Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][NH:8]O)[CH2:3][CH2:2]1.[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([O-:12])=[O:11].C(N(C(C)C)CC)(C)C.NN>C1COCC1.C(OCC)(=O)C>[N+:10]([C:13]1[CH:14]=[CH:15][C:16]([S:19]([NH:8][O:7][CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)(=[O:21])=[O:20])=[CH:17][CH:18]=1)([O-:12])=[O:11]
Reactant: ONOC1CCOCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: NN
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)NOC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.9 %

Procedure:
4-tetrahydropyranoxyhydroxylamine (33.2 mmol, 3.77 g) and 4-nitrobenzenesulfonylchloride (38.6 mmol, 8.56 g) were combined in anhydrous THF (100 mL) with diisopropylethylamine (69.3 mmol, 11.2 mL). The reaction was stirred at room temperature for 48 hours. Hydrazine (2 mL) was injected to the stirring solution to break-up the bisarylsulfonamide dimer biproduct. The reaction was stirred for an additional 24 hours. The reaction was diluted in ethyl acetate, washed in brine, filtered to remove insoluble solids and concentrated. The crude was purified by crystallization from hot ethyl acetate to provide 3.5 g (36%) of white crystals. Rf=0.3 (2:1 hexanes/ethyl acetate); H1-NMR (CDCl3): δ 8.42 (2H,d), 8.13 (2H,d), 6.93 (1H,s), 4.27 (1H,m), 3.91 (2H,m), 3.45 (2H,m), 2.02 (2H,m), 1.61 (2H,m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:24](=[O:31])[NH:25][C:26]2[NH:27][CH:28]=[CH:29][N:30]=2)[C:5]2[N:9]=[C:8]([NH:10][C:11]([C:13]3[N:14]=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:12])[NH:7][C:6]=2[CH:23]=1.[C:32](Cl)(=[O:36])[CH:33]([CH3:35])[CH3:34]>N1C=CC=CC=1>[NH:30]1[CH:29]=[CH:28][N:27]=[C:26]1[NH:25][C:24]([C:4]1[C:5]2[N:9]=[C:8]([NH:10][C:11]([C:13]3[N:14]=[CH:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[O:12])[NH:7][C:6]=2[CH:23]=[C:2]([NH:1][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:3]=1)=[O:31]
Reactant: CC(C)C(=O)Cl
Reactant: Nc1cc(C(=O)Nc2ncc[nH]2)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Solvent: c1ccncc1
Product: CC(C)C(=O)Nc1cc(C(=O)Nc2ncc[nH]2)c2nc(NC(=O)c3cc4ccccc4cn3)[nH]c2c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.3 %

Procedure:
20 mg (0.04 mmol) of isoquinoline-3-carboxylic acid [6-amino-4-(1H-imidazol-2-ylcarbamoyl)-1H-benzoimidazol-2-yl]-amide (Example 129) was dissolved in pyridine (2 mL). To this stirring solution at 0° C., 5.6 mg (0.053 mmol) of isobutyryl chloride was added in one portion. The reaction mixture was stirred for 10 min at 0° C. and warmed to room temperature. The pyridine was evaporated and water (5 mL) was added to the reaction mixture. The mixture was stirred for 10 min. and the resulting solid was filtered, washed with water (2 mL) and diethyl ether (5 mL), and dried to provide 15.5 mg (66.5%) of isoquinoline-3-carboxylic acid [4-(1H-imidazol-2-ylcarbamoyl)-6-isobutyrylamino-1H-benzoimidazol-2-yl]-amide. LCMS: 483 (M+1)+. 1H NMR (CD3OD, 400 MHz): δ 9.43 (s, 1H), 8.77 (s, 1H), 8.06-8.31 (m, 5H), 7.80-7.93 (m, 3H), 7.08 (s, 2H), 2.45 (m, 1H), 1.1 (d, 6H) ppm.
Reaction SMILES: [C:1]([C:4]1[CH:36]=[CH:35][C:7]([O:8][CH2:9][CH:10]([OH:34])[CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]3[C:17](=[O:28])[CH:18]=[C:19]([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[O:20][C:15]=3[C:14]=2[CH2:31][CH2:32][CH3:33])=[C:6]([CH2:37][CH2:38][CH3:39])[C:5]=1[OH:40])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].CCOCC>C(O)C>[C:1]([C:4]1[CH:36]=[CH:35][C:7]([O:8][CH2:9][CH:10]([OH:34])[CH2:11][O:12][C:13]2[CH:30]=[CH:29][C:16]3[C:17](=[O:28])[CH:18]=[C:19]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:31][CH2:32][CH3:33])=[C:6]([CH2:37][CH2:38][CH3:39])[C:5]=1[OH:40])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(O)COc2ccc3c(=O)cc(CCC(=O)OCC)oc3c2CCC)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCCc1c(OCC(O)COc2ccc3c(=O)cc(CCC(=O)O)oc3c2CCC)ccc(C(C)=O)c1O
Yield: 70.7 %

