Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C.C([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:12]=[C:11]([C:25]([O:27][CH3:28])=[O:26])[C:10]=1[Cl:29])(=O)C.C(=O)=O>C(=O)([O-])O.[Na+]>[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([O:22][CH3:23])[C:16]=2[F:24])[N:12]=[C:11]([C:25]([O:27][CH3:28])=[O:26])[C:10]=1[Cl:29]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1Cl
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: CC(=O)Cl
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(N)c1Cl
Temperature: 50 °C
Reaction time: 7 h
Yield: 92.6 %

Procedure:
Methyl 4-(acetylamino)-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate (Compound 4) (9.0352 g) was loaded into a 100 mL three-necked flask equipped with a magnetic stirrer, heating mantle, thermometer, and condenser under a nitrogen atmosphere. Methanol (8.1 mL) was added, followed by 4-methyl-2-pentanone (MIBK, 26 mL). The resulting slurry was mixed, and anhydrous hydrogen chloride was introduced by adding 1.2 mL of acetyl chloride via syringe over 6 min. The acetyl chloride reacts with the methanol to form one equivalent of anhydrous hydrogen chloride and one equivalent of methyl acetate. Upon completion of the acetyl chloride addition, the mixture was heated to 50° C. and stirred at that temperature for seven hours. The remaining solid compound 4 initially dissolved to give a clear solution, which again formed a slurry over time. The resulting mixture was then cooled to ambient temperature and treated with saturated aqueous sodium hydrogen carbonate solution (20 mL). The solids dissolved and gas evolution (CO2) was evident. The mixture was transferred to a separatory funnel and separated. The organic phase was washed with saturated aqueous sodium chloride (20.5 mL). The resulting organic phase was then transferred to a 100 mL three-necked flask equipped with a magnetic stir bar, thermometer, heating mantle, and distillation head. The system was placed under vacuum (115 mmHg) and was heated to distill out a portion of the solvent. Approximately 15.5 mL of solvent was taken overhead, and additional MIBK (4.8 mL) was added to the distillation bottoms and the mixture was warmed to 55° C. Heptane (50 mL) was added dropwise to the clear solution over 20 min, resulting in the precipitation of the product. The product was recovered by filtration through Whatman #50 paper using a Buchner funnel. The filter cake was washed with heptane (20 mL), then dried overnight under vacuum. A total of 4.3506 g of methyl 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylate was obtained (91.9% pure by HPLC assay, 92.6% yield based on loaded compound 4).
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[C:31]([O:37][CH3:38])[N:30]=1>C(Cl)(Cl)Cl>[Br:28][C:29]1[N:30]=[C:31]([O:37][CH3:38])[C:32]([CH:33]=[CH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1nc(Br)ccc1C=O
Solvent: ClC(Cl)Cl
Product: COc1nc(Br)ccc1C=CC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
(tert-Butoxycarbonylmethylene)triphenylphosphorane (1.74 g) was added to a solution of 6-bromo-2-methoxynicotinaldehyde (500 mg) in chloroform (5 mL) under ice-cooling, followed by stirring for one hour. The solvent was evaporated from the reaction solution under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give tert-butyl 3-(6-bromo-2-methoxypyridin-3-yl)acrylate as a colorless oil (726 mg, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([CH2:34]O)[CH2:33][CH2:32][CH2:31]1.[K+].[Br-]>>[CH:30]1([CH2:34][O:24][C:23]([C:18]2([C:20]([OH:22])=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:33][CH2:32][CH2:31]1
Reactant: OCC1CCC1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: [Br-]
Agent: [K+]
Product: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)OCC1CCC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclobutylmethanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO) δ 1.01 (d,3H), 1.75(m,4H), 1.92(m,2H), 2.49 (m, 1H), 2.65 (m,1H), 2.85-3.20 (m,4H), 4.09 (d, 2H), 4.85 (bt, 1H), 6.58 (d, 1H), 6.76 (m,2H), 7.35(m,3H), 7.46(s,1H); IR (KBr): 1652 cm- (C=O), 1761 cm-1 (C=O); MS (CI) m/z 490 (MH+). Anal. Calcd. for C25H28ClNO7 : C, 61.29; H, 5.76; N, 2.86; Cl, 7.24. Found: C, 57.13; H, 5.15; N, 2.43; Cl, 6.83.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16]Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:16][C:15]1[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C:9]2=[N:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrBr
Reactant: c1ccc(-c2cn3c(n2)CCCC3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1c(-c2ccccc2)nc2n1CCCC2
Yield: 82 %

