Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH:17]1[C:22]([S:23](Cl)(=[O:25])=[O:24])=[CH:21][CH:20]=[C:19]([I:27])[CH:18]=1.Cl>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:4]([C:3]1[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:2]=1[NH:1][S:23]([C:22]1[CH:17]=[CH:18][C:19]([I:27])=[CH:20][CH:21]=1)(=[O:25])=[O:24])(=[O:5])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(c1ccccc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(I)cc1
Temperature: 25 °C

Procedure:
To a magnetically stirred solution of 2-amino-5-chlorobenzophenone (1.62 g, 7.0 mmol) in dry pyridine (30 mL) was added dropwise a solution of pipsyl chloride in toluene (12 mL) and the reaction was stirred at ambient temperature. The reaction was added to cold (ice bath) 6M hydrochloric acid with stirring and the mixture was extracted with ethyl acetate (3×50 mL). The extracts were washed with water and with saturated aqueous NaCl. The organic layer was dried (MgSO4), filtered and concentrated to give a crystalline solid. The product was filtered, washed with hexane and dried (vacuum) to get white crystalline solid. 1H NMR (CDCl3) δ 9.63 (br s, 1H, NH), 7,75 (dm, 1H, J=8.8 Hz), 7.62 (tm, 1H, J=7.6 Hz), 7.56 (dm, 1H, J=7.6 Hz), 7.48 (m, 3H), 7.32 (m, 5H). MS: m/z 498.0 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)([CH3:6])[C:3]([NH2:5])=[O:4].C([SiH](CC)CC)C>CO.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([C:2]([CH3:6])([CH3:1])[C:3]([NH2:5])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)(C(N)=O)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: CC(C)(C(N)=O)c1cccc(N)c1
Reaction time: 0.42 h
Yield: 79.4 %

Procedure:
To a stirred solution of 2-methyl-2-(3-nitrophenyl)propanamide (0.9 g, 4.32 mmol) in methanol was added Pd—C (10%, 0.23 g) followed by slow addition of triethylsilane (6.90 ml, 43.2 mmol) at RT. Reaction was stirred at same temperature for 25 min. The reaction mixture was filtered through celite bed and washed with methanol (50 ml). Filtrate was collected and concentrated under vacuum to obtain 2-(3-aminophenyl)-2-methylpropanamide (0.611 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:4]=1.O.N1C(=O)[C:24](=O)[C:22](=[O:23])NC1=O>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:10]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:16]=[CH:24][C:22]2=[O:23])=[CH:7][CH:8]=1
Reactant: O=C1NC(=O)C(=O)C(=O)N1
Reactant: COc1ccc(Nc2ccccc2N)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-n2c(=O)cnc3ccccc32)cc1
Reaction time: 0.5 h

Procedure:
To a solution of N-(4-methoxyphenyl)benzene-1,2-diamine (9.0 g) in ethanol (150 ml) was added a solution of alloxan monohydrate (6.7 g) in water (150 ml) and the mixture was stirred for 30 minutes. The precipitate was filtered off and recrystallised from glacial acetic acid giving the title compound mp 236°-238° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[C:13]([CH:15]=[CH:16][C:17]=3[Cl:18])[NH2:14])=[N:8][C:5]2=[N:6][CH:7]=1.[O:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](Cl)=[O:25]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[C:13]([NH:14][C:24]([C:20]4[O:19][CH:23]=[CH:22][CH:21]=4)=[O:25])[CH:15]=[CH:16][C:17]=3[Cl:18])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(-c2nc3ncc(Br)cc3[nH]2)c1)c1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a suspension of 3-[6-bromo-1H-imidazo[4,5-b]pyridin-2-yl]-4-chloroaniline (15 g, 46.36 mmol, 1.00 equiv) in dichloromethane (150 mL) was added furan-2-carbonyl chloride (9.1 g, 69.72 mmol, 1.50 equiv) in a bath of ice and stirred overnight at room temperature. The reaction was then quenched by the addition of 50 mL of methanol and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/2) to give 8.9 g (46%) of N-(3-[6-bromo-1H-imidazo[4,5-b]pyridin-2-yl]-4-chlorophenyl)furan-2-carboxamide (I-2) as a light yellow solid. 1H-NMR: (DMSO, 300 MHz): 13.09-13.79 (m, 1H), 10.53 (s, 1H), 8.51 (s, 1H), 8.36 (brs, 2H), 7.98-8.02 (m, 2H), 7.68 (d, J=9.0 Hz, 1H), 7.40 (d, J=3.3 Hz, 1H), 6.74 (dd, J=3.3, 1.8 Hz, 1H). MS M/Z=419 (M+1).
Reaction SMILES: [CH3:1][C@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4]>CO.[Rh]>[CH3:1][C@H:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4]
Reactant: C[C@H](Cc1ccccc1)C(=O)O
Agent: [Rh]
Solvent: CO
Product: C[C@H](CC1CCCCC1)C(=O)O
Reaction time: 15 h
Yield: 78.3 %

