Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:18])[CH3:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:19]([O-:21])=[O:20].N([O-])=O.[Na+].S(=O)(=O)(O)N.C1(C)C=CC=CC=1.[ClH:38]>C(O)(=O)C.O>[C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([S:8][C:6]2[CH:5]=[CH:4][C:3]([N+:19]([O-:21])=[O:20])=[C:2]([Cl:38])[CH:7]=2)=[CH:10][CH:11]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1ccc(Sc2ccc([N+](=O)[O-])c(N)c2)cc1
Reactant: Cl
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Sc2ccc([N+](=O)[O-])c(Cl)c2)cc1

Procedure:
A solution of 2-amino-4-(4-acetamidophenylsulphanyl)nitrobenzene (Method 15) (2.4 g) in warm glacial acetic acid (15 ml) was poured onto ice (24 ml). Concentrated hydrochloric acid (4.5 ml) was added and the mixture was stirred and cooled to <5° C. A solution of sodium nitrite (0.601 g) in water (5 ml) was added over 7 minutes and the mixture was stirred for 2 hours at 0-5° C. Aqueous sulphamic acid solution (10% w/v) was added until a negative starch iodide test was observed. In a separate flask toluene was added to a solution of cuprous chloride (0.852 g) in water (1.2 ml) and concentrated hydrochloric acid (1.3 ml) and the mixture was cooled to <0° C. The first preparation (diazonium salt) was then added to the cold cuprous chloride mixture over 5 minutes and the resultant mixture was stirred at ambient temperature for 18 hours. The organic layer was separated and the aqueous layer was extracted with toluene (3×10 ml). The organic extracts were combined, washed with water and brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-15% ethyl acetate/hexane to give the title compound (0.789 g). NMR: 2.1 (s, 3H), 7.1 (dd, 1H), 7.3 (d, 1H), 7.5 (d, 2H), 7.7 (d, 2H), 7.95 (d, 1H), 10.2 (brs, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[CH3:11].[CH3:12]OC(OC)N(C)C.N1CCCC1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:11]=[CH:12][NH:8]2
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Solvent: C1CCNC1
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cccc2[nH]ccc12
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 68 %

Procedure:
2-Bromo-6-nitrotoluene (3.2 g, 15 mmol), N,N-dimethylformamide dimethyl acetal (5.4 g, 45 mmol) and pyrrolidine (1.1 g, 15 mmol) were combined in 30 mL of DMF and heated at 110° C. The reaction mixture was stirred at 110° C. for 2.5 hours and then water was added. The aqueous layer was extracted with Et2O and the combined organic layers were washed with water and brine, dried over MgSO4 and concentrated. The brown syrup was dissolved in 80% aqueous AcOH (80 mL) and heated to 75° C. Zn powder (8.5 g), 130 mmol) was then added portionwise over 1 hour and the temperature was raised to 85° C. for 2 hours. The reaction mixture was filtered and water was added. The aqueous layer was extracted with Et2O and the combined organic layers were washed with saturated aqueous sodium bicarbonate and water, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 20% EtOAc in Hexanes to provide 2 g of the title compound as a greenish oil used as such.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:17]([C:20]1[CH:21]=[C:22]([C:25](=[O:30])C(Cl)(Cl)Cl)[NH:23][CH:24]=1)(=[O:19])[CH3:18].C(N(CC)C(C)C)(C)C>ClCCl>[C:17]([C:20]1[CH:21]=[C:22]([C:25]([NH:8][CH2:9]/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:30])[NH:23][CH:24]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reactant: CCOC(=O)/C=C/CN
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)/C=C/CNC(=O)c1cc(C(C)=O)c[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
Ethyl (2E)-4-aminobut-2-enoate trifluoroacetate (2.665 g, 10.963 mmol) was added to a solution of 1-(4-acetyl-1H-pyrrol-2-yl)-2,2,2-trichloroethanone (1.8 g, 7.07 mmol) and N,N-diisopropylethylamine (DIPEA) (5.4 mL, 32 mmol) in dichloromethane (20 mL) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum and the residue purified by flash chromatography (SiO2, hexane-EtOAc 1:1) to obtain the title compound as an off-white solid (1.2 g, 65% yield).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([OH:17])=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:10]=1)=[O:4].[C:24]([O-])([O-])=O.[K+].[K+].IC>O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([O:17][CH3:24])=[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)c(OC)c(-c2ccccc2)c1
Reaction time: 18 h
Yield: 99 %

