Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([NH2:10])[CH3:9])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[C:17]([O:21]C(=O)N[C@@H](C)COC1C=CC(F)=CC=1C(F)(F)F)(C)(C)[CH3:18].[ClH:40]>CO>[ClH:40].[F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C@@H:8]([NH:10][CH2:18][CH2:17][OH:21])[CH3:9])=[C:4]([C:13]([F:14])([F:15])[F:16])[CH:3]=1
Reactant: C[C@@H](COc1ccc(F)cc1C(F)(F)F)NC(=O)OC(C)(C)C
Reactant: CC(N)COc1ccc(F)cc1C(F)(F)F
Agent: Cl
Solvent: CO
Product: C[C@@H](COc1ccc(F)cc1C(F)(F)F)NCCO
Reaction time: 4 h

Procedure:
Synthesis of (2S)-1-[(4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-amine (C7). To a solution of tert-butyl{(2S)-1-[4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-yl}carbamate (C6) (1.87 g, 5.54 mmol) in methanol (10 mL) was added a solution of hydrogen chloride (4 N in 1,4-dioxane, 5 mL). After 4 hours, the reaction mixture was concentrated in vacuo. The resulting residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution and water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0 to 20% methanol in ethyl acetate) afforded the title compound as a yellow liquid. Yield: 785 mg, 3.31 mmol, 60%. LCMS m/z 238.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 1.19 (d, J=6.5 Hz, 3H), 3.35-3.44 (m, 1H), 3.74 (dd, J=8.4, 7.4 Hz, 1H), 3.94 (dd, J=8.5, 4.0 Hz, 1H), 6.93 (dd, J=9.1, 4.2 Hz, 1H), 7.18 (br ddd, J=9, 8, 3 Hz, 1H), 7.30 (dd, J=8.4, 3.1 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5](/[CH:6]=[CH:7]/[C:8]2[S:9][CH:10]=[CH:11][C:12]=2[S:13](Cl)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:13]([C:12]1[CH:11]=[CH:10][S:9][C:8]=1/[CH:7]=[CH:6]/[C:5]1[CH:17]=[CH:18][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:15])=[O:14]
Reactant: Cc1ccc(/C=C/c2sccc2S(=O)(=O)Cl)cc1
Reactant: Cc1noc(N)c1Br
Product: Cc1ccc(/C=C/c2sccc2S(=O)(=O)Nc2onc(C)c2Br)cc1
Yield: 34 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-(4-methyl-trans-styryl)thiophene-3-sulfonamide was prepared in the same manner as described in Example 2 by reaction of 2-(4-methyl-trans-styryl)thiophene-3-sulfonyl chloride with 5-amino-4-bromo-3-methylisoxazole. The crude product was purified by HPLC followed by crystallization resulting in a 34% yield, m.p. 101-105° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH3:4].[C:5]1([S:11][C:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[NH:14][C:13]=2[C:21]([NH2:23])=[O:22])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+]>N1C=CC=CC=1>[C:5]1([S:11][C:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]([CH2:2][CH2:3][CH3:4])[C:13]=2[C:21]([NH2:23])=[O:22])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCCBr
Reactant: NC(=O)c1[nH]c2cccnc2c1Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Product: CCCn1c(C(N)=O)c(Sc2ccccc2)c2ncccc21
Yield: 30.8 %

Procedure:
Add 1-bromopropane (19 mg, 0.154 mmol) at r.t. to a mixture of 3-phenylsulfanyl-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid amide (Ia-1, 31.5 mg, 0.12 mmol), Cs2CO3 (60 mg, 0.185 mmol) in pyridine (0.5 ml). Heat the reaction at 80° C. in a sealed vessel for 1 hr. Cool the mixture and extract into ethyl acetate from water. Separate the organic phase and evaporate. Purify the residue (33 mg) by flash chromatography (SiO2, 2 gm, elute with heptane:DCM then MeOH 0-4% in DCM) to provide title compound (11.5 mg) as a white solid, 1H NMR (CDCl3) and LC-MS (m/e=311) are consistent for the title compound structure.
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6].[H][H]>[Pt]=O.C(O)C>[OH:1][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6]
Reactant: O=CCC(C(=O)O)c1ccc(-c2ccccc2Cl)cc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: O=C(O)C(CCO)c1ccc(-c2ccccc2Cl)cc1

