Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(OC(=S)O[CH:10]([C:35]2[CH:36]=[CH:37][C:38]([N:41]3[CH:46]=[C:45]([Cl:47])[CH:44]=[CH:43][C:42]3=[O:48])=[N:39][CH:40]=2)[C:11]2[N:12]=[CH:13][N:14]([C:16]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:15]=2)C=CC=CC=1.C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1C=CC=CC=1>[Cl:47][C:45]1[CH:44]=[CH:43][C:42](=[O:48])[N:41]([C:38]2[CH:37]=[CH:36][C:35]([CH2:10][C:11]3[N:12]=[CH:13][N:14]([C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:15]=3)=[CH:40][N:39]=2)[CH:46]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(C(OC(=S)Oc2ccccc2)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Temperature: 80 °C

Procedure:
To a solution of the thiocarbonate from Step 4 (0.263 g, 0.386 mmol) in benzene (3 ml) at room temperature was added tributyl tin hydride (0.159 ml, 3.74 mmol) and AIBN (0.012 g, 0.50 mmol) and the mixture was heated at 80° C. for 3 hrs. The solvent was evaporated in vacuo. The residue was chromatographed (silica gel, MeOH: CH2Cl2 2:98 to 4:96 gradient elution) to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[F:25])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.C(N(CC)CC)C.[CH2:33]([Si:35]([C:40]#[CH:41])([CH2:38][CH3:39])[CH2:36][CH3:37])[CH3:34]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]([F:25])=[C:18]([C:10]2[CH:9]=[C:8]([C:4]3[CH:5]=[N:6][CH:7]=[C:2]([C:34]#[C:33][Si:35]([CH2:40][CH3:41])([CH2:38][CH3:39])[CH2:36][CH3:37])[CH:3]=3)[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:23]=1
Reactant: C#C[Si](CC)(CC)CC
Reactant: Fc1ccc(Cl)cc1-c1cc(-c2cncc(Br)c2)c2cccnc2n1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC[Si](C#Cc1cncc(-c2cc(-c3cc(Cl)ccc3F)nc3ncccc23)c1)(CC)CC
Temperature: 120 °C
Reaction time: 2 h

Procedure:
A solution of 415 mg (1.00 mmol) 4-(5-bromo-pyridin-3-yl)-2-(5-chloro-2-fluoro-phenyl)-[1,8]naphthyridine in 5 ml DMF was flushed with nitrogen and subsequently treated with 70 mg (0.10 mmol) bis-(triphenylphosphine)-palladium(II)-chloride, 6.0 mg (0.03 mmol) cuprous iodide, 0.42 ml (3.0 mmol) triethylamine and 450 μl (2.5 mmol) triethylsilyl acetylene. The resulting slurry was stirred at 120° C. for two hours. The reaction mixture was cooled to room temperature and partitioned between ethylacetate and brine. The combined organic phases were dried with sodium sulfate and evaporated yielding 2-(5-chloro-2-fluoro-phenyl)-4-(5-triethylsilanylethynyl-pyridin-3-yl)-[1,8]naphthyridine as brown solid; HPLC-MS: 2.73 min, [M+H] 474.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:30])[C:3]=1[OH:31].O[C@@H:33]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:34]([O:36]C)=[O:35].BrBr>C(Cl)(Cl)Cl>[Br:30][C:4]1[CH:5]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[S:17][C:16]=3[C:15]([S:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:31][C@H:33]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:34]([OH:36])=[O:35]
Reactant: Cc1sc2c(Sc3ccccc3)c3ccccc3c(-c3cc(Br)c(O)c(Br)c3)c2c1C
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: Cc1sc2c(Sc3ccccc3)c3ccccc3c(-c3cc(Br)c(O[C@H](Cc4ccccc4)C(=O)O)c(Br)c3)c2c1C

