Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].CCO.[C:6]([O:10][C:11]([NH:13][C@H:14]([C:23]([O:25]CC)=O)[CH2:15][S:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(O)(=O)C>CCCCC.C1COCC1>[CH2:21]([O:20][C:18]([C@H:17]1[C:23](=[O:25])[CH:14]([NH:13][C:11]([O:10][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:12])[CH2:15][S:16]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)CSC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)[C@@H]1SCC(NC(=O)OC(C)(C)C)C1=O
Yield: 77.7 %

Procedure:
NaH (1.64 g, 55%-65% Fluka, 41 mmole) washed with pentane twice, was suspended in THF (20 mL), then EtOH anhydrous (2.4 mL, 41 mmole) was added slowly. When the production of H2 stopped, more THF (160 mL) was added and followed by 12 (13.73 g, 41 mmole) in THF (20 mL). After 40 min. acetic acid 4 mL was added. The solvent was removed under vacuum. The crude product was extracted with diethylether and washed with brine. Crude (12 g) was flash chromatographied (column diam. 7.5 cm, SiO2 15 cm high), elution with cyclohexane-ethylacetate (4/1) to give 9.22 g of 13 (yield 78%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([CH:9]([CH3:11])[CH3:10])=[CH:7][CH:6]=[C:5]([CH3:12])[C:4]=1[OH:13].[CH3:14]C(C)([O-])C.[K+].CI.Cl>C1COCC1.O>[CH3:12][C:5]1[C:4]([O:13][CH3:14])=[C:3]([C:8]([CH:9]([CH3:10])[CH3:11])=[CH:7][CH:6]=1)[CH2:2][OH:1]
Reactant: Cc1ccc(C(C)C)c(CO)c1O
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)ccc(C(C)C)c1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.7 %

Procedure:
2-Hydroxymethyl-6-methyl-3-(1-methylethyl)phenol (37.3 g, 207 mmol) was dissolved in THF (350 ml), and then potassium tert-butoxide (22.1 g, 197 mmol) was added. To the mixture was added methyl iodide (19.7 ml, 311 mmol) at 0° C., and the mixture was stirred at room temperature for 16 hours. The reaction mixture was combined with water, made acidic with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over sodium sulfate and purified by column chromatography on a small amount of silica gel which was eluted with ethyl acetate. The solvent was concentrated under reduced pressure, and the residue was crystallized from hexane to obtain 21.7 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([NH2:10])=O)=[N:6][CH:7]=1>O=P(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:8]#[N:10])=[N:6][CH:7]=1
Reactant: NC(=O)c1cnc(Cl)cn1
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc(Cl)cn1
Yield: 64.1 %

