Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[C@:7]([CH2:9][C:10]2[C:16](=[O:17])[CH:15]=[CH:14][C:12](=[O:13])[CH:11]=2)([CH3:8])[C@@H:6]2[CH2:18][CH2:19][CH:20]=[C:21]([CH3:22])[C@@:5]2([CH3:23])[CH2:4][CH2:3]1>C(Cl)(Cl)Cl>[CH3:1][C@@H:2]1[C@:7]([CH2:9][C:10]2[CH:11]=[C:12]([OH:13])[CH:14]=[CH:15][C:16]=2[OH:17])([CH3:8])[C@@H:6]2[CH2:18][CH2:19][CH:20]=[C:21]([CH3:22])[C@@:5]2([CH3:23])[CH2:4][CH2:3]1
Reactant: CC1=CCC[C@H]2[C@](C)(CC3=CC(=O)C=CC3=O)[C@@H](C)CC[C@]12C
Solvent: ClC(Cl)Cl
Product: CC1=CCC[C@H]2[C@](C)(Cc3cc(O)ccc3O)[C@@H](C)CC[C@]12C

Procedure:
Whitish crystals; m.p. 146°-148° C. (chloroform); other characteristics same as for Avarone.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][NH2:45])=[CH:40][CH:39]=1>CN(C)C=O>[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][NH-:45])=[CH:40][CH:39]=1.[CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2ccc(C(=O)O)cc2[nH]1
Reactant: COc1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: COc1ccc(C[NH-])cc1
Product: Cc1nc2cc(C(=O)O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 127 %

Procedure:
To a dimethylformamide (20 ml) solution of 2-methylbenzimidazol-5-carboxylic acid (1.00 g) were added hydroxybenzotriazole (844 mg), 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.21 g) and 4-methoxyphenylmethylamine (1.33 g) at room temperature, and the reaction solution was stirred at room temperature for 18 hours. The reaction solution was concentrated under reduced pressure and the obtained residue was diluted with chloroform (20 ml). The organic layer was washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution, and dried over anhydrous sodium sulfate. The residue obtained by solvent evaporation under reduced pressure was subjected to silica gel column chromatography and eluted with chloroform-methanol (30:1 (v/v)) to obtain (4-methoxyphenylmethyl)amide of 2-methyl-1H-benzimidazol-5-carboxylic acid (1.27 g, 99%).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12]Br)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[I:14].[CH2:15]([O:17][P:18]([O:22]CC)[O:19][CH2:20][CH3:21])[CH3:16]>>[Br:1][C:2]1[C:3]([I:14])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[CH:9][C:8]([CH2:12][P:18](=[O:22])([O:19][CH2:20][CH3:21])[O:17][CH2:15][CH3:16])=[CH:7]2
Reactant: BrCc1ccc2c(Br)c(I)ccc2c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc2c(Br)c(I)ccc2c1)OCC

Procedure:
To 1-bromo-6-(bromomethyl)-2-iodonaphthalene (270 mg) from step 4 was added triethylphosphite (4 mL). The reaction mixture was heated at reflux for 1 hour followed by removal of excess triethylphosphite under high vacuum distillation yielding the titled product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]2Cl.C(N(CC)CC)C.[H][H]>[Pd].O1CCOCC1>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7]2
Reactant: CCOC(=O)c1cnc2c(N)cccc2c1Cl
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2c(N)cccc2c1
Yield: 63.1 %

