Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:30]=[CH:29][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[C:19]([CH:23]=3)[C:20]([O-:22])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:31][CH3:32])[CH:4]=1)=[O:2].[CH2:33](O)C.[BH4-].[Na+].Cl>O1CCCC1>[OH:2][CH2:1][C:3]1[CH:30]=[CH:29][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[C:19]([CH:23]=3)[C:20]([O:22][CH3:33])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:31][CH3:32])[CH:4]=1
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2ccc(OS(C)(=O)=O)c(C(=O)[O-])c2)oc1C
Reactant: CCO
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)ccc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a solution of methyl (5-{4-[(4-formyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methanesulfonyloxybenzoate (5.70 g) in tetrahydrofuran (100 mL)-ethanol (10 mL) was gradually added sodium borohydride (0.23 g) at 0° C. After stirring the reaction mixture at room temperature for 2 hrs, dilute hydrochloric acid was added to acidify the solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (5:1, v/v) to give methyl 5-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methanesulfonyloxybenzoate as colorless crystals (4.02 g, yield 70%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 126-127° C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]4[CH2:53][CH2:52]4)=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1(CO)[CH2:54][OH:55])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH2:49][O:50][CH:51]5[CH2:53][CH2:52]5)=[CH:45][CH:46]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:54][OH:55])[CH2:32][O:31]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCCOC4CC4)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCCOC5CC5)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol if (320 mg, 0.4 mmol) was dissolved in 10 mL methylene chloride and cooled to −10° C., followed by addition of trifluoroacetic acid (62 mL, 0.8 mmol). The mixture was stirred for 1 hour. Thereafter, the reaction mixture was partitioned after 10 mL saturated sodium bicarbonate solution were added. The aqueous phase was extracted with dichlormethane (10 mL) and the organic extract was washed with saturated sodium chloride solution (10 mL), combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-[2-(cyclopropoxy)ethoxy]phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 1g (230 mg, colorless oil), yield: 75.3%. MS m/z (ESI): 780.3 [M+18]. 1H NMR (400 MHz, CDCl3): δ 7.33 (m, 12H), 7.15 (m, 4H), 7.05 (m, 2H), 6.86 (d, 2H), 6.76 (d, 2H), 4.77 (m, 4H), 4.27 (m, 2H), 4.00 (m, 6H), 3.83 (m, 3H), 3.70 (m, 4H), 3.38 (m, 1H), 0.63 (m, 2H), 0.48 (m, 2H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][C:14](=[O:32])[CH:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH:27]1[O:31][CH2:30][CH2:29][O:28]1)[CH2:16][CH2:17][CH3:18])[CH3:12].I[CH2:34][CH2:35][CH3:36]>C1COCC1.C(OCC)(=O)C>[CH2:11]([O:13][C:14](=[O:32])[C:15]([O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=1[CH:27]1[O:31][CH2:30][CH2:29][O:28]1)([CH2:34][CH2:35][CH3:36])[CH2:16][CH2:17][CH3:18])[CH3:12]
Reactant: CCCC(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OCC
Reactant: CCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(CCC)(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
