Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[C:15]1(/[CH:14]=[CH:13]/[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Br
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccccc1/C=C/c1ccccc1
Yield: 103.9 %

Procedure:
8.9 g (38.9 mmol) of ethyl 2-bromobenzoate, 5.1 g (49.4 mmol) of styrene, 0.18 g (0.8 mmol) of palladium diacetate, 0.48 g (1.6 mmol) of tri-o-tolylphosphine and 5 g (49.1 mmol) of triethylamine were reacted in 90 ml of anhydrous acetonitrile at 100° C. for 23 h. The mixture was then filtered and the filtrate was diluted with ethyl acetate, washed with water, dried and concentrated under reduced pressure. 10.2 g (100%) of the product were obtained.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][OH:13].C[O-].[Na+]>C(=O)=O.C(O)(C)C>[CH3:12][O:13][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: CO
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: C[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ncc([N+](=O)[O-])cc1C
Temperature: 0 °C
Yield: 97 %

Procedure:
2-Chloro-3-methyl-5-nitropyridine (139 g, 0.806 mol) from the above procedure was divided into two portions and placed in two 2-L round bottom flasks with methanol (500 mL). The solutions were cooled in dry ice/isopropanol baths as solid sodium methoxide (26.5 g, 0.467 mol) was added portion-wise to each flask so that the temperature was remained below 20° C. When the additions were complete, the resulting mixtures were heated to reflux for 1 h. The mixtures were cooled and diluted with ice water (500 mL) to give white precipitates, which were collected by filtration. The combined filtrates were washed with water and air dried to give 2-methoxy-3-methyl-5-nitropyridine (127 g, 97% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J=2.0 Hz, 1H), 8.16 (s, 1H), 4.06 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.83, 141.91, 139.37, 132.92, 121.77, 54.83, 15.84. An analytical sample was recrystallized from hexane to give white needles, mp 95-96.5° C. Anal. calcd. for C7H8N2O3: C, 50.00; H, 4.79; N, 16.66. Found: C, 49.73; H, 5.02; N, 16.48.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][CH:20]=[C:21]([C:23]([O:25]C)=[O:24])[N:22]=3)=[CH:14][C:13]=2[CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].[CH3:30]O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[O:19][C:20]([CH3:30])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)=[CH:14][C:13]=2[CH3:27])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CO
Reactant: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2C)nc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)O)c(C)o3)cc2C)nc1Cl
Yield: 80 %

Procedure:
The same operation as in Example (91d) was performed using methyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methylphenyl)-1,3-oxazole-4-carboxylate obtained in Example (109f) (0.13 g, 0.33 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and tetrahydrofuran (5 mL), to obtain 0.10 g of the title compound as a colorless solid (80%).
Reaction SMILES: C(Cl)(=O)C.[CH2:5]([N:8]1[C@@H:13]2[C@H:14]([C:16]([O:18][C:19](C)(C)C)=[O:17])[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH2:11][CH2:12]2)[CH:6]=[CH2:7]>CO>[CH2:5]([N:8]1[C@@H:13]2[C@H:14]([C:16]([O:18][CH3:19])=[O:17])[CH2:15][C@@:9]1([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@H:10]([O:23][CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:26]=1)[CH2:11][CH2:12]2)[CH:6]=[CH2:7]
Reactant: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)C[C@H]2C(=O)OC(C)(C)C
Solvent: CC(=O)Cl
Solvent: CO
Product: C=CCN1[C@H]2CC[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@]1(c1ccccc1)C[C@H]2C(=O)OC

Procedure:
Acetyl chloride (5 ml) was cautiously added to methanol (25 ml) and (1R*,2R*,5S*,6R*)-8-allyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(tert-butoxycarbonyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 94; 1.23 g, 2.16 mmol) dissolved in the resulting solution. After standing for 4 weeks, the solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (25 ml) and saturated aqueous sodium carbonate (2×15 ml), the organic layers dried (MgSO4) and evaporated to leave the title compound as a gum. (1.07 g, 94%).
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:18])[CH2:4][P:5]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH3:11])(=[O:9])[O:6][CH2:7][CH3:8].[NH3:19]>C(O)C>[NH2:19][CH2:2][C@@H:3]([OH:18])[CH2:4][P:5]([C:10]([O:15][CH2:16][CH3:17])([O:12][CH2:13][CH3:14])[CH3:11])(=[O:9])[O:6][CH2:7][CH3:8]
Reactant: CCOC(C)(OCC)P(=O)(C[C@H](O)CCl)OCC
Reactant: N
Solvent: CCO
Product: CCOC(C)(OCC)P(=O)(C[C@H](O)CN)OCC
Yield: 19 %

