Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.C(NC(C)C)(C)C.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1.[I:21]I>C([Li])CCC.O>[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([I:21])[CH:17]=[CH:16][N:15]=1
Reactant: II
Reactant: Clc1cccnc1Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Clc1nccc(I)c1Cl
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 70588.8 %

Procedure:
With cooling with ice, 2.66 M n-butyllithium (100 mL, 0.266 mmol) was added to a tetrahydrofuran (400 mL) solution of diisopropylamine (11.9 mL, 84.2 mmol), cooled to −70° C., and stirred for 0.5 hours. A tetrahydrofuran (170 mL) solution of 2,3-dichloropyridine (35 g, 0.24 mmol) was dropwise added to the solution, over 25 minutes, and then stirred at −70° C. for 1 hour. A tetrahydrofuran (170 mL) solution of iodine (75 g, 0.30 mmol) was added to the reaction mixture, and warmed up to room temperature with stirring. Water was added to the reaction mixture, and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl acetate and hexane were added to the residue, the precipitated matter was taken out through filtration and dried to obtain the entitled compound (46.4 g, 72%) as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.OS(O)(=O)=O.[OH-].[Na+]>CC(O)=O.O>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[CH:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(C=Cc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 60.1 %

Procedure:
A mixture of acetophenone (7.02 gm, 58.4 mmol), p-fluorobenzaldehyde (7.24 gm, 58.4 mmol) and concentrated H2SO4 (10 ml) in glacial HOAc (116 ml) was stirred at room temperature for 2 days. The solution was poured into H2O (250 ml) and neutralized with 10% NaOH (200 ml). The aqueous layer was extracted once with Et2O and the Et2O layer was washed successively with H2O, saturated NaHCO3 (twice) and brine, then dried (magnesium sulfate). Filtration and removal of the solvent afforded a yellow solid, which was recrystallized from hot hexane to give the title compound (7.94 gm, 60%) as light yellow needles.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[N+]([O-])([O-])=O.[Nd+3:28].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(N(CC)CC)C.C(C1C=CC=C(C(O)=O)C=1C(O)=O)CCC>C(O)C>[Nd:28].[CH2:1]([C:5]1[CH:13]=[CH:12][CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[C:14]([OH:16])=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: [Nd+3]
Agent: CCCCc1cccc(C(=O)O)c1C(=O)O
Agent: O=[N+]([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: [Nd]
Temperature: 40 °C

Procedure:
The mono-n-butylphthalic acid obtained in 5-1 was formed into a triethylamine salt in anhydrous ethanol, after which an ethanol solution of neodymium nitrate was added while stirring. That is, a reactor similar to the above was used to stir a solution obtained by adding 30 ml of an anhydrous ethanol to 68.1 g of the mono-n-butylphthalic acid obtained in 5-1, while dripping 30.4 g of triethylamine while maintaining at 30° C. or less by cooling in an ice water bath. After dripping, the solution was heated for 30 minutes at 40° C. to prepare a synthesis solution of mono-n-butylphthalic acid-triethylamine salt. Next, this synthesis solution was adjusted to 20° C., and a solution obtained by dissolving 43.8 g of neodymium nitrate into 100 ml of ethanol was dripped in while stirring. After dripping, the solution was heated to 40° C. for 30 minutes, to produce a synthesis solution of a neodymium salt of mono-n-butylphthalic acid. Then, ethanol was distilled from this synthesis solution to concentrate, 150 ml of chloroform and 200 ml of water were added to the concentrate and stirred, and the resulting neodymium salt of mono-n-butylphthalic acid was extracted and washed. After further washing this chloroform solution with, water twice, the chloroform was distilled out. The solid obtained by distillation was crushed, then dried under reduced pressure at 50° C. to obtain 72.9 g of a neodymium salt of mono-n-butylphthalic acid (yield 90%).
Reaction SMILES: [N+]([O-])([O-])=O.[Nd+3:5].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[C:14]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C>CO>[Nd:5].[C:14]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:25][CH:26]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: [Nd+3]
Agent: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: O=[N+]([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: [Nd]
Temperature: 30 °C