Lithium bis(trimethylsilyl)amide (26 mL, 26 mmol, 1 M in THF) was slowly added to a solution of 2-(4-Chloro-2-[1,3]dioxolan-2-yl-phenoxy)-pentanoic acid ethyl ester (6.6 g, 20 mmol) in 60 mL of anhydrous THF at −78° C. After the mixture was stirred for 30 min at −78° C., 1-Iodopropane (4 mL, 40 mmol) was added. The mixture was allowed to warm to room temperature and stirred for 2 h. Then the mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of NH4Cl, dried over anhydrous Na2SO4 and concentrated to give the title compound as a yellow oil (5 g).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:82][CH2:83][CH2:84][CH2:85][NH:86]C(OC(C)(C)C)=O)[C:10]([NH:12][CH2:13][CH2:14][C:15]([O:17][C@@H:18]([CH2:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[C:62]([C:63]#[N:64])=[C:61]([S:65][CH2:66][C:67]3[N:68]=[C:69]([C:72]4[CH:77]=[CH:76][C:75]([Cl:78])=[CH:74][CH:73]=4)[O:70][CH:71]=3)[N:60]=[C:59]([NH2:79])[C:58]=2[C:80]#[N:81])=[CH:53][CH:52]=1)[CH2:19][O:20][C:21](=[O:48])[CH2:22][CH2:23][NH:24][C:25](=[O:47])[C@@H:26]([NH:39]C(OC(C)(C)C)=O)[CH2:27][CH2:28][CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)=[O:16])=[O:11])=O)(C)(C)C.[F:94][C:95]([F:100])([F:99])[C:96]([OH:98])=[O:97]>ClCCl>[F:94][C:95]([F:100])([F:99])[C:96]([OH:98])=[O:97].[F:94][C:95]([F:100])([F:99])[C:96]([OH:98])=[O:97].[F:94][C:95]([F:100])([F:99])[C:96]([OH:98])=[O:97].[F:94][C:95]([F:100])([F:99])[C:96]([OH:98])=[O:97].[NH2:39][C@@H:26]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[C:25]([NH:24][CH2:23][CH2:22][C:21]([O:20][CH2:19][C@@H:18]([O:17][C:15](=[O:16])[CH2:14][CH2:13][NH:12][C:10](=[O:11])[C@@H:9]([NH2:8])[CH2:82][CH2:83][CH2:84][CH2:85][NH2:86])[CH2:49][O:50][C:51]1[CH:52]=[CH:53][C:54]([C:57]2[C:62]([C:63]#[N:64])=[C:61]([S:65][CH2:66][C:67]3[N:68]=[C:69]([C:72]4[CH:77]=[CH:76][C:75]([Cl:78])=[CH:74][CH:73]=4)[O:70][CH:71]=3)[N:60]=[C:59]([NH2:79])[C:58]=2[C:80]#[N:81])=[CH:55][CH:56]=1)=[O:48])=[O:47]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)NCCC(=O)OC[C@H](COc1ccc(-c2c(C#N)c(N)nc(SCc3coc(-c4ccc(Cl)cc4)n3)c2C#N)cc1)OC(=O)CCNC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](COC(=O)CCNC(=O)[C@@H](N)CCCCN)OC(=O)CCNC(=O)[C@@H](N)CCCCN)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An amount of 70 mg (0.058 mmol) of the compound from example 31A was introduced in 0.5 ml of dichloromethane, admixed with 0.045 ml (0.578 mmol) of trifluoroacetic acid and stirred at RT. After 3 hours, again, the same amount of trifluoroacetic acid was added and the mixture was stirred at RT overnight. The reaction mixture was then concentrated and the residue was purified by means of preparative HPLC (eluent gradient: acetonitrile/water 10:90→95:5 with addition of 0.1% TFA). This gave 45 mg (55% of theory) of the target compound.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([CH:29](F)[C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)=[C:27]([CH:42]([CH3:44])[CH3:43])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:47])[CH2:22][C:23]([CH3:46])([CH3:45])[O:24]3)=[CH:15][CH:14]=1.CO>O1CCCC1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:28]([CH2:29][C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:38])([F:39])[F:40])=[CH:32][CH:31]=3)=[C:27]([CH:42]([CH3:43])[CH3:44])[CH:26]=[C:25]3[C:20]=2[C@@H:21]([OH:47])[CH2:22][C:23]([CH3:45])([CH3:46])[O:24]3)=[CH:17][CH:18]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(F)c1ccc(OC(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1Cc1ccc(OC(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Reaction time: 0.5 h

Procedure:
230 μl (1.29 mmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 7.23 mg (50 μmol) of (1R,2S)-1-aminoindan-2-ol in 8 ml of tetrahydrofuran, and the mixture is stirred for 30 min. A solution of 163 mg (320 μmol) of rac-5-(4-fluorophenyl)-6-{fluoro[4-(trifluoromethoxy)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 25A) in 8 ml of tetrahydrofuran is then slowly added dropwise. The mixture is stirred at room temperature overnight, methanol is then added and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. Purification of the residue by preparative HPLC (method 1) gives the target product.
