Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[O:13][N:12]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]=1.[I:19]N1C(=O)CCC1=O>C(OCC)(=O)C>[I:19][C:10]1[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:12][O:13][C:9]=1[CH3:8]
Reactant: CCOC(=O)c1cc(C)on1
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)c1noc(C)c1I
Temperature: 65 °C
Yield: 71.2 %

Procedure:
To a 25 mL RB flask fitted with a magnetic stirrer was charged with 1 mL of TFA. To the stirred solvent were added ethyl 5-methyl-1,2-oxazole-3-carboxylate (0.1 g, 0.6 mmol) and N-iodosuccinimide (0.289 g, 1.2 mmol). After addition, the reaction mixture was heated at 65° C. for 3 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (10 mL), the organic layer was washed with saturated NaHCO3 solution (10 mL), thiosulfate solution (10 mL), water (25 mL) and finally with brine solution (10 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as a brown liquid (0.12 g, yield: 66.2%). 1H NMR (300 MHz, CDCl3): δ 4.36-4.43 (q, 2H), 2.49 (s, 3H), 1.34-1.39 (t, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][CH:7]=[C:8]([C:9](=O)[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C([SiH](CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[S:6][CH:7]=[C:8]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: O=C(Cc1ccccc1)c1csc2ccc(Br)cc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: Brc1ccc2scc(CCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a mixture of 1-(5-bromobenzo[b]thiophen-3-yl)-2-phenylethanone (1.1 g) and triethylsilane (1.5 g) was added trifluoro acetic acid (10 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into an ice-cooled saturated potassium carbonate aqueous solution, and the mixture was extracted with diethyl ether. The organic layer washed with water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane) to give the title compound (0.94 g).
Reaction SMILES: [C:1]([O:5][C:6]([C:8](=[C:14]([C:16](=[O:52])[N:17]([CH:27]([CH3:51])[CH:28]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:29][C:30]1[O:31][C:32]([C:35](=[O:43])[NH:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:33][CH:34]=1)[CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:15])[CH2:9][C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCCC1.O>[C:1]([O:5][C:6]([C:8](=[C:14]([C:16](=[O:52])[N:17]([CH:27]([CH3:51])[CH:28]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:29][C:30]1[O:31][C:32]([C:35](=[O:43])[NH:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:33][CH:34]=1)[CH2:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[OH:15])[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CC(C(=O)OC(C)(C)C)=C(O)C(=O)N(C/C=C/c1ccccc1)C(C)C(Cc1ccc(C(=O)Nc2ccccc2)o1)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C(Cc1ccc(C(=O)Nc2ccccc2)o1)C(=O)OC(C)(C)C)N(C/C=C/c1ccccc1)C(=O)C(O)=C(CC(=O)O)C(=O)OC(C)(C)C
Yield: 66 %

Procedure:
68 mg of methyl 3-(tert-butoxycarbonyl)-4-[N-[(1RS,2RS)-2-(tert-butoxycarbonyl)-1-methyl-3-{5-(phenylcarbamoyl)-2-furyl}propyl]-N-{(E)-3-phenyl-2-propenyl}carbamoyl]-4-hydroxy-3-butenoate was dissolved in a mixture of 3 ml of tetrahydrofuran and 1 ml of water and stirred together with 1 ml of 1N aqueous sodium hydroxide at room temperature for 40 hours. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [chloroform/methanol=20/1→10/1] to give 44 mg (yield: 66%) of the title compound as a pale yellow solid.
Reaction SMILES: Cl.[F:2][C:3]1[CH:9]=[C:8]([SH:10])[C:7]([F:11])=[CH:6][C:4]=1[NH2:5].[Cl:12][C:13]1[CH:14]=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:16]=[CH:17][C:18]=1Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:2][C:3]1[CH:9]=[C:8]([S:10][C:18]2[CH:17]=[CH:16][C:15]([C:20]([F:23])([F:22])[F:21])=[CH:14][C:13]=2[Cl:12])[C:7]([F:11])=[CH:6][C:4]=1[NH2:5]
Reactant: FC(F)(F)c1ccc(Cl)c(Cl)c1
Reactant: Nc1cc(F)c(S)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(F)c(Sc2ccc(C(F)(F)F)cc2Cl)cc1F
Reaction time: 6 h
Yield: 69 %