Procedure:
Dissolve 5-chloropyrazine-2-carboxamide (Example 389, Part A) (0.0878 g, 0.557 mmol) in POCl3 (5.6 mL) and heat at reflux for 35 minutes. Concentrate the reaction mixture. Take up the dark oil in saturated aqueous NaHCO3 (15 mL) and extract with dichloromethane (2×25 mL). Wash the organic layer with brine (1×15 mL), dry over Na2SO4, filter and concentrate. Purify by flash chromatography, eluting with 10% ethyl acetate in hexanes to give the title compound (0.0498 g, 64.0%): GC/MS, MS ES+ 139 (M)+, time 10.6 min % of total 100%; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR 8.2 min, 100% purity.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[C:13](=[O:14])[C:12]3[C:15]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=4[F:30])=[C:16]([F:21])[C:17](=[O:20])[N:18]([CH3:19])[C:11]=3[N:10]=[CH:9]2)[CH2:4][O:3]1.Cl>CO>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[C:13](=[O:14])[C:12]2[C:15]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])=[C:16]([F:21])[C:17](=[O:20])[N:18]([CH3:19])[C:11]=2[N:10]=[CH:9]1
Reactant: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H]3COC(C)(C)O3)cnc21
Agent: Cl
Solvent: CO
Product: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Combine (R)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (0.50 g, 0.919 mmol), methanol (5.0 mL) and 6.00 M hydrochloric acid (0.50 mL, 3.0 mmol) and heat to 60° C. After 2 hours, cool to 50° C. and stir for 24 hours, then cool to ambient temperature, filter to collect the solid, rinse with methanol, and dry under vacuum at 30° C. to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C[Al](C)C.C([O:16][C:17]([C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[C:24]([NH:29][C@H:30]1[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[CH2:32][CH2:31]1)[CH:23]=[CH:22]2)=O)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCOCC1.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:17]([C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([NH:29][C@H:30]2[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31]2)[CH:23]=[CH:22]3)=[O:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: NCc1ccc(F)cc1
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(F)cc1)c1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a stirred solution of commercially available 4-fluoro-benzylamine (250 mg, 2.0 mmol) in dioxane (10 ml) was added drop wise at room temperature a 2M solution of trimethylaluminum in toluene (1 ml). The reaction mixture was allowed to stir for 1 h at room temperature, a solution of 2-((R)-indan-1-ylamino)-quinoline-6-carboxylic acid ethyl ester (166 mg, 0.5 mmol) in dioxane (4 ml) was added and the reaction mixture was heated for 2 h at 90° C. The reaction mixture was poured into 0.886M sodium-potassium-tartrate solution (25 ml) and extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with brine (25 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/MeOH/hexane) to yield the title compound as an off-white solid (164 mg, 80%), MS (ISP) 412.2 [(M+H)+]; m.p. 175° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[C:11]([C:13](OCC)=[O:14])[N:10]([CH3:18])[N:9]=2)=[C:4]2[NH:19][CH:20]=[C:21]([C:22](=[O:42])[C:23](=[O:41])[N:24]3[CH2:29][CH2:28][N:27]([C:30]4[N:34]([C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:33]=[N:32][N:31]=4)[CH2:26][CH2:25]3)[C:3]=12.[CH2:43]([CH2:45][NH2:46])[OH:44]>CN(C=O)C>[F:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:46][CH2:45][CH2:43][OH:44])=[O:14])[N:10]([CH3:18])[N:9]=2)=[C:4]2[NH:19][CH:20]=[C:21]([C:22](=[O:42])[C:23](=[O:41])[N:24]3[CH2:25][CH2:26][N:27]([C:30]4[N:34]([C:35]5[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=5)[N:33]=[N:32][N:31]=4)[CH2:28][CH2:29]3)[C:3]=12
Reactant: CCOC(=O)c1cc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)nn1C
Reactant: NCCO
Solvent: CN(C)C=O
Product: Cn1nc(-c2ncc(F)c3c(C(=O)C(=O)N4CCN(c5nnnn5-c5ccccc5)CC4)c[nH]c23)cc1C(=O)NCCO
Temperature: 50 °C

Procedure:
To a sealable flask containing ethyl 3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxylate (0.047 g, 0.08 mmol) was added ethanolamine (0.7 mL). The mixture was sealed and heated to 50° C. for 20.5 h. The mixture was cooled to rt, and was diluted with DMF and was passed through a plug of celite to remove any solids. The DMF solution was purified by prep HPLC to give 3-(4-fluoro-3-(2-oxo-2-(4-(1-phenyl-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-N-(2-hydroxyethyl)-1-methyl-1H-pyrazole-5-carboxamide.TFA (0.014g) as an off-white solid. LCMS: m/e 588.7 (M+H)+, ret time 2.03 min (method 2) 1H NMR (500 MHz, CDCl3) δ ppm 8.35 (s, 1 H) 8.23 (s, 1 H) 7.50-7.61 (m, 6 H) 4.29 (s, 3 H) 3.78-3.85 (m, 4 H) 3.54-3.64 (m, 4 H) 3.40 (s, 2 H) 3.29-3.34 (m, 2 H) 2.79 (s, 1 H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:26]([Cl:27])=[C:25]([S:28][CH3:29])[CH:24]=[CH:23][C:14]=1[C:15]([C:17]1[CH:18]=[N:19][O:20][C:21]=1[CH3:22])=[O:16]>ClCCl>[Cl:12][C:13]1[C:26]([Cl:27])=[C:25]([S:28]([CH3:29])=[O:9])[CH:24]=[CH:23][C:14]=1[C:15]([C:17]1[CH:18]=[N:19][O:20][C:21]=1[CH3:22])=[O:16]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(C(=O)c2cnoc2C)c(Cl)c1Cl
Solvent: ClCCl
Product: Cc1oncc1C(=O)c1ccc(S(C)=O)c(Cl)c1Cl
Temperature: -20 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
3-Chloroperbenzoic acid (85%, 0.99 g) was added portionwise to a stirred solution of 4-(2,3-dichloro-4-methylsulphenylbenzoyl)-5-methylisoxazole (1.5 g) in dichloromethane (50 ml) whilst maintaining the temperature below -20° C. The mixture was stirred at -20° C. for 1 hour. Dichloromethane (50 ml) was added and the solid was removed by filtration. The filtrate was evaporated to dryness and the residue was chromatographed on silica eluted with a mixture of ethyl acetate and cyclohexane (1:5) to give 4-(2,3-dichloro-4-methylsulphinylbenzoyl)-5-methylisoxazole (compound 46, 0.8 g) as a white solid, mp 125°-126.4° C.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@@:19]([C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)([CH2:22][CH2:23][CH2:24][OH:25])[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[C:5]([CH3:7])[N:6]=1.[NH3:34]>>[CH3:1][C:2]1[S:3][C:4]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:22][CH2:23][C:24]([NH2:34])=[O:25])([C:26]4[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:12][CH:13]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: N
Reactant: Cc1nc(C)c(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)s1
Product: Cc1nc(C)c(-c2ccc([C@H](C)N3CC[C@](CCC(N)=O)(c4ccc(F)cc4)OC3=O)cc2)s1

