Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1[N:12]([CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:13]2[C:22]3[N:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:23])[C:14]=2[N:24]=1)C1C=CC=CC=1.Cl>CO.[Pd].C(O)C>[NH2:23][C:15]1[C:14]2[N:24]=[C:11]([CH2:10][CH2:9][OH:8])[N:12]([CH2:25][C:26]([F:29])([CH3:28])[CH3:27])[C:13]=2[C:22]2[N:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:16]=1
Reactant: CC(C)(F)Cn1c(CCOCc2ccccc2)nc2c(N)nc3cccnc3c21
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC(C)(F)Cn1c(CCO)nc2c(N)nc3cccnc3c21
Reaction time: 8 h
Yield: 46 %

Procedure:
A solution of 2-[2-(benzyloxy)ethyl]-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (0.78 g, 1.98 mmol) dissolved in 20 mL of methanol was treated with 10% palladium on carbon (200 mg) and 0.68 mL of 3 M HCl in ethanol. The mixture was shaken under H2 at 50 PSI (3.4×105 Pa) overnight. Additional 10% palladium on carbon (200 mg) and 3 M HCl in ethanol (0.33 mL) were added and shaking was continued for 24 hours. The reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with methanol and the combined filtrates were concentrated under reduced pressure. The resulting material was treated with 20 mL of H2O and 2 mL of concentrated NH4OH solution and extracted into CHCl3 (3×25 mL). The combined organic layers were concentrated under reduced pressure. Chromatography (SiO2, 15-30% CMA/CHCl3) gave a white powder. Crystallization from ethanol/H2O gave 276 mg of 2-[4-amino-1-(2-fluoro-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-2-yl]ethanol as white needles, mp 224-225° C.
Reaction SMILES: [NH2:1][C:2]([CH3:18])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:17])=[C:10]([Cl:16])[CH:11]=[C:12]2[Cl:15])=[N:7]1)[C:3]#[N:4].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[S:26])=[CH:23][CH:22]=1>>[C:3]([C:2]([NH:1][C:25](=[S:26])[C:24]1[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:29][CH:28]=1)([CH3:18])[CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:17])=[C:10]([Cl:16])[CH:11]=[C:12]2[Cl:15])=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (60 mg, described in Example 136) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (40 mg, 40%). Rf=0.65 (1:1 EA/heptane). 1H NMR: (400 MHz, DMSO-d6): 1.70 (s, 3H), 5.11 (d, 1H), 5.25 (d, 1H), 7.47 (s, 1H), 7.79-7.80 (m, 4H), 8.73 (s, 1H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −42.0 (s, 3F).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[CH3:24]>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[CH:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:20]3[CH:21]=[CH:22][C:23]([CH3:24])=[C:18]([CH:19]=3)[NH2:17])=[CH:7][N:6]=1)[CH2:10]2
Reactant: Brc1cnc(OC2CN3CCC2CC3)nc1
Reactant: Cc1ccc(B(O)O)cc1N
Product: Cc1ccc(-c2cnc(OC3CN4CCC3CC4)nc2)cc1N

Procedure:
The product of Example 18A (160 mg, 0.57 mmol) was treated with 3-amino-4-methyl-phenylboronic acid (Lancaster, 302 mg, 2.0 mmol) according to the procedure of Example 1B. The title product was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.1) as solid (45 mg, yield, 26%). 1H NMR (300 MHz, MeOH-d4) δ 1.48-1.62 (m, 1H), 1.65-1.90 (m, 2H), 2.01-2.16 (m, 1H), 2.19 (s, 3H), 2.22-2.29 (m, 1H), 2.74-3.01 (m, 5H), 3.36-3.47 (m, 1H), 5.12-5.20 (m, 1H), 6.86 (dd, J=7.51.7 Hz, 1H), 6.95 (d, J=1.7 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 8.73 (s, 2H) ppm. MS (DCl/NH3) m/z 311 (M+H)+.
Reaction SMILES: [Li+].[OH-].C[CH:4]([C@@H:8]1[CH2:13][CH2:12][N:11]([C@@H:14]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[O:33])[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:22][CH:21]=2)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:10]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[CH2:9]1)[C:5]([O-:7])=[O:6]>O.C1COCC1>[C:26]([C:23]1[CH:22]=[CH:21][C:20]([C@H:14]([N:11]2[CH2:12][CH2:13][C@@H:8]([CH2:4][C:5]([OH:7])=[O:6])[CH2:9][C@H:10]2[C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:41])[F:43])=[CH:36][CH:35]=2)[CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])=[CH:25][CH:24]=1)(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)CC[C@H](c1ccc(C(=O)c2ccccc2)cc1)N1CC[C@@H](C(C)C(=O)[O-])C[C@H]1c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CC[C@H](c1ccc(C(=O)c2ccccc2)cc1)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 53.9 %