Procedure:
3.00 Grams of 2,5-difluoro-4-mercaptoaniline hydrochloride, 6.60 g of 3,4-dichlorobenzotrifluoride and 4.90 g of potassium carbonate were dissolved in 30 ml of dimethylformamide, and the resulting solution was stirred for 6 hours at a temperature of from 100° to 110° C. in an oil bath. Thereafter, the reaction solution was poured into water and extracted with three 100-ml portions of diethyl ether. The extract obtained was washed with water, dried, filtered and concentrated. The residue obtained was subjected to chromatography on silica gel to obtain 3.60 g of 2,5-difluoro-4-[2-chloro-4-(trifluoromethyl)phenylthio]aniline.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH2:22][C:21](=O)[N:11]3[CH2:12][CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[CH:10]3[CH2:9]2)C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>CN(P(N(C)C)(N(C)C)=O)C>[S:45]=[C:21]1[N:11]2[CH2:12][CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[CH:10]2[CH2:9][NH:8][CH2:22]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CC2c3ccccc3CCCN12
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: S=C1CNCC2c3ccccc3CCCN12
Reaction time: 3 h

Procedure:
A mixture of 2-(triphenylmethyl)-4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine (0.66 g) and Lawesson's reagent (2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide) (0.29 g) in HMPA (10 ml) was heated to 80° under a nitrogen atmosphere. The mixture was stirred at this temperature for 3 hr, cooled and partitioned between water and diethyl ether. The organic layer was washed with water and evaporated to a yellow foam. This residue was dissolved in acetone (20 ml), cooled to 0° and concentrated hydrochloric acid (0.5 ml) added. After stirring at room temperature for 30 min the mixture was evaporated and the residue partitioned between dilute hydrochloric acid and chloroform. The aqueous fraction was basified with sodium carbonate and extracted with chloroform. This chloroform fraction was washed with brine, dried (K2CO3) and evaporated to give the title compound as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1.C([O:36][C@@H:37]([CH3:41])[C:38](Cl)=[O:39])(=O)C>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:7]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][CH:27]4[CH2:28][CH2:29][N:30]([C:38](=[O:39])[C@@H:37]([OH:36])[CH3:41])[CH2:31][CH2:32]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: COc1ccc(-c2ncnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide (example D.f18) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[Br:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([F:21])[CH:13]=1.C(Cl)Cl.C([O-])([O-])=O.[K+].[K+]>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].O.O1CCOCC1>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[N:3]=[C:4]3[CH:5]=[CH:6][NH:7][C:8]3=[N:9][CH:10]=2)=[C:14]([F:21])[CH:13]=1
Reactant: Brc1cnc2[nH]ccc2n1
Reactant: OB(O)c1ccc(Br)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: Fc1cc(Br)ccc1-c1cnc2[nH]ccc2n1
Temperature: 95 °C
Yield: 34.9 %