Procedure:
The compound was synthesized by the same method as that for Synthesis Example 1-2 above, that is, after forming a triethylamine salt of 4-tertiary-butylbenzoic acid in anhydrous methanol, a methanol solution of neodymium nitrate was added while stirring. Specifically, a reactor similar to that of 1-1 was used to stir a slurry solution obtained by adding 100 ml of an anhydrous methanol to 53.48 g (0.3 mol) of 4-tertiary-butylbenzoic acid, while dripping 30.4 g (0.3 mol) of triethylamine while maintaining at 30° C. by cooling in an ice water bath. After dripping, the solution was heated for 30 minutes at 40° C. to prepare a transparent synthesis solution of 4-tertiary-butylbenzoic acid-triethylamine salts. Next, 200 ml of methanol were further added to this synthesis solution and maintained at about 30° C., and a solution obtained by dissolving 43.8 g of neodymium nitrate into 100 ml of methanol was dripped in while stirring. Upon dripping of about half of the neodymium nitrate solution, it began to cloud, upon completion of dripping, a high-concentration slurry solution was obtained. After completion of dripping, the solution was heated to 40° C. for 30 minutes, to produce a slurry solution of a neodymium salt of 4-tertiary-butylbenzoic acid. Crystals obtained by filtering this slurry solution were added to 400 ml of methanol, stirred and washed, then refiltered, and 400 ml of methanol were once again added to the crystals stirred and washed, then filtered. The resulting crystals were dried under reduced pressure at 50° C., to obtain 59.3 g of a neodymium salt of 4-tertiary-butylbenzoic acid (yield 88%
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[O:5][C:6]=1C=O.[CH:13]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])OCC>C(=O)([O-])[O-].[Na+].[Na+]>[Br:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[O:5][C:6]=1[CH:13]([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22]
Reactant: CCOC(OCC)OCC
Reactant: O=Cc1oc2ccccc2c1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCOC(OCC)c1oc2ccccc2c1Br
Reaction time: 8 h

Procedure:
To a solution of 2.6 g of 3-bromo-2-benzo[b]furancarboxaldehyde (see M. Cugnon de Sevricourt and M. Robba, Bull. Chim. Soc. Fr., 1977, 142) in 2.7 ml of triethyl orthoformate was added 33 mg of paraoluene sulfonic acid and the solution stirred at at roon temperature overnight. The solution was diluted with a 5% sodium carbonate solution and extracted with ether. The ether extracts were dried over sodium sulfate and evaporated to give 3-bromo-2-(diethoxymethyl)-benzo[b]furan as a liquid; 1H-NMR (200 MHz, CDCl3) d 5.76 (CHOEt).
Reaction SMILES: [Br-].[Mg+2].[Br-].C1([Li])C=CC=CC=1.CC(C)([O-])C.[Li+].COC1C=CC(C#N)=CC=1.CCCCCCCCCCCCC.[CH3:40][O:41][C:42]1[CH:55]=[CH:54][C:45]([C:46](=N)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49]C=2)=[CH:44][CH:43]=1>C1COCC1>[C:46]1([C:45]2[CH:44]=[CH:43][C:42]([O:41][CH3:40])=[CH:55][CH:54]=2)[CH:47]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: COc1ccc(C(=N)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: CCCCCCCCCCCCC
Agent: COc1ccc(C#N)cc1
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 927.8 %

