Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=2)[N:3]=1.[N:20]1[C:28]2[CH2:27][CH2:26][NH:25][CH2:24][C:23]=2[NH:22][CH:21]=1>>[N:20]1[C:28]2[CH2:27][CH2:26][N:25]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]([CH2:15][S:16]([NH2:19])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=4)[N:3]=3)[CH2:24][C:23]=2[NH:22][CH:21]=1
Reactant: c1nc2c([nH]1)CNCC2
Reactant: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: NS(=O)(=O)Cc1cccc(Nc2ncnc(N3CCc4nc[nH]c4C3)n2)c1

Procedure:
B44 was prepared following the general procedure reported for B10 using A1 and 4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine. The title compound (B44) was purified by reverse phase RP-HPLC (column: C18), using H2O and MeOH as eluents; yield: 34.3 mg (9%), white amorphous solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 2.59-2.71 (m, 2H), 4.07 (t, J=5.7 Hz, 2H), 4.22 (s, 2H), 4.72 (s, 2H), 6.83 and 6.89 (2 s, 2H), 7.00 (d, J=7.5 Hz, 1H), 7.29 (t, J=7.9 Hz, 1H), 7.51 (s, 1H), 7.58 and 7.65 (2 d, J=7.0 Hz and J=7.5 Hz, 1H), 7.74 and 7.88 (2 s, 1H), 8.26 (s, 1H), 9.70 (s, 1H), 11.86 (bs, 1H). MS (ES) C16H18N8O2S requires: 386. found: 387 (M+H)+.
Reaction SMILES: CO[C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:6][C:5]=1[NH2:18].[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]=[C:30]=[O:31])=[CH:25][CH:24]=1)([O-])=O.C(NC(C)C)(C)C>CN(C)C=O.CO.[Pd]>[NH2:20][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:3](=[O:19])[C:4]3[C:5](=[CH:6][C:7]([NH:10][C:11](=[O:12])[O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[CH:8][CH:9]=3)[NH:18][C:30]2=[O:31])=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1N
Agent: [Pd]
Solvent: CO
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccc2c(=O)n(-c3ccc(N)cc3)c(=O)[nH]c2c1
Temperature: 25 °C
Yield: 47.2 %

Procedure:
A solution of 2-amino-4-(tert-butoxycarbonylamino)-benzoic acid methyl ester (6.3 g, 23.6 mmol) and 4-nitrophenyl isocyanate (7.8 g, 47.4 mmoles) in 100 mL dry dimethylformamide was stirred at room temperature for 20 hrs. To it was then added diisopropylamine (8.2 mL, 47.4 mmol), and the reaction mixture was heated in 80° C. bath for 2 hrs. It was cooled to room temperature and the solid precipitates were filtered off. The dimethylformamide filtrate was concentrated in vacuo to evaporate the solvent. To the residue was added 400 mL dichloromethane. After stirred and swirled, the solid was isolated by filtration. This solid was then dissolved in 100 mL dimethylformamide and 200 mL methanol. To it was added 1.0 g 10% Pd/C, and the mixture was subjected to standard hydrogenation using a balloon for 20 hrs. It was filtered through a celite bed. The filtrate was concentrated in vacuo and purified using flash column to afford the title compound (4.1 g, 44%). ES+ MS showed 397 m/z, the correct mass for the product.
Reaction SMILES: CS(C)=O.F[C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[CH:8]=O.C(N(CC)CC)C.[C:22]([O:26][CH3:27])(=[O:25])[CH2:23][SH:24]>ClCCl.CCCCCC>[F:14][C:10]1[C:7]2[CH:8]=[C:23]([C:22]([O:26][CH3:27])=[O:25])[S:24][C:6]=2[CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1c(F)cccc1F
Reactant: COC(=O)CS
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc2c(F)cccc2s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.9 %