Procedure:
To a suspension of γ-keto-(2'-chloro-4-biphenylyl)butyric acid 8.64 g. (0.031 mole) in 300 ml. of 90% ethanol is added 1 ml. of 0.1M ferrous sulfate solution followed by 0.5 g. of platinum oxide catalyst. The mixture is shaken with hydrogen for 31/2 hours. The catalyst is filtered off. The filtrate is distilled under reduced pressure to yield γ-hydroxy(2'-chloro-4-biphenylyl)butyric acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]2[C:9]([CH2:12][CH:13](N)CO)=[CH:10][NH:11][C:3]=12.[C:17]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:21])[CH2:18][CH2:19][CH3:20].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][C:17]1([CH2:18][CH2:19][CH3:20])[C:10]2[NH:11][C:3]3[C:4]([C:9]=2[CH2:12][CH2:13][O:21]1)=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH3:27]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Cc1ccc(Br)c2c(CC(N)CO)c[nH]c12
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)ccc(Br)c21
Reaction time: 2 h
Yield: 93.2 %

Procedure:
To a solution of 4-bromo-7-methyl tryptophol (1.12 g, 4.41 mmol) and ethyl butyrylacetate (0.71 mL, 4.41 mmol) in CH2Cl2 (20 mL) was added BF3.OEt2 (0.56 mL, 4.41 mmol) dropwise at room temperature. The solution was stirred for 2 hours and then washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL). The organic phase was dried (Na2SO4) and filtered through a pad of silica gel. The filter cake was washed with additional CH2Cl2 and the combined organic layer was evaporated to provide 1.62 g (93%) of title compound as a white solid. 1H NMR (CDCl3): 300 MHz δ 9.33 (bs, 1H), 7.11 (d, J=7.65 Hz, 1H), 6.76 (d, J=7.65 Hz, 1H), 4.19 (m, 2H), 4.03 (m, 1H), 3.90 (m, 1H), 3.15 (m, 2H), 3.03 (d, J=16.6 Hz, 1H), 2.89 (d, J=16.6 Hz, 1H), 2.43 (s, 3H), 2.08 (m, 1H), 1.96 (m, 1H), 1.38 (m, 1H), 1.27 (t, J=7.14 Hz, 3H), 1.18 (m, 1H), 0.87 (t, J=7.29 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([C:5]1[S:9][C:8]([C:10]([OH:12])=O)=[CH:7][CH:6]=1)=[O:4].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:27]([O:29][C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32]([NH:34][NH2:35])=O)[CH3:28]>C(Cl)Cl.C(Cl)Cl.CN(C=O)C>[CH2:27]([O:29][C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32]1[O:12][C:10]([C:8]2[S:9][C:5]([C:3](=[O:4])[C:2]([F:1])([F:14])[F:13])=[CH:6][CH:7]=2)=[N:35][N:34]=1)[CH3:28]
Reactant: CCOc1ccccc1C(=O)NN
Reactant: O=C(O)c1ccc(C(=O)C(F)(F)F)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1ccccc1-c1nnc(-c2ccc(C(=O)C(F)(F)F)s2)o1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the carboxylic acid (A1) in DCM was added to PS-CDI (1.7 eq., loading 1.30 mmol/g), and the suspension stirred at RT for 30 min. 2-Ethoxybenzohydrazide (1.3 eq.) dissolved in DCM/DMF was added, and the resulting suspension was stirred at RT overnight. The suspension was filtered and the filtrate evaporated. The crude N′-(2-ethoxybenzoyl)-5-(trifluoroacetyl)thiophene-2-carbohydrazide (MS (ES) C16H13F3N2O4S requires: 386, found: 427 (M+H20+Na)+ and 385 (M−H+e)−) was used as such, without any purification. It was dissolved in excess thionyl chloride and the solution was heated in a microwave oven (sealed tube, 100° C., 5 min) and the thionyl chloride was evaporated. The desired product was isolated by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents (column: C18). The pooled product fractions were evaporated to afford the title compound. 1H NMR (300 MHz, CD3CN): 8.1-8.08 (1H, m), 8.06-8.01 (1H, m), 7.95-7.90 (1H, m), 7.63-7.56 (1H, m), 7.23-7.17 (1H, m), 7.16-7.09 (1H, m), 4.23 (2H, q, J=7 Hz), 1.48 (3H, t, J=7 Hz). 19F NMR (282 MHz, CD3CN); δ −74.25 (keto form), −86.14 (hydrate form). MS (ES) C16H11F3N2O3S requires: 368, found: 369 (M+H)+ and 387 (M+H2O+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[Br:9][C:10]1[CH:17]=[C:14]([CH:15]=O)[C:13]([OH:18])=[CH:12][CH:11]=1>N1C=CC=CC=1>[OH:18][C:13]1[CH:12]=[CH:11][C:10]([Br:9])=[CH:17][C:14]=1[C:15]1[S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccccc1S
Reactant: O=Cc1cc(Br)ccc1O
Solvent: c1ccncc1
Product: Oc1ccc(Br)cc1-c1nc2ccccc2s1

