Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])([OH:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:3]([OH:10])([CH2:2][NH:1][S:27]([C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:26][CH:25]=1)(=[O:29])=[O:28])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1
Reactant: NCC(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Product: O=S(=O)(NCC(O)(Cn1cncn1)c1ccc(F)cc1F)c1ccc(C(F)(F)F)cc1

Procedure:
Following the procedure described in the preceeding examples but using 3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol and 4-trifluoromethylbenzenesulfonylchloride, the title compound was obtained in a similar yield: mp 161°-162° C.; 1H NMR (80 MHz, CDCl3)δ(TMS) 8.04 (s, 1H, N=CH), 7.77 (s, 1H, N=CH), 8.0-6.5 (m, 7H, atom), 5.35 (br t, 1H, NH), 4.75 (AB system, Δv=0.098, J=14.6 Hz, 2H, CH2 -Tr), 3.8-3.1 (m, 2H, NCH2). Anal. calcd. for C18H15F5N4O3S: C 46.76%; H 3.27%; N 12.12%. Found: C 47.04%; H 3.29%; N 12.07%.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:19][CH2:20][C:21](Cl)=[O:22].C(N(CC)CC)C>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:21](=[O:22])[CH2:20][CH2:19][C:15]2[O:14][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C(Cl)CCc1ccco1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCc1ccco1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.3 %

Procedure:
A solution of 1-benzylpiperazine (352 mg, 2 mmol) in dry dichloromethane (6 mL) is cooled in an ice bath, and 3-(furan-2-yl)propionyl chloride (396.5 mg, 2.5 mmol, 1.25 eq) and triethylamine (417 μL, 3 mmol, 1.5 eq) are added. After stirring for 6 hours at room temperature the reaction mixture is diluted with dichloromethane (10 mL). The organic solution is subsequently washed with 1 M KHSO4, 5% NaHCO3 and brine. After drying over Na2SO4, dichloromethane is removed in vacuo and the crude material is purified by flash chromatography (silicagel, ethyl acetate/toluene 1:2). The fractions containing the 1-(4-benzylpiperazin-1-yl)-3-(furan-2-yl)propan-1-one are collected and the solvent is removed in vacuo to give 497 mg of colorless oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:25])[NH:7][C:6]=2[CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:2]2[C:10]3[NH:9][C:8]([N:11]4[CH2:16][CH2:15][N:14]([C:17]5[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=5)[CH2:13][C@H:12]4[CH3:25])=[N:7][C:6]=3[CH:5]=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=2)=[CH:33][CH:32]=1
Reactant: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2c(Br)cc(C(F)(F)F)cc2[nH]1
Reactant: OB(O)c1ccc(Cl)cc1
Product: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3ccc(Cl)cc3)c2[nH]1

Procedure:
4-Bromo-2-[(2R)-4-(3,5-dichloro-pyridin-2-yl)-2-methyl-piperazin-1-yl]-6-trifluoromethyl-1H-benzoimidazole (204 mg, 0.4 mmol, Example 149b) and 4-chlorophenylboronic acid (124 mg, 0.8 mmol, Aldrich) reacted under the conditions of Example 158 to give the title compound. MS (ESI, pos. ion) m/z: 504 (M+1).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.C(N(CC)CC)C.[CH3:13][C:14]1[C:23]([CH3:24])=[C:22]([O:25][C:26](=[O:28])[CH3:27])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N+:15]=1[O-]>C(Cl)Cl>[Cl:3][CH2:13][C:14]1[C:23]([CH3:24])=[C:22]([O:25][C:26](=[O:28])[CH3:27])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1
Reactant: CC(=O)Oc1c(C)c(C)[n+]([O-])c2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1c(C)c(CCl)nc2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
A solution of 1.38 g (9.04 mmols) of phosphorus oxychloride in 5 ml of methylene chloride and a solution of 913 mg (9.04 mmols) of triethylamine in 5 ml of methylene chloride were, respectively, dropped almost simultaneously in 15 minutes into a solution of 1.85 g (8.00 mmols) of the crude product of 2, 3-dimethyl-4-acetoxyquinoline oxide in 5 ml of methylene chloride, followed by stirring at room temperature for 10 minutes. The reaction solution was washed with a saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution, and dried with sodium sulfate. The solvent was distilled off under reduced pressure to obtain a crude product, followed by purification by silica gel column chromatography (Wako (solvent: n-hexane : ethyl acetate=5:1) to obtain 700 mg (yield 36%) of 2-chloromethyl-3-methyl-4-acetoxyquinoline.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:11][CH3:12].C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)CCC.[Cl-].[Li+]>C1(C)C=CC=CC=1.[Pd]>[CH2:11]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH3:12]
Reactant: CCc1nc2ccccn2c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CCc1nc2ccccn2c1-c1ccncc1
Yield: 38.7 %