Procedure:
A 100 ml 3-necked round-bottomed flask, reflux condenser, thermometer adapter, gas inlet, and Teflon stirrer were oven-dried for 12 hours at 160° C. The apparatus was rapidly assembled, fitted with a thermometer, flushed with dry nitrogen gas, sealed with rubber septa, and allowed to cool to room temperature. The cooled reaction flask was charged with anhydrous dimethyl sulfoxide (40 ml), 2, 6-difluorobenzaldehyde (5 g, 35.18 mmole), anhydrous triethylamine (2.5 equivalents, 87.95 mmole, 8,952 g, 12.33 ml) and methyl thioglycolate (1.1 equivalents, 4.10 g, 38.70 mmole). The mixture was heated to 75° C. with rapid stirring. The progress of the reaction was monitored by TLC (silica, 10% dichloromethane-hexane, UV visualization). After 19 hours the reaction mixture was cooled to room temperature and poured onto an ice/water mixture (250 ml). The resulting slurry was stirred for 20 minutes, filtered, washed with cold water (2×100 ml) and dried in vacuo to give 5.76 g (78%) of methyl 4-fluorobenzo[b]thiophene-2-carboxylate. See, A. J. Bridges, A. Lee, E. C. Madukor, and C. E. Schwartz, Tetrahedron Letters, 33:7499 (1992).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[C:7]1([CH3:14])[CH3:13])=[O:5])C.CO.[OH-].[Na+].Cl>O>[CH3:13][C:7]1([CH3:14])[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[CH:6]1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)C1C(C=C(Cl)Cl)C1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
100 kg. of 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropane-1-carboxylic acid ethyl ester (prepared by the so called "Farkas process",/Coll.Czech.Commun.242230 (1959)), 100 lit. of methanol of technical grade and 90 kg of a 20% by weight aqueous sodium hydroxide solution are admixed with stirring and the mixture is boiled for 2 hours. 100 lit. of water are then added and 200 ml. of aqueous methanol are distilled off by a suitable condenser. The distillate contains also the by-products derived from the ester synthesis. The mixture is then cooled to 25° C. and 300 lit. of gasoline are pumped into it followed by a slow addition of 50 lit. of a concentrated hydrochloric acid solution. After stirring for half an hour the lower phase is separated carefully. The petrol solution remained in the equipment is washed with water, dried, decoloured and 200 lit. of petrol are distilled off, whereupon carboxylic acid is crystallized with stirring. The product is filtered off and dried (90 kg.). From the mother liquor a second crop (30 kg.) is obtained. The mother liquor of the second crop is stored till further use. Altogether 120 kg. of 2,2-dimethyl-3-(2,2-dichlorovinyl)-cyclopropane-1-carboxylic acid are obtained. Yield: 80 to 82% when the starting material contained 90% of pure ester.
Reaction SMILES: [C:1]([C:3]1[NH:7][CH:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])#[N:2].[H-].[Na+].[NH2:24]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:24][N:7]1[C:3]([C:1]#[N:2])=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6]1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1c[nH]c(C#N)c1-c1ccccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c(C#N)c1-c1ccccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
A 3 L 3 neck round bottomed flask was fitted with a reflux condenser and overhead stirrer and charged with ethyl 5-cyano-4-(nitrophenyl)-1H-pyrrole-3-carboxylate (20 g, 70.11 mmol). To a rapidly stirred solution in DMF (1 L) was added NaH (5×500 mg, 98 mmol) portion wise over 20 min. The dark brown solution was allowed to stir for an additional 10 min. The aminating reagent ((aminooxy)(diphenyl)phosphine oxide) was added in one portion (21.26 g, 91.14 mmol). The reaction mixture immediately solidified. Upon heating to 60° C. the solids began to disperse. The mixture was eventually heated to 80° C. and stirred over night. The reaction mixture was cooled and the solids were filtered off. The filter cake was washed with EtOAc (200 mL) and the filtrate was concentrated in vacuo. The resulting solid was suspended in Et2O (300 mL) and filtered to provide a 69% yield of the product (14.37 g, 47.86 mmol) as a light tan powder. The product was used without further purification. 1H-NMR (DMSO-d6) δ 8.29-8.24 (m, 2H), 7.72 (s, 1H), 7.71-7.68 (m, 2H), 6.71 (s, 2H), 4.09 (q, J=7.2 Hz, 2H), 1.12 (t, J=7.2 Hz, 3H); HPLC RT=3.15 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].[C:20]([O:24][C:25](=[O:35])[CH2:26][NH:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)([CH3:23])([CH3:22])[CH3:21].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.C(N(C(C)C)CC)(C)C>CN(C)C=O>[C:20]([O:24][C:25](=[O:35])[CH2:26][N:27]([C:11](=[O:13])[CH:10]([CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH2:28][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1)([CH3:23])([CH3:21])[CH3:22]
Reactant: N#Cc1ccc(CC(C(=O)O)C2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)CNCC1CCCCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN(CC1CCCCC1)C(=O)C(Cc1ccc(C#N)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.3 %