Procedure:
To a solution of 2-phenyl-5,6,7,8-tetrahydro-imidazo[1,2-a]pyridine (1.7 g, 8.9 mmol) in dry CH2Cl2 (55 mL) slowly add bromine (0.5 mL, 9.8 mmol) and stir at room temperature for 3 hours. Then, add a saturated aqueous solution of NaHCO3 (100 mL) and extract with CH2Cl2 (3×100 mL). Wash the combined organic layers with NaHSO3 (40%, 30 mL) followed by saturated aqueous sodium chloride (50 mL), dry (MgSO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, eluent:CH2Cl2 to CH2Cl2/MeOH 20:1) to obtain a brown solid, 2.0 g, 82% yield. MS((ES+): m/z=277.0, (M+H)+
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=2[CH3:39])[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][CH2:21][C:22]([NH:24][CH:25]([C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=2[CH3:39])[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cccc(NC=NN)c1)c1cc(C)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C)c(C(CC(=O)O)NC(=O)CNC(=O)c2cccc(NC=NN)c2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 87.8 %

Procedure:
To the product from Example 180 (710 mg, 0.0013 mole) in H2O (10 mL) and CH3CN (10 mL) was added LiOH (215 mg, 0.005 mole). The reaction mixture was stirred at room temperature for 2.5 hours. The pH was lowered to ~3 with TFA and the product was isolated by RPHPLC to yield the title compound (600 mg after lyophilization) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:14][CH2:15][C:16]3(C(F)(F)F)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:6][C:7]([F:13])=[C:8]([CH:12]=2)[C:9]([OH:11])=O)[CH2:3][CH2:2]1.C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)CCCCC1.CS(N)(=O)=O.[F:52][CH:53]1[CH2:56][N:55]([S:57]([NH2:60])(=[O:59])=[O:58])[CH2:54]1>>[CH:16]1([CH2:15][O:14][C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:12][C:8]([C:9]([NH:60][S:57]([N:55]3[CH2:56][CH:53]([F:52])[CH2:54]3)(=[O:59])=[O:58])=[O:11])=[C:7]([F:13])[CH:6]=2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Reactant: NS(=O)(=O)N1CC(F)C1
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2CCCCC2)cc1F
Product: O=C(NS(=O)(=O)N1CC(F)C1)c1cc(C2CC2)c(OCC2CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)benzoic acid with 4-(cyclohexylmethoxy)-5-cyclopropyl-2-fluorobenzoic acid and to replace methanesulfonamide with 3-fluoroazetidine-1-sulfonamide, the title compound was obtained (0.09 g, 35%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.80-8.64 (m, 1H), 7.62-7.52 (m, 1H), 6.64-6.52 (m, 1H), 5.45-5.12 (m, 1H), 4.59-4.31 (m, 4H), 3.89-3.76 (m, 2H), 2.13-1.99 (m, 1H), 1.96-1.68 (m, 6H), 1.42-1.03 (m, 5H), 1.00-0.89 (m, 2H), 0.72-0.62 (m, 2H); MS (ES+) m/z 429.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19]C3C=CC(CC(OC)=O)=CC=3)=[CH:14][C:13]=2[CH3:31])[CH2:11][CH2:10]1)[C:2]1C=CC=CC=1.[C:32](=O)([O-])[O-].[K+].[K+]>CO>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([C:9]2([O:8][CH:1]([CH3:2])[CH3:32])[CH2:10][CH2:11]2)=[C:13]([CH3:31])[CH:14]=1)#[CH:19]
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(OC(C)C)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; [4-(1-isopropoxycyclopropyl)-3-methyl-phenylethynyl]-trimethylsilane (Intermediate 80, 250.0 mg, 0.87 mmol) in methanol (10 mL) was treated with potassium carbonate (100.0 mg, 0.72 mmol) and stirred overnight at ambient temperature. The crude alkyne (180 mg, 98%) was used directly in the next reaction.
Reaction SMILES: [CH3:1][N:2]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:3](=[CH2:7])[C:4]([OH:6])=O.CCOC(OC(OCC)=O)=O.[F:29][C:30]([F:47])([F:46])[O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH2:44][NH2:45])[CH:41]=[CH:40][N:39]=2)=[CH:34][CH:33]=1>C1COCC1>[CH3:1][N:2]([S:8]([C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[C:3](=[CH2:7])[C:4]([NH:45][CH2:44][C:42]1[CH:41]=[CH:40][N:39]=[C:38]([C:35]2[CH:34]=[CH:33][C:32]([O:31][C:30]([F:47])([F:29])[F:46])=[CH:37][CH:36]=2)[CH:43]=1)=[O:6]
Reactant: NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Reactant: C=C(C(=O)O)N(C)S(=O)(=O)c1ccc(C)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1)N(C)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 24.3 %

