Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.C[Si]([N-:23][Si](C)(C)C)(C)C.[Li+].[F:29][C:30]([F:39])([F:38])[C:31]([N:33]1C=CN=C1)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:11]3[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=3)=[N:23][NH:33][C:31]=2[C:30]([F:39])([F:38])[F:29])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C(n1ccnc1)C(F)(F)F
Reactant: CSc1ccc(C(=O)Cc2ccc(F)cc2)cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A suspension of 2-(4-fluorophenyl)-1-[4-(methylthio)phenyl]ethanone from Step 1 (11.53 g. 44 mmol) in 225 mL dry tetrahydrofuran (THF) was treated with 52.8 mL lithium bis(trimethylsilyl) amide (1.0M in THF) at -70° C. under nitrogen for 30 minutes and warmed to 0° C. for 30 minutes. Upon cooling to -70° C., a solution of 10.0 g (61 mmol) 1-trifluoroacetylimidazole in 25 mL THF was added and the mixture warmed to 0° C., during which time the solids dissolved. After 45 minutes, the reaction was quenched with saturated aqueous NH4Cl. The organic layer was diluted with ethyl acetate, washed sequentially with dilute HCl and brine, dried over MgSO4 and concentrated in vacuo. The crude mixture was washed with ether to remove unreacted starting ketone and the yellow solid (11.3 g) used without further purification. The crude mixture (11.3 g) was stirred with 60 mL glacial acetic acid and 4.5 mL hydrazine hydrane at reflux under nitrogen for 18 hours. The acetic acid was then removed in vacuo, and the residue dissolved in ethyl acetate, washed sequentially with dilute HCl and brine, dried over MgSO4 and reconcentrated in vacuo. Recrystallization from chloroform-hexane gave 8.24 g of the pyrazole as a pale yellow solid. Elemental analysis for C17H12N2F4S Calc'd.: C, 57.95, H, 3.43, N, 7.95, S, 9.10. Found: C, 57.58, H, 3.50, N, 7.88, S, 8.97.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH3:9][C:10]([CH3:14])([CH3:13])[C:11]#[CH:12].O>C(N(CC)CC)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.[Cu]I>[CH3:9][C:10]([CH3:14])([CH3:13])[C:11]#[C:12][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5]
Reactant: Nc1cccc(I)c1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)C#Cc1cccc(N)c1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
1.05 g (1.5 mmol) of bis(triphenylphosphine)palladium(II) chloride and 0.26 g (1.5 mmol) of copper(I) iodide are added to a solution consisting of 5.47 g (25 mmol) of 3-iodoaniline in 40 ml of triethylamine. With ice-cooling, 3.08 g (37.5 mmol) of 3,3-dimethyl-1-butyne are added dropwise such that the temperature remains at 20° C. After the addition has ended, the mixture is stirred at 20° C. for 20 hours. The reaction solution is concentrated under reduced pressure and the residue formed is stirred into 1 l of water. The mixture is then extracted three times with diethyl ether. The combined organic phases are once more washed with water, dried with sodium sulphate and concentrated under reduced pressure. The crude product obtained is purified by silica gel chromatography (mobile phase methylene chloride). This gives 2.70 g (60% of theory) of 3-(3,3-dimethylbut-1-yn-1-yl)aniline having a content of 97% according to HPLC. log P=2.71.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][CH2:19][C:20]([O:22]C)=[O:21])[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([N:26]([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:27][CH3:28])[CH3:25]>ClCCl>[OH2:21].[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:29][CH2:30][CH2:31][NH:32][C:20](=[O:22])[CH2:19][CH2:18][N:10]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[N:9]1)[CH3:25].[CH2:24]([N:26]([CH2:29][CH2:30][CH2:31][NH:32][C:20](=[O:22])[CH2:19][CH2:18][N:10]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[N:9]1)[CH2:27][CH3:28])[CH3:25]
Reactant: COC(=O)CCn1ncc(-c2ccccc2)c1-c1ccccc1
Reactant: CCN(CC)CCCN
Solvent: ClCCl
Product: CCN(CC)CCCNC(=O)CCn1ncc(-c2ccccc2)c1-c1ccccc1
Product: O