Reaction SMILES: [H][H].[CH2:3]=[CH:4]CCCC.[CH2:9]=[CH:10][CH2:11][CH2:12][CH:13]=[CH2:14].[CH:15]([CH:17]1CC[CH2:20][CH2:19][CH2:18]1)=[CH2:16]>>[CH2:3]=[CH2:4].[CH2:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14].[CH2:16]=[CH:15][CH2:17][CH2:18][CH:19]=[CH2:20]
Reactant: [H][H]
Reactant: C=CC1CCCCC1
Agent: C=CCCC=C
Solvent: C=CCCCC
Product: C=C
Reaction time: 0.1 h

Procedure:
Polymerization was conducted in the same manner as in Example 7 except that 0.0547 MPa of hydrogen was charged, 11 mL of 1-hexene and 3 mL of 1,5-hexadiene were charged as addition polymerizable monomers instead of vinylcyclohexane, and 1.5 μmol of dimethylsilylene(tetramethylcyclopentadienyl)(3-tert-butyl-5-methyl-2-phenoxy)titanium dichloride instead of isopropylidene(cyclopentadienyl)(3-tert-butyl-5-methyl-2-phenoxy)titanium dichloride, and 7.5 μmol of dimethylaniliniumtetrakis(pentafluorophenyl) borate were used, the charging temperature was changed to 80° C. and the polymerization time was changed to 6 minutes. As a result of the polymerization, 53 g of an ethylene/1-hexene/1,5-hexadiene ternary copolymer was obtained having a melt viscosity η*190 of 1.20×103 Pa·se, a fusion heat quantity ΔH of 123 kJ/kg, a melting temperature of 113° C., and a Mw/Mn of 2.2. The resulted ethylene-based copolymer had a tensile impact strength TI of 890 kJ/m2 and a melt tension MT of 7.2 cN The results are shown in Table 5.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:16])[C:3]=1[C:17](Cl)=[O:18].[NH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1>>[S:22]1[CH:23]=[CH:24][N:25]=[C:21]1[NH:20][C:17]([C:3]1[C:4]([CH3:16])=[N:5][C:6]2[C:11]([C:2]=1[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])=[O:18]
Reactant: Nc1nccs1
Reactant: Cc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Cl
Product: Cc1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1

Procedure:
Using the procedure of Example 1, the product of Step D and 2-aminothiazole were reacted to obtain N-(2-thiazolyl)-4-hydroxy-2-methyl-8-trifluoromethyl-quinoline-3-carboxamide melting at 267° C.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8](Cl)[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][O-:15].[Na+]>CO>[Cl:1][C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]([O:15][CH3:14])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(Cl)cc(Cl)nc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(OC)cc(Cl)nc1Cl
Reaction time: 17 h

Procedure:
To a solution of methyl 2,4,6-trichloronicotinate [(5.04 g, 20.96 mmol), prepared as described in WO2010/31589] in methanol (52 mL) was added the sodium methoxide (25 wt % in methanol, 5.04 mL, 22.0 mmol) at room temperature. The cloudy white mixture was stirred for 17 h, then partitioned between EtOAc and water. The layers were separated and the aqueous layer was further extracted with EtOAc (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by FCC (0-20% EtOAc:heptane) to provide methyl 2,6-dichloro-4-methoxynicotinate. MS (ESI+) m/z 236.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:21][CH:22]([CH2:30][CH3:31])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20].[CH:32](NC(C)C)(C)[CH3:33].[Li].C(I)C.[NH4+].[Cl-]>O1CCCC1>[CH2:30]([C:22]([O:21][CH2:1][CH2:2][CH2:3][CH2:4]/[CH:5]=[CH:6]\[CH2:7]/[CH:8]=[CH:9]\[CH2:10]/[CH:11]=[CH:12]\[CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH3:20])([CH2:32][CH3:33])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH3:31]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)C(=O)OC(C)(C)C
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CCI
Solvent: C1CCOC1
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCCCOC(CC)(CC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