Procedure:
At ambient temperature, to a stirred mixture containing 2′-hydroxy-[1,1′;3′,1″]terphenyl-5′-carboxylic acid methyl ester (1.232 g, 4.049 mmol) and K2CO3 (0.6155 g, 4.454 mmol) in N,N-DMF (10.1 mL) was added iodomethane (0.353 mL, 5.67 mmol). After 18 h, the reaction was diluted with H2O (100 mL) and the reaction was stirred vigorously. The resulting precipitate was collected, dissolved in CH2Cl2, dried (K2CO3) and concentrated to give 1.167 g, (99%) of the title compound. 1H NMR (DMSO-d6) δ 3.16 (s, 3H), 3.87 (s, 3H), 7.41-7.53 (m, 6H), 7.58-7.60 (m, 4H), 7.89 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:7]2=[C:8]([CH3:21])[N:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH3:20])=[CH:14][CH:13]=3)[C:10]([CH3:11])=[C:6]2[C:5]([CH3:22])=[N:4][N:3]=1.[CH3:23][O-:24].[Na+].[Na]>CO>[CH2:19]([O:18][C:15]1[CH:16]=[CH:17][C:12]([N:9]2[C:10]([CH3:11])=[C:6]3[C:7]([C:2]([O:24][CH3:23])=[N:3][N:4]=[C:5]3[CH3:22])=[C:8]2[CH3:21])=[CH:13][CH:14]=1)[CH3:20]
Reactant: CCOc1ccc(-n2c(C)c3c(C)nnc(Cl)c3c2C)cc1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: CCOc1ccc(-n2c(C)c3c(C)nnc(OC)c3c2C)cc1
Temperature: 100 °C

Procedure:
A solution of 1-chloro-6-(4-ethoxyphenyl)-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine (EXAMPLE 85) (100 mg, 0.32 mmol) and MeOH (5 mL) was treated with a solution of NaOMe (freshly prepared from MeOH (5 mL) and sodium metal (22 mg, 0.96 mmol)). The resulting mixture was placed in a resealable reaction vessel and heated at 100° C. for 12 h. The reaction was allowed to cool to rt, and poured into ice water (100 mL) to give 6-(4-ethoxyphenyl)-1-methoxy-4,5,7-trimethyl-6H-pyrrolo[3,4-d]pyridazine: 1H NMR (CDCl3, 500 MHz) δ 7.11-7.25 (m, 4H), 4.16 (q, 2H), 2.71 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H), 1.43-1.46 (t, 3H); MS (ESI) 312 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:17](OC)(=[O:25])[C:18]1[C:19](=[CH:21][CH:22]=[CH:23][CH:24]=1)[SH:20].C(N(CC)CC)C.C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:16][CH:10]([CH2:9][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]2[S:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[C:17](=[O:25])[N:2]=2)[CH:8]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)Cc1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)Cc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 52.7 %

Procedure:
Ethyl 3-(2-cyano-4-pyridyl)-2-methylpropionate (0.50 g, 2.3 mmol) and methyl thiosalicylate (0.96 g, 5.7 mmol) were dissolved in toluene (2 ml), and triethylamine (11.0 ml, 5.7 mmol) was added thereto. The reaction mixture was refluxed for 8 hrs and combined with isopropyl ether to precipitate crystals, which were collected by filtration and recrystallized from ethyl acetate to give the titled compound (0.43 g, 53%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][NH:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11])=[O:4].[C:14](=O)([O-])[O-].[K+].[K+].CI>C(#N)C>[CH3:13][O:12][C:10]([C:9]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][N:7]([CH3:14])[N:8]=1)=[O:11].[CH3:13][O:12][C:10]([C:9]1[N:8]=[N:7][N:6]([CH3:14])[C:5]=1[C:3]([O:2][CH3:1])=[O:4])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1nn[nH]c1C(=O)OC
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1nn(C)nc1C(=O)OC
Product: COC(=O)c1nnn(C)c1C(=O)OC
Reaction time: 20 h
Yield: 46 %
Yield: 34 %