Procedure:
A mixture of α(R)-methylbenzenepropionic acid (3.0 g, 18 mmol) and 5% rhodium on alumina (800 mg) in methanol (100 mL) was shaken under 40 p.s.i. of H2 on a Parr hydrogenation apparatus. After 15 h, the mixture was filtered through diatomaceous earth and concentrated to afford α(R)-methylcyclohexanepropionic acid as a clear liquid (2.4 g, 77%). 1H NMR (CDCl3) δ 2.62-2.53 (m, 1H), 1.79-1.59 (m, 6H), 1.38-1.16 (m, 5H), 1.17 (d, J=7 Hz, 3H), 0.95-0.83 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27](Cl)[CH:26]=2)=[CH:4][C:5]([F:23])=[C:6]([NH:8][C:9]([N:11]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12]2=[O:22])=[O:10])[CH:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][NH:43][CH:44]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:42]1[CH:41]=[C:40]([C:27]2[CH:26]=[C:25]([O:24][C:3]3[C:2]([Cl:1])=[CH:7][C:6]([NH:8][C:9]([N:11]4[CH2:15][CH2:14][N:13]([CH:16]5[CH2:21][CH2:20][O:19][CH2:18][CH2:17]5)[C:12]4=[O:22])=[O:10])=[C:5]([F:23])[CH:4]=3)[CH:30]=[CH:29][N:28]=2)[CH:44]=[N:43]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: O=C(Nc1cc(Cl)c(Oc2ccnc(Cl)c2)cc1F)N1CCN(C2CCOCC2)C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1cc(Cl)c(Oc2ccnc(-c3cn[nH]c3)c2)cc1F)N1CCN(C2CCOCC2)C1=O
Temperature: 80 °C
Yield: 75 %

Procedure:
A mixture of Example C8 (0.200 g, 0.426 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.124 g, 0.639 mmol) and K2CO3 (0.177 g, 1.279 mmol) in dioxane (4 mL) and water (1 mL) was sparged with Ar, treated with Pd(PPh3)4 (0.025 g, 0.021 mmol), sparged again with Ar and heated at 80° C. overnight. The mixture was cooled to RT, treated with satd. NaHCO3, extracted with EtOAc (2×) and the combined organics were washed with brine, dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(4-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (160 mg, 75%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 13.05 (s, 1H), 10.91 (d, J=2.7 Hz, 1 H), 8.40 (1H, d, J=8.1 Hz, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.33 (s, 1 H), 8.04 (s, 1 H), 7.57 (d, J=11.2 Hz, 1 H), 7.30 (d, J=2.5 Hz, 1 H), 6.61 (dd, J=5.7, 2.5 Hz, 1 H), 3.94-3.77 (m, 5 H), 3.47 (t, J=8.2 Hz, 2 H), 3.37 (t, J=11.8 Hz, 2 H), 1.75-1.64 (m, 2 H), 1.59 (m, 2H); MS (ESI) m/z: 501.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][CH2:29][CH2:30][NH2:31])[CH3:27]>>[CH2:26]([O:28][CH2:29][CH2:30][NH:31][C:20]([C:14]1[C:15](=[O:19])[NH:16][C:17]2[C:12]([C:13]=1[OH:25])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH:18]=2)=[O:21])[CH3:27]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: CCOCCN
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-ethoxyethylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.82 (1H, br s), 10.58 (1H, br s), 8.19 (1H, br s), 7.35-7.26 (3H, m), 7.15-7.10 (2H, m), 4.03 (2H, br s), 3.48-3.41 (6H, m), 1.11 (3H, t, J=8.4 Hz); HRMS calcd for C20H20FN3O4+H+: 386.1516. Found 386.1501.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]1[CH2:6][CH2:7][CH:9]([C:8]([O:15][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:15])[CH2:5][CH2:4]1)[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)C1CCN(Cc2ccccc2)CC1
Yield: 96.4 %