Procedure:
A solution of ethyl (2S)-(3-chloro-2-hydroxypropyl)(1,1-diethoxyethyl)phosphinate (5.0 g, 17 mmol) in ethanol containing 9% of ammonia was stirred in an autoclave at room temperature for 6 days and at 55° C. for one further day. The solution was evaporated and the residue was purified by chromatography on a wet-packed silica gel column eluting with methylene chloride/methanol (5–8% MeOH) containing 5% triethylamine. The appropriate fractions were combined, evaporated and diluted with methylene chloride and water. The aqueous layer was pH adjusted by the addition of a few mL of 10% aqueous Na2CO3 and repeatedly extracted with methylene chloride. The combined organic layers were dried over Na2SO4 and evaporated to give 0.9 g (19%) of ethyl (2R)-(3-amino-2-hydroxypropyl)(1,1-diethoxyethyl)phosphinate as a clear oil. Data: 1H NMR (500 MHz, CDCl3) δ 4.1–4.3 (m, 2H), 4.05 (b, 1H), 3.60–3.80 (m, 4H), 2.4–2.9 (m, 2H), 1.7–2.1 (m, 2H), 1.4–1.5 (dd,3H), 1.3–1.4 (m, 3H), 1.2 (m, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.4 %

Procedure:
A mixture of the 6-nitroindan-1-one (10 g, 56 mmol) and 10% Pd/C (2.0 g) in MeOH (200 mL) was stirred under 30 psi of H2 at RT for 3 h. After filtration, the filtrate was concentrated to afford 6-aminoindan-1-one (7.2 g, 87% yield). 1H NMR (300 MHz, DMSO-d6): δ 7.17 (d, J1=8.1 Hz, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.71 (s, 1H), 5.24 (s, 2H), 2.85 (t, J=5.4 Hz, 2H), 2.49 (t, J=5.7 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12](=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19]CC1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[NH2:1][C:2]1[C:6]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:12](=[O:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19]
Reactant: Nc1c(C(=O)c2ccccc2OCc2ccccc2)oc2ccc(Cl)cc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1c(C(=O)c2ccccc2O)oc2ccc(Cl)cc12

Procedure:
3-Amino-5-chloro-2-(2-benzyloxybenzoyl)-benzofuran (Example 1, 0.5 g, 1.3 mmol) in ethyl acetate (15 ml) is stirred at room temperature under an atmosphere of hydrogen in the presence of palladium on charcoal (0.025 g). After 3 h the mixture is filtered over Celite® and evaporated to dryness. Purification of the residue by chromatography yields the title compound, having a m.p. of 208-210° C.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:8]3[C:13]([CH:14]=[C:15]4[C:20]=2[CH:19]=[CH:18][CH:17]=[CH:16]4)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:3][CH:2]=1.[Br:27]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)(Cl)Cl>[C:1]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:20]3[C:15]([C:14]([Br:27])=[C:13]4[C:8]=2[CH:9]=[CH:10][CH:11]=[CH:12]4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ccc(-c3c4ccccc4cc4ccccc34)cc2)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: Brc1c2ccccc2c(-c2ccc(-c3ccccc3)cc2)c2ccccc12

Procedure:
5.3 g (16 mmol) of 9-(biphenyl-4-yl)anthracene and 90 mL of carbon tetrachloride were put into a 200-mL three-neck flask and were stirred. A solution in which 2.8 g (18 mmol) of bromine was dissolved in 10 mL of carbon tetrachloride was dropped into the above solution through a dropping funnel. After that, the solution was stirred at the room temperature for 1 hour, and a sodium thiosulfate aqueous solution was added to the reaction solution to complete the reaction. A water layer of the reaction mixture was extracted by chloroform, and the extracted solution and an organic layer were together washed with a saturated sodium hydrogen carbonate solution and saturated saline in this order. The organic layer was dried with magnesium sulfate, and the mixture was filtrated naturally to remove the magnesium sulfate. Then, the filtrate was condensed to obtain a solid. The obtained solid was recrystallized with ethanol, whereby 5.4 g of a yellow powdery solid, which was a target matter, was obtained with the yield of 82%.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:5]2[C:14]([CH3:21])=[C:15]([NH2:20])[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]=2[O:3]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28](Cl)=[O:29]>C(OCC)(=O)C.CCCCCC>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[C:28]([NH:20][C:15]1[C:16]([CH3:19])=[C:17]([CH3:18])[C:4]2[O:3][C:2]([CH3:22])([CH3:1])[CH:6]([C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[C:5]=2[C:14]=1[CH3:21])=[O:29]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: Cc1ccc(C2c3c(C)c(N)c(C)c(C)c3OC2(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C)cc2)C(C)(C)O3)cc1OC
Yield: 90 %