Procedure:
A mixture of 8-amino-4-chloro-3-ethoxycarbonylquinoline (45 mg), triethylamine (0.026 ml) and 10%o palladium on carbon (15 mg) in dioxane was stirred for 7 hours at ambient temperature under 3 atmospheric pressure of hydrogen. Insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-dichloromethane) to give 8-amino-3-ethoxycarbonylquinoline (24.5 mg).
Reaction SMILES: C(O[CH2:9][CH:10]1[CH:14]([CH2:15][N:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([NH:28][C:29]4[N:34]=[C:33]([CH:35]([F:37])[F:36])[CH:32]=[CH:31][N:30]=4)[CH:22]=3)[CH:18]=[N:17]2)[O:13][C:12](=[O:38])[NH:11]1)C1C=CC=CC=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>>[F:42][C:41]([F:44])([F:43])[C:39]([O:45][CH2:9][CH:10]1[CH:14]([CH2:15][N:16]2[CH:20]=[C:19]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([NH:28][C:29]4[N:34]=[C:33]([CH:35]([F:36])[F:37])[CH:32]=[CH:31][N:30]=4)[CH:22]=3)[CH:18]=[N:17]2)[O:13][C:12](=[O:38])[NH:11]1)=[O:40]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC3OC(=O)NC3COCc3ccccc3)c2)c1
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC3OC(=O)NC3COC(=O)C(F)(F)F)c2)c1
Temperature: 120 °C

Procedure:
A solution of 4-[(benzyloxy)methyl]-5-{[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]methyl}-1,3-oxazolidin-2-one (100 mg, 0.199 mmol) in TFA (1.0 mL) was stirred and heated at 120° C. in a microwave reactor for 40 minutes. The reaction mixture was concentrated under reduced pressure to afford (5-{[4-(3-{[4-(difluoromethyl)pyrimidin-2-yl]amino}-5-methylphenyl)-1H-pyrazol-1-yl]methyl}-2-oxo-1,3-oxazolidin-4-yl)methyl trifluoroacetate, which was used in the next step without further purification. MS ESI calc'd. for C22H20F5N6O4 [M+H]+ 527. found 527.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:26]=[CH:25][C:24]([S:27]([CH3:34])(=[N:29][C:30](=[O:33])[CH2:31]Cl)=[O:28])=[CH:23][CH:22]=2)=[O:20])=[O:10])=[N:6][CH:7]=1.[CH3:35][NH:36][CH3:37]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=2[NH:18][C:19]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([CH3:34])(=[N:29][C:30](=[O:33])[CH2:31][N:36]([CH3:37])[CH3:35])=[O:28])=[CH:25][CH:26]=2)=[O:20])=[O:10])=[N:6][CH:7]=1
Reactant: CS(=O)(=NC(=O)CCl)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: CNC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N=S(C)(=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 27.5 °C
Reaction time: 12 h
Yield: 56.3 %