Procedure:
A solution of LiOH (10 mg, 0.42 mmol) in water (0.5 ml) was added to a stirred solution of the ester (Step 3, 42 mg, 0.074 mmol) in THF (1 ml) at RT. The reaction was stirred at RT O/N then quenched with 2N HCl (1 ml). The mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc (×2). The combined extracts were washed with brine (×1), dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, 2-8% MeOH/DCM) to give the acid (22 mg) as a colourless solid. 1H NMR (400 MHz, CD3OD): δ 0.60-0.70 (1H, m), 0.82-1.02 (7H, m), 1.14-1.24 (1H, m), 1.38-1.49 (2H, m), 1.72-1.75 (1H, m), 1.84-1.95 (4H, m), 2.18-2.20 (2H, m), 2.52 (1H, brt, J 11), 2.82 (1H, brd, J 11), 3.53 (1H, dd, J 9.8, 4.0), 3.87 (1H, brd, J 10), 7.45 (2H, d, J 8.2), 7.52 (2H, t, J 7.6), 7.64 (1H, J 7.4), 7.70-7.80 (8H, m); M/Z (ES+) 552 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[O:10][C:3]=12.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[O:10][C:3]=23)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(-c2cc3nccc(Cl)c3o2)cc(OC)c1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cc3nccc(-c4ccccc4)c3o2)cc(OC)c1OC
Temperature: 150 °C
Yield: 32 %

Procedure:
7-Chloro-2-(3,4,5-trimethoxy-phenyl)-furo[3,2-b]pyridine (0.061 mmol), phenyl boronic acid (0.064 mmol), palladium(II)-acetate (0.004 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.006 mmol) and K2CO3 (0.181 mmol) are suspended in 1,4-dioxane (1.00 ml) and water (100.00 μl). The suspension is heated to 150° C. in the microwave for 45 min. The solvent is removed in vacuo and the product purified over column chromatography (SiO2, heptan, ethyl acetate). The product is isolated as yellow solid (yield 32%); HPLC (method A): Rt 2.6 min (purity 93.2%); LCMS (ESI+) (method E): Rt 2.416 min, M+H+ 362.1 m/z; 1H NMR (500 MHz, DMSO-d6) δ [ppm] 8.57 (d, J=5.1, 1H), 8.16-8.10 (m, 2H), 7.74 (s, 1H), 7.65 (t, J=7.7, 2H), 7.60 (d, J=5.1, 1H), 7.56 (t, J=7.4, 1H), 7.31 (s, 2H), 3.91 (s, 6H), 3.74 (s, 3H).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([CH3:3])[CH3:2].[OH-].[Na+].[Br:11]Br>O>[Br:11][C:8]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][NH:6][CH:7]=1
Reactant: BrBr
Reactant: CC(C)c1cc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1n[nH]cc1Br
Temperature: 0 °C
Reaction time: 5 h
Yield: 99.6 %

