)[C:40]([CH3:53])=[N:39]1
Reactant: Cc1nn(Cc2cc(F)ccc2F)c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CNS(=O)(=O)c1cc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cc(F)ccc4F)c2C)cn3S(=O)(=O)c2ccc(C)cc2)ccc1OC
Yield: 61.3 %

Procedure:
Using similar reaction conditions as described in step-ii of example 15-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-methoxy-N-methylbenzenesulfonamide (intermediate 22) (200 mg, 0.335 mmol) was coupled with 1-(2,5-difluorobenzyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Intermediate 25) (146 mg, 0.418 mmol) in sodium carbonate (106 mg, 1.0 mmol), Pd(PPh3)2Cl2 (11.7 mg, 0.011 mmol), Toluene/ethanol/water (20/10/2 ml) to afford 142 mg (61.4% yield) of the titled compound after purification by column (SiO2-eluted by 0.4 to 1.2% MeOH in CHCl3). MS: m/z=692.1 (M+1).
Reaction SMILES: [Br-].[CH3:2][N:3]([CH3:25])[CH2:4][CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[CH2:31]([O:38][C:39]1[C:40]([NH:47][C:48]2[S:49][CH:50]=[C:51]([CH3:53])[N:52]=2)=[N:41][CH:42]=[C:43]([CH:46]=1)[CH:44]=O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[ClH:54]>C1COCC1>[ClH:54].[ClH:54].[CH2:31]([O:38][C:39]1[C:40]([NH:47][C:48]2[S:49][CH:50]=[C:51]([CH3:53])[N:52]=2)=[N:41][CH:42]=[C:43](/[CH:44]=[CH:5]/[CH2:4][N:3]([CH3:25])[CH3:2])[CH:46]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CN(C)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1csc(Nc2ncc(C=O)cc2OCc2ccccc2)n1
Agent: Cl
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1csc(Nc2ncc(/C=C/CN(C)C)cc2OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.83 h
Yield: 51.3 %

Procedure:
A 25 mL round-bottomed flask was charged with [2-(dimethylamino)ethyl]triphenylphosphonium bromide (1114 mg, 2.69 mmol) and THF (5 mL). The reaction was cooled to 0° C. under nitrogen. Butyllithium (1.08 ml, 2.69 mmol) was added slowly and the reaction was stirred for 50 minutes. A solution of 5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)nicotinaldehyde (350 mg, 1.08 mmol) in THF (5 mL) was added and the reaction was stirred at ambient temperature for 1.5 hours. The reaction was partitioned between EtOAc and water. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified on a silica gel column (10 to 20% methanol in EtOAc with NH4OH) to afford the title compound (250 mg, 51.3% yield) after HCl salt formation. 1H NMR (DMSO-d6) δ 10.85 (bs, 1H), 10.49 (bs, 1H), 8.03 (d, 1H), 7.78 (s, 1H), 7.63 (d, 2H), 7.45-7.33 (m, 3H), 6.82 (m, 3H), 6.45 (m, 1H), 5.37 (s, 2H), 3.85 (m, 2H), 2.77 (d, 6H), 2.30 (s, 3H). Mass spectrum (apci) m/z=381.1 (M+H-2HCl).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([NH2:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1)=[O:5])C.[H-].[Na+].Br[CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].[OH-].[Na+]>O1CCOCC1.CO.O>[O:25]=[C:24]1[CH2:23][CH2:22][CH2:21][N:11]1[C:9]1[N:8]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:10]=1
Reactant: CCOC(=O)c1cc(N)n(-c2ccccc2)n1
Reactant: O=C(Cl)CCCBr
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc(N2CCCC2=O)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
700 mg (3.0 mmol) of 5-Amino-1-phenyl-1H-pyrazole-3-carboxylic acid ethyl ester are dissolved in 20 ml of dioxane and added to a suspension of NaH (266 mg 60% suspension in mineral oil, 6.66 mmol) in 10 ml of dioxane. After stirring for 10 minutes at RT 4-bromobutyryl chloride (617.5 mg, 3.3 mmol) is added and the resulting mixture is stirred overnight at RT. A MeOH/H2O mixture (10 ml, 1:1) is added to destroy excess NaH and the solvent is removed in vacuo. The crude product is redissolved in 15 ml of EtOH and 8 mmol of 1M NaOH is added and the mixture is stirred overnight. The solvent is removed in vacuo and the residue subjected to HPLC chromatography: Yield: 554 mg, 68%
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[OH:15]O>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N+:10]=2[O-:15])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: OO
Reactant: N#Cc1cccc(-c2ccccn2)c1
Solvent: CC(=O)O
Product: N#Cc1cccc(-c2cccc[n+]2[O-])c1