Procedure:
A slurry of magnesium bromide (0.74 g; 4.0 mmol) in THF (3 mL) was treated at room temperature with phenyllithium (2.4 mL of 1.7M solution; 4.0 mmol). The solution was heated at 60° C. for 30 min, and was then treated at 600 with lithium t-butoxide (4.4 mL of 1.0M solution in THF; 4.4 mmol) and heating was continued for lh. The reaction solution was cooled to room temperature and treated with a solution of 4-methoxybenzonitrile (0.27 g, 2.0 mmol), dichlorobis(trimethylphosphine)nickel (0.028 g; 5 mol %), and tridecane (0.18 g; 1.0 mmol; internal GC standard) in THF (2 mL). The reaction was then heated to 60° and stirred for 2 h. A sample was withdrawn and quenched in a mixture of 1M sodium citrate (aq) and ether. GC analysis of the organic phase of the hydrolyzed reaction sample showed the presence of 1.67 mmol (84% yield) of 4-phenylanisole, 0.18 mmol of 4-methoxybenzophenone imine, and no remaining 4-methoxybenzonitrile in the reaction mixture.
Reaction SMILES: C(O[C@@H]([C@H](OC(=O)C1C=CC=CC=1)C(O)=O)C(O)=O)(=O)C1C=CC=CC=1.[NH2:27][C@@:28]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])[CH2:32][O:31][C@H:30]([C:33]([F:36])([F:35])[F:34])[C@H:29]1[CH2:37][OH:38].CCOC(C)=O.[OH-].[Na+].[C:54]([N:62]=[C:63]=[S:64])(=[O:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C(Cl)Cl>[F:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C@@:28]1([NH:27][C:63]([NH:62][C:54](=[O:61])[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)=[S:64])[C@H:29]([CH2:37][OH:38])[C@@H:30]([C:33]([F:36])([F:34])[F:35])[O:31][CH2:32]1
Reactant: N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO
Reactant: O=C(N=C=S)c1ccccc1
Agent: O=C(O[C@H](C(=O)O)[C@H](OC(=O)c1ccccc1)C(=O)O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(NC(=S)N[C@@]1(c2ccccc2F)CO[C@H](C(F)(F)F)[C@H]1CO)c1ccccc1
Temperature: -3 °C
Reaction time: 0.08 h
Yield: 106.1 %

Procedure:
To chiral salt ((2S,3R,4S)-4-Amino-4-(2-fluorophenyl)-2-(trifluoromethyl)tetrahydrofuran-3-yl)methanol (2S,3S)-2,3-bis(benzoyloxy)succinate (0.361 kg, 0.556 mol) was added EtOAc (1.08 L) and the suspension was cooled to −3° C. 1.0 N aq. NaOH (1.30 L) was added over 20 mins while maintaining T<5° C. After 5 mins, benzoyl isothiocyanate (80.0 mL, 594 mmol) was added over 8 mins while maintaining T<5° C. After 1 h, EtOAc (722 mL) was charged. The aq. layer was removed, and the organics were washed with sat. aq. NaHCO3 (361 mL) and sat. aq. NaCl (361 mL). The organics were filtered over celite (90 g) and rinsed with EtOAc (360 mL). The organics were concentrated under vacuum to afford a residue which was re-dissolved into CH2Cl2 (1.1 L) and concentrated to afford the title compound as yellow foam (261 g, 99% yield accounting for residual solvents) which was used in the following step. 1H NMR (500 MHz, DMSO) δ ppm 12.04 (s, 2H), 11.20 (s, 2H), 7.95 (d, J=7.4 Hz, 2H), 7.69-7.60 (m, 1H), 7.56-7.42 (m, 2H), 7.37-7.28 (m, 1H), 7.24-7.12 (m, 2H). 5.59 (t, J=4.5 Hz, 1H), 5.03 (d, J=9.7 Hz, 1H), 4.92 (d, J=9.7 Hz, 1H), 4.75-4.63 (m, 1H), 3.92-3.74 (m, 2H), 2.77-2.66 (m, 1H); 13C NMR (125 MHz, DMSO) δ ppm 179.98, 167.85, 159.75 (d, JCF=245.0 Hz), 133.44, 132.58, 129.88, 129.81, 129.04, 128.85, 126.31 (d, JCF=9.8 Hz), 124.36, 116.83 (d, JCF=23.4 Hz), 76.11 (q, JCF=31.0 Hz). 74.37 (d, JCF=6.1 Hz), 68.77 (d, JCF=3.4 Hz), 57.03, 52.23.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4].O.C([O-])=[O:15].[Na+].Cl>C(O)=O>[OH:15][CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4]
Reactant: O=C[O-]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: O=C(CO)c1ccc(O)c(O)c1
Temperature: 100 °C
Yield: 98.9 %