Procedure:
A solution of 4.8 g (0.016 mol) of methyl 4,5-diphenyl-1H-pyrazole-1-propanoate of example 4 and 48 mL of diethylaminopropylamine was heated at 120°-125° C. under nitrogen for 14 hours. The excess diethylaminopropylamine was stripped in vacuo at 85° C. The residue was dissolved in dichloromethane, an unwanted solid residue was filtered off, and the methylene chloride solution was washed twice with water and once with brine. The product was extracted into chilled dilute hydrochloric acid, and the chilled aqueous acid was made basic with solid sodium bicarbonate and then sodium carbonate. The basic water was extracted 4 times with dichloromethane, the combined washings were dried over sodium sulfate, and stripped to yield 2.4 g viscous amber oil. The oily product was dried at 40° C. and 0.1 mm vacuum for 7 days to yield 1.6 g of the hemihydrate still as a viscous oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[N:2]1.Cl.[CH:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)([CH3:16])[CH3:15].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.O>CN(C=O)C.CCN(CC)CC>[CH:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:12])[CH2:19][CH2:18]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2n[nH]c3ccccc23)CC1
Reaction time: 16 h

Procedure:
To a solution of 300 mg 1H-Indazole-3-carboxylic acid in 3 mL DMF and 1 mL NEt3, 398 mg 1-Isopropyl-piperidin-4-ylamine hydrochloride and 471 mg BOP-Cl were added at RT and the mixture was stirred for 16 h. After the addition of 5 mL water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent alkylation reaction without further purification. Yield: 340 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](O)=[O:14])=[O:7])(C)([CH3:3])[CH3:2].[F:16][C:17]([F:37])([F:36])[C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)(=[O:26])=[O:25])=[CH:20][CH:19]=1.FC(F)(F)C1C=C(S(N2C[C@H]3[C@H](N)CC[C@H]3C2)(=O)=O)C=CC=1>>[O:14]=[C:13]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([S:24]([C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:36])[F:37])=[CH:23][CH:22]=3)(=[O:25])=[O:26])[CH2:31]2)[CH2:34][CH2:33]1)[C@@H:9]([NH:8][C:6](=[O:7])[O:5][CH:1]([CH3:3])[CH3:2])[CH2:10][CH2:11][CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21
Agent: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Product: CCC[C@H](NC(=O)OC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(S(=O)(=O)c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting (S)-2-(isopropoxycarbonylamino)pentanoic acid from Step A of Example 263 for (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid and (3aR,4S,6aS)-2-(4-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine from Step A of Example 256 for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 266: 1H NMR (501 MHz, pyridine-d5) δ ppm 8.08 (d, J=8.2, 2H), 7.96 (d, J=4.8, 1H), 7.82 (d, J=8.3, 2H), 7.18 (d, J=4.5, 2H), 5.01 (hept, J=6.2, 1H), 4.45 (dd, J=14.0, 7.7, 1H), 4.11 (dt, J=13.0, 6.7, 1H), 3.67 (dd, J=10.2, 3.0, 1H), 3.30 (dd, J=10.2, 7.6, 1H), 3.16-3.07 (m, 2H), 2.57 (h, J=9.3, 2H), 1.99-1.85 (m, 2H), 1.86-1.72 (m, 2H), 1.58-1.50 (m, 1H), 1.45 (ddd, J=20.8, 11.7, 7.2, 2H), 1.26 (ddd, J=13.1, 10.9, 6.6, 1H), 1.19 (d, J=6.2, 3H), 1.16 (d, J=6.2, 3H), 0.84 (t, J=7.4, 3H); MS (ESI+) m/z 520 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][C@@H:8]2[N:10]([CH2:11][C:12]3[NH:17][C:16]([C:18]4[S:19][CH:20]=[CH:21][N:22]=4)=[N:15][C@@H:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[Cl:30])[C:13]=3[C:31]([O:33][CH3:34])=[O:32])[C@@H:4]([CH2:5][O:6][CH2:7]2)[CH2:3]1.C(N(CC)CC)C.Cl[S:43]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])(=[O:45])=[O:44]>C(Cl)Cl>[C:49]([O:48][C:47]([NH:46][S:43]([NH:1][CH:2]1[CH2:3][C@@H:4]2[N:10]([CH2:11][C:12]3[NH:17][C:16]([C:18]4[S:19][CH:20]=[CH:21][N:22]=4)=[N:15][C@@H:14]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=4[Cl:30])[C:13]=3[C:31]([O:33][CH3:34])=[O:32])[C@@H:8]([CH2:7][O:6][CH2:5]2)[CH2:9]1)(=[O:45])=[O:44])=[O:53])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)Cl
Reactant: COC(=O)C1=C(CN2[C@@H]3COC[C@H]2CC(N)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(CN2[C@@H]3COC[C@H]2CC(NS(=O)(=O)NC(=O)OC(C)(C)C)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a solution of methyl (4R)-6-[[(1S,5R)-7-amino-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 60b (60 mg, 0.12 mmol) and triethylamine (0.17 mL, 1.2 mmol) in DCM (5 mL) was added a 0.05 M solution of tert-butyl N-chlorosulfonylcarbamate in DCM (2.5 mL, 0.125 mmol) dropwise at 0° C. The mixture was allowed to warm to room temperature while stirred for 16 h, and then concentrated in vacuo. The residue was purified by silica gel chromatography to afford 0.08 g of methyl (4R)-6-[[(1S,5R)-7-(tert-butoxycarbonylsulfamoylamino)-3-oxa-9-azabicyclo[3.3.1]nonan-9-yl]methyl]-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 63a as a yellow oil (yield was 97%). MS: calc'd (MH+) 684, measured (MH+) 684.
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=[O:2].[OH-].[Na+:13].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.Cl>O>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:9][C:6]2[CH:5]=[CH:4][C:3]([S:1]([O-:11])(=[O:10])=[O:2])=[CH:8][CH:7]=2)=[CH:17][CH:16]=1.[Na+:13]
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: Fc1ccc(CCl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)([O-])c1ccc(NCc2ccc(F)cc2)cc1