Procedure:
To a 150 mL screw-cap vessel under nitrogen was added 5-bromo-4,7-diazaindole (1.0 g, 5.05 mmol), 4-bromo-2-fluorophenyl boronic acid (1.33 g, 6.06 mmol), Pd(dppf)Cl2.CH2Cl2 (0.2 g, 0.24 mmol), K2CO3 (2.09 g, 15.2 mmol), 1,4-dioxane (35 mL) and water (13 mL). The mixture was sparged with nitrogen for 10 minutes, the vessel capped and the reaction heated at 95° Celsius for 24 hours. The reaction was then cooled to rt, diluted with ethyl acetate (200 mL) and washed with water (1×100 mL) and brine (1×100 mL). The organic layer was dried with Na2SO4 and evaporated to dryness. The crude product was purified by HPLC giving the title compound (515 mg, 35%). MS (ESI): mass calcd. for C12H7BrFN2, 290.98; m/z found, 292.0 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][C:8]([N:10]([CH2:24][C:25]2[CH:47]=[CH:46][C:28]([C:29]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:35][CH:34]=3)=[O:30])=[CH:27][CH:26]=2)[C:11]2[CH:23]=[CH:22][C:14]3[O:15]C(C)(C)[O:17][C:18](=[O:19])[C:13]=3[CH:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CCO>[CH:1]1([CH2:6][CH2:7][C:8]([N:10]([CH2:24][C:25]2[CH:47]=[CH:46][C:28]([C:29]([NH:31][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([O:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:37][CH:38]=3)=[O:30])=[CH:27][CH:26]=2)[C:11]2[CH:23]=[CH:22][C:14]([OH:15])=[C:13]([CH:12]=2)[C:18]([OH:19])=[O:17])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)c2cc(N(Cc3ccc(C(=O)NCc4ccc(Oc5ccccc5)cc4)cc3)C(=O)CCC3CCCC3)ccc2O1
Agent: Cl
Solvent: CCO
Product: O=C(NCc1ccc(Oc2ccccc2)cc1)c1ccc(CN(C(=O)CCC2CCCC2)c2ccc(O)c(C(=O)O)c2)cc1
Temperature: 70 °C
Yield: 85.4 %

Procedure:
To a solution of 4-{[(3-cyclopentylpropanoyl)(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)amino]methyl}-N-(4-phenoxybenzyl)benzamide (200 mg) in EtOH (3 mL) was added an aqueous solution (0.071 mL, 1N). The mixture was heated at 70° C. for 3 h. After cooling to rt, an aqueous solution of HCl (2 mL, 1N) was added and the resulting reaction mixture was extracted (EtOAc). The combined organic layers were washed with water, brine, dried over MgSO4, filtered and evaporated to give the title compound as a white powder (160 mg, 85%). 1H NMR (DMSO-d) δ 8.99 (t, J=6.0 Hz, 1H), 7.82 (d, J=8.2 Hz, 2H), 7.50 (d, J=2.6 Hz, 1H), 7.42-7.06 (m, 8H), 7.03-6.89 (m, 5H), 4.85 (s, 2H), 4.45 (s, 1H), 4.43 (s, 1H), 3.40 (brs, 1H), 2.05 (t, J=7.5 Hz, 2H), 1.70-1.32 (m, 9H), 1.00-0.81 (m, 2H). M+(ESI): 593.0; M−(ESI): 591.0. HPLC, Rt: 4.9 min purity: 99.3%).
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17][C:18](=[O:28])[C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[CH2:9][C@H:10]([C:12]([O:14]CC)=[O:13])[CH3:11])=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=[CH:3][C:4]([CH2:7][C@@H:8]([NH:17][C:18](=[O:28])[C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]([OH:24])=[O:23])[CH2:9][C@H:10]([C:12]([OH:14])=[O:13])[CH3:11])=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cccc(C(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cccc(C(=O)O)c1)C(=O)O
Temperature: 55 °C
Reaction time: 5 h