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-(2,4-dimethylthiazol-5-yl)phenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one employing a procedure analogous to that described in Example 12 Step 2, followed by a procedure analogous to that described in Example 8 Step 2 using ammonia. LC-MS Method 1 tR=1.38 min, m/z=482 (M+1); 1H NMR (CDCl3) 7.32 (m, 5H), 7.18 (d, 2H), 7.04 (m, 4H), 5.69 (q, 1H), 2.84 (s, 3H), 2.45 (s, 3H), 2.02 (m, 1H), 1.55 (d, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=1.N12CCCN=C1CCCCC2.[I-].[NH2:27][N+:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>C(#N)C>[CH2:3]([C:4]1[C:5]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]([S:12][CH3:13])[N:7]=2)=[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][N:28]2[N:27]=1)[CH:2]([CH3:14])[CH3:1]
Reactant: CSc1nccc(C#CCC(C)C)n1
Reactant: N[n+]1ccccc1
Agent: [I-]
Solvent: O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CSc1nccc(-c2c(CC(C)C)nn3ccccc23)n1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
To a cold (0° C.) solution of 4-(4-methylpent-1-ynyl)-2-(methylthio)pyrimidine (2.5 g, 12 mmol) in acetonitrile (40 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.7 mL, 18 mmol) and 1-aminopyridinium iodide (3.49 g, 15.7 mmol). The resultant dark solution was allowed to warm to room temperature and stirred vigorously. The mixture was heated to 50° C. for 18 h then cooled to room temperature. Water was added and the mixture concentrated in vacuo. The residue was partitioned between water and ether. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed flash chromatography on silica gel (6:1 to 4:1 to 2:1 hexane-ethyl acetate) provided 2-isobutyl-3-[2-(methylthio)pyrimidin-4-yl]pyrazolo[1,5-a]pyridine (2.0 g, 56%) as a yellow solid. 1H NMR (CDCl3) δ 8.51–8.48 (m, 2H), 8.36 (d, 1H), 7.35 (t, 1H), 7.19 (d, 1H), 6.91 (t, 1H), 3.04 (d, 2H), 2.68 (s, 3H), 2.20 (m, 1H), 1.03 (d, 6H); MS m/z 299 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.[C:20](Cl)(=[S:28])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1>[O:21]([C:20]([O:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18][CH3:19])=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:3]1)=[S:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: S=C(Cl)Oc1ccccc1
Reactant: COC(=O)[C@@H]1[C@@H]2C[C@@H](O)[C@@H](C2)N1C(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: COC(=O)[C@@H]1[C@H]2C[C@H]([C@H](OC(=S)Oc3ccccc3)C2)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
To a solution of 2-tert-butyl 3-methyl (1R,3S,4S, 6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (4.5 g) in pyridine (10 mL), was added O-phenyl chlorothiocarbonate (3.15 g). The mixture was then stirred at room temperature for 3 hrs. The resulting mixture was evaporated in vacuo. To the residue, water was added. The mixture was extracted with ethyl acetate. The combined organic phase was washed successively with diluted hydrochloric acid, sodium hydrogen carbonate solution and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with hexane and ethyl acetate (2:1) to give the target compound (5.22 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1I.CC1(C)C(C)(C)OB([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2Br)CC1
Yield: 73.1 %