Procedure:
A solution of acid 4E (0.57 g, 2.2 mmol) in THF (30 mL) was added with DEPC (0.43 mL, 1.3 mol eq) and the mixture was stirred at room temperature for about 5 minutes. Then [2-[4-(trifluoromethoxy)phenyl]-4-pyridyl]methanamine 21B (0.66 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc and washed with water and brine. The separated organic phase was evaporated under reduced pressure and the residue was purified by flash chromatography (7:3 EtOAc:Petroleum ether) to afford a pale yellow solid (0.27 g) after crystallization from a mixture of diethyl ether/petroleum ether. Yield=25%, 1HNMR (DMSO, 200 MHz) δ 2.48 (s, 3H), 2.86 (s, 3H), 4.49 (d, 2H, J=6), 5.00 (s, 1H), 5.85 (s, 1H), 7.35 (d, 1H), 7.42 (m, 4H), 7.71 (d, 2H, J=8.2), 7.97 (s, 1H), 8.21 (dd, 2H, J=2.2), 8.61 (d, 1H, J=4), 8.90 (t, 1H); [M+1] 505.51 (C24H22F3N3O4S requires 505.12).
Reaction SMILES: O=P(Cl)(Cl)Cl.[Cl:6][C:7]1[C:8]([CH:13]([NH:24][C:25]([CH:27]2[CH2:30][CH2:29][CH2:28]2)=O)[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][N:12]=1>>[Cl:6][C:7]1[C:8]2[N:9]([C:25]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[N:24][C:13]=2[C:14]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][CH:20]=[N:21]3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][N:12]=1
Reactant: O=C(NC(c1ccc2cccnc2c1)c1nccnc1Cl)C1CCC1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nccn2c(C3CCC3)nc(-c3ccc4cccnc4c3)c12
Temperature: 70 °C