Procedure:
Starting from 2-(3-cyanophenyl)-pyridine, the title compound is prepared by oxidation with H2O2 in glacial acetic acid [J. Heterocycl. Chem. 11. 299 (974)].
Reaction SMILES: [NH2:1][C:2]1([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:11]1[C:23]2[CH:22]([CH2:24][O:25][C:26](Cl)=[O:27])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1>O1CCOCC1>[CH:11]1[C:23]2[CH:22]([CH2:24][O:25][C:26]([NH:1][C:2]3([C:8]([OH:10])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)=[O:27])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: NC1(C(=O)O)CCCCC1
Solvent: C1COCCO1
Product: O=C(NC1(C(=O)O)CCCCC1)OCC1c2ccccc2-c2ccccc21
Temperature: 20 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
To a chilled (ice bath) suspension of aminocyclohexanecarboxylic acid (2.51 g, 17.5 mmol) in alumina-filtered dioxane (17 mL) were added 10% Na2CO3 (35 mL) and a solution of 9-fluorenylmethylchloroformate (4.57 g, 17.7 mmol) in 26 mL of dioxane (added slowly). The reaction mixture was allowed to warm to about 20° C. and stirred overnight under N2. The reaction mixture was poured into ~300 mL of ice water and washed with anhydrous ether (some product went into the ether layer). The aqueous layer was chilled in an ice bath and acidified with concentrated hydrochloric acid to pH about 2. The aqueous layer was then extracted with ethyl acetate (3×100 mL). The combined ethyl acetate layers were washed with 0.1N HCl and H2O. The ether and ethyl acetate layers were dried over anhydrous MgSO4, combined and concentrated. The resulting compound was flash chromatographed with a gradient of 40-50% EtOAc/Hexane to yield 0.383 g (1.05 mmol, 6.0% yield) of the title compound as a white foam DEI M+@m/z=365.
Reaction SMILES: Cl[C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>C(#N)C>[Cl:8][C:6]1[N:7]=[C:2]([N:25]2[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]2)[C:3](=[O:20])[N:4]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1ccc(C)c(-n2cc(Cl)nc(Cl)c2=O)c1
Solvent: CC#N
Product: COC(=O)c1ccc(C)c(-n2cc(Cl)nc(N3CCN(C)CC3)c2=O)c1
Reaction time: 12 h

Procedure:
To a stirred solution of 3-(3,5-dichloro-2-oxo-1(2H)-pyrazinyl)-4-methyl-benzoic acid, methyl ester, (Example 107a, 250 mg) in acetonitrile (5 mL) was added 1-methyl-piperazine (0.2 mL). After 12 h, the reaction mixture was concentrated in vacuo. The residue was diluted with dichloromethane, washed with sat. aqueous NaHCO3, dried (MgSO4), filtered and the solvent removed to afford the subtitle compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[I:12]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([I:12])[CH:10]=1
Reactant: II
Reactant: OCCCc1ccc(O)cc1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: OCCCc1ccc(O)c(I)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(3-hydroxypropyl)phenol (2.00 g, 13.14 mmol) in MeOH (10 ml) under nitrogen at RT was added silver sulfate (4.10 g, 13.14 mmol) followed by iodine (3.34 g, 13.14 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then, the solids were filtered washing with MeOH. The filtrate was concentrated and purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford the title compound. 1H NMR (500 MHz, CD3OD): δ 7.51 (d, J=2.1 Hz, 1H); 7.02-6.97 (m, 1H); 6.73 (d, J=8.2 Hz, 1H); 3.53 (t, J=6.5 Hz, 2H); 2.59-2.51 (m, 2H); 1.80-1.71 (m, 2H).
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)[CH:4]=1.[C:13]1([S:19]([O:22][C@@H:23]([CH3:27])[C:24](Cl)=[O:25])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:24](=[O:25])[C@@H:23]([O:22][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20])[CH3:27])[CH:7]=[CH:6]2
Reactant: C[C@H](OS(=O)(=O)c1ccccc1)C(=O)Cl
Reactant: COc1ccc2ccccc2c1
Product: COc1ccc2cc(C(=O)[C@H](C)OS(=O)(=O)c3ccccc3)ccc2c1