Procedure:
A solution of ethyl 3-[7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-2-hydroxypropyloxy]-4-oxo-8-n-propyl-4H-1-benzopyran-2-yl]propionate (0.79 g) and sodium carbonate (0.79 g) in aqueous ethanol was refluxed for 1 hour. Ethanol was removed by distillation and the residual aqueous solution cooled. Acidification afforded a gum which solidified on prolonged treatment with refluxing ether. Crystallisation from acetone-ether yielded 3-[7-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-2-hydroxypropyloxy]-4-oxo-8-n-propyl-4H-1-benzo pyran-2-yl]propionic acid (0.53 g) mp 79°-80° C. The sodium salt was prepared therefrom by the method of Example 1(h).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:9]1)(C)(C)C.[ClH:30]>O1CCCC1>[ClH:30].[NH2:7][CH:8]1[CH2:9][N:10]([C:14]2[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[CH:18][CH:19]=2)[C:11](=[O:13])[CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CC(=O)N(c2ccc(/C=C/c3cccc(F)c3)cc2)C1
Agent: Cl
Solvent: C1CCOC1
Product: NC1CC(=O)N(c2ccc(/C=C/c3cccc(F)c3)cc2)C1
Temperature: 45 °C
Reaction time: 18 h
Yield: 85.5 %

Procedure:
A solution of 104 mg (0.26 mmol) of (RS)-(E)- (1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-5-oxo-pyrrolidin-3-yl)-carbamic acid tert-butyl ester in 2.5 ml of tetrahydrofurane is treated with 192 mg of hydrochloric acid (37%). The mixture is warmed to 45° C. for 2 hours, then left under stirring for 18 hours at RT. The product precipitates partially from the reaction mixture which is evaporated to yield the crude hydrochloride. This is recrystallised from ether to give 74 mg (85% of theory) of (RS)-(E)-4-amino-1-{4-[2-(3-fluoro-phenyl)-vinyl]-phenyl}-pyrrolidin-2-one hydrochloride as a white solid; MS: m/e=297 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:22]C)[N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N>Cl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][OH:14])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:22])[N:6]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1nc2c(N)nc(OCCO)nc2n1Cc1ccccc1
Agent: Cl
Agent: N
Product: Nc1nc(OCCO)nc2c1nc(O)n2Cc1ccccc1
Yield: 57.3 %