Procedure:
By using 2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine and 3,4-dimethoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 90%. Melting point: 169-171° C. (Ethyl acetate-hexane)
Reaction SMILES: [CH2:1]([Si:9]([CH3:12])(Cl)Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH:13]1[C:25]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:1]([Si:9]([CH3:12])([CH:24]1[C:25]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[C:18]2[C:23]1=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:25]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Si](C)(Cl)Cl
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Solvent: C1CCOC1
Product: CCCCCCCC[Si](C)(C1c2ccccc2-c2ccccc21)C1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
n-Octylmethyldichlorosilane (32.68 g, 0.144 mol) and 200 mL of dry THF were charged to a one liter Schlenk flask equipped with an addition funnel. Fluorene anion (49.50 g, 0.288 mol) was dissolved in approximately 200 mL of dry THF and charged to the addition funnel. The temperature of the stirring solution was lowered to −20° C. under positive nitrogen pressure. The fluorene anion was added dropwise over two hours. After the addition of anion was complete the reaction mixture was allowed to warm to room temperature. The solution was then stirred overnight. The solution was washed with three 200 mL aliquots of water, retaining the organic layer after each washing. The organic layer was dried with magnesium sulfate and filtered. The product was recrystallized from a diethyl ether/methanol solution. The yield of this reaction is 10%.
Reaction SMILES: CN(C)C=O.[CH3:6][S-:7].[Na+].Cl[C:10]1[N:19]=[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:31])[CH:16]=2)[N:11]=1.Cl>O>[CH3:6][S:7][C:10]1[N:19]=[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([Cl:31])[CH:16]=2)[N:11]=1
Reactant: Clc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
20 ml of N,N-dimethylformamide and 221 mg of sodium thiomethoxide were added to 1 g of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline. The obtained mixture was stirred at 110° C. for one hour, neutralized with 1N hydrochloric acid and stirred at room temperature for one hour, followed by the addition of water. The crystals thus precipitated were recovered by filtration to give 780 mg of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[N:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21].C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[C:20]([CH2:19][O:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]=[N:9][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][CH:7]=2)=[CH:12][CH:13]=1)([O:22][CH3:23])=[O:21]
Reactant: COC(=O)CBr
Reactant: OCc1ccc(N=Nc2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(N=Nc2ccc(CO)cc2)cc1
Reaction time: 8 h