Procedure:
1.10 g of 3-i-propyl-1H-pyrazole was suspended in 20 ml of water, and 1.6 g of 50% aqueous solution of sodium hydroxide was added to it. The mixture was cooled to 0° C., and then 1.76 g of bromine was added to the mixture, followed by stirring at room temperature for 5 hours. The reaction mixture was extracted by ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.88 g of 4-bromo-3-i-propyl-1H-pyrazole.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[CH2:11]([NH2:14])[CH2:12][CH3:13]>>[CH2:11]([NH:14][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([I:1])[CH:3]=1)[CH2:12][CH3:13]
Reactant: CCCN
Reactant: O=C(O)c1cccc(I)c1
Product: CCCNC(=O)c1cccc(I)c1
Yield: 82 %

Procedure:
Using Preparation Method 1, 3-iodobenzoic acid was reacted with n-propylamine. The resulting reaction mixture was purified using SiO2 with CH2Cl2/petroleum ether 95:5 to CH2Cl2/AcOEt 95:5 to give N-n-propyl-3-iodobenzamide as an off-white solid (82%). NMR 1H (ppm, CDCl3): 8.07 (t, J4=1.6 Hz, 1H), 7.80 (d. t., J3=7.9 Hz, J4=1.1 Hz, 1H), 7.69 (d. t., J3=7.8 Hz, J4=1.1 Hz, 1H), 7.15 (t, J3=7.8 Hz, 1H), 6.06 (br. s., 1H), 3.43-3.36 (m, 2H), 1.62 (sext., J3=7.3 Hz, 2H), 0.97 (t, J3=7.4 Hz, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][O:12][CH2:13][CH2:14]O>[Ni].C1COCC1>[CH3:11][O:12][CH2:13][CH2:14][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: COCCO
Reactant: O=C1Cc2ccccc2N1
Agent: [Ni]
Solvent: C1CCOC1
Product: COCCC1C(=O)Nc2ccccc21

Procedure:
2.0 g (15 mmol) indolin-2-one, 5 mL (63 mmol) 2-methoxyethanol and 1.5 g Raney nickel in 20 mL THF were stirred for 4 h at 200° C. in an autoclave. After the catalyst had been filtered off the mother liquor was evaporated down, the residue was triturated with diisopropylether, suction filtered and dried
Reaction SMILES: P(Cl)(Cl)(Cl)=O.P(Cl)(Cl)([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=O>>[CH2:9]([OH:8])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCCCCOP(=O)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCCCCCCCCCCO

Procedure:
Using the procedure described in Preparation 7 but utilizing 184.4 g. (1.38 equivs.) of the polymethylene polyphenyl polyisocyanate, 7.97 g. (0.052 mole) of phosphoryl chloride and 9.67 g. (0.052 mole) of lauryl alcohol, there was obtained a solution of predominantly lauryl dichlorophosphate in polymethylene polyphenyl polyisocyanate which was used, without further treatment, in the preparation of a particle board as described in Example 1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([C:18]2([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21][NH:20][CH2:19]2)[CH:13]=[C:14]([Cl:17])[C:15]=1[Cl:16].CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>C(OCC)(=O)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:20]2[CH2:21][CH2:22][C:18]([C:12]3[CH:13]=[C:14]([Cl:17])[C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=3)([C:23]([F:24])([F:25])[F:26])[CH2:19]2)[N:3]=1
Reactant: Cc1cccc(Cl)n1
Reactant: FC(F)(F)C1(c2cc(Cl)c(Cl)c(Cl)c2)CCNC1
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cccc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)n1
Temperature: 120 °C
Yield: 66.2 %

Procedure:
2-Chloro-6-methylpyridine (1.6 g), 3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)-pyrrolidine (4.0 g), sodium t-butoxide (1.5 g), tris(dibenzylidenacetone)dipalladium (0)-chloroform adduct (0.2 g) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.25 g) were added to toluene (15 ml), and heated for 1 hour at 120° C. using a microwave reactor (trade name: INITIATOR™, manufactured by Biotage). Upon the completion of the reaction, the reaction mixture was diluted with ethyl acetate, and the precipitate was filtered off through a short silica gel layer. The filtrate was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 2-methyl-6-[3-(3,4,5-trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]pyridine (3.4 g).
Reaction SMILES: Br[C:2]1[C:3](=[O:9])[N:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[CH3:10][O:11][C:12](=[O:42])[C@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Sn](CCCC)(CCCC)CCCC)=[CH:25][CH:24]=1)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CN(C=O)C.ClCCl.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>[CH3:10][O:11][C:12](=[O:42])[C@H:13]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:2]2[C:3](=[O:9])[N:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)=[CH:27][CH:28]=1)[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16]
Reactant: Cn1cccc(Br)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cccn(C)c2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 4 h
Yield: 33.1 %