Procedure:
6-Amino-9-benzyl-2-(2-hydroxyethoxy)-8-methoxypurine (70 mg, 0.22 mmol) in concentrated hydrochloric acid (5 ml) was stirred at room temperature for 5 hours. The reaction mixture was neutralized with 28% aqueous ammonia and the resulting crystals were filtered and washed with water to give the subject compound (38 mg, yield 57%).
Reaction SMILES: [CH:1]([C@H:4]1[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][C:6](=[S:21])[NH:5]1)([CH3:3])[CH3:2].CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC.[C:43]1([CH2:49][CH2:50][CH2:51][CH2:52][C:53]2([CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]/[CH:64]=[CH:65]/[CH2:66][C:67](O)=[O:68])[O:57][CH2:56][CH2:55][O:54]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.P([O-])(O)(O)=O.[Na+]>ClCCl.C(OCC)(=O)C>[CH:1]([C@H:4]1[C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:7][C:6](=[S:21])[N:5]1[C:67](=[O:68])[CH2:66]/[CH:65]=[CH:64]/[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][C:53]1([CH2:52][CH2:51][CH2:50][CH2:49][C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[O:57][CH2:56][CH2:55][O:54]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1NC(=S)OC1(c1ccccc1)c1ccccc1
Reactant: O=C(O)C/C=C/CCCCCCC1(CCCCc2ccccc2)OCCO1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)[C@@H]1N(C(=O)C/C=C/CCCCCCC2(CCCCc3ccccc3)OCCO2)C(=S)OC1(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
(S)-4-Isopropyl-5,5-diphenyl-oxazolidine-2-thione (412 mg, 1.39 mmol) was suspended in dichloromethane (3.3 mL), and then cooled to 0° C. in an ice bath. Dimethylaminopyridine (16 mg, 0.131 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (315 mg, 1.64 mmol) were added in this order. A solution of a commercially available reagent of (E)-10-[2-(4-phenyl-butyl)-[1,3]dioxolan-2-yl]-dec-3-enoic acid (476 mg, 1.27 mmol) in dichloromethane (3.4 mL) was then added. After stirring at 0° C. for 2 hours, an aqueous solution (50 mL) of 10% sodium dihydrogen phosphate and ethyl acetate (50 mL) were added and the mixture was separated. The organic layer was washed with a saturated aqueous solution (40 mL) of sodium chloride, then dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The residue was purified on Biotage (silica gel, n-hexane/ethyl acetate) to obtain 445 mg (0.681 mmol, 54% yield) of (E)-1-((S)-4-isopropyl-5,5-diphenyl-2-thioxo-oxazolidin-3-yl)-10-[2-(4-phenyl-butyl)-[1,3]dioxolan-2-yl]-dec-3-en-1-one (ESI (LC/MS positive mode) m/z 654 (M+H); Rt 3.07 min.).
Reaction SMILES: C(OP([CH2:9][C:10]([N:12]([CH3:14])[CH3:13])=[O:11])(=O)OCC)C.[H-].[Na+].[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:35]([O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])=[O:36])[CH:33]=3)[CH:28]=[N:27][CH:26]=2)=[CH:21][CH:20]=1)=O.[Cl-].[NH4+]>ClCCl>[CH3:14][N:12]([CH3:13])[C:10](=[O:11])/[CH:9]=[CH:17]/[C:19]1[CH:20]=[CH:21][C:22]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([C:35]([O:37][CH2:38][CH2:39][Si:40]([CH3:41])([CH3:43])[CH3:42])=[O:36])[CH:33]=3)[CH:28]=[N:27][CH:26]=2)=[CH:23][CH:24]=1
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2cncc(-c3ccc(C=O)cc3)c2c1
Reactant: CCOP(=O)(CC(=O)N(C)C)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: ClCCl
Product: CN(C)C(=O)/C=C/c1ccc(-c2cncc3ccc(C(=O)OCC[Si](C)(C)C)cc23)cc1
Reaction time: 0.17 h
Yield: 94 %

Procedure:
Diethyl[2-(dimethylamino)-2-oxoethyl]phosphonate (133 mg, 0.597 mmol) was dissolved in dichloromethane (4 mL), to which 55% sodium hydride (21 mg, 0.48 mmol) was added at 0° C., followed by stirring for 10 minutes. To this solution, 2-(trimethylsilyl)ethyl 4-(4-formylphenyl)isoquinoline-6-carboxylate (150 mg, 0.40 mmol) synthesized in Example 13 (13a) was added, followed by stirring for one hour. To the resulting reaction liquid, a saturated aqueous solution of ammonium chloride was added, followed by extraction with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:ethyl acetate, 100:0-35:65, V/V) to give the desired title compound (168 mg, yield 95%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12])[CH3:2].[CH:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([C:18]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:3]([CH2:1][CH3:2])[C:4](=[O:12])[CH2:5]3)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCN1C(=O)Cc2ccccc21
Reactant: O=C(Cl)C1CCCC1
Product: CCN1C(=O)Cc2cc(C(=O)C3CCCC3)ccc21