Procedure:
2-Aminothiophenol (12.5 g, 0.1 mole) was dissolved in 30 ml. of pyridine and 20.1 g (0.1 mole) of 5-bromosalicylaldehyde was added dropwise during 15 minutes. The solution was warmed on a steam bath for 2 hours and then a stream of air was bubbled through the mixture while heating for another hour. The mixture was poured into 300 ml. of 2 N HCl which was then stirred until crystals formed. The product was removed by filtration, washed with water and recrystallized from ethanol, mp. 164°-165°. Yield, 8.0 g. (26%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14](C(C)=C)[C:13]2=[O:24])[CH:4]=[C:3]1[CH3:25].O.Cl>C(O)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:24])[CH:4]=[C:3]1[CH3:25]
Reactant: C=C(C)n1c(=O)n(Cc2cccc3cc(C)n(C)c23)c2ccccc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc2cccc(Cn3c(=O)[nH]c4ccccc43)c2n1C
Temperature: 60 °C
Yield: 97.2 %

Procedure:
(1,2-dimethyl-1H-indol-7-ylmethyl)-3-isopropenyl-1,3-dihydro-benzimidazol-2-one (200 mg, 0.60 mmol) was suspended in ethanol (0.5 ml) and water (0.5 ml) and treated with 37% HCl (0.2 ml). The reaction was warmed to 60° C. for 1.5 h, cooled to room temperature and concentrated to low volume. The remaining residue was dissolved into DCM and sequentially washed with water and NaHCO3 (sat.). The organic phase was dried (MgSO4), filtered and concentrated to give 170 mg (97%) of 1-(1,2-dimethyl-1H-indol-7-ylmethyl)-1,3-dihydro-benzimidazol-2-one which was used without further purification.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([S:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:27])=[O:26])=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:36]([Li])CCC.IC>C1COCC1>[CH2:1]([N:8]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([S:25]([CH:28]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[CH3:36])(=[O:27])=[O:26])=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Li]CCCC
Reactant: Cc1ccc(CS(=O)(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccc(C(C)S(=O)(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 59.6 %