Procedure:
A 0.1 liter reactor equipped with a reflux condenser and magnetic stirring bar was charged under argon with 5.05 g of 4-chloroacetyl-catechol of a purity of ca. 99%, 50 ml of water, 2.8 g of sodium formate and 1.55 ml (˜1.9 g) of formic acid. The stirred mixture was heated under reflux (˜100° C.) for 22 hours. The solution was cooled to about 25° C. and acidified by addition of 2 g of conc. hydrochloric acid (37%) resulting in a pH of about 0.5. The mixture was extracted with ethyl acetate, once with 100 ml then 3 times with 50 ml each. The organic extracts have been back washed 3 times with 30 ml 10% brine. The combined organic phases were dried with sodium sulfate, filtered and evaporated at reduced pressure at 40° C. This resulted in a light tan solid crystalline product of 4.56 g of 97.4% purity corresponding to a yield of 98.9%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH3:11])[CH3:2].C1(C)C=C(C)C=C(C)C=1S(ON)(=O)=O.CO[CH:29](OC)[N:30](C)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[N:7]([N:30]=[CH:29][CH:11]=2)[CH:8]=[CH:9][CH:10]=1)=[O:12])[CH3:2]
Reactant: COC(OC)N(C)C
Reactant: CCOC(=O)c1cccnc1C
Agent: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1cccn2nccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To a clear solution of 2-methyl-nicotinic acid ethyl ester (50.6 g, 306 mmol) in anhydrous methylene chloride (200 mL) was added O-mesitylenesulfonylhydroxylamine (73 g, 337 mmol; prepared according to a literature procedure described in Krause; J. G., Synthesis 1972, 140); in portions at 0° C. The solution obtained was stirred at 0° C. for 15 min, and then at rt for 1 h. Concentration under reduced pressure gave a yellow solid. After the solid was dissolved in anhydrous DMF (300 mL), N,N-dimethylformamide dimethyl acetal (122 mL, 918 mmol) was added at 0° C. The mixture was stirred at 0° C. for 15 min, and then at 90° C. for 3 h. The reaction mixture was concentrated under reduced pressure, mixed with H2O (200 mL), and extracted with Et2O (3×180 mL). The combined organic solutions were washed sequentially with brine (50 mL), 1N aqueous HCl (50 mL), and brine (50 mL), and dried over Na2SO4. Filtration through a SiO2 column, which was then eluted with 30% EtOAc in heptane, gave compound 777A (43.3 g, 74%) as a yellow solid. HPLC: 80% at 3.20 min (retention time) plus 20% corresponding methyl ester at 2.83 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 191 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[CH:5]2.[CH3:14][O-:15].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]=[C:7]([O:15][CH3:14])[CH:6]=[CH:5]2
Reactant: C[O-]
Reactant: Cc1cc(Br)cc2ccc(Cl)nc12
Agent: [Na+]
Solvent: CO
Product: COc1ccc2cc(Br)cc(C)c2n1