Procedure:
To a solution of 3-bromo-2-ethyl-imidazo[1,2-a]pyridine (1.4 g, 6.28 mmol), 4-tributylstannylpyridine (2.31 g, 6.28 mmol) and Pd (II) (Ph3P)2Cl2 (442 mg, 0.63 mmol) in toluene (5 mL) was added lithium chloride (26.7 mg, 0.63). After refluxing for 18 h, the mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×). Combined organic phase was washed with brine and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography eluting with 100% ethyl acetate, then 10% methanol in methylene chloride afforded the title compound (543 mg) as a viscous oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[NH:22][C:21](=[O:23])[C@H:20]([CH:24]([CH3:26])[CH3:25])[NH:19][C:18](=[O:27])[C@@H:17]([NH2:28])[CH2:16][C:15]2=[CH:29][CH:30]=[C:12]([CH:13]=[CH:14]2)[O:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[NH:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](O)=[O:37].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.C(Cl)CCl>[CH3:2][O:3][C:4]([C@H:6]1[NH:22][C:21](=[O:23])[C@H:20]([CH:24]([CH3:26])[CH3:25])[NH:19][C:18](=[O:27])[C@@H:17]([NH:28][C:36]([C:32]2[NH:31][CH:35]=[CH:34][CH:33]=2)=[O:37])[CH2:16][C:15]2=[CH:29][CH:30]=[C:12]([CH:13]=[CH:14]2)[O:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N1
Reactant: O=C(O)c1ccc[nH]1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](NC(=O)c2ccc[nH]2)C(=O)N[C@@H](C(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Amine 47 (0.37 g) was dissolved in anhydrous DMF (5 mL). 1H-pyrrole-carboxylic acid (0.11 g), DIPEA (0.72 mL), EDC (0.25 g) and HOBt (0.2 g) were added and the reaction mixture was stirred at rt for 18 h before being partitioned between chloroform and 1M hydrochloric acid. The aqueous phase was extracted three more times with chloroform and the combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification was achieved using flash chromatography, eluting with a gradient of 20% EtOAc/(50/70) petroleum ether to EtOAc to yield an off-white solid, 279 mg, 55%. Rf=0.15 (20% EtOAc/(50/70) petroleum ether).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])[CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[OH-].[Na+].Cl>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9]
Reactant: CCOC(=O)CCc1cc(C)c(OC)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1c(C)cc(CCC(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.1 %

Procedure:
To a solution of 17.0 g (56.4 mmol) of ethyl 3-(3bromo-4-methoxy-5-methylphenyl)propionate in methanol (30 ml) was added a 8N aqueous solution of sodium hydroxide (200 ml). The mixture was stirred for 18 hours at room temperature. The reaction mixture was acidified with 5N HCl, which was subjected to extraction with chloroform. The extract solution was washed with brine, which was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 14.8 g (yield 96%) of the above-titled compound as an oily product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:23](=[O:24])[N:22]([CH2:25][CH3:26])[C:14]3[N:15]=[C:16](S(C)=O)[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[NH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:23](=[O:24])[N:22]([CH2:25][CH3:26])[C:14]3[N:15]=[C:16]([NH:27][C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(S(C)=O)nc21
Reactant: Nc1ccncc1
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(Nc3ccncc3)nc21
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 2.6 %