Procedure:
To 17.3 g (0.1 mole) of sulfanilic acid, 100 ml of 5N sodium hydroxide solution and 100 ml of water was added 14.4 g (0.1 mole) of 4-fluorobenzyl chloride which was then mixed and heated to about 45°-55° C. in a 500-ml Erlenmeyer flask for 48 hours. After heating, the reaction mixture was poured over approximately 1 liter of cold water and acidified with concentrated hydrochloric acid. The resulting slurry was slowly filtered through a fine sintered glass funnel and a top clear yellow solution which did not pass through the filter was decanted away and discarded. The remaining off-white solid was mixed with 100 ml of ethanol and aqueous NaOH solution was added slowly until solution was achieved. The solution was then carbon treated, filtered and concentrated under reduced pressure to obtain 9.0 g of the crude product. Recrystallization from 80 ml of glacial acetic acid, followed by vacuum oven drying gave 2.4 g of the purified product, sodium 4-(((4-fluorophenyl)methyl)amino)benzenesulfonate, as white crystals which decomposed at 275° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10](I)=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH:29]=[CH:28][C:27]([O:31][CH3:32])=[O:30])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC(=O)OC
Reactant: COc1ccc2c(c1)c(I)nn2C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1nn(C(=O)OC(C)(C)C)c2ccc(OC)cc12
Temperature: 50 °C