Procedure:
To 3-(4-cyano-phenyl)-2-(R,S)-cyclohexyl-propionic acid (5 g, 19.43 mmol) and (cyclohexylmethyl-amino)-acetic acid tert-butyl ester (4.42 g, 19.43 mmol) in dimethylformamide (50 ml) were added TOTU (7.01 g, 21.37 mmol) and diisopropylethyl amine (2.51 g, 19.43 mmol) at −15° C. The mixture was stirred for 1 hour and then allowed to warm to room temperature. After evaporation, the residue was treated with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was evaporated to yield 10 g of crude material which was used in the next step without further purification, MS m/z: 467.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:15])[S:13][C:6]=12.[BH4-].[Na+].Cl>CO.C1COCC1.Cl[Ni]Cl>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]([NH:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:15])[S:13][C:6]=23)=[C:2]([F:1])[CH:30]=1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: Cl[Ni]Cl
Agent: Cl
Agent: [BH4-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCNC(=O)c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reaction time: 0.25 h

Procedure:
To a solution of 292 (80mg, 0.17 mmol) in MeOH/THF (1.7 mL/1.7 mL) at 0° C., was added NiCl2×6H2O (85 mg, 0.35 mmol), followed by addition of NaBH4 (26 mg, 0.68 mmol), portion wise. The reaction mixture was stirred for 15 min, treated with 2N aqueous HCl (2 mL), filtered; the filtrate was neutralized with aqueous NH4OH to pH 7 and partitioned between EtOAc and water. Organic phase was collected, dried over anhydrous Na2SO4 and concentrated. The residue (75 mg, quantitative yield, crude) was used directly in next step without further purification. MS (m/z): 447.1(M+H) (found).
Reaction SMILES: BrC1C=CC(O)=CC=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]#[CH:24])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.I[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=1[CH:34]1[CH2:43][CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH3:45])[CH:40]=2)[CH2:35]1>>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[C:24][C:26]2[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:27]=2[CH:34]2[CH2:43][CH2:42][C:41]3[C:36](=[CH:37][CH:38]=[C:39]([O:44][CH3:45])[CH:40]=3)[CH2:35]2)=[CH:21][CH:22]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(I)c1
Reactant: C#Cc1ccc(OCc2ccccc2)cc1
Agent: Oc1ccc(Br)cc1
Product: COc1ccc(C2CCc3cc(OC)ccc3C2)c(C#Cc2ccc(OCc3ccccc3)cc2)c1
Yield: 67.3 %