Procedure:
A solution of 0.23 g (0.47 mmol) of 6 in 4 mL of THF was cooled to 0° C. and treated with 0.24 mL (0.59 mmol) of n-butyllithium (2.5 M solution in hexanes) and allowed to reach room temperature for 20 min. After cooling the reaction to 0° C., 0.103 mL (1.66 mmol) of iodomethane was added as a solution in 2 mL of THF. The reaction was allowed to warm to room temperature for 30 min at which time the reaction was quenched with a few drops of saturated ammonium chloride. The reaction was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 80% hexanes/AcOEt to give 0.14 g (60%) of the title compound as a white solid. MS Calcd.: 499. Found: 500 (M+H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=2)[CH2:6][CH:5]1[CH3:27])(=[O:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)[CH2:6][CH:5]1[CH3:27])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(NC2CC(C)N(C(C)=O)c3ccc(F)cc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)N1c2ccc(F)cc2C(Nc2ccc(C(=O)O)cc2)CC1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
[Step 2] 500 mg of the crude product of 1-acetyl-4-[(4-ethoxycarbonylphenyl)amino]-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 1.5 mL of ethanol, and 0.5 mL of a 4 N aqueous solution of sodium hydroxide was added to the solution under ice cooling. The mixture was stirred for 6 hours at room temperature, and then was stirred for 6.5 hours at 60° C. After completion of the reaction, the reaction liquid was washed with diethyl ether, and was adjusted to pH 6 with a 1 N aqueous solution of hydrochloric acid. Subsequently, the reaction liquid was extracted three times with chloroform. The extraction product was dehydrated over anhydrous sodium sulfate, and then was concentrated under reduced pressure. Thus, 160 mg (cis:trans=3:1, 87%) of 1-acetyl-4-[(4-carboxyphenyl)amino]-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinoline was obtained as a yellow solid.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:6]([N+:19]([O-])=O)=[CH:7][C:8]([N+:16]([O-])=O)=[C:9]([CH:15]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[H][H]>[Ni].CCO>[NH2:16][C:8]1[CH:7]=[C:6]2[C:5]([CH:4]=[CH:3][NH:19]2)=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc(/C=C/N(C)C)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1cc2cc[nH]c2cc1N
Yield: 29.4 %

Procedure:
A mixture of (E)-ethyl 5-(2-(dimethylamino)vinyl)-2,4-dinitrobenzoate (15 g, 0.050 mol) and Raney Nickel (5 g) in EtOH (500 mL) was hydrogenated at room temperature under 50 psi of hydrogen for 2 h. The catalyst was filtered off and the filtrate was concentrated to dryness. The residue was purified by column on silica gel to give ethyl 6-amino-1H-indole-5-carboxylate (3.0 g, 30%). 1H NMR (DMSO-d6) δ 10.68 (s, 1H); 7.99 (s, 1H), 7.01-7.06 (m, 1H), 6.62 (s, 1H), 6.27-6.28 (m, 1H), 6.16 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 1.32-1.27 (t, J=7.2 Hz, 3H).
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:18])[NH:12][C@H:13]([CH3:17])[C:14](O)=[O:15])[S:2]1.[S:19]([NH2:23])([NH2:22])(=[O:21])=[O:20].[H-].[Na+]>CN(C)C=O>[S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:18])[NH:12][C@H:13]([CH3:17])[C:14]([NH:22][S:19]([NH2:23])(=[O:21])=[O:20])=[O:15])[S:2]1
Reactant: C[C@@H](NC(=O)NCCCCC1CCSS1)C(=O)O
Reactant: NS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)NCCCCC1CCSS1)C(=O)NS(N)(=O)=O
Yield: 42.8 %