Procedure:
Prepared from readily available starting materials (N-ethyloxindole and cyclopentanecarbonyl chloride) in a manner analogous to that set forth in Preparation 18.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH3:22].[Cl-].[NH4+]>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH2:19][CH2:20][CH2:21][CH3:22])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CCCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCCCC(C(=O)OCC)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
10.46 g of ethyl 4-nitrophenylacetate are dissolved in 30 ml of DMF, added dropwise to a suspension of 2.0 g of sodium hydride in 20 ml of DMF with ice-cooling and stirred for 30 min. 5.394 ml of 1-bromobutane in 20 ml of DMF are subsequently added, and the mixture is stirred at 23° C. for 12 h. The reaction mixture is subsequently stirred into 100 ml of saturated ammonium chloride solution. The mixture is washed 4 times with 100 ml of ethyl acetate each time, the combined organic phases with 100 ml of sodium chloride solution, dried over sodium sulfate and, after filtration, evaporated to dryness in vacuo. The residue is purified by column chromatography (reversed phase). Yield: 11 g (83%) of ethyl 2-(4-nitrophenyl)hexanoate; LC-MS retention time: 2.44 min (“nonpolar” gradient).
Reaction SMILES: [CH3:1][NH:2][N:3]=[CH:4][C:5](=[O:7])[CH3:6].[Cl:8][C:9]1[CH:10]=[C:11]([C:16](=O)[CH:17]=[O:18])[CH:12]=[CH:13][C:14]=1[Cl:15]>C(O)(=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2[N:2]([CH3:1])[N:3]=[C:4]([C:5](=[O:7])[CH3:6])[C:17]=2[OH:18])[CH:12]=[CH:13][C:14]=1[Cl:15]
Reactant: CNN=CC(C)=O
Reactant: O=CC(=O)c1ccc(Cl)c(Cl)c1
Solvent: CC(=O)O
Product: CC(=O)c1nn(C)c(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 13.3 %

Procedure:
2-Oxopropanal methylhydrazone (1.525 mmol, 152.7 mg) synthesized in Reference Synthetic Example 1 and (3,4-dichlorophenyl)(oxo)acetaldehyde (1.525 mmol, 310 mg) synthesized in Reference Synthetic Example 3 were dissolved in acetic acid (10 mL) and stirred at 110° C. for 1.5 hours. Then, the solvent was evaporated, and the residue was dried by means of a vacuum pump, resolved by silica gel thin layer chromatography (n-hexane/AcOEt=3/2) and purified by silica gel thin layer chromatography (n-hexane/AcOEt=2/1) to give the desired product as a yellow solid (57.8 mg, yield 13%).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=4[F:33])=[CH:16][C:17]([C:21]([O:23]C)=O)=[N:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].[NH3:34].CO>CO>[C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[CH:20]=[C:19]3[C:14]([C:15]([C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:26]=4[F:33])=[CH:16][C:17]([C:21]([NH2:34])=[O:23])=[N:18]3)=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: N
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2F)c2ccc(CCc3ccc(C#N)nc3)cc2n1
Solvent: CO
Product: COc1ccc(-c2cc(C(N)=O)nc3cc(CCc4ccc(C#N)nc4)ccc23)c(F)c1
Temperature: 60 °C
Yield: 67.9 %

Procedure:
A stirred solution of methyl 7-[2-(6-cyanopyridin-3-yl)ethyl]-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxylate (160 mg, 0.362 mmol) and MeOH (1450 μl) was treated with 5 ml 7N NH3/MeOH and then heated to 60° C. in a sealed tube for 30 minutes. The reaction was allowed to cool to ambient temperature and then was concentrated. The solid was trituated with EtOH, collected, washed with 5 ml Et2O and then dried in vacuo to afford 7-[2-(6-cyanopyridin-3-yl)ethyl]-4-(2-fluoro-4-methoxyphenyl)quinoline-2-carboxamide (105 mg, 0.246 mmol, 67.9% yield) as a colorless solid.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7](I)[N:6]=[C:5]2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:3][CH2:2]1.[N:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH:1]1([N:4]2[C:8]([C:9]([N:11]3[CH2:16][CH2:15][CH:14]([N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[O:10])=[C:7]([C:36]3[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=3)[N:6]=[C:5]2[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccncc1
Reactant: O=C(c1c(I)nc(-c2cccc(C(F)(F)F)c2)n1C1CC1)N1CCC(N2CCCC2)CC1
Product: O=C(c1c(-c2ccncc2)nc(-c2cccc(C(F)(F)F)c2)n1C1CC1)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [3-cyclopropyl-5-iodo-2-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 63) was reacted with pyridine-4-yl-boronic acid to give the title compound as light brown oil. MS: 510.3 (MH+).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]([C:20](=[O:34])[CH2:21][C:22]1[NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=2[S:24](=[O:33])(=[O:32])[N:23]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=O)C.[O-]CC.[Na+].Cl>C(O)C>[O:32]=[S:24]1(=[O:33])[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[NH:27][C:22]([C:21]2[C:20](=[O:34])[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH:7]3[CH:6]([C:4]=2[OH:3])[CH2:10][CH2:9][CH2:8]3)=[N:23]1
Reactant: CCOC(=O)C1CCCC1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2ccccc2N1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)C2CCCC2N1Cc1ccc(F)cc1
Reaction time: 16 h
Yield: 51.5 %