Procedure:
Synthesized from 4-bromophenol according to an analogous synthetic method to Preparation Example 117 described below, 1-benzyloxy-4-ethynylbenzene (470 mg) and 2-(2-iodo-4-methoxyphenyl)-6-methoxy-1,2,3,4-tetrahydronaphthalene (690 mg) were used according to an analogous synthetic method to Preparation Example 45 to provide 2-[2-(4-benzyloxyphenylethynyl)-4-methoxyphenyl]-6-methoxy-1,2,3,4-tetrahydronaphthalene (559 mg). This compound (557 mg) was used according to an analogous synthetic method to Example 22 to provide the title compound (482 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[NH2:16][C@H:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:18][OH:19]>>[OH:19][CH2:18][C@H:17]([NH:16][C:8]([C:5]1[CH:4]=[C:3]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[C:2]([Cl:1])=[CH:7][N:6]=1)=[O:10])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[C@@H](N)CO
Reactant: O=C(O)c1cc(OCC2CC2)c(Cl)cn1
Product: CC(C)(C)[C@H](CO)NC(=O)c1cc(OCC2CC2)c(Cl)cn1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-chloro-4-cyclopropylmethoxy-pyridine-2-carboxylic acid and (2R)-2-amino-3,3-dimethyl-1-butanol (CAN 112245-09-7) as starting materials and isolated (80 mg, 80%) as colorless oil; LC-MS (UV peak area, m/z) 100%, 327.1476 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C@H:7]([NH2:20])[CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])([CH3:4])([CH3:3])[CH3:2].C[Si](C#N)(C)C.[CH3:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([CH3:37])[C:30]=1[S:38](Cl)(=[O:40])=[O:39].Cl>C(#N)C.C(OCC)(=O)C>[CH3:28][C:29]1[CH:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([CH3:37])[C:30]=1[S:38]([NH:20][C@H:7]([CH2:8][N:9]1[C:10](=[O:19])[C:11]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]2[C:13]1=[O:14])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])(=[O:39])=[O:40]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC(C)(C)OC(=O)[C@H](N)CN1C(=O)c2ccccc2C1=O
Agent: C[Si](C)(C)C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc(C)c(S(=O)(=O)N[C@H](CN2C(=O)c3ccccc3C2=O)C(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a stirred solution of tert-butyl-2(R)-amino-3-phthalimido-propionate (5.7 g, 19.63 mmol) in dry acetonitrile (60 ml) was added trimethylsilylcyanide (8.6 ml, 68.7 mmol). After 5 minutes 2,6-dimethyl-4-methoxybenzenesulfonyl chloride (4.84 g, 20.6 mmol) was added in one portion. The material was stirred at ambient temperature for 1 hour and then ethyl acetate (80 ml) was added and the mixture was transferred to a seperatory funnel. The organic phase was partioned with aqueous hydrochloric acid (1.5%, 100 ml), collected and washed with an equal volume of brine. The aqueous phases were back extracted with ethyl acetate (2×80 ml) and the organic phases combined, dried (magnesium sulfate), filtered and condensed. The residue was chromatographed (flash silica gel, 30% ethyl acetate-hexanes) to provide tert-butyl 2(R)-(2,6-dimethyl-4-methoxybenzene sulfonylamino)-3-phthalimido-propionate as white semi-solid (6.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11](=[O:16])[C:12]([O:14][CH3:15])=[O:13].[BH4-].[Na+].Cl>C(O)C.O>[Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(=O)c1ccccc1Nc1c(Cl)cccc1Cl
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)C(O)c1ccccc1Nc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of 6.5 g of methyl 2-(2,6-dichloroanilino)phenylglyoxylate in 130 ml of ethanol was added 0.5 g of sodium borohydride while cooling at -15° to -20° C., and the mixture was stirred at 0° C. for 2 hours and then at room temperature for further 1 hour. Thereafter, the reaction mixture was mixed with diluted hydrochloric acid for decomposition, diluted with 500 ml of water and extracted with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate and then concentrated without heating. The resulting residue was recrystallized from ethanol to give 6.2 g of methyl 2-(2,6-dichloroanilino)phenylglycolate. m.p. 123°-124° C. Yield: 95% of theoretical amount
Reaction SMILES: [C:1]([C:4]1[C:9]([CH:10]([CH3:12])[CH3:11])=[CH:8][C:7]([S:13]([NH2:16])(=[O:15])=[O:14])=[C:6]([CH:17]([CH3:19])[CH3:18])[CH:5]=1)(O)=[O:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>CCOCC.O1CCCC1>[OH:2][CH2:1][C:4]1[C:9]([CH:10]([CH3:11])[CH3:12])=[CH:8][C:7]([S:13]([NH2:16])(=[O:14])=[O:15])=[C:6]([CH:17]([CH3:19])[CH3:18])[CH:5]=1
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1C(=O)O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)cc1CO