Procedure:
To a stirring solution of S-[4-(N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]-4-chlorophenyl}carbamoyl)phenyl]-S-methyl-N-chloroacetyl sulfoximide (100 mg, 0.185 mmol, Example 6) in DMF (0.2 mL) was added 50% aqueous dimethylamine solution (164 mg, 0.162 mmol) followed by catalytic amount of KI. The reaction mixture was stirred at 25-30° C. for 12 hr and then diluted with water (5 mL). Filtration and drying afforded 50 mg of titled compound in 49% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:16][N:17]=1)(=[O:12])=[O:11])[CH3:2].O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[N:52]1([CH2:61][C:62](O)=[O:63])[CH:60]=[C:58]([CH3:59])[C:56](=[O:57])[NH:55][C:53]1=[O:54]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:16][N:17]=1)(=[O:12])=[O:11])[C:62](=[O:63])[CH2:61][N:52]1[CH:60]=[C:58]([CH3:59])[C:56](=[O:57])[NH:55][C:53]1=[O:54])[CH3:2]
Reactant: Cc1cn(CC(=O)O)c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nnc(-c2ccc(Cl)cc2)s1)C(=O)Cn1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To the solution of N-{2-[5-(4-Chlorophenyl)-1,3,4-thiadiazole-2-sulfonylamino]-ethyl}-glycine ethyl ester (4.05 g, 10 mmol) in 30 mL of DMF, were added 1.68 g (11 mmol) of 1-hydroxybenzotriazole monohydrate, 2.27 g (11 mmol) of dicyclohexylcarbodiimide and 1.84 g (10 mmol) of (thymin-1-yl)-acetic acid. The reaction mixture was stirred for 3 hours at room temperature. The precipitated dicyclohexylurea was filtered off and the filtrate was concentrated in vacuo, followed by column chromatography on silica gel to give the title compound (4.85 g, 8.5 mmol, 85%). 1H NMR (500 MHz; DMSO-d6) δ 11.28 (s, 0.6H), 11.26 (s, 0.4H), 9.15 (brs, 0.6H), 9.00 (brs, 0.4H), 8.07 (d, 2H), 7.67 (d, 2H), 7.31 (s, 0.6H), 7.24 (s, 0.4H), 4.65 (s, 1.2H), 4.47 (s, 0.8H), 4.31 (s, 0.8H), 4.16 (q, 0.8H), 4.06 (q, 1.2H), 4.03 (s, 1.2H), 3.55 (t, 1.2H), 3.45–3.38 (m, 2H), 3.23 (t, 0.8H), 1.73 (s, 3H), 1.21 (t, 1.2H), 1.16 (t, 1.8H).
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:11]([Sn:15](Cl)([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>C1COCC1.CCOCC>[CH2:20]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])/[CH:3]=[CH:2]\[CH2:1][OH:4])[CH2:21][CH2:22][CH3:23]
Reactant: C#CCO
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCC[Sn](/C=C\CO)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Propargyl alcohol (5 mL) was added to a solution of lithium aluminium hydride (1M in THF, 43 mL) in THF (70 mL) at −78° C. The resultant mixture was warmed to room temperature and stirred for 18 hours. It was re-cooled to −78° and a solution of tri-n-butyl tin chloride (8.3 mL) in ether (50 mL) was added and the mixture was stirred for 3 hours whilst gradually warming to room temperature. The reaction mixture was cooled to −5° C. and quenched by addition of water and 15% aqueous sodium hydroxide solution then it was allowed to warm to room temperature. Ethyl acetate was added and the mixture was stirred for 1 hour. The mixture was filtered through Celite and the filtrate was evaporated to dryness. The residue was purified by chromatography on a silica column which had been pre-washed with 20% triethylamine in acetonitrile. The column was eluted with a mixture of ethyl acetate and pentane with a gradient of 0-10% to give (Z)-3-tributylstannanylprop-2-en-1-ol (5.06 g) as a clear oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].[C:24](Cl)(Cl)=[O:25]>O1CCCC1.C1(C)C=CC=CC=1>[Si:16]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:1]=[C:24]=[O:25])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: Nc1ccccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1N=C=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 1.0 g (9.16 mmol) of o-aminophenol in 10 mL of tetrahydrofuran was added 3.57 mL (2.59 g; 25.6 mmol) of triethylamine and 3.46 g (22.9 mmol) of t-butyldimethylsilyl chloride. The reaction mixture was stirred for 15 hours at room temperature, filtered and concentrated in vacuo. The residue was dissolved in 10 mL of toluene and this solution was cooled to -15° C. The solution was treated with 1.4 mL (1.02 g; 10.0 mmol) of triethylamine, followed by the dropwise addition of 4.75 mL (9.17 mmol) of a 1.93M solution of phosgene in toluene. After the addition was complete, the reaction mixture was allowed to warm up to room temperature and stirred at that temperature for 1 hour. The mixture was filtered and the filtrate was concentrated in vacuo to give a pink oil. IR (neat) 2251 cm-1 ; 1H NMR (CDCl3) δ7.060 (dt, J=8.4, 2.0 Hz, 1H, ArH), 7.018 (dd, J=7.6, 2.0 Hz, 1H, ArH), 6.950-6.850 (m, with d at 6.894, J=7.6 Hz, 2H, ArH), 1.08 (s, 9H, CCH3), 0.350 (s, 6H, SiCH3); MS (EI) m/z=192 (100%), 249 (M+).
Reaction SMILES: [Mg].Cl[Si:3]([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].Br[C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:16]=2[CH:15]=1>C1COCC1>[CH2:5]([O:4][Si:3]([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])[C:14]1[CH:27]=[CH:26][C:25]2[S:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[S:17][C:16]=2[CH:15]=1)[CH3:6]
Reactant: Brc1ccc2c(c1)Sc1ccccc1S2
Reactant: CCO[Si](Cl)(OCC)OCC
Agent: [Mg]
Solvent: C1CCOC1
Product: CCO[Si](OCC)(OCC)c1ccc2c(c1)Sc1ccccc1S2
Yield: 69.8 %