Procedure:
A mixture of the product of Example 7, 6-(3,5-dimethoxy-phenyl)-8-ethyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.280 g, 10.75 mmol), and 4-aminopyridine (0.5 g, 15.3 mmol) was placed in a small round bottom flask and immersed in an oil bath at 180° C. for 5 minutes with stirring. The reaction mixture was cooled to 20° C. and the mixture triturated with water (10 mL). The insoluble product was filtered and dried in air on the filter. The crude product was purified by column chromatography eluting with a solvent gradient starting with pure chloroform and finishing with methanol/chloroform (1:20). The product was crystallized by suspending it in methanol (10 mL) and adding methylene chloride (30 mL) until a solution resulted. The solution was concentrated on a steam bath to approximately 8 mL in volume. The precipitated product was filtered and washed with methanol (0.5 mL) to afford 112 mg of the titled compound. mp 305–307° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH:21]4[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]4)[CH:20]=3)[CH:15]=[C:10]2[N:9]=[CH:8]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=1)[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:20]=3)[CH:15]=[C:10]2[N:9]=[CH:8]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(-c5cnn(C6CCN(C(=O)OC(C)(C)C)CC6)c5)cnc43)cc2OC)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(COc2ccc(Cn3cnc4cc(-c5cnn(C6CCNCC6)c5)cnc43)cc2OC)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
To a stirred solution of tert-butyl 4-(4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.15 g, 0.24 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (0.5 mL). The resulting mixture was stirred at room temperature. After 1 h, the reaction mixture was concentrated, and the residue was diluted with 1M potassium carbonate solution (20 mL) and extracted with dichloromethane (3×10 mL). The combined organic phases were washed with brine (3×20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by Prep-HPLC to afford 0.065 g (52%) of the product as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.59 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.67 (d, J=8.0 Hz, 1H), 6.93 (s, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 5.40 (s, 2H), 5.03 (s, 2H), 4.30 (m, 1H), 3.94 (s, 3H), 3.82 (s, 3H), 3.31-3.28 (m, 2H), 2.84-2.80 (m, 2H), 2.24-2.22 (m, 2H), 2.04-1.97 (m, 2H) ppm; (M+1)=526.
Reaction SMILES: [C:1]1([O:8][CH3:9])[C:2](=[CH:4][CH:5]=[CH:6][CH:7]=1)[OH:3]>[Ru]>[CH3:9][O:8][CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:2]1[OH:3]
Reactant: COc1ccccc1O
Agent: [Ru]
Product: COC1CCCCC1O
Yield: 60 %