Procedure:
A solution of 3-iodo-5-methoxy-indazole-1-carboxylic acid tert-butyl ester [0.500 g, Reference Example 22(a)] in dioxane (15 ml) and under an atmosphere of nitrogen was treated with triethylamine (1.86 ml) followed by methyl acrylate (1.20 ml), triphenylphosphine (0.105 g), and palladium (II) acetate (60 mg). The resulting mixture was heated at 50° C. for 16 hours, then cooled to ambient temperature and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and 40/60 petrol (1:9, v/v) to yield 5-methoxy-3-(2-methoxycarbonyl-vinyl)-indazole-1-carboxylic acid tert-butyl ester (282 mg). LC-MS (METHOD B): RT=3.33 minutes; 333 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18])C=O.[Cl-].C([O:33][C:34]([CH:36]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:37][CH2:38][CH3:39])=[O:35])C1C=CC=CC=1.[Cl-].[CH2:60](OC(C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)OC)=O)C1C=CC=CC=1>>[CH2:38]([O:37][CH:36]([CH2:60][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[O:16][C:17]=2[CH3:18])=[C:2]([F:1])[CH:3]=1)[C:34]([OH:33])=[O:35])[CH3:39]
Reactant: COC(C(=O)OCc1ccccc1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(C(=O)OCc1ccccc1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)cc1F
Agent: [Cl-]
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c(F)c1)C(=O)O

Procedure:
In analogy to the procedures described in examples 114 b], c] and d], 3-fluoro-4-hydroxy-benzaldehyde was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester [PCT Int. Appl. (2000) WO0008002] to give 3-fluoro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde. Treatment of 3-fluoro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde with (benzyloxycarbonyl-ethoxy-methyl)-triphenyl-phosphonium chloride (prepared in analogy to the procedure described for the synthesis of (benzyloxycarbonyl-methoxy-methyl)-triphenyl-phosphonium chloride in example 114 a]) then gave 2(Z,E)-ethoxy-3-{3-fluoro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid benzyl ester, which was hydrogenated to yield [rac]-2-ethoxy-3-{3-fluoro-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH3:27])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH3:26])([CH2:21][C:22](OC)=[O:23])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>CCCCC>[CH2:1]([O:8][C:9]1[C:10]([CH3:27])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH3:26])([CH2:21][CH:22]=[O:23])[CH2:13][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC1(C)CCc2c(C)c(OCc3ccccc3)c(C)c(C)c2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCCCC
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CCC(C)(CC=O)O2
Reaction time: 1 h

Procedure:
A solution of 31.17 g. of (±)-methyl 6-benzyloxy-2,5,7,8-tetramethylchroman-2-acetate in 3.11. of pentane was cooled under N2 to -70° Diisobutylaluminum hydride (24.4% in toluene; 87.3 ml.) in 87 ml. of pentane was added over 14 minutes. After 1.0 hour at -70°, another 8.73 ml. of diisobutylaluminum hydride was added and stirring was continued an additional 0.25 hour. The reaction was quenched by the careful addition of 250 ml. of methanol at -70°. The mixture was diluted with 1.01. of ether, washed with 0.5 N HCl, H2O, and brine and dried over sodium sulfate. Solvent removal gave a light yellow oil, which was filtered through 500 g. of silica gel with 90:10 benzene-ethyl acetate. Crystallization of the resulting oil from hexane - 30°-60° petroleum ether gave (±) 6-benzyloxy-2,5,7,8-tetramethylchroman-2-acetaldehyde as a white solid, m.p. 70°-75°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)=[CH:4][C:3]=1[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:43]=[CH:42][C:36]([O:37][CH2:38][C:39](O)=[O:40])=[CH:35][CH:34]=2)[S:27]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:25]=[C:26]1[NH:30][C:29](=[O:31])[CH:28]([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([O:37][CH2:38][C:39]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=4)=[CH:4][C:3]=3[N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:40])=[CH:42][CH:43]=2)[S:27]1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(O)c2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(O)c2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 69.1 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(3-hydroxyphenoxy)phenyl]-N-methylcarbamate (0.95 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.89 g), diethyl cyanophosphonate (0.52 g), triethylamine (0.32 g) and anhydrous tetrahydrofuran (30 ml) and the reaction mixture was purified to give the desired product (1.18 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][OH:14])=[C:11]([C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]2[CH2:23][C@@H:22]([C:24]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:19]2)=[O:16])[N:10]=[N:9]1.[CH2:43](N(CC)CC)C.CS(Cl)(=O)=O.C[O-].[Na+]>C1COCC1.O.CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([CH2:13][O:14][CH3:43])=[C:11]([C:15]([N:17]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:18]2[CH2:23][C@@H:22]([C:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[O:25])[CH2:21][N:20]([C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[CH2:19]2)=[O:16])[N:10]=[N:9]1
Reactant: CCN(CC)CC
Reactant: CC(C)CN(C(=O)c1nnn(-c2ccccc2F)c1CO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Agent: CS(=O)(=O)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
tert-Butyl(3S,5R)-3-[{[1-(2-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (210 mg) and triethylamine (150 μl) were dissolved in THF (4 ml), and methanesulfonyl chloride (45 μl) was added under ice-cooling. The mixture was stirred at 0° C. for 4 hr, sodium methoxide (28% methanol solution, 350 mg) and methanol (4 ml) were added and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (195 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].[S-:10][C:11]#[N:12].[NH4+].N>CO>[Cl:1][C:2]1[CH:7]=[C:6]([S:10][C:11]#[N:12])[CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9]
Reactant: Oc1c(Cl)cccc1Cl
Reactant: N#C[S-]
Agent: N
Agent: [NH4+]
Solvent: CO
Product: N#CSc1cc(Cl)c(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 14.8 %