Procedure:
0.278 g (0.00127 mol) of 1-benzylpiperidine-4-carboxylic acid was boiled at reflux in 5 ml of oxalyl chloride for 2 hrs. The excess oxalyl chloride was distilled off. The residue was taken up twice in toluene and concentrated each time. 0.3 g (99%) of 1-benzylpiperidine-4-carboxylic acid chloride was obtained as a pale beige solid. This was dissolved in 20 ml of toluene, treated with 0.265 ml (0.0019 mol) of triethylamine and 0.17 g (0.00165 mol) of benzyl alcohol and boiled at reflux for 18 hrs. After removal of the solvent the residue was chromatographed on silica gel with ether/hexane (1:2) as the eluent. 0.246 g (80%) of benzyl 1-benzylpiperidin-4-carboxylate was obtained as a yellow oil. MS: me/e=310 (C2H23NO2+).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[N:7]=[CH:6][NH:5][N:4]=1.[CH2:10]=[O:11]>CC(C)=O>[F:1][C:2]([F:9])([F:8])[C:3]1[N:7]=[CH:6][N:5]([CH2:10][OH:11])[N:4]=1
Reactant: FC(F)(F)c1nc[nH]n1
Reactant: C=O
Solvent: CC(C)=O
Product: OCn1cnc(C(F)(F)F)n1
Temperature: 150 °C
Reaction time: 5 h
Yield: 94.3 %

Procedure:
The mixture of 2.74 g of 3-(trifluoromethyl)-1H-1,2,4-triazole and 1.20 g of paraformaldehyde was stirred at 150° C. for 5 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture, and the mixture was filtered. The filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 3.15 g of 3-(trifluoromethyl)-1H-1,2,4-triazole 1-ylmethanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][C:25]#[CH:26])[CH2:21][CH:22]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(N(CC)CC)C.C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([C:26]#[C:25][CH2:24][CH2:23][N:20]2[CH2:19][CH:18]=[C:17]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:22][CH2:21]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C#CCCN1CC=C(c2ccccc2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C#CCCN2CC=C(c3ccccc3)CC2)nc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2-bromo-5-nitropyridine (4.23 g, 0.02 mol) and the alkyne prepared in Step (a) (4.0 g, 0.019 mol) in 7.9 mL of triethylamine and 100 mL of acetonitrile is degassed by bubbling in dry nitrogen for 15 minutes, and 0.27 g (0.0004 mol) of bis(triphenylphosphine)palladium chloride and 0.07 g (0.0004 mol) of cuprous iodide are added. The flask is flushed with nitrogen and the mixture is stirred at room temperature for 6 hours. The solvent is removed under reduced pressure and the residue is partitioned between 100 mL of dichloromethane and 100 mL of saturated aqueous sodium bicarbonate. The aqueous layer is extracted with 50 mL of dichloromethane and the combined organic layers are washed with 50 mL of water and dried (sodium sulfate), and the solvent is removed in vacuo. The residue is chromatographed (silica gel, 1% methanol/99% dichloromethane) to give the title compound, containing 0.3 mol of water; mp 133°-134° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45]([OH:47])=O)([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.[CH2:52]([OH:59])[C:53]([NH2:58])([CH2:56][OH:57])[CH2:54][OH:55].OCCN1CCNCC1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](=[O:47])[NH:58][C:53]([CH2:56][OH:57])([CH2:54][OH:55])[CH2:52][OH:59])([CH3:44])[CH3:43])=[CH:35][CH:36]=3)=[C:28]([CH:49]([CH3:50])[CH3:51])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: NC(CO)(CO)CO
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: OCCN1CCNCC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)NC(CO)(CO)CO)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 48 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and tris(hydroxymethyl)aminomethane instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)-ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)-piperazine, respectively.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([CH2:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=2)[O:21][CH2:22][C:23]([O:25]C)=[O:24])[O:9][C:10]=1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.[OH-].[Na+]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([CH2:16][CH2:17][C:18]2[CH:19]=[C:20]([CH:27]=[CH:28][CH:29]=2)[O:21][CH2:22][C:23]([OH:25])=[O:24])[O:9][C:10]=1[C:11]1[S:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)COc1cccc(CCc2nc(-c3cccs3)c(-c3cccs3)o2)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)COc1cccc(CCc2nc(-c3cccs3)c(-c3cccs3)o2)c1