Procedure:
To a mixture of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methyl-pentanoic acid ethyl ester hydrochloride (Intermediate 29: 70 mg, 0.201 mmol) and 3-chlorocarbonylbenzoic acid methyl ester (0.302 mmol) in methylene chloride (0.5 mL) is added pyridine (0.5 mL) and the mixture is stirred at room temperature for 24 hours. The solvents are removed under reduced pressure and ethyl acetate is added. The solution is washed with aqueous 1M HCl and brine and the organic phase is dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography using methylene chloride to furnish N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid. Next, to a solution of N-((1S,3R)-1-biphenyl-4-ylmethyl-3-ethoxycarbonyl-butyl)-isophthalamic acid (0.287 mmol) in ethanol (10 mL) is added aqueous 1M NaOH (1.2 mL, 1.12 mmol) and the mixture is stirred at 50-60° C. for 5 hours. The ethanol is removed under reduced pressure and water is added. The solution is acidified with 1M HCl and the mixture is extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC using a gradient of MeCN/water (0.1% TFA). The proper fractions are lyophilized to furnish N-((1S,3R)-1-biphenyl-4-ylmethyl-3-carboxy-butyl)-isophthalamic acid. HPLC Retention time 1.05 minutes (condition F); MS 432.3 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (d, J=7.07 Hz, 3H), 1.60 (m, 1H), 1.89 (m, 1H), 2.47 (m, 1H), 2.86 (m, 2H), 4.27 (m, 1H), 7.27-7.35 (m, 3H), 7.34 (t, 1H), 7.43 (t, 2H), 7.55-7.66 (m, 5H), 8.01-8.07 (m, 2H), 8.39 (s, 1H), 8.47 (d, J=8.46 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH:9]=[CH:10][CH3:11])[C:3]=1[OH:12].O[C@@H:14]([CH:27]=[CH2:28])[CH2:15][O:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([O:16][CH2:15][C@H:14]([O:12][C:3]2[C:4]([CH:9]=[CH:10][CH3:11])=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Br:1])[CH:27]=[CH2:28])(=[O:19])=[O:18])=[CH:21][CH:22]=1
Reactant: C=C[C@H](O)COS(=O)(=O)c1ccc(C)cc1
Reactant: CC=Cc1cc(F)cc(Br)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=C[C@H](COS(=O)(=O)c1ccc(C)cc1)Oc1c(Br)cc(F)cc1C=CC
Temperature: 25 °C
Reaction time: 19 h
Yield: 82 %