Procedure:
Prepared from 2,6-dibromo-4-(2,3-dimethyl-9-phenylsulfanyl-naphtho[2,3-b]thiophen-4-yl)-phenol (Example 13) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 25) according to the procedure of Example 30. White solid: opt. rot. [a]25/D=+22.84° (10.068 mg/mL, CHCl3); NMR (DMSO-d6); δ 13.13 (broad s, 1H), 8.42 (d, J=8 Hz, 1H), 7.75 (t, J=2 Hz, 2H), 7.58 (ddd, J=8, 7, 1 Hz, 1H), 7.50 (ddd, J=8, 7, 1 Hz, 1H), 7.44 (d, J=8 Hz, 1H), 7.37-7.19 (m, 7H), 7.15-7.11 (m, 1H), 7.03-7.00 (m, 2H), 5.22 (t, J=7 Hz, 1H), 3.37-3.28 (m, 2H), 2.39 (s, 3H), 1.62 (s, 3H); MS (EI): [M+], 2 bromine isotope pattern, 716 (10%), 718 (20%), 720 (10%); Anal. Calc. for C35H26Br2O3S2: C, 58.50, H, 3.65, N, 0.00. Found: C, 58.77, H, 3.94, N, 0.16.
Reaction SMILES: [O:1]=[C:2]1[NH:22][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1.Cl>CO>[O:1]=[C:2]1[NH:22][C:5]2=[N:6][C:7]3[CH:8]=[CH:9][C:10]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][C:12]=3[CH:13]=[C:4]2[NH:3]1
Reactant: COC(=O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Agent: Cl
Solvent: CO
Product: O=C(O)CCCOc1ccc2nc3[nH]c(=O)[nH]c3cc2c1
Reaction time: 1 h

Procedure:
Methyl 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butanoate (1.0 g, 3.3 mmol) was added to a solution of 50% aqueous methanol containing 4N NaOH (2 mL). After stirring for 1 hour, the mixture was acidified to pH=3 by the addition of 2N HCl. The precipitate was washed with water, methanol and diethyl ether to give 4-[(2,3-dihydro-2-oxo-1H-imidazo[4,5-b]quinolin-7-yl)oxy]butyric acid as a partial hydrate (0.84 g, 88%). An analytical sample was prepared by crystalization from dimethylformamide/H2O and had m.p.>320°.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4].[C:7](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:7]([O:1][CH2:2][CH:3]([CH2:5][OH:6])[OH:4])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OCC(O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: OCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
In 50 ml of pyridine was dissolved 4.6 g (50 mmol) of glycerol followed by addition of 13.9 g (50 mmol) of trityl chloride and the mixture was stirred at ambient temperature overnight. The reaction mixture was then concentrated under reduced pressure and the residue was diluted with water and extracted with ether. The organic layer was washed with water, dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography (silica gel/chloroform-methanol) to provide 9.5 g (59%) of 1-O-tritylglycerol.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)#[CH:10]>C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:18][C:17]([F:19])([F:20])[C:14]1[CH:13]=[CH:12][C:11]([C:9]#[C:10][C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[CH:16][CH:15]=1
Reactant: Brc1ccncc1
Reactant: C#Cc1ccc(C(F)(F)F)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc(C#Cc2ccncc2)cc1
Temperature: 90 °C