Procedure:
Ruthenium Catalyzed Hydrogenations. For guaiacol hydrogenation in the presence of ruthenium catalyst the products were similar to those identified earlier in our laboratory. At 150° C., 30% of the guaiacol had already been converted by the time the reactor reached temperature, time zero in FIG. 1. The primary product was that resulting from saturation of the phenolic ring, 2-methoxycyclohexanol (60% yield @ 4 h). Cyclohexanediol was the secondary product (11%), although cyclohexanol was also significant (6%). The methanol byproduct was found (1%). There was little phenol formed at this temperature. At 200° C. the initial conversion of guaiacol during heatup was 44%. As shown in FIG. 2 the methoxycyclohexanols were still the main product (54% yield @ 4 h), but cyclohexanediol became less important (4%) while more cyclohexanol was formed (12%). More methanol was present (2%), as was more phenol. At 250° C., 60% of the guaiacol was converted by the time the reactor reached temperature. As shown in FIG. 3 cyclohexanol almost surpassed methoxycyclohexanols as the main product. Methoxycyclohexanol yield peaked at 17% in the 1 to 2 h range before reacting on to secondary products. The maximum cyclohexanol yield was 13%. Cyclohexanediol was only a minor product (1%). More phenol was evident and cyclohexane became a significant product (2%); however, the hexane recovery is likely limited by its low solubility in the water. More cyclohexane may have been actually produced and remained in the reactor as a separate light phase, which could not be sampled by our method. Over the period of the test, the amount of aqueous phase products is reduced. A large methane gas product was produced in this test, as has been reported for processing at these conditions of temperature and catalyst wherein phenol was extensively gasified at as low as 250° C.xi At 300° C., phenol is the primary product that was recoverable. Cyclohexanol and methoxycyclohexanol are early products which are reduced to low levels within the first hour at temperature. All three isomers of methyl-phenol (cresols) are significant byproducts, as is benzene. Cyclohexane is present in the water product only at low concentration, but is likely present as a significant product in a separate phase. Because of the large amount of methane gas formation, this test was hydrogen limited with the reactor pressure surpassing the pressure set point after 1 h of operation and this factor is expected to have skewed the mechanism away from the high-use hydrogenation pathways, such as saturation of the aromatic ring. xiElliott, D. C.; Hart, T. R.; Neuenschwander, G. G. “Chemical Processing in High-Pressure Aqueous Environments. 8. Improved Catalysts for Hydrothermal Gasification.” Ind Eng. Chem. Res. 45(11) 3776-81, 2006.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2].[OH-].[K+].[F:20][C:21]([F:31])([F:30])[C:22]1[CH:27]=[CH:26][C:25]([CH:28]=[CH2:29])=[CH:24][N:23]=1>CN1CCCC1=O.[Cl-].[Na+].O>[CH:1]([C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:29][CH2:28][C:25]3[CH:24]=[N:23][C:22]([C:21]([F:31])([F:20])[F:30])=[CH:27][CH:26]=3)[C:8]3[CH2:13][CH2:14][N:15]([CH3:17])[CH2:16][C:7]=3[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)c1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.5 %

Procedure:
To a solution of 8-Isopropyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.43 mmol) in N-methyl 2-pyrolidone (0.5 mL) was added powdered potassium hydroxide (0.096 g, 1.72 mmol) and allowed to stir for 10 min at RT. 2-trifluoromethyl-5-vinyl pyridine (0.19 g, 1.1 mmol) was added and stirred for further at 35 deg C. for 3 h. Reaction mixture was diluted with brine (5 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (5% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) to provide the desired compound as brown oil (0.17 g, 45% yield). Isopropyl-2-methyl-5-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.080 g, 0.19 mmol) was dissolved in THF (2.0 mL). A solution of oxalic acid dihydrate (0.017 g, 0.19 mmol) in THF (2 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as white solid (0.045 g, 46% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][C:11](Cl)=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:20][CH2:21][CH2:22][OH:23]>>[CH2:1]([N:8]1[CH:16]=[N:15][C:14]2[C:9]1=[N:10][C:11]([NH:20][CH2:21][CH2:22][OH:23])=[N:12][C:13]=2[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Solvent: O
Product: Nc1nc(NCCO)nc2c1ncn2Cc1ccccc1
Yield: 100 %

Procedure:
9-Benzyl-2-chloroadenine (1.0 g, 3.8 mmol) was stirred in 2-aminoethanol (8 ml) at 110° C. for 4 hours. Water (100 ml) was added to the reaction mixture and the resulting precipitate was filtered to give the captioned compound (1.1 g, 3.8 mmol, yield: 100%) as a white solid.
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.[F:13][C:14]([F:31])([F:30])[C:15](=[O:29])[CH2:16][C:17]([C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[O:27][CH3:28])([CH3:19])[CH3:18]>C1COCC1>[F:31][C:14]([F:13])([F:30])[C:15]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)([OH:29])[CH2:16][C:17]([C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[O:27][CH3:28])([CH3:19])[CH3:18]
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)C(F)(F)F
Reactant: Cc1ccccn1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1ccccn1)C(F)(F)F
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 53.4 %