Procedure:
The reaction was carried out as described in Example 73, but using 0.21 g of 2(R)-{3-[4-(1,2-dithiolan-3-yl)butyl]ureido}propionic acid (prepared as described in Example 71), 5 ml of anhydrous dimethylformamide, 0.13 g of N,N'-carbonyldiimidazole, 0.15 g of sulfamide and 0.04 g of sodium hydride (as a 55% w/w dispersion in mineral oil). The solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue. The mixture was neutralized by the addition of 2 N aqueous hydrochloric acid, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was recrystallized from ethyl acetate, to obtain 114 mg of the title compound as a pale yellow powder, melting at 156 to 157° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:22](=[O:24])[CH3:23])[CH:8]=[C:9]([CH2:11][O:12][CH2:13][CH2:14][O:15]C2CCCCO2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C(Cl)[Cl:59]>CO.C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([C:22](=[O:24])[CH2:23][Cl:59])[CH:8]=[C:9]([CH2:11][O:12][CH2:13][CH2:14][OH:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: CC(=O)c1cc(COCCOC2CCCCO2)cc(C(C)(C)C)c1
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(COCCO)cc(C(=O)CCl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-{3-tert-Butyl-5-[2-(tetrahydropyran-2-yloxy)ethoxymethyl]phenyl}ethanone (O2.063; 2.0 g) was dissolved in methanol/THF (30 ml/30 ml) and admixed while stirring with phenyltrimethylammonium tribromide (2.25 g). After stirring at RT for 3 h, the mixture was diluted with DCM and washed once with 5% sodium thiosulfate solution, and the DCM phase was dried over magnesium sulfate and concentrated by rotary evaporation. The residue was dissolved in THF (200 ml), and 3 N HCl (30 ml) was added. After standing for 1 h, EA and water were added, and the EA phase was removed. The EA phase was dried over magnesium sulfate and concentrated by rotary evaporation. The residue was purified using silica gel (40 g cartridge, n-heptane/EA gradient of 0-50% within 40 min). 774 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[F:10][C:11]1[C:16]([CH:17]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])=[C:15]([F:32])[C:14]([F:33])=[C:13](F)[C:12]=1[F:35].O.Cl>N1C=CC=CC=1>[CH2:1]([O:7][C:13]1[C:12]([F:35])=[C:11]([F:10])[C:16]([CH:17]([S:18]([C:21]([F:24])([F:22])[F:23])(=[O:19])=[O:20])[S:25]([C:28]([F:29])([F:30])[F:31])(=[O:26])=[O:27])=[C:15]([F:32])[C:14]=1[F:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCO
Reactant: O=S(=O)(C(c1c(F)c(F)c(F)c(F)c1F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCOc1c(F)c(F)c(C(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)c(F)c1F
Temperature: -20 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
Hexanol (1.5 mL, 12 mmol) was added to a pyridine (10 mL) solution dissolved with 60% sodium hydride containing mineral oil (0.56 g, 14 mmol) at 0° C., and the resultant solution was stirred for 1 hour at room temperature. After the solution was cooled to −20° C., pentafluorophenylbis(triflyl)methane (0.89 g, 2 mmol) was added. The reaction solution was stirred at −20° C. for 5 hours. After the reaction, the solution was acidified with 4 M hydrochloric acid water, and was extracted with diethylether. After drying with magnesium sulfate, the solution was filtrated, and the solvent was removed under reduced pressure. The crude product was purified by sublimation (0.2 to 0.3 torr, 65° C.), and 4-hexanoxy-2,3,5, 6-tetrafluorophenylbis(triflyl)methane was obtained at 99% yield (1.02 g, 1.98 mmol). 1H NMR (CDCl3, 300 MHz) δ 0.91 (t, J=7.1 Hz, 3H), 1.32 to 1.37 (m, 4H), 1.43 to 1.51 (m, 2H), 1.83 (quintet, J=6.8 Hz, 2H), 4.44 (t, J=6.8 Hz, 2H), 6.19 (s, 1H); 19F NMR (CDCl3, 282 MHz) δ−75.35 (s, 6F, 2CF3), −130.64 (dt, J=9.9, 21.2 Hz, 1F), −143.16 (br, 1F), −155.31 (d, J=21.2 Hz, 1F).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]#[CH:21]>C(#N)C>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:21][C:20]#[CH:19])=[C:3]([S:9]([NH2:12])(=[O:10])=[O:11])[CH:4]=1
Reactant: Cc1ccc(O)c(S(N)(=O)=O)c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1ccc(C)cc1S(N)(=O)=O
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
A mixture of 24.3 g of 2-hydroxy-5-methylphenylsulfonamide, 36.0 g of potassium carbonate, 16.7 g of propargyl bromide and 500 ml of acetonitrile is stirred at 50° C. for 4.5 hours. The reaction mixture is then filtered, and concentrated by evaporation. The yield after recrystallisation from ethyl acetate is 23.9 g of 5-methyl-2-propargyloxyphenylsulfonamide, m.p. 169°-170° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:31][CH:30]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: Nc1ccc(Cl)cc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(Cl)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-chloroaniline
Reaction SMILES: [OH-].[Na+].O.[CH3:4]/[C:5](/[CH:11]=[CH:12]/[C:13](/[F:26])=[C:14](\[CH3:25])/[CH:15]=[CH:16]/[C:17]1[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:18]=1[CH3:24])=[CH:6]\[C:7]([O:9]C)=[O:8].Cl>C(O)C>[CH3:4]/[C:5](/[CH:11]=[CH:12]/[C:13](/[F:26])=[C:14](\[CH3:25])/[CH:15]=[CH:16]/[C:17]1[C:21]([CH3:22])=[C:20]([CH3:23])[S:19][C:18]=1[CH3:24])=[CH:6]\[C:7]([OH:9])=[O:8]
Reactant: COC(=O)/C=C(C)/C=C/C(F)=C(C)/C=C/c1c(C)sc(C)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(/C=C/c1c(C)sc(C)c1C)=C(F)\C=C\C(C)=C\C(=O)O
Temperature: 45 °C
Reaction time: 4 h