Procedure:
Under argon, a mixture of 1.20 g (6.17 mmol) of 4-bromopyridine hydrochloride, 1.57 g (9.26 mmol) of 1-ethynyl-4-(trifluoromethyl)benzene, 88 mg (0.46 mmol) of copper(I) iodide and 251 mg (0.31 mmol) of Pd(dppf)Cl2 in 10 ml of triethylamine is heated at 90° C. for 3 h. After concentration, the reaction mixture is taken up in 100 ml of ethyl acetate and washed with 2×100 ml of 1M HCl. The aqueous phase is adjusted to pH 10 using aqueous sodium hydroxide solution and extracted with 3×100 ml of chloroform. The combined organic phases are washed with saturated aqueous NaCl solution, dried over Na2SO4 and freed from the solvent under reduced pressure. This gives 380 mg (24%) of the desired product; log P(HCOOH): 2.86; 1H-NMR (DMSO-d6) δ: 8.66 (d, 2H), 7.84 (s, 4H), 7.58 (d, 2H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[H-].[Na+].[CH3:15]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH3:15])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1ccc(OC)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a solution of 4-methoxy-2-nitro-phenylamine (5.0 g, 0.029 mol) in DMF (25 ml) was added NaH (0.9 g, 0.035 mol) at 0° C. and stirred at that temperature for 30 min. Methyl iodide (2.17 ml, 0.035 mol) was added and the resulting solution was stirred at room temperature for 30 min. The reaction was quenched with ice-water and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to afford the title compound (4-methoxy-2-nitro-phenyl)-methyl-amine as a red solid. C8H10N2O3; 1H NMR (400 MHz, CDCl3), δ: 8.00 (brs, 1H), 7.62 (d, J=2.4 Hz, 1H), 7.18 (dd,1=9.2 Hz, J2=2.0 Hz, 1H), 6.82 (d, J=9.6 Hz, 1H), 3.81 (d, J=14.8 Hz, 3H), 3.02 (s, 3H). MS (M+1): 183.1.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29].C(OCC)C>C(Cl)Cl>[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[O:12]
Reactant: COC(=O)CCCCCCCCCCCCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCCCCCCCCCCCCCC=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
65.6 gm of pyridinium chlorochromate was dissolved into 400 ml of methylene chloride. To the solution was added 55 gm of methyl 16-hydroxyhexadecanoate which had been dissolved in 40 ml of methylene chloride in advance. After stirring for 2 hours at room temperature, 400 ml of anhydrous diethyl ether was added. The supernatant was removed and the insolbles were washed three times with 100 ml of anhydrous diethyl ether. The supernatant and the washing were combined together and passed through 40 gm of a silica gel column, and the eluent was concentrated under reduced pressure. The crude crystals thus obtained were purified by flash column chromatography (chloroform:hexane=4:l) to obtain 43.6 gm of methyl 15-formylpentadecanoate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH2:14]([O:17][NH2:18])[CH:15]=[CH2:16]>>[CH2:14]([O:17][N:18]=[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1)[C:9]([OH:11])=[O:10])[CH:15]=[CH2:16]
Reactant: O=C(O)C(=O)c1cccc(O)c1
Reactant: C=CCON
Agent: Cl
Product: C=CCON=C(C(=O)O)c1cccc(O)c1
Yield: 101.4 %

Procedure:
2-(3-Hydroxyphenyl)glyoxylic acid (2.0 g.) and O-allylhydroxylamine hydrochloride (1.7 g.) were reacted according to a similar manner to that of Preparation 5-(2)(a) to give oil of 2-allyloxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (2.7 g.).
Reaction SMILES: O.[C:2]1([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[CH:18]([O-])=O.[NH4+]>[Pd].CO>[CH3:18][NH:15][C:14]1[C:9]([NH:8][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C[O-]
Reactant: Nc1cccnc1Nc1ccccc1
Agent: [Pd]
Agent: C=O
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: CNc1cccnc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