Procedure:
2,6-Dichlorophenol (lOOg, 0.613 mole) and ammonium thiocyanate (102.73 g, 1.350 mole) were mixed in methanol and the solution cooled to 0° C. Chlorine gas was bubbled throught the reaction, maintaining the temperature below 10° C. The solution turned a pale yellow color. The reaction was stirred for a total of 3 hours until acidic, at which time ammonia gas was bubbled through and the solution stirred for an additional three hours at 0° to 10° C. The reaction was poured into iced distilled water, and filtered, yielding approximately 20 g of a yellow solid which was dried overnight in vacuo. The filtrate was extracted with ethyl acetate, the extracts dried over magnesium sulfate and solvent removed in vacuo to yield approximately 100 g of crude product. Following purification by silica chromatography, the material was taken up in 1 liter of toluene, charcoal added, filtered and recrystallized from hexane to yield 55.03 g of product as a yellow solid, m.p. about 94.5°-97° C. The structure was confirmed by NMR.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:18]#[N:19].NN.O>C(O)C>[NH2:3][CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH3:29])[C:18]#[N:19]
Reactant: COCCOCOc1ccc(C#N)cc1/C=C/CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: COCCOCOc1ccc(C#N)cc1/C=C/CN
Yield: 90 %

Procedure:
(E)-3-[3-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)propenyl]-4-(2-methoxy-ethoxymethoxy)benzonitrile (3.1 g, 8.0 mmol) and NH2NH2 hydrate (0.96 mL, 20 mmol) in ethanol (100 mL) is refluxed for 1.5 hours. The mixture is concentrated, treated with aqueous NaOH, and extracted with CH2Cl2 (3×). The CH2Cl2 layer is dried and concentrated to obtain the product as a clear oil (1.9 g, 7.2 mmol). 1H NMR (CDCl3, 300 MHz) δ7.70 (d, 1H), 7.47 (dd, 1H), 7.22 (d, 1H), 6.75 (d, 1H), 6.34 (m, 1H), 5.35 (s, 2H), 3.80 (t, 2H), 3.50 (m, 4H), 3.27 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17].CO>C1COCC1>[Cl:12][CH2:13][CH2:14][NH:15][C:16]([NH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1)=[O:17]
Reactant: O=C=NCCCl
Reactant: Nc1ccnc2ccccc12
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NCCCl)Nc1ccnc2ccccc12
Reaction time: 18 h

Procedure:
To a solution of 4-aminoquinoline (3.46 g, 24 mmol) in dry THF is added chloroethylisocyanate (3.1 mL, 36 mmol). The reaction mixture is stirred for 18 h. MeOH (10 mL) is added, and stirring is continued for an additional hour. The reaction mixture is evaporated, and partitioned between DCM and aqueous 5% citric acid (150 mL). The aqueous layer is carefully adjusted to pH 9 with solid NaHCO3. The precipitate is filtered, washed with H2O (5×20 mL) and Et2O (2×20 mL), and dried in vacuo at 45° C. to provide the title compound.