Procedure:
A solution of 3-bromo-1-methyl-2-pyridone (94 mg, 0.50 mmol) and N-[(1,1-dimethylethoxy)carbonyl]-4-[(tributyl)stannyl]-L-phenylalanine methyl ester (284 mg, 0.50 mmol) in DMF (3 mL) was deoxygenated by alternately freezing the mixture in a liquid nitrogen bath under vacuum and thawing under argon (3 ×). bis(triphenylphosphine)palladium dichloride (40 mg, 0.057 mmol) was added and the mixture was heated to 90° C. for 3 hr as the mixture turned dark. TLC indicated that the reaction was not complete and an additional 20 mg portion of the catalyst was added and heating continued for 4 hr. The mixture was allowed to cool and was diluted with dichloromethane (20 mL) and was filtered through a pad of celite. The filtrate was evaporated to dryness and the residue was dissolved in 1:1 ether:ethyl acetate (20 mL). The solution was washed with water (1×10 mL), 5% potassium fluoride (2×5 mL) and water (1×10 mL) and was dried (MgSO4). The residue obtained upon concentration was chromatographed over 25 g of silica gel eluting with 4:6 ethyl acetate:hexane to give N-[(1,1-dimethylethoxyl)carbonyl]-4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (64 mg, 33%). LRMS-Electrospray: m/z positive ion, 795 (2M+Na) 409 (M+Na) 387 (M+H). HRMS: Obs. Mass 387.1935. Calcd. Mass 387.1920 (M+H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>C1COCC1>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][S:11]([C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[CH:10]=1)(=[O:13])=[O:12]
Reactant: CN(C)CCN
Reactant: Cc1nc2ccc(S(=O)(=O)Cl)cc2s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc2ccc(S(=O)(=O)NCCN(C)C)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
To a solution of Compound 8 (7.0 g, 28.26 mmol) in THF (70 mL), a mixture of triethylamine (7.9 mL, 56.52 mmol) and N,N-dimethylethylene-diamine (4.67 mL, 42.38 mmol) in 20 mL THF was added dropwise. The combined mixture was stirred at room temperature for 2 hours during which time TLC showed complete disappearance of Compound 8. Solvents were removed in the rotary evaporator and the residue thus obtained was partitioned between chloroform (100 mL) and water (100 mL). The organic layer was washed with water (2×100 mL), brine (1×100 mL), dried (sodium sulfate) and evaporated to provide Compound 9 as a sticky oily solid (7.1 g, 84% yield). It was used further in the synthesis without any purification. The structure of Compound 9 is given below:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=O)[O:19]CC)[CH3:16].C([N-]C(C)C)(C)C.[Li+].[Cl-].[NH4+]>O1CCCC1>[CH2:15]([O:17][C:18](=[O:19])[CH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][N:7]=1)[CH3:16]
Reactant: Cc1ccc(CN2CCOCC2)cn1
Reactant: CCOC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(CN2CCOCC2)cn1
Temperature: -13 °C
Reaction time: 0.58 h
Yield: 92 %