Procedure:
A mixture of POCl3 (8 mL, 13 g, 87 mmol) and cyclobutanecarboxylic acid [(3-chloropyrazin-2-yl)-quinolin-7-ylmethyl]-amide (566 mg, 1.60 mmol) was heated to 55° C. for 21.5 h and to 70° C. for 6 h. POCl3 was evaporated, a cold solution of NH3 in iPrOH (2 M, 10 mL) was added, the suspension was filtered, and the solid was washed with iPrOH. The crude material contained in the combined filtrate and washings was adsorbed onto Hydromatrix and chromatographed on silica gel [Jones Flashmaster, 20 g/70 mL cartridge, eluting with hexanes: EtOAc 1:1 (1-13)→1:3 (14-38)], yielding the title compound as a yellow foam; 1H NMR (CDCl3, 400 MHz)δ 2.05-2.14 (m, 1H), 2.16-2.28 (m, 1H), 2.50-2.60 (m, 2H), 2.63-2.75 (m, 2H), 3.89 (quint, J=8.4 Hz, 1H), 7.35 (d, J=4.4 Hz, 1H), 7.44 (dd, J=4.2, 8.2 Hz, 1H), 7.55 (d, J=5.2 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 8.13 (dd, J=1.6, 8.4 Hz, 1H), 8.22 (d, J=8.2 Hz, 1H), 8.46 (s, 1H), 8.98 (dd, J=1.6, 4.2 Hz, 1H); MS (ES+): m/z 335.1/337.1 (100/44) [MH+].
Reaction SMILES: C(OC([NH:8][C:9]1[S:13][C:12]([C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)=[N:11][C:10]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=O)(C)(C)C.O1CCOCC1.C(O)C>Cl>[NH2:8][C:9]1[S:13][C:12]([C:14]2[CH:15]=[N:16][C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:19]=2)=[N:11][C:10]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)c1nc(-c2ccc(N3CCOCC3)nc2)sc1N

Procedure:
Ethyl 5-[(tert-butoxycarbonyl)amino]-2-(6-morpholin-4-ylpyridin-3-yl)-1,3-thiazole-4-carboxylate (634 mg, 1.46 mmol) was taken up in 4 N HCl in dioxane (7.3 ml, 29.2 mmol) and ethanol (5 ml) and stirred at ambient temperature for 20 hours. The mixture was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice with ethyl acetate. Combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified via flash chromatography (silica, 0-100% ethyl acetate/hexanes) to afford the title compound. LRMS (APCI) calc'd for (C15H19N4O3S) [M+H]+, 335.1; found 335.0.
Reaction SMILES: [Br-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:4].[OH:11]O>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:11])[CH3:4]
Reactant: OO
Reactant: CCc1ccccc1
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: O
Product: CC(=O)c1ccccc1
Yield: 91.1 %

Procedure:
The procedure of Example I was repeated, but this time cobalt (II) acetate tetrahydrate (0.003 moles), sodium bromide (0.005 moles), ethylbenzene (0.027 moles) and hydrogen peroxide (35%, 0.22 moles) were used. The final reaction mixture, analysed by HPLC, revealed that 97.0% of the ethylbenzene had been consumed, yielding products including acetophenone (91.1% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:16][C:17]([CH3:19])=[CH2:18])[C:5]([OH:15])=[C:6]([CH:14]=1)[C:7]([O:9]CC(C)=C)=[O:8]>C(O)=O>[Br:1][C:2]1[CH:14]=[C:6]([C:7]([OH:9])=[O:8])[C:5]2[O:15][C:17]([CH3:19])([CH3:18])[CH2:16][C:4]=2[CH:3]=1
Reactant: C=C(C)COC(=O)c1cc(Br)cc(CC(=C)C)c1O
Solvent: O=CO
Product: CC1(C)Cc2cc(Br)cc(C(=O)O)c2O1
Yield: 20 %

Procedure:
The title intermediate was prepared in 20% yield from 2-methyl-2-propenyl 5-bromo-3-(2-methyl-2-propenyl)-2-hydroxybenzoate upon heating at reflux with 90% formic acid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:52])[CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH2:13][N:14]2[CH2:20][CH2:19][CH2:18][CH:17]([N:21]([CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)[C:22]3[O:26][N:25]=[C:24]([CH3:27])[CH:23]=3)[C:16]3[CH:43]=[C:44]([CH3:51])[C:45]([C:47]([F:50])([F:49])[F:48])=[CH:46][C:15]2=3)[CH2:9][CH2:8]1.Cl>CO>[F:42][C:39]([F:40])([F:41])[C:31]1[CH:30]=[C:29]([CH:34]=[C:33]([C:35]([F:36])([F:38])[F:37])[CH:32]=1)[CH2:28][N:21]([C:22]1[O:26][N:25]=[C:24]([CH3:27])[CH:23]=1)[CH:17]1[CH2:18][CH2:19][CH2:20][N:14]([CH2:13][CH:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]([OH:52])=[O:4])[CH2:12][CH2:11]2)[C:15]2[CH:46]=[C:45]([C:47]([F:49])([F:48])[F:50])[C:44]([CH3:51])=[CH:43][C:16]1=2
Reactant: COC(=O)CC1CCC(CN2CCCC(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3cc(C)no3)c3cc(C)c(C(F)(F)F)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C2CCCN(CC3CCC(CC(=O)O)CC3)c3cc(C(F)(F)F)c(C)cc32)on1
Temperature: 60 °C
Yield: 93.4 %