Pd/C (10%, 11.49 g) was added to a three-neck flask. A gentle nitrogen flow was applied to the flask. Water (40 mL) and methanol (800 mL) were added to the flask. Then, N2-phenylpyridine-2,3-diamine (20 g, 108 mmol), formaldehyde (8.76 g, 108 mmol), and ammonium formate (136 g, 2160 mmol) were added. The reaction was stirred at room temperature overnight. The solution was filtered through a Celite® plug. The filtrate was concentrated and water was added. The solution was extracted with dichloromethane. The combined organic layer was concentrated and purified by column chromatography (30% ethyl acetate in hexanes) to give N3-methyl-N2-phenylpyridine-2,3-diamine (12 g, 55.8% yield).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl-].[CH3:18][O:19][C:20]1([NH3+:23])[CH2:22][CH2:21]1>O1CCCC1>[CH3:18][O:19][C:20]1([NH:23][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:22][CH2:21]1
Reactant: COC1([NH3+])CC1
Reactant: O=C(Cl)c1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC1(NC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (3.1 g, 30.5 mmol) is added dropwise (30 min) at 0° to a solution of benzoyl chloride (1.5 g, 12.2 mmol) in tetrahydrofuran (25 ml) containing suspended 1-methoxycyclopropylammonium chloride (1.82 g, 13.0 mmol). The mixture is then stirred at room temperature for 30 min. The precipitate is filtered off and washed thoroughly with tetrahydrofuran. The filtrate is evaporated in vacuo yielding a crystalline residue. Recrystallisation from methanol gives pure N-(-methoxycyclopropyl)-benzamide, mp 190°-191° (1.2 g, 55%); NMR (60 MHz)=δCDCl 3=1.00-1.30 (m, 4H), 3.40 (s, 3H), 7.0 (br. s, 1H), 7.35-7.95 (m, 5H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[OH:16])[C:11]#[N:12].I[CH2:18][CH3:19].O>CC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH2:18][CH3:19])[C:11]#[N:12]
Reactant: N#Cc1ccc(O)c(Br)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOc1ccc(C#N)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add potassium carbonate (5.2 g, 37.9 mmol) to 3-bromo-4-hydroxy-benzonitrile (5.0 g, 25.2 mmol) in acetone with stirring at room temperature. After 15 minutes, add iodoethane (2.4 mL, 130.3 mmol) and continue stirring at room temperature. After 18 hours, pour the reaction mixture into water and extract with EtOAc. Combine the organic extracts, wash with water and brine, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography eluting with ethyl acetate:hexanes to provide the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH2:13]([N:21]=[C:22]=[S:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCOCC>[CH2:13]([NH:21][C:22]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[S:23])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1cnc(N2CCNCC2)cn1
Reactant: S=C=NCCc1ccccc1
Solvent: CCOCC
Product: S=C(NCCc1ccccc1)N1CCN(c2cnccn2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 4.92 g. of 1-(2-pyrazinyl)piperazine in 30 ml. of anhydrous ether is added dropwise a solution of 4.89 g. of phenethyl isothiocyanate in 30 ml. of anhydrous ether over 10 minutes. An additional30 ml. of anhydrous ether is required to maintain stirring over 30 minutes.The resulting solid is collected, dissolved in 100 ml. of benzene and 25 ml. of ethanol and cooled. The resulting solid is collected, giving 5.68 g. of the desired product as a white solid, m.p. 162°-163° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:20]=2)[NH:17][C:16]([C:28]([O:30]CC)=[O:29])=[CH:15]3)=NC=1)(=[O:4])=[O:3].[OH-].[Na+].O1CC[CH2:37][CH2:36]1>C(O)C>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:11][C:12]2[CH:13]=[C:14]3[C:18](=[C:19]([O:21][CH:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)[CH:20]=2)[NH:17][C:16]([C:28]([OH:30])=[O:29])=[CH:15]3)=[CH:37][CH:36]=1)(=[O:3])=[O:4]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(OC3CCOCC3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2cc(OC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)cc1
Temperature: 60 °C
Reaction time: 0.67 h
Yield: 74 %