Procedure:
A solution of 6-bromo-2-chloro-8-methylquinoline (10.7 g) in methanol (80 cm3) was heated under reflux with a solution of sodium methoxide [made from sodium (2.76 g) in methanol (50 cm3)] for 24 hours. The cooled solution was then evaporated in vacuo and the residue was partitioned between chloroform (100 cm3) and water (50 cm3). The aqueous phase was further extracted with chloroform (2×50 cm3) and the combined and dried (MgSO4) organic phases were evaporated in vacuo to give a solid which was recrystallised from ethyl acetate:hexane, 1:9, to afford 6-bromo-2-methoxy-8-methylquinoline, m.p. 89°-91° (8.3 g).
Reaction SMILES: [OH:1][C:2]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[O:14]=[C:15]([NH:30][CH2:31][C:32](=O)[NH:33][C@@H:34]1[CH2:38]CNC1)[CH2:16][NH:17][C:18](=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl.CCOC(C)=O>[OH:1][C:2]1([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][CH:5]([N:33]2[CH2:34][CH2:38][C@@H:31]([NH:30][C:15](=[O:14])[CH2:16][NH:17][C:18](=[O:29])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH2:32]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC(=O)N[C@@H]1CCNC1
Reactant: O=C1CCC(O)(c2nccs2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(O)(c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a mixture of 4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexanone (0.075 g, 0.38 mmol) and N-[2-oxo-2-({2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}amino)ethyl]-3-(trifluoromethyl)benzamide (0.10 g, 0.317 mmol) in 2% AcOH/CH2Cl2 (10 mL) was added NaB(OAc)3H (0.134 g, 0.634 mmol). After being stirred overnight at room temperature under N2, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed [EtOAc to MeOH/EtOAc (1:9) then to 5% MeOH/EtOAc/Et3N (1:9:0.5)] to give 0.141 g of the title compound in 90% yield. MS (EI) calcd: (M+H)+=497.2. Found: 497.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.C1C(=O)N([Br:26])C(=O)C1.C(Cl)Cl>CN(C=O)C>[Br:26][C:7]1[N:8]([CH:11]([CH3:12])[CH3:13])[C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]=2[C:6]=1[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Cl)cc2c1c(C)cn2C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cc2c1c(C)c(Br)n2C(C)C
Reaction time: 18 h
Yield: 55.2 %

Procedure:
To a stirred solution of methyl 6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (2.5 g, 9.41 mmol) in DMF (25 mL) was added NBS (1.7 g, 9.55 mmol). The reaction was stirred for 18 h then evaporated to dryness under vacuum. The reaction was purified by silica gel chromatography (Analogix, SF40-80g, 0 to 5% EtOAc in hexanes) then (Analogix, SF25-60g, 25% CH2Cl2 in hexanes) to give the product methyl 2-bromo-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (1.79 g, 5.19 mmol, 55.2% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ=7.98 (d, J=1.8 Hz, 1H), 7.41 (d, J=1.8 Hz, 1H), 5.05 (dt, J=6.7, 13.4 Hz, 1H), 3.89 (s, 3H), 2.22 (s, 3H), 1.57 (d, J=7.1 Hz, 6H). MS(ES)+ m/e 344.0 [M+H]+.
Reaction SMILES: [CH2:1]=[O:2].[Mg+2].[Cl-].[Cl-].[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13].Cl>C(#N)C.C(N(CC)CC)C>[Br:6][C:7]1[C:8]([OH:13])=[C:9]([CH:10]=[CH:11][CH:12]=1)[CH:1]=[O:2]
Reactant: Oc1ccccc1Br
Reactant: C=O
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=Cc1cccc(Br)c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 15.8 %