Procedure:
1,2,3-Triazole-4,5-dicarboxylic acid dimethyl ester (Y. Tanaka et al. Tetrahedron 29, 3271 (1973)) (74.06 g; 0.40 mol), potassium carbonate (110.57 g; 0.80 mol) and methyl iodide (73.81 g; 0.52 mol) were reacted in acetonitrile (1000 ml) at 40° C. for 20 minutes and then for 20 hours at ambient temperature. The mixture was poured onto ice-water and extracted with ether to give the crude product (70.66 g) as a mixture of isomers. Separation on silica gel in ethyl acetate-hexane (2:3) yielded 36.51 g (46%) of 2-methyl-2H-1,2,3-triazole-4,5-dicarboxylic acid dimethylester [m.p. 86-87° C.; 1H-NMR (300 MHz, DMSO-d6), δ(ppm): 4.27(s,3H), 3.88(s,6H)] and 26.92 g (34%) of 1-methyl-1H-1,2,3-triazole-4,5-dicarboxylic dimethylester [m.p. 63-64° C.; 1H-NMR (300 MHz, DMSO-d6), δ(ppm): 4.19(s,3H), 3.93(s,3H), 3.87(s,3H)].
Reaction SMILES: CCN(CC)CC.Cl.[NH2:9][OH:10].[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[CH3:23]>O1CCOCC1.CCOC(C)=O>[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[N:9][OH:10])=[CH:17][C:16]=1[CH3:23]
Reactant: NO
Reactant: COCOc1ccc(C=O)cc1C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCOc1ccc(C=NO)cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 86.4 %

Procedure:
Et3N (1.68 mL, 12.0 mmol) and hydroxylamine hydrochloride (320 mg, 4.64 mmol) were added to a solution of 4-(methoxymethoxy)-3-methylbenzaldehyde (620 mg, 3.44 mmol) in 1,4-dioxane (12 mL). The reaction mixture was sonicated for 10 min and stirred at 25° C. for 3 d. The reaction mixture was diluted with EtOAc and successively washed with water and brine, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Hexane:EtOAc, 3:1) to provide the title compound (580 mg, 86% yield) as a clear gum.
Reaction SMILES: O[Li].O.[Br:4][C:5]1[CH:6]=[C:7]([C:20]([O:22]C)=[O:21])[N:8]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])[CH:9]=1>C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]([C:20]([OH:22])=[O:21])[N:8]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])[CH:9]=1
Reactant: COC(=O)c1cc(Br)cn1CC(=O)c1ccc(Cl)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cn1cc(Br)cc1C(=O)O)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
LiOH H2O (0.2 M, 6.8 mL, 1.36 mmol) was added portionwise to a solution of crude methyl 4-bromo-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (210 mg, 0.39 mmol) in THF (0.5 mL), and the mixture stirred at 40° C. for 3 h, after which time the TLC analysis showed consumption of starting material ester. The reaction mixture was diluted with aqueous NaOH solution (1 M) (50 mL) and the mixture washed with CH2Cl2 (100 mL). The aqueous layer was acidified to pH 2 with aqueous HCl solution (1 M) and was extracted with CH2Cl2 containing 30% of propan-2-ol (2×150 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo to give 4-bromo-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid (100 mg, yield 75%). This crude material was used in the next step without further purification.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][C:6]1[N:10]=[N:9][N:8]([CH:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]=[CH:18][C:17]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[CH:16]3)[CH3:12])[C:7]=1[C:28]([NH:30][C:31]1[S:35][N:34]=[C:33]([CH3:36])[CH:32]=1)=[O:29])C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC(Cl)C.ClCCl>[CH3:27][O:26][CH2:25][CH2:24][O:23][C:17]1[CH:18]=[N:19][C:20]2[C:15]([CH:16]=1)=[CH:14][C:13]([C@@H:11]([N:8]1[C:7]3[C:28](=[O:29])[N:30]([C:31]4[S:35][N:34]=[C:33]([CH3:36])[CH:32]=4)[CH:4]=[CH:5][C:6]=3[N:10]=[N:9]1)[CH3:12])=[CH:22][CH:21]=2
Reactant: CCOC(Cc1nnn(C(C)c2ccc3ncc(OCCOC)cc3c2)c1C(=O)Nc1cc(C)ns1)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COCCOc1cnc2ccc([C@H](C)n3nnc4ccn(-c5cc(C)ns5)c(=O)c43)cc2c1
Temperature: 100 °C