tert-Butyl 2-((5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaen-1-yloxy)butanoate (480 mg, 1.11 mmol) was added dropwise over 30 minutes to a solution of lithium diisopropylamine (LDA) (2.0 M, 750 μL, 1.50 mmol) in dry tetrahydrofuran (10 mL) held at −70° C. under nitrogen. The reaction mixture was stirred for 30 minutes. Ethyl iodide (312 mg, 2.00 mmol) was added in one portion and the resulting mixture was warmed to ambient temperature during 1 hour. The reaction mixture was stirred at ambient temperature for 17 hours. The mixture was poured into saturated NH4Cl (aq.) (50 mL) and extracted with heptane (2×50 mL). The combined organic phases was washed successively with brine (50 mL), 0.25 M HCl (50 mL) and brine (50 mL), dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel using increasingly polar mixtures of heptane and ethyl acetate (100:0→95:5) as eluent. Concentration of the appropriate fractions afforded 343 mg (67% yield) of the title compound as an oil. 1H NMR (300 MHz, CDCl3): δ 0.84 (t, 6H), 0.99 (td, 3H), 1.35-1.55 (m, 11H), 1.54-1.69 (m, 2H), 1.68-1.87 (m, 4H), 1.99-2.24 (m, 4H), 2.74-2.99 (m, 8H), 3.31 (t, 2H), 5.23-5.52 (m, 10H); MS (electro spray): 401.3 [M−1]−.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[OH:20][C:21]1[CH:34]=[CH:33][C:24]2[C:25]([C:29]([O:31][CH3:32])=[O:30])=[C:26]([CH3:28])[O:27][C:23]=2[CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:19][O:18][CH:15]1[CH2:16][CH2:17][N:13]([C:11]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:20][C:21]3[CH:34]=[CH:33][C:24]4[C:25]([C:29]([O:31][CH3:32])=[O:30])=[C:26]([CH3:28])[O:27][C:23]=4[CH:22]=3)[CH:8]=2)=[O:12])[CH2:14]1
Reactant: COC(=O)c1c(C)oc2cc(O)ccc12
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1c(C)oc2cc(Oc3ccnc4cc(C(=O)N5CCC(OC)C5)sc34)ccc12
Yield: 58.5 %

Procedure:
This material was prepared by the reaction of 7-chloro-2-[(R)-3-methoxypyrrolidine-1-carbonyl]thieno[3,2-b]pyridine 4b (707 mg, 2.38 mmole) with methyl 6-hydroxy-2-methyl-benzofuran-3-carboxylate 89c (565 mg, 2.74 mmole) and Cs2CO3 (3.10 g, 9.53 mmole) in a manner as previously described for example to give 650 mg (58%) of an off-white solid. 1H NMR (DMSO-d6) δ8.57 (1H, d, J=5.3 Hz), 8.07 (1H, s), 7.96 (1H, d, J=8.6 Hz), 7.75 (1H, d, J=2.0 Hz), 7.31 (1H, dd, J=8.6, 2.0 Hz), 6.74 (1H, d, J=5.6 Hz), 4.10-3.85 (3H, m), 3.90 (3H, s), 3.65-3.45 (2H, m), 3.25 (3H, d, J=12.6 Hz), 2.77 (3H, s), 2.15-1.95 (2H, m).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[N:8]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([OH:21])=[CH:11][CH:10]=2)[CH3:2].Br[CH2:34][C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([F:45])[CH:41]=2)[N:36]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH2:1]([O:3][C:4](=[O:32])[C:5]([CH3:31])([CH3:30])[CH2:6][C:7]1[N:8]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([Br:29])=[CH:27][CH:28]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([O:21][CH2:34][C:35]1[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([F:45])[CH:41]=3)[N:36]=1)=[CH:11][CH:10]=2)[CH3:2]
Reactant: Fc1ccc2nc(CBr)ccc2c1
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3ccc4cc(F)ccc4n3)ccc2n1Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To 3-[1-(4-Bromo-benzyl)-3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester (C-3; 2.0 g, 3.9 mmol) in MeCN (25 mL) was added 2-bromomethyl-6-fluoro-quinoline (1.0 g, 4.2 mmol), and Cs2CO3 (2.5 g, 7.7 mmol). The reaction was stirred at room temperature overnight, after which LCMS showed the reaction was complete. The reaction mixture was partitioned between EtOAc and water, the aqueous layer was extracted with EtOAc, and the combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was recrystallized in EtOAc:hexane to give the desired product (F-1, 1.9 g). The filtrate was concentrated and purified on silica gel (0 to 15% EtOAc in hexanes) to give an additional 1 g of F-1.