Procedure:
4-(6-Methyl-pyridin-3-ylmethyl)-morpholine (30 g, 156 mmol) and diethylcarbonate (23.96 g, 202.9 mmol) were dissolved in tetrahydrofuran (150 ml) under an inert atmosphere. The solution was cooled to −13° C. and lithium diisopropylamide solution (190.8 ml, 1.8M, 343.3 mmol) added dropwise over 1 hr 45 min. After stirring for an additional 35 min the reaction mixture was added to a cold aqueous solution of ammonium chloride (204.5 ml, 4.58M, 936.2 mmol) at 0° C. The biphasic mixture was warmed to 30° C. and separated. The aqueous layer was extracted twice with toluene (120 ml) and the combined organic layers were concentrated by vacuum distillation to give (5-Morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester as a toluene solution (204 ml) (55.38 g, 92% yield (based on assay of 74.5 w/w %). An aliquot was removed and purified by column chromatography eluting with dichloromethane/methanol (40:1), which gave (5-morpholin-4-ylmethyl-pyridin-2-yl)-acetic acid ethyl ester as a yellow oil. 1H NMR (400 MHz; CDCl3,): δ 8.45 (d, J=1.88 Hz, 1H), 7.65 (dd, J=2.21, 7.93 Hz, 1H), 7.25 (d, J=6.12 Hz, 1H), 4.15 (q, J=7.17, 14.29 Hz, 2H), 3.82 (s, 2H), 3.69 (t, J=4.61, 9.28 Hz, 4H), 3.45 (s, 2H), 2.42 (t, J=4.52, 9.1 Hz, 4H), 1.25 (t, J=7.13, 14.29 Hz, 3H); 13C NMR: (100 MHz, CDCl3): δ 170.7, 153.4, 150.1, 137.4, 131.6, 123.5, 66.9, 61.03, 60.3, 53.5, 43.6, 14.2 ppm; MS (ESI) m/z 265 [M+1]+.
Reaction SMILES: C[O-].[Na+:3].[CH3:4][C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[N:23]=[C:22]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:21]=[C:20]([O:30][CH2:31][CH2:32][OH:33])[C:19]=2[O:34][C:35]2[C:40]([O:41][CH3:42])=[CH:39][CH:38]=[CH:37][CH:36]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1)([CH3:7])[CH3:6].O>CO.C(OCC)(=O)C>[CH3:7][C:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([N-:17][C:18]2[C:19]([O:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:40]=3[O:41][CH3:42])=[C:20]([O:30][CH2:31][CH2:32][OH:33])[N:21]=[C:22]([C:24]3[N:25]=[CH:26][CH:27]=[CH:28][N:29]=3)[N:23]=2)(=[O:15])=[O:16])=[CH:10][CH:9]=1)([CH3:4])[CH3:6].[Na+:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccccc1Oc1c([N-]S(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCO
Reaction time: 3 h

Procedure:
Sodium methoxide solution (30% methanolic solution) was added to a mixture of bosentan monohydrate (10 g) in methanol (20 mL) and ethyl acetate (80 mL). The reaction mixture was stirred for 3 hours and the solid was filtered, washed with ethyl acetate (20 mL) and dried at hot air oven at 50° C. to 55° C. to obtain the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[C:12]2[C:7]=1[C:8](=[O:22])[CH:9]=[C:10]([C:19]([OH:21])=[O:20])[S:11]2.C(=O)(O)[O-].[Na+:28]>O>[Na+:28].[CH3:23][CH:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH3:18])=[C:12]2[C:7]=1[C:8](=[O:22])[CH:9]=[C:10]([C:19]([O-:21])=[O:20])[S:11]2
Reactant: CCCc1ccc(OCCC(C)C)c2c(=O)cc(C(=O)O)sc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCc1ccc(OCCC(C)C)c2c(=O)cc(C(=O)[O-])sc12

Procedure:
5.9 Parts of 5-(3-methylbutoxy)-8-propyl-1-thiachromone-2-carboxylic acid was reacted with 1.83 parts of sodium bicarbonate in 50 parts of water. The resulting yellowish solution was freeze dried to give 5.7 parts of 5-(3-methylbutoxy)-8-propyl-1-thiachromone-2-carboxylic acid sodium salt.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.[B]1OC2C(=CC=CC=2)O1>C1(C)C=CC=CC=1>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C@@H:11]([OH:13])[CH3:12])=[CH:7][CH:8]=1
Reactant: CC(=O)/C=C/c1ccc(C(F)(F)F)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Agent: [B]1Oc2ccccc2O1
Solvent: Cc1ccccc1
Product: C[C@H](O)/C=C/c1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 99.1 %