Procedure:
The crude 2-[[2-(1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(4-fluoro-benzyl)-amino]-cyclopentanecarboxylic acid ethyl ester (0.503 mmol) was dissolved in ethanol (4 mL). A 21% w/w solution of sodium ethoxide in ethanol (1.8 mL) was added and the resulting reaction mixture was shaken for 16 h. A 1.0 M aqueous hydrochloric acid solution (9 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, which was further purified by flash chromatography (Teledyne Isco RediSep Column; 0-100% ethyl acetate in hexanes) to afford the desired product, 3-(1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-1-(4-fluoro-benzyl)-4-hydroxy-1,4a,5,6,7,7a-hexahydro-[1]pyrindin-2-one (114.2 mg, 0.259 mmol, 51.5% over two steps), as an off-white solid. LC-MS (ESI) calcd for C22H20FN3O4S 441.12, found 442.4 [M+H+]. The 1H NMR spectrum indicated a 4:1 mixture of cis- and trans-isomers. 1H NMR (CDCl3, 400 MHz): δ 1.54-1.77 (m, 3H), 1.87-2.13 (m, 2H), 2.26-2.34 (m, 1H, 80%), 2.36-2.49 (m, 1H, 20%), 2.88-2.93 (m, 1H, 20%), 3.11-3.16 (m. 1H, 80%), 3.69-3.77 (m, 1H), 4.30 (d, 1H, 80%, J=14.8 Hz), 4.43 (d, 1H, 20%, J=14.8 Hz), 5.00 (d, 1H, 20%, J=14.8 Hz), 5.09 (d, 1H, 80%, J=15.2 Hz), 7.03-7.10 (m, 2H), 7.17-7.35 (m, 3H), 7.36-7.42 (m, 1H), 7.55-7.60 (m, 1H), 7.91-7.95 (m, 1H). Anal. calcd for C22H20FN3O4S H2O: C, 57.50; H, 4.83; N, 9.15; found: C, 57.54; H, 4.53; N, 8.79.
Reaction SMILES: C[Si](C)(C)[N-:3][Si](C)(C)C.[Li+].[Cl:11][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].Cl>CCCCCC.C(OCC)C>[Cl:11][C:12]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]([NH2:3])=[NH:15]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: N#Cc1cccc(F)c1Cl
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: CCCCCC
Product: N=C(N)c1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
320 ml (0.32 mmol) of a 1 molar solution of lithium hexamethyl disilazide (LiHMDS) in hexane are placed in 800 ml diethyl ether and combined at ambient temperature with 25.0 g (0.161) 2-chloro-3-fluoro-benzonitrile. The mixture is stirred for 2 h at ambient temperature and after cooling to 0° C. it is combined with 280 ml 3 normal hydrochloric acid. The precipitate formed is suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].Cl[CH2:20][C:21]1[N:22]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:29][CH:28]=2)[O:24][C:25]=1[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]([O:15][CH2:16][CH3:17])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH:34]([CH3:36])[CH3:35])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])=[CH:8][C:7]=1[CH3:14]
Reactant: CCO[C@@H](Cc1c(C)cc(O)cc1C)C(=O)OC
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1c(C)cc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionic acid methyl ester (example 29 e]) was reacted with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (example 2 b]) in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[N:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]([O:28]C)=[O:27])[CH:23]=[CH:22][CH:21]=3)[O:17][N:16]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O.CCOC(C)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([C:15]2[N:19]=[C:18]([C:20]3[N:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)[O:17][N:16]=2)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(-c2nc(C(=O)CCCCCCc3ccccc3)no2)n1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1cccc(-c2nc(C(=O)CCCCCCc3ccccc3)no2)n1
Yield: 98.8 %