Procedure:
5-(2,2-diethoxyethyl)-3-(1-(3-(2-methoxyethoxy)quinolin-6-yl)ethyl)-N-(3-methylisothiazol-5-yl)-3H-1,2,3-triazole-4-carboxamide (0.296 g, 0.53 mmol) was dissolved in dichloroethane (5 mL) and to the solution was added p-toluenesulfonic acid monohydrate (0.11 g, 0.59 mmol). The reaction mixture was heated at 100° C. overnight. The reaction mixture was diluted with dichloromethane then washed with sat. aq. sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The enantiomers were separated via preparative SFC (ChiralPak® AD-H, 20×250 mm, 40:60:0.2 IPA:CO2:DEA, 80 mL/min; tr 1.38 min) to yield (S)-3-(1-(3-(2-methoxyethoxy)quinolin-6-yl)ethyl)-5-(3-methylisothiazol-5-yl)-3H-[1,2,3]triazolo[4,5-c]pyridin-4(5H)-one as a pale yellow solid. On the basis of previous crystallographic data and potency recorded for related compounds in the same program, the absolute stereochemistry was assigned as the S enantiomer. MS m/z=463.2 [M+1]+. Calc'd 462.5 for C23H22N6O3S. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.15 (d, 3 H) 2.39-2.44 (m, 3 H) 3.30-3.32 (m, 3 H) 3.71 (dd, 2 H) 4.23 (dd, 2 H) 6.89 (q, 1 H) 7.33 (d, 1 H) 7.64 (dd, 1 H) 7.74-7.82 (m, 3 H) 7.94 (d, 1 H) 8.34 (d, 1 H) 8.61 (d, 1 H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:5]=2[S:6][C:7]=1C(OCC)=O.ClC1C=CC2SC=C(C)C=2C=1>>[Br:1][CH2:2][C:3]1[C:4]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:5]=2[S:6][CH:7]=1
Reactant: CCOC(=O)c1sc2ccc(Cl)cc2c1CBr
Agent: Cc1csc2ccc(Cl)cc12
Product: Clc1ccc2scc(CBr)c2c1
Yield: 57 %

Procedure:
Using the general procedure of Example 1, Method A, (iv), replacing ethyl 5-chloro-3-methylbenzo[b]thiophene-2-carboxylate with 5-chloro-3-methylbenzo[b]thiophene gave 2.78 g (57%) of 3-bromomethyl-5-chlorobenzo[b]thiophene: mp 126°-128° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[OH:35])O1.C([O-])([O-])=O.[K+].[K+].CC#N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[OH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1
Reactant: CC1(C)OB(c2ccccc2O)OC1(C)C
Reactant: CC(C)COC(=O)N1CCN(c2cc(Cl)ncn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)COC(=O)N1CCN(c2cc(-c3ccccc3O)ncn2)CC1
Temperature: 130 °C