Procedure:
Hydrolysis of methyl [3-[2-[4,5-di(2-thienyl)-2-oxazolyl]ethyl]phenoxy]acetate with aqueous sodium hydroxide provided the hydrated title compound, m.p. 105.5°-107° C.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[C:15]([F:22])[CH:14]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CCO.CC(=O)OCC>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([F:22])[CH:14]=1)[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH3:12]
Reactant: CCOC(=O)C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(c1ccccc1)c1ccc(N)c(F)c1
Yield: 97.5 %

Procedure:
Ethyl 2-phenyl-2-(3-fluoro-4-nitrophenyl)acetate was dissolved in a 1:1 mixture of EtOH and EA (465 mL) and hydrogenation was carried out in an H-cube (1 bar, 25° C., 1 mL/min and 0.25 mol/L). Following removal of the solvent and drying, 5.2 g (97.5%) of product were obtained.
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>O.C(O)C>[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: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OCCO
Agent: [Ba+2]
Agent: [K]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Temperature: 110 °C
Reaction time: 4 h

Procedure:
10 gms of p-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-[2,2′-bipyrimidin]-4-yl]benzenesulfonamide potassium salt and barium hydroxide (1.5 gms) were charged to a reaction vessel. Ethylene glycol (30 ml) and toluene (150 ml) were added thereto. The reaction mass was heated at a temperature of 110° C. for 2 hours. Further 1.5 gms of barium hydroxide was added and heating was continued for another 4 hours. After completion of the reaction, toluene was removed by distillation and water (150 ml) was added. The pH of the reaction mass was adjusted to a value ranging from 1 to 2 with a mixture of 1:1 HCl:water and extracted in dichloromethane. The organic layer was collected and washed with water (150 ml) and the solvent was distilled off to obtain a residue. To the residue a mixture of ethanol and water (1:1) was added and stirred. The resulting suspension was heated to reflux to obtain a clear solution. The clear solution was further cooled to 25° C. to isolate bosentan.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][C:18](=O)[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].Cl.[NH2:36][OH:37]>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][C:18](=[N:36][OH:37])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: CC(C)(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Reactant: NO
Agent: Cl
Product: CC(C)(Oc1ccc(CCC(=NO)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O

Procedure:
2-(2,3-Dichloro-4-(3-(hydroxyimino)-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methyl propanoic acid and hydroxylamine hydrochloride according to general procedure I.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[CH3:3].ClCCl.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:2]([O:4][C:5](=[O:27])[C@@H:6]([O:24][CH2:25][CH3:26])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([NH:23][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(N)cc2)cc1)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OCCc2ccc(NS(C)(=O)=O)cc2)cc1)OCC
Reaction time: 3 h
Yield: 32.8 %