Procedure:
(E)-4-(4-(trifluoromethyl)phenyl)but-3-en-2-one (15 g, 70 mmol) was taken up in 500 mL of toluene. (R)-2-Methyl-CBS-oxazaborolidine, 1.09 M in toluene (6.4 mL, 7.0 mmol) was added, and the mixture was chilled to −78° C. Catecholborane (13 mL, 119 mmol) was added dropwise via addition funnel in 125 mL of toluene. The mixture was stirred for 25 minutes and then gradually warmed to −45° C. and stirred for 2 hours. The yellow color taken on during the catecholborane addition faded during this time and the solution cleared. The mixture was quenched with 300 mL of water and warmed to room temperature. The mixture was partitioned in a separatory funnel. The organic portion was washed 3 times with 200 mL of 5% aq. KOH (to remove the catechol), twice with 200 mL of 10% aq. HCl (to remove the (R)-2-methyl-CBS-oxazaborolidine catalyst), and once with 200 mL of brine, then dried over MgSO4. Filtration and concentration under reduced pressure afforded (S,E)-4-(4-(trifluoromethyl)phenyl)but-3-en-2-ol (15 g, 99% yield) as a yellow oil that slowly crystallized on the bench top. 1H NMR (400 MHz, CDCl3) δ ppm 7.57 (d, J=8.22 Hz, 2H) 7.50-7.45 (m, 2H) 6.62 (d, J=16.04 Hz, 1H) 6.36 (dd, J=16.04, 6.06 Hz, 1H) 4.49-4.57 (m, 1H) 1.61 (d, J=4.30 Hz, 1H) 1.39 (d, J=6.46 Hz, 3H).
Reaction SMILES: [C:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:5]=1)(=O)[CH3:2].C([BH3-])#N.[Na+].[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH2:30]([S:27]([N:24]1[CH2:23][CH2:22][CH:21]([C:12]2[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=[C:9]([C:6]4[CH:5]=[C:4]([C@H:1]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[CH3:2])[S:8][CH:7]=4)[CH:10]=3)[NH:14][CH:13]=2)[CH2:26][CH2:25]1)(=[O:29])=[O:28])[CH3:31]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C(C)=O)c4)cc23)CC1
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc([C@@H](C)N5CCCC5)c4)cc23)CC1

Procedure:
To 5-(5-acetyl-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (10 mg, 0.02 mmol) was added sodium cyanoborohydride (7.5 mg, 0.12 mmol) and pyrrolidine (0.03 mL, 0.30 mmol). The resulting mixture was reacted in a microwave for 40 min at 150° C. All the solvent was evaporated and the crude product was partitioned between ethyl acetate (1.5 mL) and 1 M sodium hydroxide (0.2 mL). The reaction was purified by SFC to give the title compound as 100% chirally pure.
Reaction SMILES: S(Cl)([Cl:3])=O.[OH:5][C:6]1[C:14]([N:15]=[N:16][C:17]2[NH:18][C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)=[CH:13][C:9]([C:10](O)=[O:11])=[C:8]([N+:34]([O-:36])=[O:35])[CH:7]=1>O1CCCC1>[OH:5][C:6]1[C:14]([N:15]=[N:16][C:17]2[NH:18][C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:21]=2)=[CH:13][C:9]([C:10]([Cl:3])=[O:11])=[C:8]([N+:34]([O-:36])=[O:35])[CH:7]=1
Reactant: O=C(O)c1cc(N=Nc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)c(O)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cl)c1cc(N=Nc2nc(-c3ccccc3)c(-c3ccccc3)[nH]2)c(O)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
Thionyl chloride (120 ml) was added with stirring to a suspension of VI (11.1 g, 0.026 mole) in dry tetrahydrofuran (120 ml) at 20° C. The mixture became warm and the suspension dissolved, giving a dark-red solution. After a few minutes, a bright-red solid precipitated. The mixture was stirred for a further 15 minutes, cooled to 5° C. and the product filtered off and dried at 50° C. for one hour. TLC analysis showed the product to be pure.