Procedure:
A solution of 0.5 g. (12.5 mmol) of sodium hydroxide in 4 ml. of water was added to a solution of 1.0 g. (3 mmole) of methyl 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenoate in 10 ml. of absolute ethanol. The mixture was stirred at 45° C. for 4 hours. The solution was cooled to room temperature, acidified with 3N hydrochloric acid and filtered. The crude orange solid was purified by silica gel chromatography, eluted with hexane-ethyl acetate (3:5 parts by volume) and crystallized from hexane-ethyl acetate (1:1 parts by volume) to give 600 mg. (62% yield) of 2E,4E,6Z,8E-3,7-dimethyl-6-fluoro-9-(2,4,5-trimethyl-3-thienyl)-2,4,6,8-nonatetraenoic acid orange crystals, m.p. 217°-223° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[O:22]([CH2:29][CH:30]1[CH2:32][O:31]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:31][CH:30]([CH2:29][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:32][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: c1ccc(OCC2CO2)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC(O)COc3ccccc3)CC1)O2

Procedure:
Compound 158 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-(phenoxymethyl)oxirane and conditions outlined in procedure X. M.p.=174-176° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 7.15 (m, 2H), 6.95 (t, 1H), 6.9 (d, 2H), 4.15 (m, 1H), 4.0 (d, 2H), 2.95 (m, 3H), 2.8 (m, 2H), 2.65 (m, 2H), 2.55 (t, 2H), 2.15 (d, 2H), 1.9 (m, 2H); LCMS: 452 [M+H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([OH:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][C:20]=1[OH:26].C(Cl)CCl>C(#N)C>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:15](=[O:17])[CH2:14][CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[C:20]([OH:26])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Reactant: Nc1ccc(Br)cc1O
Solvent: CC#N
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2ccc(Br)cc2O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.5 %

Procedure:
To a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (0.5 g, 2.055 mmol) in acetonitrile (6 mL) was added 2-amino-5-bromophenol (0.421 g, 2.24 mmol), followed by EDC (0.508 g, 2.65 mmol). The mixture was stirred at rt overnight. It was quenched with NH4Cl (aq, sat, 5 mL). The organic layer was separated; the aqueous layer was back extracted with EtOAc (3×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 60% EtOAc) to afford Compound 29A as a light yellow oil (412 mg, 47% yield). 1H NMR (500 MHz, CDCl3) δ 8.96 (s, 1H), 7.65 (s, 1H), 7.17 (d, J=1.9 Hz, 1H), 7.03-6.91 (m, 2H), 2.83-2.66 (m, 2H), 2.36 (d, J=7.1 Hz, 2H), 2.10 (m, 2H), 1.76 (d, J=12.6 Hz, 2H), 1.46 (s, 9H), 1.23-1.13 (m, 2H). LCMS (m/z)=414 (M+H)+.