Procedure:
A solution of 1-bromo-2-iodo-4-(trifluoromethyl)benzene (1.408 ml, 8.55 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (Frontier Scientific, Logan, Utah, 2.78 g, 8.98 mmol), Pd(dppf)Cl2—CH2Cl2 adduct (Strem Chemicals Inc., Newburyport, Mass., 0.349 g, 0.427 mmol), and potassium carbonate (2.052 g, 34.2 mmol) in dioxane (32.1 ml) and water (10.69 ml) was stirred at 70° C. for three hours. (LC-MS MH+ 430.1) The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (silica gel 80 g, gradient elution 0 to 100% Et2O:Heptane) to afford tert-butyl 4-(2-bromo-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (2.54 g, 6.25 mmol) as a light yellow oil. [M+H]+=428.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.69 (d, J=8.3 Hz, 1H), 7.43 (d, J=2.2 Hz, 1H), 7.41-7.36 (m, 1H), 5.69 (br. s., 1H), 4.08 (q, J=2.7 Hz, 2H), 3.66 (t, J=5.6 Hz, 2H), 2.48-2.40 (m, 2H), 1.52 (s, 9H)
Reaction SMILES: [OH-].[Na+].[SH:3][C:4]1O[CH:6]=[CH:7][CH:8]=1.Cl[CH2:10][C:11]([OH:13])=[O:12].Cl>O.CO.C(O)C>[C:11]([CH2:10][C:4]1[S:3][CH:6]=[CH:7][CH:8]=1)([OH:13])=[O:12]
Reactant: O=C(O)CCl
Reactant: Sc1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: O
Product: O=C(O)Cc1cccs1
Temperature: 25 °C
Yield: 74 %

Procedure:
Aqueous solution of sodium hydroxide 8.8 g (0.22 mol) in water of 15 ml was added drop by drop to mixture of 2-mercapto furan 20.0 g (0.20 mol), chloroacetic acid 27.0 g (0.22 mol) and ethanol 300 ml with stirring at room temperature. After 20 minutes of stirring it was heated to 50° C., and further aqueous solution of sodium hydroxide 8.8 g (0.22 mol) in 15 ml of water was added slowly drop by drop. After stirring for 3 hours at 50° C., it was cooled to room temperature, and water was added till reaction liquid became uniform. Hydrochloric acid was added for neutralization. Prepared crystal was collected by filtration and 23.5 g (0.148 mol) of 2-carboxymethylthiofuran was obtained by recrystallization in methanol. Synthesis of yield 74%.
Reaction SMILES: [CH2:1]([P:3]([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])(=O)[OH:4])[CH3:2].S(Cl)([Cl:29])=O>>[CH2:1]([P:3]([Cl:29])([C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[Cl:23])[CH:9]=[CH:8][C:7]=1[N+:24]([O-:26])=[O:25])=[O:4])[CH3:2]
Reactant: CCP(=O)(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Product: CCP(=O)(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
A solution of P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic acid (500 mg, 1.22 mmol) and thionyl chloride (4 ml) is heated under reflux for about 1.5 hours. The reaction mixture is then concentrated to dryness to give P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinic chloride. To a solution of the phosphinic chloride and methylene chloride (10 ml) is added slowly a solution of ethyl 2-hydroxyiminopropionate (320 mg, 2 eq.) and methylene chloride (5 ml) containing triethylamine (0.2 ml, 1.2 eq.). The resulting mixture is stirred at RT for 2 hours. The reaction is then worked up in methylene chloride, washed, dried and evaporated to dryness to give an oily product. The oily product is purified by preparative thin layer chromatography (prep. TLC) in silica gel (50% ethyl acetate/hexane) to yield ethyl 2-[P-ethyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenylphosphinyloxyimino]propionate.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([S:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][NH2:17])[CH:13]=[CH:14][CH:15]=2)=[N:2]1.[C:18]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([C:30](OCC)=[O:31])[NH:24][C:23]2=[O:35])#[N:19].C(N(C(C)C)CC)(C)C>C(O)C>[C:18]([C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[N:26]=[C:25]([C:30]([NH:17][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][S:6][C:3]3[N:4]=[CH:5][NH:1][N:2]=3)[CH:11]=1)=[O:31])[NH:24][C:23]2=[O:35])#[N:19]
Reactant: NCc1cccc(OCCSc2nc[nH]n2)c1
Reactant: CCOC(=O)c1nc2ccc(C#N)cc2c(=O)[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: N#Cc1ccc2nc(C(=O)NCc3cccc(OCCSc4nc[nH]n4)c3)[nH]c(=O)c2c1
Temperature: 90 °C
Reaction time: 48 h
Yield: 26 %