Procedure:
A mixture of isobutyl 4-(6-chloropyrimidin-4-yl)piperazine-1-carboxylate (0.10 g, 0.33 mmol), 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenol (87 mg, 0.11 mmol), Pd(PPh3)4 (3.8 mg, 3.3 μmol), K2CO3 (91 mg, 0.66 mmol), CH3CN (1 mL), and H2O (0.1 mL) was sealed in a microwave reactor vial. The reaction mixture was heated by microwave irradiation at 130° C. for two minutes. The reaction was filtered and purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give isobutyl 4-(6-(2-hydroxyphenyl)pyrimidin-4-yl)piperazine-1-carboxylate. LC/MS: m/z 357.3 (M+H)+ at 2.72 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C([C@H]1CSC(=O)N1[C:14]([C@@H:16]([C@@H:29]([OH:46])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=2)=[CH:34][CH:33]=1)[CH2:17][N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]=[N:19]1)=[O:15])C1C=CC=CC=1.[OH:47]O.O.[OH-].[Li+]>O1CCCC1.O.O>[F:45][C:40]1[CH:39]=[C:38]([C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][C@@H:29]([OH:46])[C@H:16]([CH2:17][N:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[N:20]=[N:19]3)[C:14]([OH:15])=[O:47])=[CH:37][CH:36]=2)[CH:43]=[C:42]([F:44])[CH:41]=1
Reactant: OO
Reactant: O=C1SC[C@H](Cc2ccccc2)N1C(=O)[C@H](Cn1nnc2ccccc2c1=O)[C@@H](O)CCc1ccc(-c2cc(F)cc(F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H](Cn1nnc2ccccc2c1=O)[C@H](O)CCc1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of the compound obtained from step f above (0.2 g) in tetrahydrofuran:water (3:1, 10 mL) aqueous hydrogen peroxide solution (30%, 0.16 mL) was added at 0° C., followed by the addition of lithium hydroxide monohydrate (19.53 mg) in water (2 mL). The reaction mixture was stirred at 0° C. until the completion of the hydrolysis. The reaction mixture was concentrated and the residue was extracted with ethyl acetate. The aqueous layer was acidified with sodium hydrogen sulphate and extracted with ethyl acetate. The combined layers were washed with water and brine and dried over anhydrous sodium sulphate. The solvents were evaporated under reduced pressure, and the crude residue was purified by silica gel flash column chromatography using 10% methanol in dichloromethane as eluant to afford the title compound (0.090 g).
Reaction SMILES: [F:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[CH3:9][C@@H:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C>[CH3:9][CH:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[F:1][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(C)C(F)C(=O)O
Solvent: CCOC(C)=O
Product: CC(C)[C@H](F)C(=O)O
Product: CC(N)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The 2-fluoro-3-methylbutyric acid (˜235.5 g, 1.96 mol), is taken up in ethyl acetate (2.9 L) and R-(+)-α-methylbenzylamine (237.5 g, 1.96 mol) is added dropwise via an addition funnel. A temperature rise to 40° C. is observed. Upon allowing the solution to cool, a slurry results and is stirred at room temperature for 45 minutes. The slurry is then filtered and the filter cake rinsed with ethyl acetate (300 mL). The wet cake is suspended in ethyl acetate (4.5 L) and heated to reflux. Additional ethyl acetate (450 mL) is added to provide a solution, and then the solution is allowed to stand at room temperature overnight. The resulting slurry is filtered and the filter cake rinsed with ethyl acetate (200 mL). The filter cake is vacuum dried at 40° C. to afford 262.3 g of the (R)-+-α-methylbenzylamine salt of (S)-2-fluoro-3-methylbutyric acid as a powder. The enantiomeric excess of this salt is found to be >94% by chiral capillary electrophoresis analysis for the desired (S) isomer.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:45][NH:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>ClCCl>[CH2:47]([N:46]([CH3:45])[C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Reactant: CNCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CN(Cc1ccccc1)C(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 2.5 °C
Reaction time: 0.25 h

Procedure:
(S)-N-tert-butoxycarbonyl-2-phenylglycine (250 g) and 1-hydroxybenzotriazole hydrate (136.2 g) and N,N′-dicyclohexylcarbodimide (205.1 g) were combined in dichloromethane (3000 mL) at 0-5° C. and the mixture stirred for 15 minutes. A solution of N-methylbenzylamine (128.1 mL) in dichloromethane (835 mL) was added slowly, maintaining 0-5° C. The resulting slurry was allowed to warm to room temperature overnight before being filtered, washing the by-product solids with dichloromethane (500 mL). The combined filtrate was twice washed with saturated aqueous sodium hydrogen carbonate (2×1500 mL), twice washed with 50% saturated aqueous sodium hydrogen carbonate solution (2×1500 mL), once washed with 2.5% aqueous citric acid solution (1500 mL) and once washed with demineralized water (1500 mL), providing a dichloromethane solution of tert-butyl (S)-2-[benzyl(methyl)amino]-2-oxo-1-phenylethylcarbamate. Analysis by chiral HPLC showed that 2% of the wrong enantiomer (tert-butyl (R)-2-[benzyl(methyl)amino]-2-oxo-1-phenylethylcarbamate) to be present at this stage.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:12]=[C:13]([CH:17]=[O:18])[CH:14]=[N:15][CH:16]=3)[NH:8]2)=[CH:4][CH:3]=1.CI.[CH3:21]N(C=O)C.[H-].[Na+]>O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]3[CH:16]=[N:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=3)[N:8]2[CH3:21])=[CH:4][CH:3]=1
Reactant: O=Cc1cncc(-c2cc3ccc(Cl)cc3[nH]2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1c(-c2cncc(C=O)c2)cc2ccc(Cl)cc21
Reaction time: 2 h