Procedure:
To a 500 mL 3-neck round flask, paraformaldehyde (5.96 g, 199 mmol), and 12.60 g of anhydrous MgCl2 (12.60 g, 132 mmol) was added in acetonitrile (300 mL). Then 13.40 g of triethylamine was introduced slowly at room temperature. The mixture was stirred at room temperature for 20 min. 2-bromophenol (11.45 g, 66.2 mmol) was added to the above mixture. Then the reaction mixture was refluxed overnight. Then the mixture was cooled to room temperature, HCl (3N, 150 mL) were added to dilute the mixture. The resulted mixture was filtered through celite, and washed with tertbutyl methyl ether (200 mL). The organic solution was washed with 1N HCl (100 mL×2). The combined acid phase was extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL×2), water (100 mL×2), dried over sodium sulphate and concentrated to give 3-bromo-2-hydroxybenzaldehyde (D98) (2.1 g) as yellow oil, which was directly used in next step. MS (ES): C7H5BrO2 requires 199.9. found 201.0 (M+H+).
Reaction SMILES: COC(C1C(C)=C(C2C=CC=CC=2C(F)(F)F)NC=1)=O.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[O:32][C:33]([C:35]1[C:39]([CH3:40])=[C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:50])([F:49])[F:48])[N:37]([CH3:51])[CH:36]=1)=[O:34].[OH-].[Na+]>CO.O.C(O)=O.C1COCC1>[CH3:51][N:37]1[C:38]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=2[C:47]([F:49])([F:50])[F:48])=[C:39]([CH3:40])[C:35]([C:33]([OH:34])=[O:32])=[CH:36]1
Reactant: COC(=O)c1cn(C)c(-c2ccccc2C(F)(F)F)c1C
Agent: COC(=O)c1c[nH]c(-c2ccccc2C(F)(F)F)c1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: O=CO
Solvent: O
Product: Cc1c(C(=O)O)cn(C)c1-c1ccccc1C(F)(F)F
Yield: 90.4 %

Procedure:
To a solution of 4-methyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester (2.9 g, 10.2 mmol) in anhyd THF (40 mL) was added lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 12.3 mL, 12.3 mmol) slowly at 20° C. After stirring 0.5 h, iodomethane (0.96 mL, 15.4 mmol) was added and the mixture was stirred for 3 h at 20° C. After quenching with water, the organic layer was separated and the aqueous layer was extracted with EtOAc. The combined extracts were washed with water, dried (anhyd Na2SO4) and concentrated under reduced pressure to yield 1,4-dimethyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester as an oil (2.8 g, 92%), which was used in the next step without purification. MS (ES): 298 (MH+). To a solution of 4-methyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester (2.9 g, 10.2 mmol) in anhyd THF (40 mL) was added lithium bis(trimethylsilyl)amide C. To a solution of 1,4-dimethyl-5-(2-trifluoromethyl-phenyl)-1H-pyrrole-3-carboxylic acid methyl ester (2.5 g, 8.4 mmol) in MeOH (20 mL) was added 4N NaOH (10 mL) and the mixture was heated to reflux overnight. Evaporation of solvent gave a solid, which was re-dissolved in water. The solution was acidified with formic acid. The resulting solids were collected by filtration, washed with water and then dried under high vacuum to afford the title compound as an off-white solid (2.15 g, 90%). MS (ES): 284 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)=[O:5])[CH3:2].S(Cl)([Cl:19])(=O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:15])[N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:10]=1[Cl:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1C
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(Cl)c(C(C)(C)C)nn1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-tert-butyl-2-methyl-pyrazole-3-carboxylic acid ethyl ester (2.10 g, 10.0 mmol) in 25 mL of DCM was added sulfuryl chloride (1.05 mL, 13.0 mmol) slowly under Ar. After stirring at room temperature for 3 h under Ar, the resulting mixture was treated with DCM (30 mL), washed with ice H2O, saturated aqueous NaHCO3 and brine, and dried with Na2SO4. Removal of the solvent under reduced pressure yielded the title compound as a white solid. 1H-NMR (400 MHz, CDCl3) δ: 4.40 (q, J=7.2 Hz, 2H), 4.07 (s, 3H), 1.42 (t, J=7.2 Hz, 3H), 1.40 (s, 9H). Mass Spectrum (LCMS, ESI pos.) Calculated For C11H17ClN2O2: 245.1 (M+H). Measured: 245.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[O:9][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: Cc1ccc(O)cc1F
Reactant: O=Cc1ccc(F)cc1
Product: Cc1ccc(Oc2ccc(C=O)cc2)cc1F

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3-fluoro-4-methylphenol and 4-fluorobenzaldehyde