Procedure:
4-Carboxy-2,5-diisopropylbenzenesulfonamide, 60 parts in 250 parts of ether and 350 parts of tetrahydrofuran is added dropwise to 24 parts of lithium aluminum hydride in 500 parts of ether at a rate where the ether refluxes gently. The reactants are then refluxed for 16 hours. Dilute hydrochloric acid is then added dropwise until the inorganic salts precipitate. The mixture is filtered and dried over sodium sulfate. After filtration and solvent removal there remains 41 parts of 4-hydroxymethyl-2,5-diisopropylbenzenesulfonamide having a m.p. of 185°-189°.
Reaction SMILES: N1C(F)=NC(F)=NC=1F.[C:10]1([C:16]2([CH2:22][CH2:23][C:24]([OH:26])=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1C=CC=CC=1.[OH:33][CH:34]([C:46]1[CH:51]=[CH:50][C:49](/[C:52](=[N:54]/O)/[NH2:53])=[CH:48][CH:47]=1)[CH2:35][NH:36][CH2:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40].C(N(C(C)C)CC)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>ClCCl.C(OCC)(=O)C>[OH:33][CH:34]([C:46]1[CH:47]=[CH:48][C:49]([C:52]2[N:53]=[C:24]([CH2:23][CH2:22][C:16]3([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[O:26][N:54]=2)=[CH:50][CH:51]=1)[CH2:35][NH:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40]
Reactant: CC(C)(C)OC(=O)CCNCC(O)c1ccc(/C(N)=N/O)cc1
Reactant: O=C(O)CCC1(c2ccccc2)CCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Fc1nc(F)nc(F)n1
Agent: [F-]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(O)CCNCC(O)c1ccc(-c2noc(CCC3(c4ccccc4)CCCCC3)n2)cc1
Temperature: 75 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
Cyanuric fluoride (0.018 mL, 0.215 mmol) was added to a mixture of 3-(1-phenylcyclohexyl)propanoic acid (50 mg, 0.215 mmol) and pyridine (0.017 mL, 0.215 mmol) in dichloromethane (5 mL). After 1 h, the reaction mixture was diluted with dichloromethane and washed with 1M aq. HCl solution. The organic layer was dried (MgSO4), filtered and concentrated. The residue was diluted with ethyl acetate and washed with saturated aqueous NaCl solution. The organic layer was dried (MgSO4), filtered and concentrated. This crude residue was dissolved in acetonitrile (5 mL). (Z)-tert-butyl 3-(2-hydroxy-2-(4-(N′-hydroxycarbamimidoyl)phenyl)ethylamino)propanoate (69.6 mg, 0.215 mmol) and diisopropylethyl amine (0.038 mL, 0.215 mmol) were added and the mixture was heated to 75° C. After 2 h, a 1M solution of tetra-n-butylammonium fluoride in THF (0.215 mL, 0.215 mmol) was added and the mixture was heated at 75° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous NaCl solution. The organic layer was dried (MgSO4), filtered and concentrated. The crude residue was treated with 1:1 mixture of dichloromethane and trifluoroacetic acid for 1 h. The mixture was concentrated, diluted with AcCN, filtered, and purified by HPLC (HPLC conditions: Phenomenex Luna C18 5 micron column (250×30 mm); 25-100% AcCN/water (0.1% TFA); 25 minute gradient; 20 mL/min) to obtain N-(2-hydroxy-2-(4-(5-(2-(1-phenylcyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)-beta-alanine (35 mg, 24% yield) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.63 (1H, d), 7.95 (2H, d, J=8.57 Hz), 7.56 (2H, d, J=8.35 Hz), 7.30-7.45 (4H, m), 6.33 (1H, br, s), 4.95 (1H, dd, J=10.11, 2.2 Hz), 3.13-3.32 (3H, m), 2.99-3.09 (1H, m), 2.69 (2H, td, J=7.25, 2.64 Hz), 2.52-2.59 (2H, m), 2.15 (2H, d, J=14.5 Hz), 1.16-1.72 (11H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([N:29]2[CH:33]=[N:32][CH:31]=[N:30]2)[CH:22]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:25]1[C:24]1[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][C:23]=1[N:29]1[CH:33]=[N:32][CH:31]=[N:30]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: O=Cc1ccc(Cl)cc1-n1cncn1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC(C)(C)n1c(-c2ccc(Cl)cc2-n2cncn2)nc2cc(-c3cnc(N)nc3)ccc21
Temperature: 65 °C
Reaction time: 18 h

Procedure:
The 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (185 mg, 0.72 mmol) and 4-chloro-2-1,2,4-triazol-1-yl-benzaldehyde (150 mg, 0.72 mmol) are combined in methanol (5 mL) and warmed to 65° C. After 18 hours, catalytic TsOH is added and heating is continued at 65° C. for 48 hours. The reaction mixture is cooled to room temperature and concentrated. The residue is purified via flash chromatography (12 g silica gel, 0-10% MeOH/CH2Cl2). Product-containing fractions are combined and concentrated. The residue is diluted with acetonitrile and the resulting solid product is collected via filtration (55 mg, 17%). LCMS (ESMS): m/z 445.20 (M++1)
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[CH:17]([OH:21])[CH2:16][CH2:15]3)[C:7](=[O:22])[C:6]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:40][C:39](=[O:41])[O:38][N:37]=2)=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH3:4].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[CH2:1]([C:5]1[N:10]=[C:9]([CH3:11])[N:8]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[CH2:16][CH2:15]3)[C:7](=[O:22])[C:6]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:40][C:39](=[O:41])[O:38][N:37]=2)=[CH:26][CH:25]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ccc3c(c2)CCC3O)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccc3c(c2)CCC3=O)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 2 h
Yield: 49.3 %

Procedure:
To a solution of 6-butyl-3-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3 H)-one (0.055 g) in acetonitrile (2 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.085 g), and the mixture was stirred for 2 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.027 g, 49%).