Procedure:
A flask is charged with 5-(6-chloro-1H-indol-2-yl)-pyridine-3-carbaldehyde (Example 104, 7.8 g, 28.9 mmol), MeI (5.33 g, 37.5 mmol) and DMF (300 mL), and 60% NaH in mineral oil (1.386 g, 34.6 mmol) is added at 0° C. The mixture is stirred for 2 h. Water (100 mL) is added. The mixture is extracted with EtOAc twice and the combined organic phase is washed with water (2×200 mL) and brine (200 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography with a 0 to 2% methanol-DCM gradient to give 6-chloro-2-(5-formyl-pyridin-3-yl)-1-methyl-1H-indole. MS (ESI) m/z 271.0, 272.9 (M+H)+.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][CH:5]([O:7][CH:8]1[CH2:20][CH2:19][C:18]([O:22][CH:23]([O:25][CH2:26][CH3:27])[CH3:24])([CH3:21])[CH:17]([O:28][C:29]2C=CC([N+]([O-])=O)=CC=2)[CH:16]=[CH:15][CH:14]([CH3:38])[CH:13](/[C:39](/[CH3:60])=[CH:40]/[CH:41]=[CH:42]/[CH:43]([CH3:59])[CH2:44][CH:45]2[O:58][CH:46]2[CH:47]([CH3:57])[CH:48]([O:51][CH:52]([O:54][CH2:55][CH3:56])[CH3:53])[CH2:49][CH3:50])[O:12][C:10](=[O:11])[CH:9]1C(O)=O)[CH3:6])[CH3:3].C(OCC)(=O)C.[OH2:70]>O1CCCC1>[C:29]([O:28][CH:17]1[C:18]([O:22][CH:23]([O:25][CH2:26][CH3:27])[CH3:24])([CH3:21])[CH2:19][CH2:20][CH:8]([O:7][CH:5]([O:4][CH2:2][CH3:3])[CH3:6])[CH2:9][C:10]([O:12][CH:13](/[C:39](/[CH3:60])=[CH:40]/[CH:41]=[CH:42]/[CH:43]([CH3:59])[CH2:44][CH:45]2[O:58][CH:46]2[CH:47]([CH3:57])[CH:48]([O:51][CH:52]([O:54][CH2:55][CH3:56])[CH3:53])[CH2:49][CH3:50])[CH:14]([CH3:38])[CH:15]=[CH:16]1)=[O:11])(=[O:70])[NH2:1]
Reactant: CCOC(C)OC1CCC(C)(OC(C)OCC)C(Oc2ccc([N+](=O)[O-])cc2)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1C(=O)O
Reactant: N
Reactant: O
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(N)=O)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Agent: CCOC(C)OC1CCC(C)(OC(C)OCC)C(Oc2ccc([N+](=O)[O-])cc2)/C=C/C(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1C(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(C)OC1CCC(C)(OC(C)OCC)C(OC(N)=O)C=CC(C)C(/C(C)=C/C=C/C(C)CC2OC2C(C)C(CC)OC(C)OCC)OC(=O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
28% Aqueous ammonia solution (20 μL, 300 μmol) was added dropwise to a solution of the crude (8E,12E,14E)-3,6,21-tri(1-ethoxyethoxy)-6,10,12,16,20-pentamethyl-7-(4-nitrophenoxy)carboxy-18,19-epoxytricosa-8,12,14-trien-11-olide (10 mg, about 5.3 μmol) in tetrahydrofuran (1.5 mL), followed by stirring at room temperature for 3 hours. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate, filtered and then evaporated. The resulting residue was purified by thin layer chromatography (MERCK Silica gel 60 F254, 0.2 mm, developing solution; ethyl acetate-hexane, 1:1) to give the title compound (3.6 mg, 90%, 2 steps) as a colorless oil.