Procedure:
Compound 1 (0.4 g, 1.75 mmol) and methyl bromoacetate (0.28 g, 1.83 mmol) were dissolved in 40 mL of acetone, and K2CO3 (0.726 mg, 5.26 mmol) was added at room temperature followed by stirring overnight. The reaction mixture was diluted with 100 mL of EtOAc and washed with water (2×50 ml), brine (50 ml), and dried over Mg2SO4. After evaporation of solvents under reduced pressure the residue was purified by silica gel column chromatography (EtOAc:n-hexane 4:6) affording compound 3. Yield: 0.395 g (75%). 1H NMR (400 MHz, DMSO-d6) δ 3.71 (s, 3H, Hg), 4.58 (s, 2H, He), 4.92 (s, 2H, Hf), 5.33 (s, 1H, —OH), 7.10-7.14 (m, 2H, Ha), 7.47-7.49 (m, 2H, Hd), 7.80-7.86 (m, 4H, Hb, Hc). 13C NMR (100 MH, DMSO-d6) δ 52.4 (Cg), 62.9 (Cf), 65.3 (Ce), 115.7, 122.6, 124.8, 127.6, 146.3, 147.1, 151.4, 160.6169.4. HRMS (ESI+) m/z: [M+H]+ calcd for C16H17N2O4 301.1188. Found 301.1176.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[NH:9][C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1>[Br:7][C:8]1[N:9]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:10]([Br:16])=[C:11]([Br:15])[C:12]=1[C:13]#[N:14]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1c(Br)[nH]c(Br)c1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(Br)c(Br)c(C#N)c1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
Potassium t-butoxide (0.75 g, 6.7 mmol) is added in portions at room temperature to a solution of 2,4,5-tribromopyrrole-3-carbonitrile (2.0 g, 6.1 mmol) in anhydrous tetrahydrofuran (20 mL). After 30 minutes, ethyl bromoacetate (1.12 g, 6.7 mmol) is added dropwise and the mixture stirred for 4-5 hours at room temperature. Work-up as described in Example 15 gives the product as white solid (0.42 g) mp 140°-143° C.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[C:15]([S:16][CH2:17][CH2:18][CH3:19])=[C:14]([C:20](=[O:28])[NH:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:13]=[N:12]2)=[CH:6][CH:5]=1.[Li+].[OH-].O>CO>[CH:22]1([NH:21][C:20]([C:14]2[CH:13]=[N:12][N:11]([CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:29])=[O:2])=[CH:5][CH:6]=3)[C:15]=2[S:16][CH2:17][CH2:18][CH3:19])=[O:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CCCSc1c(C(=O)NC2CCCCC2)cnn1Cc1ccc(C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCSc1c(C(=O)NC2CCCCC2)cnn1Cc1ccc(C(=O)O)cc1
Yield: 90.7 %

Procedure:
A solution of 4-(4-Cyclohexylcarbamoyl-5-propylsulfanyl-pyrazol-1-ylmethyl)-benzoic acid methyl ester (116 mg, 0.28 mmol) (Intermediate #40) and LiOH (47 mg, 1.12 mmol) in MeOH (2 ml)/Water (1 ml) was stirred overnight at ambient temperature. The bulk of the MeOH was removed in vacuo and the resulting solution was treated with citric acid (˜10 ml) then extracted with EtOAc (2×˜15 ml). The organic layers were combined, washed with brine (˜10 ml), dried (MgSO4), filtered and evaporated to yield the title compound as a white solid (102 mg, 91%).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([O-:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[K+].F[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].S1(CCCC1)(=O)=O>>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([NH:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[CH:12][CH:13]=1
Reactant: CC(C)[C@H](N)C(=O)[O-]
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 100 °C
Yield: 7 %

Procedure:
A mixture of 30 parts of potassium valinate, 15 parts of p-fluoro-benzotrifluoride, 7 parts of dichlorohexano-18-crown-6 ether catalyst, 10 parts of potassium carbonate and 126 parts of sulfolane was placed in a pressure reactor. The reactor was degassed, placed under an argon atmosphere and sealed. The reaction mixture was then heated and maintained at about 100° C. for about 15 hours. Analysis of the reaction product indicated a 7.0% yield of 2-(4-trifluoromethylphenylamino)-3-methylbutanoic acid based on p-fluorobenzotrifluoride starting material.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:34])[CH3:33])[C:27]=1[NH:35][C:36]([NH:38][NH2:39])=[S:37]>CO>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]([CH3:33])[CH3:34])[C:27]=1[NH:35][C:36]([NH:38]/[N:39]=[CH:19]/[C:18]1[CH:21]=[CH:22][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:24])([F:23])[F:1])=[CH:5][CH:6]=3)[N:11]=2)=[CH:16][CH:17]=1)=[S:37]
Reactant: CC(C)c1cccc(F)c1NC(=S)NN
Reactant: O=Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Solvent: CO
Product: CC(C)c1cccc(F)c1NC(=S)N/N=C/c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 65 °C
Reaction time: 6 h
Yield: 73.2 %