Reaction SMILES: [S:1]([O:5]S([O-])(=O)=O)([O-:4])(=[O:3])=[O:2].[NH4+:10].[NH4+].[S:12](=[O:16])(=[O:15])([OH:14])[O-:13].[NH4+].S(OS([O-])(=O)=O)([O-])(=O)=O.S(=O)(=O)(O)[O-]>S([O-])([O-])(=O)=O.[NH4+].[NH4+].O>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[NH4+:10].[NH4+:10].[S:12](=[O:14])(=[O:13])([OH:16])[OH:15]
Reactant: O=S(=O)([O-])O
Reactant: O=S(=O)([O-])OS(=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: O=S(=O)(O)O

Procedure:
At the conclusion of the thermal decomposition reaction, solids or molten liquid comprising the decomposition product are removed from the reactor or allowed to cool in the reactor. In either case, water is added to the decomposition product to produce a second stream. With ammonium sulfate as the primary compound in the ammonium sulfate (first) stream, the addition of water converts preferably all or most of the ammonium pyrosulfate which may be present to ammonium bisulfate. With other sulfate salts present in the ammonium sulfate stream, the corresponding pyrosulfate salts, if present, are converted into bisulfate salts. Without wishing to be bound by theory, when water is added to the decomposition product, salts may be formed in equilibrium with ammonium sulfate and sulfuric acid.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23](=[O:31])[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:17]=2)=[C:10]([CH3:32])[CH:9]=1)=[O:6]>CCO.CCOC(C)=O.[Ni]>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH:23]([OH:31])[C:18]2[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=2[OH:22])[O:15][C:11]2[C:12]([CH3:14])=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([OH:33])=[O:2])=[CH:9][C:10]=2[CH3:32])=[CH:25][CH:26]=1
Reactant: COC(=O)CC(=O)Nc1cc(C)c(Oc2ccc(O)c(C(=O)c3ccc(F)cc3)c2)c(C)c1
Agent: [Ni]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)CC(=O)O)cc(C)c1Oc1ccc(O)c(C(O)c2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of N-{4-[3-(4-fluoro-benzoyl)-4-hydroxy-phenoxy]-3,5-dimethyl-phenyl}-malonamic acid methyl ester (222 mg, 0.49 mmol) in a mixture of EtOH/EtOAc (4:1, 25 mL) was added nickel catalyst (2 mL, water and methanol washed). The mixture was hydrogenated under 50 psi at room temperature for 1 h. The catalyst was filtered off and the filtrate was concentrated. The residue was purified by preparative TLC to give the title compound of Step A (159 mg) as a white solid. MS (APCl−) Calc.: 453.2, Found: 452.2 (M−1).
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:25]=[CH:24][C:23](OS(C(F)(F)F)(=O)=O)=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].CN(C=O)C.[CH3:41][C:42]([OH:46])([C:44]#[CH:45])[CH3:43]>CCOCC>[O:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:25]=[CH:24][C:23]([C:45]#[C:44][C:42]([CH3:43])([OH:46])[CH3:41])=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[Si:2]([C:5]([CH3:7])([CH3:8])[CH3:6])([CH3:4])[CH3:3]
Reactant: C#CC(C)(C)O
Reactant: CCC(CC)(c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1)c1ccc(OS(=O)(=O)C(F)(F)F)c(C)c1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCC(CC)(c1ccc(C#CC(C)(C)O)c(C)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1
Temperature: 65 °C
Yield: 32.3 %

Procedure:
To an oven-dried, argon-sparged flask was added Pd[PPh3]4 (46 mg) and anhyd Cul (15 mg). To the flask under argon was added a solution of trifluoromethanesulfonic acid 4-{1-[4-(tert-butyl-dimethylsiloxy)-3-methylphenyl]-1-ethyl-propyl}-2-methylphenyl ester (0.42 g, 0.80 mmol) in anhyd DMF (2.5 mL), TEA (0.56 mL, 4.0 mmol) and 2-methyl-3-butyn-2-ol (0.12 mL, 1.2 mmol). After heating at 65° C. for 15 h, the reaction mixture was diluted with Et2O (50 mL), washed with H2O (2×30 mL) and brine, then dried (Na2SO4) and concentrated under reduced pressure. The crude material was chromatographed (silica, EtOAc/Hex, 0:100 to 10:90) to afford the title compound (0.12 g, 32%) as an orange oil. 1H-NMR (CDCl3) δ 7.26 (1.4H, d, J=8.1), 7.01 (1H, d, J=1.8), 6.94 (1H, dd, J=1.8, 8.1), 6.85 (1H, d, J=2.3), 6.80 (1H, dd, J=2.3, 8.3), 6.63 (1H, d, J=8.3), 2.36 (3H, s), 2.14 (3H, s), 2.03 (4H, q, J=7.3), 1.63 (6H, s), 1.01 (9H, s), 0.59 (6H, t, J=7.3), 0.20 (6H, s); Rf=0.10 (silica, 1:9 EtOAct/Hx).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CCN(C(C)C)C(C)C>[OH:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCOCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCCOCCO)ccc21
Yield: 72.5 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide (220 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (250 mg), 2-(2-aminoethoxy)ethanol (71 mg), HBTU (279 mg), and DIEA (160 uL). LC/MS: m/z 496.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.39 (bs, 1H), 8.47 (t, 1H), 8.09 (s, 1H), 7.91 (s, 1H), 7.78 (d, 1H), 7.73 (d, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 4.61 (t, 1H), 3.64 (s, 3H), 3.57 (t, 2H), 3.51 (t, 2H), 3.49-3.41 (m, 4H).