Procedure:
Add 5 N sodium hydroxide solution (2 mL) to a solution of (4-{5-[(3,5-bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepin-1-ylmethyl}-cyclohexyl)-acetic acid methyl ester (63 mg, 0.088 mmol) in methanol (5 mL) and heat at 60° C. for 4 h. After the reaction cools to room temperature, acidify to pH 4 with 2 N hydrochloric acid solution and extract the aqueous mixture with ethyl acetate (3×10 mL). Wash the organic layer with water and brine (10 mL each). Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure to provide the title compound as an off-white solid (58 mg, 95%). 1H NMR (CDCl3, 300 MHz) δ 0.78-2.45 (m, 22H), 2.63-3.10 (m, 4H), 4.61-4.82 (m, 3H), 5.12-5.19 (m, 1H), 6.89 (s, 1H), 7.12-7.33 (m, 2H), 7.62-7.81 (m, 3H); ESI MS m/z 706 [C34H36F9N3O3+H]+; HPLC 96.3%, tR 18.9 min.
Reaction SMILES: [CH:1]([C:4]1[S:5][CH:6]=[C:7]([CH2:9]P(=O)(OCC)OCC)[N:8]=1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:20][O:21][CH2:22][O:23][C:24]1[C:28]([CH:29]=O)=[CH:27][N:26]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:25]=1.O>O1CCCC1>[CH:1]([C:4]1[S:5][CH:6]=[C:7](/[CH:9]=[CH:29]/[C:28]2[C:24]([O:23][CH2:22][O:21][CH3:20])=[N:25][N:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)[N:8]=1)([CH3:2])[CH3:3]
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Reactant: CCOP(=O)(Cc1csc(C(C)C)n1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(C(C)C)n1
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a solution of diethyl [(2-isopropyl-1,3-thiazol-4-yl)methyl]phosphonate (2.47 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 0.36 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (1.72 g) was added to the reaction mixture and the mixture was heated under reflux for 2 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate 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 (1:3, v/v) to give 2-isopropyl-4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazole as pale-yellow oil (1.59 g, yield 60%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH:29]2[CH2:31][CH2:30]2)[C:8]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)=[N:9][C:10]=1[C:11]1[CH:12]=[N:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:5])C.[OH-].[Na+]>CCO>[CH:29]1([N:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:10]([C:11]3[CH:12]=[N:13][C:14]([OH:17])=[CH:15][CH:16]=3)[N:9]=[C:8]2[C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][CH:19]=2)[CH2:31][CH2:30]1
Reactant: CCOC(=O)c1c(-c2ccc(O)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(-c2ccc(O)nc2)nc(-c2ccc(OC(F)(F)F)cc2)n1C1CC1
Yield: 95.9 %

Procedure:
To 0.8 g (1.8 mmol) of 3-cyclopropyl-5-(6-hydroxy-pyridin-3-yl)-2-(4-trifluoromethoxy-phenyl)-3H-imidazole-4-carboxylic acid ethyl ester in 3 ml of EtOH was added 0.6 ml of 6 M sodium hydroxide solution (3.8 mmol) and the mixture was heated to reflux for 16 h. The solvent was then evaporated, 1M hydrochloric acid solution was added and the resulting precipitate was isolated by filtration, affording 0.7 g (94%) of the title compound as a white solid. MS: 406.1 (MH+).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:15]1[C:28]2[C:27](=[O:29])[C:26]3[C:21](=[C:22](Cl)[CH:23]=[CH:24][CH:25]=3)[C:20](=[O:31])[C:19]=2[CH:18]=[CH:17][CH:16]=1>CO>[C:2]1([S:1][C:15]2[C:28]3[C:27](=[O:29])[C:26]4[C:21](=[C:22]([S:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:23]=[CH:24][CH:25]=4)[C:20](=[O:31])[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(Cl)c2C(=O)c2cccc(Cl)c21
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C1c2cccc(Sc3ccccc3)c2C(=O)c2cccc(Sc3ccccc3)c21
Temperature: 80 °C