Procedure:
In the same manner as described in Example 10 but using β-methoxynaphthalene and (S)-2-(benzenesulfonyloxy)-propionyl chloride, (S)-1-(6-methoxy-2-naphthyl)-2-benzenesulfonyloxy-1-propanone was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[C:13]([C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[N:14]=1)[N:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2ccncc2)c2c(cc(-c3ccccc3)c(=O)n2-c2ccccc2)c1O
Temperature: 120 °C
Yield: 31.8 %

Procedure:
A mixture of 8-bromo-5-hydroxy-2-oxo-1,3-diphenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (126 mg, 0.28 mmol), 4-tributylstannanyl-pyridine (154 mg, 0.42 mmol) and PdCl2(PPh3)2 (39 mg, 0.056 mmol) in 6 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and water were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (5-100% EtOAc/hexanes+1% AcOH) to give 40 mg of the title compound. MS: (+) m/z 450.36 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[C:9]([N+:14]([O-])=O)=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:2].C.O.NN>CO>[CH2:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[C:9]([NH2:14])=[N:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2cccnc2[N+](=O)[O-])c(OC)c1
Agent: NN
Solvent: CO
Solvent: O
Product: CCc1ccc(Oc2cccnc2N)c(OC)c1
Yield: 96.7 %

Procedure:
To a stirred solution of 3-(4-ethyl-2-methoxyphenoxy)-2-nitropyridine (1.3 g, 4.7 mmol) in methanol (30 ml) were added anhydrous Ferric chloride (66 mg) and activated charcoal (66 mg). The resulting mixture was heated to reflux and Hydrazine hydrate (80%) (2 mL, 39 mmol) was added dropwise. The reaction was allowed to stir under reflux condition for 5 hours, then filtered through celite. The filtrate was concentrated under reduced pressure, taken in ethyl acetate (150 ml). The organic phase was washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1.11 g of the title compound, 100% yield.
Reaction SMILES: Cl.[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:24])[F:23])(=[O:15])=[O:14])[CH2:10][NH:9]1)=[O:7])#[N:3].[CH:26]1([C:32](O)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[C:2]([CH2:4][NH:5][C:6]([C@@H:8]1[CH2:12][C@@H:11]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([F:25])([F:23])[F:24])(=[O:15])=[O:14])[CH2:10][N:9]1[C:32]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=[O:33])=[O:7])#[N:3]
Reactant: O=C(O)C1CCCCC1
Reactant: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Agent: Cl
Product: N#CCNC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)C1CCCCC1

Procedure:
(2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide hydrochloride from experiment K2 was coupled with cyclohexanecarboxylic acid in analogy to experiment A1 to give (2S,4R)-1-cyclohexanecarbonyl-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid cyanomethyl-amide as a colorless oil. MS: 472.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([O:15][CH2:16][C@@H:17]2[CH2:19][O:18]2)=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:24][CH2:23]1>>[Cl:1][C:2]1[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[C:5]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH2:24][CH2:23]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(OC[C@@H]2CO2)c2c1[nH]c1ccccc12
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Product: O[C@@H](CNCC1CCN(CCC(F)(F)F)CC1)COc1ccc(Cl)c2[nH]c3ccccc3c12
Yield: 53.3 %

Procedure:
Prepared from 1-chloro-4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.085 g, 0.31 mmol) and 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine (0.10 g, 0.48 mmol) according to the procedure used for Example 2 without heating to give 0.080 g of the title compound as a white solid.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][N:4]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].[ClH:24]>O>[ClH:24].[ClH:24].[OH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][NH:17][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][N:4]=1
Reactant: CSc1ncc(Cc2cccnc2)c(=O)[nH]1
Reactant: NCCCCCO
Agent: Cl
Solvent: O
Product: O=c1[nH]c(NCCCCCO)ncc1Cc1cccnc1

Procedure:
2-Methylthio-5-(3-pyridylmethyl)-4-pyrimidone (23.3 g) and 5-aminopentanol (24.5 g) were fused together at 170°-180° for 2 hours. Water was added to the cooled residue and the mixture was adjusted to pH7 with dilute hydrochloric acid. The solid (23.8 g) which crystallised out was recrystallised from 2-propanol containing hydrogen chloride to give 2-(5-hydroxypentylamino)-5-(3-pyridylmethyl)-4-pyrimidone dihydrochloride, m.p. 203°-205°.