Procedure:
3-{4-[2-(4-Aminophenyl)ethoxy]phenyl}-(S)-2-ethoxypropanoic acid ethyl ester hydro chloride (described in Example 41b) (0.45 g; 1.26 mmole), dichloromethane (10 ml), methanesulfonyl chloride (0.216 g; 1.88 mmole) and triethylamine (0.318 g; 3.14 mmole) were mixed at 0° C. and stirred for 3 hours at that temperature and then at room temperature over night. The reaction mixture was poured into ethyl acetate (50 ml). Triethylamine hydrochloride salt was filtered off and the filtrate evaporated. The residue was redissolved and extracted with ethyl acetate and water. The organic phase was washed once more with water, dried with sodium sulfate and evaporated. Chromatography with diethyl ether:petroleum ether (1:3, 1:1, 3:1) as eluant gave 0.18 g (32.8% yield) of (S)-2-ethoxy-3-[4-{2-(4-[methylsulfonylamino]phenyl)ethoxy}phenyl]propanoic acid ethyl ester.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]#[N:32])[CH:28]=[CH:27][C:26]=2[F:33])[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.O=[C:35]([CH3:49])[CH2:36][CH2:37][N:38]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:38][CH2:37][CH2:36][CH:35]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:24][C:25]2[CH:30]=[C:29]([CH:28]=[CH:27][C:26]=2[F:33])[C:31]#[N:32])[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][CH:19]=[CH:18]3)[CH2:12][CH2:13]1)[CH3:49]
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc3[nH]ccc3c2)CC1
Product: CC(CCN)N1CCC(N(Cc2cc(C#N)ccc2F)c2ccc3[nH]ccc3c2)CC1

Procedure:
Using general procedure C with the above carbamate (400 mg, 0.891 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (386 mg, 1.78 mmol) followed by general procedure D afforded 3-{[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(1H-indol-5-yl)-amino]-methyl}-4-fluoro-benzonitrile as a white solid (92 mg, 26% over 3 steps).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:15])=[O:16])=[CH:12][CH:13]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COc1ccc(Cl)cc1-c1ccc(S(=O)(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared from the product of step (iii) (0.6 g) which was stirred in TFA/DCM (1:1, 10 ml) overnight. The mixture was concentrated under reduced pressure to give an oil. The residue was purified by reverse phase HPLC, yield 0.31 g.
Reaction SMILES: C([N:5]1[C:13]2[CH:12]=[CH:11][N:10]=[C:9]([O:14][CH3:15])[C:8]=2[C:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[N:6]1)(C)(C)C>FC(F)(F)C(O)=O.O>[CH3:15][O:14][C:9]1[C:8]2[C:7]([C:16]3[CH:17]=[CH:18][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:20][CH:21]=3)=[N:6][NH:5][C:13]=2[CH:12]=[CH:11][N:10]=1
Reactant: COc1nccc2c1c(-c1ccc(S(N)(=O)=O)cc1)nn2C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1nccc2[nH]nc(-c3ccc(S(N)(=O)=O)cc3)c12
Temperature: 25 °C
Yield: 75.7 %

Procedure:
4-(1-tert-Butyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzenesulfonamide (878 mg) obtained in Step D of Example 86 was dissolved in a mixed solvent of trifluoroacetic acid (50 mL)/water (5 mL), and the solution was heated with reflux for 24 hr. The reaction mixture was allowed to be cooled to room temperature, and concentrated under reduced pressure. The residue was extracted with ethyl acetate and saturated aqueous sodium hydrogencarbonate solution, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (561 mg).
Reaction SMILES: [P:1]([OH:12])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:13][C:14]1[CH:19]2[C:20]([CH3:22])([CH3:21])[CH:17]([CH2:18]2)[CH2:16][CH:15]=1>>[CH:14]1([CH3:13])[CH:15]([P:1](=[O:12])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH:17]([CH:20]([CH3:21])[CH3:22])[CH2:18][CH:19]1[P:1](=[O:12])([O:7][CH2:8][CH2:9][CH2:10][CH3:11])[O:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CC1=CCC2CC1C2(C)C
Reactant: CCCCOP(O)OCCCC
Product: CCCCOP(=O)(OCCCC)C1CC(C(C)C)CC(P(=O)(OCCCC)OCCCC)C1C
Yield: 69 %

Procedure:
Dibutyl hydrogen phosphite and α-pinene were reacted in substantially the same manner as reported in Example 3 to make the titled compound (69% theory yield). The NMR spectrum was in agreement with the expected structure.