Procedure:
To a solution of 2-bromo-4-fluoro-6-(prop-1-enyl)phenol, prepared in Example 37, step 4 (4.5 g, 0.019 mol) and (S)-toluene-4-sulfonic acid 2-hydroxy-but-3-enyl ester (7.07 g, 0.028 mol) and triphenylphosphine (11.22 g, 0.043 mol) in anhydrous THF (200 mL) at room temperature was added diethyl azodicarboxylate (7.7 mL, 0.047 mol) then the reaction mixture stirred at room temperature for 19 hours. The reaction was quenched by the addition of water (100 mL), stirred vigorously for 5 minutes and the resulting oily suspension extracted with methylene chloride (300 mL). The organic phase was separated, washed with water (2×100 mL), and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a yellow oil. Purification by flash chromatography using a solvent gradient of 0 to 20% ethyl acetate in hexane gave 7.26 g (82%) of (R)-2-[2-bromo-4-fluoro-6-(prop-1-enyl)phenoxy]but-3-enyl 4-methylbenzenesulfonate as a colorless oil. MS (ES) m/z 472.1 ([M+NH4]+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:18])([CH2:16]O)[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.CS(Cl)(=O)=O.[OH-].[K+]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[CH2:16][O:18]1
Reactant: OCC(O)(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Product: Clc1ccc(C2(Cn3ccnc3)CO2)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To an ice-cooled solution of (-)-2-(2,4-dichlorophenyl)-1-(imidazol-1-yl)-2,3-propanediol (5.4 g) in pyridine (50 ml) was added dropwise methanesulfonyl chloride (2.15 g). The reaction mixture was stirred at 0°-10° C. for 2 hours. An ice-cooled solution of 85.5% potassium hydroxide (3.7 g) in methanol (60 ml) was added dropwise thereto, and then the mixture was stirred at 0°-10° C. for 1 hour. The solvent was removed in vacuo, and the residue was extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and evaporated to give a red oil. The oily residue was purified by chromatography on silica gel (60 g) with chloroform as a solvent and recrystallized from ether-hexane to give (-)-2-(2,4-dichlorophenyl)-2-(imidazol-1-yl)methyloxirane (4.3 g) as colorless needles. Yield, 84.6%. M.P., 107°-108.5° C. [α]D21.5, -8.4° (C=1.0, MeOH).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11](Br)[CH:12]=[CH2:13].CCCCCC.CCOCC>C1COCC1.C(Br)C=C.[Zn]>[C:1]1([CH2:7][CH2:8][CH:9]([OH:10])[CH2:13][CH:12]=[CH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CCBr
Reactant: O=CCCc1ccccc1
Agent: [Zn]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCC(O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a mixture of 3-phenylpropionaldehyde (1.06 mL, 8 mmol, 1 eq) and activated zinc (628 mg, 9.6 mmol, 1.2 eq) in THF (3.2 mL) at 0° C. was added one drop of allyl bromide. After the reaction was initiated, the remaining allyl bromide (total 0.831 mL, 9.6 mmol, 1.2 eq) was added slowly. The contents were stirred overnight at room temperature. After 20 hours the reaction was quenched with saturated aq. NH4Cl solution (15 mL), extracted with ether (3×20 mL) and the combined organic phases washed with brine (15 mL). The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure to give crude 1-phenyl-hex-5-en-3-ol as a yellow oil. Column chromatography (hexane:ether, 85:15, 80:20, 75:25) gave a colourless oil, (966 mg, 69% yield). 1H NMR (400 MHz, CDCl3) δ 1.80-1.85 (m, 3H, CCH2CH2, +COH), 2.19-2.26 (m, 1H, CHOHCH2CH), 2.33-2.39 (m, 1H, CHOHCH2CH) 2.69-2.76 (m, 1H, PhCH2CH2), 2.82-2.89 (m, 1H, PhCH2CH2), 3.69-3.74 (m, 1H, CHOH), 5.16-5.19 (s, 1H, CHCH2 (cisH)), 5.19-5.20 (d, 1H, CHCH2 (trans H)), 7.21-7.26 (m, 3H, PhCH2), 7.30-7.34 (m, 2H, PhCH2); 13C NMR (100 MHz, CDCl3) δ 32.0 (PhCH2CH2), 38.4 (CH2CH2CH), 42.0 (CHOHCH2CH), 69.9 (CHOH), 118.1 (CHCH2), 125.7 (Ph), 128.4 (Ph), 128.5 (Ph), 134.6 (CHCH2), 142.0 (Ph); IR (v, cm−1) 3385 (OH), 3027 (Ar), 2932 (CH2), 1641 (CH═CH2), 1496 (Ph), 916 (CH═CH2); MS (GCT, CI+) m/z 194.2 [M+NH4]+ HRMS required for C12H20NO: 194.1545, found 194.1543.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:28])[C:21]([CH2:26][CH3:27])([O:24][CH3:25])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:46])[C@@H:15]2[CH2:29][CH2:30][C@H:31]2[O:36][C:35](=[O:37])[CH2:34][C@H:33]([O:38][Si](C(C)(C)C)(C)C)[CH2:32]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:28])[C:21]([CH2:26][CH3:27])([O:24][CH3:25])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:46])[C@@H:15]2[CH2:29][CH2:30][C@H:31]2[O:36][C:35](=[O:37])[CH2:34][C@H:33]([OH:38])[CH2:32]2)=[CH:10]1
Reactant: CCC(CC)(OC)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(CC)(OC)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 79.2 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 548 mg of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-(2-ethyl-2-methoxybutyryloxy)-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsiloxy-2H-pyran-2-one [prepared as described in Example 154, above] and 11.3 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 288 mg of the title compound as a colorless foam.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]([C:10]([NH2:12])=[O:11])=[CH:8][C:7]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6]1.C(Cl)(=O)[C:24](Cl)=[O:25]>ClCCCl>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]([C:10]([N:12]=[C:24]=[O:25])=[O:11])=[CH:8][C:7]([C:13]2[N:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:6]1
Reactant: NC(=O)c1cc(-c2ncccn2)nn1Cc1ccccc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: O=C=NC(=O)c1cc(-c2ncccn2)nn1Cc1ccccc1F
Temperature: 25 °C
Yield: 52 %