Procedure:
The title compound was prepared from 10f (5.2 mg, 0.008 mmol) following general procedure A. Flash chromatography (SiO2, 0.5×6 cm, 0-2% AcOH-EtOAc) afforded the title compound (3 mg, 99%) as a white solid: NMR (acetone-d6+0.1% TFA, 500 MHz) δ 8.58 (dd, 1H, J=1.0, 7.7 Hz), 8.44 (dd, 1H, J=1.1, 7.8 Hz), 8.38 (t, 1H, J=7.7 Hz), 7.25 (t, 2H, J=7.5 Hz), 7.20 (d, 2H, J=6.9 Hz), 7.14 (t, 1H, J=7.2 Hz), 3.18 (t, 2H, J=7.3 Hz), 2.63 (t, 2H, J=7.7 Hz), 1.78 (m, 2H), 1.65 (m, 2H), 1.44 (m, 4H); 13C NMR (acetone-d6+0.1% TFA, 150 MHz) δ 192.7, 176.7, 168.3, 166.2, 150.7, 144.7, 144.6, 141.8, 130.2, 130.1, 129.7, 129.6, 127.4, 42.4, 37.5, 33.2, 31.3, 30.5, 24.9; HRMS-ESI-TOF m/z 380.1601 ([M+H]+, C21H21N3O4 requires 380.1605).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][CH3:9])=[O:7].Cl[C:15]1[CH:20]=[C:19]([Cl:21])[N:18]=[CH:17][C:16]=1[C:22]#[N:23]>C1COCC1.CCOC(C)=O>[Cl:21][C:19]1[CH:20]=[C:15]([NH:3][C:4]2[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=2[C:6]([NH:8][CH3:9])=[O:7])[C:16]([C:22]#[N:23])=[CH:17][N:18]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: N#Cc1cnc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccccc1Nc1cc(Cl)ncc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.3 %

Procedure:
Sodium hydride (2.345 g, 58.64 mmol) was added portionwise to a mixture of 2-amino-N-methylbenzamide (2.201 g, 14.66 mmol), in THF (40 mL) at room temperature under an atmosphere of nitrogen. The resulting suspension was stirred at room temperature for 30 minutes and then 4,6-dichloropyridine-3-carbonitrile (2.536 g, 14.66 mmol) was added portionwise (caution—exotherm and effervescence); the mixture was then heated overnight at 60° C. The mixture was allowed to cool to room temperature and then diluted with EtOAc (200 mL). The mixture was washed sequentially with water (200 mL), water (150 mL), and finally with a saturated solution of NaCl (200 mL). The organic layer was filtered and the residue washed with water followed by EtOAc and then allowed to dry to leave 2-[(2-chloro-5-cyanopyridin-4-yl)amino]-N-methylbenzamide (0.687 g, 16% yield). The filtrate was dried over MgSO4 and then evaporated to leave a solid. The solid was crystallised from MeOH/Et2O to afford a second crop of 2-[(2-chloro-5-cyanopyridin-4-yl)amino]-N-methylbenzamide (2.471 g, 59% yield); 1H NMR spectrum: (300 MHz, DMSO) δ 2.76 (3H, t), 7.10 (1H, d), 7.26-7.32 (1H, m), 7.57 (2H, dd), 7.72-7.74 (1H, m), 8.56 (1H, s), 8.68 (1H, d), 10.63 (1H, s); Mass spectrum: m/z (ESI+) (M+H)+=286.98 and 288.94.
Reaction SMILES: [OH-].[Na+].[S:3]=[C:4]1[NH:9][C:8](=[O:10])[CH:7]=[CH:6][NH:5]1.I[CH3:12]>C(O)(=O)C>[CH3:12][S:3][C:4]1[NH:9][C:8](=[O:10])[CH:7]=[CH:6][N:5]=1
Reactant: CI
Reactant: O=c1cc[nH]c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CSc1nccc(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an aqueous solution (200 mL) of sodium hydroxide (23 g) were added 2-thioxo-2,3-dihydropyrimidin-4(1H)-one (37 g) and iodomethane (20 mL), and the mixture was stirred overnight at room temperature. To the reaction mixture was added acetic acid (17 mL), and the precipitate was collected by filtration, and washed with ice water. The residue was dried to give the title compound (28 g).