Procedure:
tert-Butyl lithium (1.7 M in pentane, 0.5 mL) was added dropwise to a solution of 2-methylpyridine (0.050 g) in THF (0.5 mL) cooled to −70° C. under argon. The mixture was stirred at −70° C. for 10 minutes and 1,1,1-trifluoro-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (0.080 g) (Example 1) in THF (0.5 mL) was added over 1 minute. The reaction mixture was stirred for 5 minutes and then quenched with MeOH. The reaction mixture was concentrated in vacuo and the residue fractionated directly by preparative layer chromatography on silica gel (methylene chloride-hexanes (1:1)) to give the 57 mg of the title compound, m.p. 94° C.-96° C.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1.[Cl-].[CH3:13][O:14]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].Cl>C(OC)(C)(C)C.O1CCCC1.O>[CH:13]([CH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:3][CH2:2]1)=[O:14]
Reactant: CCOC(=O)C1CCCCC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 425.5 g of ethyl 4-cyclohexanecarboxylate and 856.7 g of methoxymethyltriphenylphosphonium chloride were suspended in 2.2 l of methyl tert-butyl ether. A solution of 280.4 g of potassium tert-butoxide in 400 ml of tetrahydrofuran was then added dropwise to the stirred suspension. The suspension was then stirred overnight at RT, and the next day 430 ml of 10% hydrochloric acid were added and the mixture was warmed at 55° C. for 1 hour. 50 ml of water were then added to the suspension. Conventional work-up gave ethyl 4-formylcyclohexanecarboxylate.
Reaction SMILES: [K].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:20](Cl)[N:19]=[C:18]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[OH-].[Ba+2].[OH-].[CH2:41]([OH:44])[CH2:42][OH:43]>C1(C)C=CC=CC=1>[CH3:3][C:2]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[C:21]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:20]([O:43][CH2:42][CH2:41][OH:44])[N:19]=[C:18]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)([CH3:5])[CH3:4]
Reactant: OCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Agent: [Ba+2]
Agent: [K]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Temperature: 110 °C
Reaction time: 4 h

Procedure:
5 gms of p-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-[2,2′-bipyrimidin]-4-yl]benzenesulfonamide potassium salt and barium hydroxide (0.75 gms) were charged to a reaction vessel. Ethylene glycol (15 ml) and toluene (75 ml) were added thereto. The reaction mass was heated at a temperature of 110° C. for 2 hours. Further, 0.75 gms of barium hydroxide was added and heating was continued for another 4 hours. After completion of the reaction, the solid was filtered and isolated as barium salt of bosentan. It was further purified by crystallizing with a mixture of methanol and isopropyl acetate.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][O:29][CH:28]([C:32]([OH:34])=O)[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:35]([N:38](CC)C(C)C)(C)C.CN.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:17])([F:18])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][O:29][C@@H:28]([C:32]([NH:38][CH3:35])=[O:34])[CH2:27]3)(=[O:24])=[O:25])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCOC(C(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)[C@H]1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)CCO1
Yield: 78 %

Procedure:
Following the same procedure in Example 112, Step A, using 4-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)morpholine-2-carboxylic acid (500 mg, 1 mmol), N,N-diisopropylethylamine (1 mL, 5 mmol), methylamine (0.75 mL, 2.0M in THF, 1.5 mmol) and HATU (456 mg, 1.2 mmol) in DMF (10 mL). The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 400 mg (78% yield) as white solid racemic mixture of the title compound. The two enantiomers were separated on a chiral OD 5 microns column using 20% ethanol:hexane. [α]D: +37.4 (c=1.00, MeOH). 1H NMR (400 MHz, METHANOL-D4) δ 1.37-1.46 (m, 2 H), 1.48 (s, 9 H), 1.53-1.73 (m, 4 H), 1.88-2.01 (m, 2 H), 2.04-2.18 (m, 2 H), 2.29 (m, 1 H), 2.59 (s, 3 H), 3.43-3.49 (m, 1 H), 3.59 (m, 1 H), 3.77-3.85 (m, 1 H), 3.87-3.96 (m, 2 H), 4.30 (d, J=7.62 Hz, 2 H), 7.54 (dd, J=8.69, 1.66 Hz, 1 H), 7.67 (d, J=8.59 Hz, 1 H), 7.93 (d, J=1.76 Hz, 1 H); MS (APPI) (M+H)+=513.3; Anal. Calc. for C24H34F2N4O4S+1.5 TFA: C, 47.44; H, 5.23; N, 8.20. Found: C, 47.54; H, 4.91; N, 8.00.