Procedure:
A mixture of ethyl 5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-7-(tetrahydro-2H-pyran-4-yloxy)-1H-indole-2-carboxylate (5.33 g), 1M aqueous sodium hydroxide solution (20 mL), tetrahydrofuran (20 mL), and ethanol (20 mL) was stirred at 60° C. for 40 min. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in water, and washed with ethyl acetate. To the aqueous layer was added 1M hydrochloric acid (30 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (1.95 g, yield 74%) as an orange amorphous solid.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:21](=[C:22]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=4)[N:23]=2)[N:20]=[CH:19][CH:18]=[CH:17]3)[CH2:10][CH2:9]1)=[O:7])C>C1COCC1.C(O)C.C(OCC)(=O)C>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([C:22]2[N:23]=[C:14]([CH:11]3[CH2:10][CH2:9][CH:8]([C:6]([OH:7])=[O:5])[CH2:13][CH2:12]3)[CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1CCC(c2cc3cccnc3c(-c3cccc(OC)c3)n2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(-c2nc(C3CCC(C(=O)O)CC3)cc3cccnc23)c1
Temperature: 80 °C

Procedure:
Potassium hydroxide (2 M, 0.9 ml) is added to a solution of 4-[8-(3-Methoxy-phenyl)-[1,7]naphthyridin-6-yl]-cyclohexanecarboxylic acid ethyl ester (230 mg, 0.6 mmol) in THF/ethanol (6 ml:2 ml) and heated at 80° C. for 3 hours. The solution is then diluted with ethyl acetate (120 ml) and extracted with water. The aqueous layer is taken to pH 4 with 1M HCl to give a white precipitate, which is extracted into dichloromethane (DCM). The DCM layer is washed with water, then dried over magnesium sulfate, filtered and concentrated to yield the desired product. M.p 209-212° C. MS (AP+) 362.9
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([CH:21]=[CH:22][S:23]([O:26][CH2:27][CH3:28])(=[O:25])=[O:24])[O:12]1.C(O)C.[BH4-].[Na+]>O.[Cl-].[NH4+]>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:19])([CH3:20])[O:18][C@@H:14]2[C@@H:13]([CH2:21][CH2:22][S:23]([O:26][CH2:27][CH3:28])(=[O:24])=[O:25])[O:12]1
Reactant: CCOS(=O)(=O)C=C[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOS(=O)(=O)CC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
Ethyl 2-[(3aR,4R,6R,6aR)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]ethenesulfonate (10.500 g, 0.024370 mol) was dissolved in ethanol (200 mL, 3 mol) in a 1-necked round-bottom flask. Sodium borohydride (507.1 mg, 0.01340 mol) was added in 2 portions, 10 min apart. The reaction was stirred for a further 15 min at 25° C. The reaction was diluted with water (400 mL) and 5M ammonium chloride in water (50 mL) and was concentrated in vacuo to remove most of the ethanol. The aqueous residue was extracted with methylene chloride (2×250 mL) and the organic phase was concentrated in vacuo to yield crude product (9.83 g).
Reaction SMILES: C[O:2][C:3]1[CH:30]=[CH:29][C:6]2[N:7]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH2:15][CH2:14]3)[C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1.Br>O>[OH:2][C:3]1[CH:30]=[CH:29][C:6]2[N:7]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH2:17][CH2:18]3)[C:8](=[O:10])[NH:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)[nH]c(=O)n2CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Agent: Br
Solvent: O
Product: O=c1[nH]c2cc(O)ccc2n1CCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Yield: 70.3 %

Procedure:
A mixture of 5-methoxy-1-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}-1,3-dihydrobenzimidazol-2-one (0.6 g; 1.4 mmol) and 48% HBr (30 ml) was refluxed for 1 hour. The reaction was then cooled and water was added (30 ml). The precipitated solid was collected and recrystallized from 95% EtOH to give the title compound as a white solid 0.4 g; m.p. 275° C. (as hydrobromide salt, from 95% ethanol). 1H-NMR (DMSO; 200 MHz): 10.82 (1H, s); 9.6, (1H, b); 9.11(1H, s); 7.47 (1H, m); 7.2-7.4 (2H, ov); 7.16 (1H, d); 7.03 (1H, d); 6.4-6.6 (2H, ov); 4.17 (2H, t); 4.03 (2H, d); 3.82 (2H, d); 3.51 (2H, b); 2.9-3.5 (4H, ov).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:19])[CH:4]([O:16][CH2:17][CH3:18])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([O:15][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH:35]([CH3:37])[CH3:36])=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:8][CH:7]=1
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Reactant: CCOC(Cc1ccc(O)c2ccoc12)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CCOC(Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)c2ccoc12)C(=O)OC

Procedure:
In analogy to the procedure described in example 120 f], 2-ethoxy-3-(4-hydroxy-benzofuran-7-yl)-propionic acid methyl ester (example 120 e]) was reacted with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole in the presence of potassium carbonate and potassium iodide to yield [rac]-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-propionic acid methyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield [rac]-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-benzofuran-7-yl}-propionic acid as white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:13]([OH:37])[C@@H:14]([N:22](CC1C=CC=CC=1)CC1C=CC=CC=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[C@@H:13]([OH:37])[C@@H:14]([NH2:22])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@@H](O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1[C@@H](O)[C@@H](N)Cc1ccccc1
Yield: 94.3 %

Procedure:
Dissolve 2-(R)-(2-(S)-dibenzylamino-1-(S)-hydroxy-3-phenylpropyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.75 g, 1.49 mmol) in methanol (20 mL). Add 20% palladium hydroxide on carbon (0.33 g) and stir 1 h under one atmosphere of hydrogen gas. Filter through filter agent and concentrate to give the title compound as a white foam (0.45 g, 93%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O>C(Cl)Cl>[Cl:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)c(Cl)n1
Solvent: ClCCl
Product: COC(=O)c1ccc(C)nc1Cl
Reaction time: 2 h

Procedure:
To the solution of 2-chloro-6-methylnicotinic acid (5 g, 29.1 mmol) in CH2Cl2 (40 mL) was added oxalyl dichloride (8.1 g, 63.8 mmol) at 0° C. and the reaction mixture was stirred for 2 h. The mixture was concentrated and 40 mL of methanol was then added at 0° C. and the reaction mixture was stirred at RT for 12 h. The mixture was then concentrated in vacuo and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide methyl 2-chloro-6-methylnicotinate that is used without further purification as a light yellow solid.