Procedure:
A suspension of 1-(3-{[2-(1H-1,2,4-triazol-3-ylthio)ethyl]oxy}phenyl)methanamine obtained in Reference Example 3 (300 mg, 0.999 mmol), ethyl 6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxylate obtained in Reference Example 51 (200 mg, 0.822 mmol) and diisopropylethylamine (0.180 mL, 1.05 mmol) in ethanol (2 mL) was stirred at 90° C. for 2 days. The reaction solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC (GILSON 215LIQUD HANDLER, 322PUMP, UV/VIS-156, SHISEIDO CAPCELL PACK C-18 UG120 S-5 (20 mmφ×50 mm), mobile phase: distilled water (containing 0.1% trifluoroacetic acid)/acetonitrile (containing 0.1% trifluoroacetic acid), gradient: distilled water/acetonitrile=90/100/100, time: 10 min, flow rate: 25 mL/min, detection wavelength: 220 nm), and the obtained crude crystals were recrystallized from ethanol to give the title compound as a white powder (97.4 mg, 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][C:11]=2[Cl:15])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].O[CH2:17][C@@H:18]([NH:20]C(=O)OC(C)(C)C)[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[NH2:20][C@@H:18]([CH3:19])[CH2:17][N:13]1[CH:12]=[C:11]([Cl:15])[C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[CH:9]=2)=[N:14]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(-c2[nH]ncc2Cl)cc1Cl
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](N)Cn1cc(Cl)c(-c2ccc(C#N)c(Cl)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-1H-pyrazol-5-yl)benzonitrile (0.690 g, 2.9 mmol), (S)-tert-butyl 1-hydroxypropan-2-ylcarbamate (0.508 g, 2.9), triphenylphosphine (1.14 g, 4.35 mmol) and di-tert-butyl azodicarboxylate (1 g, 4.35 mmol) using the method of Example 34(c). Yield 0.518 g. 1H NMR (400 MHz; CDCl3): δ 1.16 (d, 3H), 1.32 (bs, 2H), 3.47 (m, 1H), 3.88 (dd, 1H), 4.09 (dd, 1H), 7.56 (s, 1H), 7.69 (d, 1H), 7.99 (dd, 1H), 8.13 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH:11]1[C:20]2[C:15](=[C:16]([CH:21]([CH3:25])[C:22](O)=[O:23])[CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][N:12]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:22](=[O:23])[CH:21]([C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:15]=1[CH:14]=[CH:13][N:12]=[CH:11]2)[CH3:25]
Reactant: Cc1ccc(CN)c(C)c1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: Cc1ccc(CNC(=O)C(C)c2cccc3cnccc23)c(C)c1

Procedure:
The title compound was prepared using the procedure described in Example 222B using 2,4-dimethylbenzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 319 (M+H)+; MS (ESI−) m/z 317 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.52 (d, J 7.1, 3H), 2.13 (s, 3H), 2.21 (s, 3H), 4.20 (m, 2H), 4.51 (q, J 7.1, 1H), 6.88 (d, J 7.5, 1H), 6.94 (s, 1H), 6.98 (d, J 7.5, 1H), 7.82 (t, J 7.8, 1H), 7.99 (d, J 6.5, 1H), 8.21 (d, J 8.1, 1H), 8.35 (d, J 6.4, 1H), 8.44 (t, J 5.8, 1H), 8.62 (d, J 6.2, 1H), 9.57 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: NCCc1ccccn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCCc3ccccn3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 2-(2-aminoethyl)pyridine (0.012 mL, 0.10 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-{1-(tert-butoxycarbonyl)-5-[(2-(pyridin-2-yl)ethyl)aminomethyl]indol-2-yl}isoindolinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C(Cl)Cl.[Br:20]N1C(=O)CCC1=O>>[Br:20][CH:10]([C:9](=[O:16])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC(=O)C(Br)C(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.4 %

Procedure:
In a 250 mL round bottomed flask, to a solution of ethyl 4-(4-chlorophenyl)-3-oxobutanoate (4.04 g, 16.8 mmol) in methylene chloride (100 mL, 2000 mmol) was added N-bromosuccinimide (3.13 g, 17.6 mmol) and the mixture was stirred for 3 h at room temperature. Reaction was quenched via addition of a 10% aqueous solution of NaHSO3 (50 mL), and the resulting biphasic mixture was vigorously stirred for 15 minutes. The reaction mixture was transferred to a separatory funnel, the layers were separated, and the aqueous layer was extracted with CH2Cl2 (30 mL). The combined organic layers were washed with a saturated aqueous solution of NaHCO3 (50 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford ethyl 2-bromo-4-(4-chlorophenyl)-3-oxobutanoate (5.23 g, yield 97.5%) as a yellow oil that was used without further purification. LC/MS (FA) ES− 317, 319, 321.