Procedure:
The yellow pleochroic 1,5-bis(phenylthio)anthraquinone was prepared as follows: Two equivalents (2.2 g) mercaptobenzene were added to 30 g NN'Dimethylformamide, 5 g potassium carbonate, one equivalent (2.7 g) 1,5-dichloroanthraquinone and heated to reflux for 4 hours, after which 100 ml methanol were added after cooling to 80° C. Upon collecting the crystalline product by filtration, chromatography on alumina using toluene-methanol, and drying, the bright yellow orange crystalline product was obtained.
Reaction SMILES: O.[NH2:2][CH:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]1=2.C([O-])([O-])=O.[K+].[K+].Cl[C:35]([O:37][CH:38]1[CH:43]([CH:44]([CH3:46])[CH3:45])[CH2:42][CH2:41][C@@H:40]([CH3:47])[CH2:39]1)=[O:36]>C1COCC1>[CH:44]([C@@H:43]1[CH2:42][CH2:41][C@@H:40]([CH3:47])[CH2:39][C@H:38]1[O:37][C:35](=[O:36])[NH:2][C@@H:3]1[C:9](=[O:10])[N:8]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C:7]2[CH:20]=[CH:21][CH:22]=[CH:23][C:6]=2[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]1=2)([CH3:45])[CH3:46]
Reactant: COc1ccc(CN2C(=O)C(N)c3ccccc3-c3ccccc32)cc1
Reactant: CC(C)C1CC[C@@H](C)CC1OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)O[C@@H]3C[C@H](C)CC[C@H]3C(C)C)c3ccccc3-c3ccccc32)cc1
Reaction time: 0.25 h
Yield: 41.7 %

Procedure:
Water (40 mL) was added to a yellow solution of 7-amino-5-(4-methoxy-benzyl)-5H,7H-dibenzo[b,d]azepin-6-one (7.45 g) in THF (40 mL) at room temperature forming a light yellow suspension. To this suspension were added K2CO3 (5.53 g) in one portion and, after 15 minutes of stirring, (−)-(1R)-menthyl chloroformate (4.96 g) was added within 30 minutes. The dropping funnel was washed with THF. The emulsion was stirred for 105 minutes at room temperature. Heptane (486 mL) was added within 40 minutes and, after 60 more minutes of stirring, the precipitate was filtered off, washed with heptane, water, and then heptane in that order and dried under vacuum at 55° C. to afford [(S)-5-(4-methoxy-benzyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-carbamic acid (1R,2S,5R)-2-isopropyl-5-methyl-cyclohexyl ester (4.75 g, 45%), d.e=99.8:0.2 (HPLC), as a white powder.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.[OH-].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:12][CH:11]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Oc1ccc(I)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 47.8 %

Procedure:
Palladium(II) acetate (52 mg, 0.23 mmol) was added to a mixture of 4-iodophenol (5.00 g, 22.7 mmol), 4-methyl-phenyl-boronic acid (3.4 g, 25.0 mmol), sodium hydroxide (3.6 g, 90 mmol), and water (9 mL). The mixture was diluted twice with water (9 mL) to facilitate stirring. An exotherm occurred, and after 15 minutes the internal temperature was 50° C. The reaction mixture was cooled to room temperature and allowed to stir overnight, and the solid was filtered off, washed with water, and dissolved in ethyl acetate. The organic solution was washed with water, three times with 1 M NaOH, and then again with water until the washings were neutral. The solution was then dried (sodium sulfate), filtered, and evaporated to give 4′-methyl-biphenyl-4-ol (2 g, 48%).