Procedure:
To a solution of 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzaldehyde (0.760 g, 2.28 mmol) in methanol (22.8 mL) in a 100 mL round-bottomed flask equipped with a magnetic stir bar and reflux condenser was added N-(2-fluoro-6-isopropylphenyl)hydrazinecarbothioamide (0.518 g, 2.28 mmol), and the reaction was heated to 65° C. and stirred for 6 hours. The temperature was lowered to 50° C. and the reaction was stirred overnight. The reaction was cooled to room temperature and the resulting solid was filtered, washed with methanol, and dried under vacuum (25 in Hg) at 55° C. to give the title compound (0.907 g, 1.67 mmol, 73% yield) as a white solid: mp 210-212° C.; 1H NMR (400 MHz, CDCl3) δ 9.54 (s, 1H), 8.60 (s, 1H), 8.56 (s, 1H), 8.30-8.22 (m, 2H), 7.92 (s, 1H), 7.86-7.76 (m, 4H), 7.44-7.38 (m, 2H), 7.35 (dd, J=8.1, 5.6 Hz, 1H), 7.18 (d, J=7.9 Hz, 1H), 7.04 (ddd, J=9.4, 8.2, 1.3 Hz, 1H), 3.22 (p, J=6.9 Hz, 1H), 1.29 (d, J=6.9 Hz, 6H); ESIMS m/z 544 ([M+H]+).
Reaction SMILES: C([Li])CCC.CCCCCC.Br[C:13]1[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[CH:15][C:14]=1[O:23][CH3:24].[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>O1CCCC1>[C:19]([C:17]1[CH:16]=[CH:15][C:14]([O:23][CH3:24])=[C:13]([B:25]([OH:30])[OH:26])[CH:18]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1ccc(C(C)(C)C)cc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)C)cc1B(O)O
Temperature: -78 °C
Reaction time: 3 h
Yield: 74.2 %

Procedure:
n-Butyllithium in hexane (2.5 M, 18.1 mL, 45.24 mmol) was added dropwise to a solution of 2-bromo-4-(tert-butyl)-1-methoxybenzene (10.0 g, 41.13 mmol) and triisopropyl borate (11.39 mL, 49.35 mmol) in tetrahydrofuran (90 mL) at −78° C. under nitrogen. The reaction mixture was stirred at −78° C. for 3 hours then allowed to warm slowly to 0° C. over 90 minutes. The reaction was then quenched by the addition of water (90 mL) and the tetrahydrofuran removed under reduced pressure. The resulting aqueous suspension was partitioned between diethyl ether (80 mL) and 1.0 M aqueous sodium hydroxide solution (100 mL). The aqueous phase was separated, cooled to 0° C. then acidified to pH 1 by the addition of concentrated hydrochloric acid. The resulting white suspension was stood at 0° C. for 15 minutes then filtered washing the solid product with water and cold hexane to give (5-(tert-butyl)-2-methoxyphenyl)boronic acid (6.349 g, 74% yield) as a white crystalline solid.
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.C(N(CC)C(C)C)(C)C.[SH:32][CH2:33][C:34]([O:36][CH3:37])=[O:35].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:6]([CH2:14][CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[CH:21]=[CH:22][C:2]([S:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:3][C:4]=2[N:8]=1
Reactant: CC(C)(C)Cc1nc2cc(Br)ccc2n1CC1CCOCC1
Reactant: COC(=O)CS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)CSc1ccc2c(c1)nc(CC(C)(C)C)n2CC1CCOCC1
Temperature: 25 °C
Yield: 99.3 %

Procedure:
A mixture of 5-bromo-2-(2,2-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole (Step C, 300 mg, 0.82 mmol), N,N-diisopropylethylamine (286 μL, 1.64 mmol), methyl mercaptoacetate (73 μL, 0.82 mmol), tris(dibenzylideneacetone)dipalladium(0) (37.5 mg, 0.041 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (47.4 mg, 0.082 mmol) in 1,4-dioxane was microwaved at 120° C. for 30 min. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=3:2 then 1:1 as eluent) to afford the title compound (318 mg, 99%) as a yellow viscous oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]([OH:30])=O)=[CH:15]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.O[N:33]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N.Cl>CN(C)C=O>[CH3:1][S:2]([C:5]1[N:10]=[CH:9][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]([NH2:33])=[O:30])=[CH:15]3)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: On1nnc2ccccc21
Reactant: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(N)=O)cc3c2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To a solution of 5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxylic acid (3 g) in N,N-dimethylformamide (20 mL) were added 1-hydroxybenzotriazole monohydrate (1.6 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2 g), and 10% aqueous ammonia (27 mL), and the mixture was stirred at room temperature for 1 hr. 1N HCl was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was crystallized from diethyl ether to give the title compound (1.35 g, yield 45%) as yellow powder.