Procedure:
A mixture of 1-(2-fluorobenzyl)-3-(pyrimidin-2-yl)-1H-pyrazole-5-carboxamide (120 mg, 1 equiv) and oxalyl chloride (106 μl, 3 equiv) in 1,2-dichloroethane (2.0 ml) was heated to reflux for 24 h. The mixture was cooled to room temperature and purified by column chromatography (0 to 100% ethyl acetate in hexanes) to give 68 mg of 1-(2-fluorobenzyl)-3-(pyrimidin-2-yl)-1H-pyrazole-5-carbonyl isocyanate (52% yield) as a brown solid.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:4]1.Br[CH2:13][C:14]([O:16][CH3:17])=[O:15]>CN(C)C=O>[N:3]1([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[CH:5]=[CH:4]1
Reactant: COC(=O)CBr
Reactant: c1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2cccnc21

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 1.90 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 4.95 g of 7-azaindol, 100 ml of dimethylformamide and 4.2 ml of methyl bromoacetate were used, to give 7.70 g of the title compound having Rf=0.33 (on silica gel thin layer chromatography using a 2:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:37]2[CH2:49][CH2:48][N:40]3[C:41]4[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=4[CH:47]=[C:39]3[C:38]2=[O:50])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]3[C@@H:32]([CH3:33])[CH2:31][O:30][CH2:29][C@H:28]3[CH3:34])=[O:26])=[CH:21][N:20]=2)[C:15](=[O:35])[N:14]([CH3:36])[CH:13]=1)(=O)C.[OH-].[Li+].O>C1COCC1.C(O)(C)C.O>[CH3:34][C@H:28]1[CH2:29][O:30][CH2:31][C@@H:32]([CH3:33])[N:27]1[C:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[C:15](=[O:35])[N:14]([CH3:36])[CH:13]=[C:12]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:37]4[CH2:49][CH2:48][N:40]5[C:41]6[CH2:42][CH2:43][CH2:44][CH2:45][C:46]=6[CH:47]=[C:39]5[C:38]4=[O:50])[C:6]=3[CH2:5][OH:4])[CH:17]=2)=[N:20][CH:21]=1)=[O:26]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4[C@H](C)COC[C@@H]4C)cn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C[C@@H]1COC[C@H](C)N1C(=O)c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CCCC6)C4=O)c3CO)cn(C)c2=O)nc1
Reaction time: 2 h
Yield: 39.2 %

Procedure:
To a solution of 322a (136 mg, 0.20 mmol) in THF/i-propanol/water (4/2/1 mL) was added lithium hydroxide (48 mg, 2.0 mmol) at room temperature. After the reaction was stirred for 2 h, LCMS indicated the reaction was complete. Then the mixture was poured into water (15 mL) and extracted with dichloromethane (3×15 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC (A: 1% NH4HCO3/water, B: acetonitrile) to afford 322 (50 mg, 40%) as a white solid. MS-ESI: [M+H]+ 638.3. 1HNMR (500 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.77 (d, J=5.5 Hz, 1H), 8.48 (d, J=5.0 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.64-7.62 (m, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.37-7.35 (m, 2H), 6.57 (s, 1H), 4.95 (t, J=4.5 Hz, 1H), 4.47-4.38 (m, 2H), 4.23-3.99 (m, 5H), 3.88-3.87 (m, 1H), 3.65-3.61 (m, overlap, 5H), 3.56-3.53 (m, 2H), 2.66-2.56 (m, 2H), 2.47-2.44 (m, 2H), 1.80-1.79 (m, 2H), 1.70-1.66 (m, 2H), 1.25 (d, J=6.0 Hz, 6H)