Procedure:
A 3-neck 3 L flask was filled with magnesium turnings (20 g), THF (650 g) and chlorotriethoxysilane (146 g), and heated to reflux. 2-Bromothianthrene from Example 3A was added to the flask in small portions. Grignard started instantly. The reaction was allowed to cool for 1 hour, after which magnesium salts were precipitated with hexanes (500 mL). The solution was filtered, followed by evaporation of volatiles by rotary evaporator. The material was distilled twice at 190 . . . 200° C./<1 mbar, giving colorless 2-(triethoxysilyl)thianthrene (125.9 g, 69.8% overall yield based on thianthrene, purity >99% by GC/MS).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:24]2[CH:28]=[N:27][N:26]=[N:25]2)=[C:6]([CH:23]=1)[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:15][CH2:14][O:13][N:12]1C(OC(C)(C)C)=O)=[O:10].Cl>CO>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:24]2[CH:28]=[N:27][N:26]=[N:25]2)=[C:6]([CH:23]=1)[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:15][CH2:14][O:13][NH:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N1OCC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1
Agent: Cl
Solvent: CO
Product: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CCON1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (3S)-3-{[5-chloro-2-(1H-tetrazol-1-yl)benzyl]carbamoyl}isoxazolidine-2-carboxylate (357 mg, 0.873 mmol) in MeOH (5 mL) was added conc. HCl (aq., 5 mL) and the mixture was stirred at rt for 1 h and then evaporated to dryness to give crude (3S)—N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]isoxazolidine-3-carboxamide hydrochloride as a solid which was used as such in the next reaction without further purification.
Reaction SMILES: [ClH:1].C([O:6][C:7]([CH2:9][O:10][N:11]=[C:12]([C:38]1[N:39]=[C:40]([NH2:43])[S:41][CH:42]=1)[C:13]([NH:15][CH:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([OH:35])=[O:34])=[C:20]([CH2:23][S:24][C:25]3[N:29]([CH2:30][C:31]#[CH:32])[N:28]=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12)=[O:14])=[O:8])(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>>[ClH:1].[C:7]([CH2:9][O:10][N:11]=[C:12]([C:38]1[N:39]=[C:40]([NH2:43])[S:41][CH:42]=1)[C:13]([NH:15][CH:16]1[C:36](=[O:37])[N:18]2[C:19]([C:33]([OH:35])=[O:34])=[C:20]([CH2:23][S:24][C:25]3[N:29]([CH2:30][C:31]#[CH:32])[N:28]=[N:27][N:26]=3)[CH2:21][S:22][C@H:17]12)=[O:14])([OH:8])=[O:6]
Reactant: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3csc(N)n3)[C@H]2SC1
Agent: Cl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)OC(C)C
Product: C#CCn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3csc(N)n3)[C@H]2SC1
Reaction time: 3 h
Yield: 95.9 %

Procedure:
A mixture of 7-[2-tert-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (1.57 g.), anisole (1.57 ml.) and trifluoroacetic acid (8 ml.) was stirred for 3 hours at 10° to 15° C. After the addition of diisopropyl ether to the reaction mixture with stirring, the precipitates were collected by filtration, washed with diisopropyl ether and then dried to give 7-[2-carboxymethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[1-(2-propynyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer) (1.38 g.).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:9]=2[C:10]([O:12]C)=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl>CO>[OH:1][C:2]1[C:7]([C:8]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:9]=2[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cccnc1O
Agent: Cl
Solvent: CO
Product: O=C(O)c1cc([N+](=O)[O-])ccc1-c1cccnc1O
Yield: 93 %

Procedure:
Methyl 2-(2-hydroxypyridin-3-yl)-5-nitrobenzoate (Reference Compound No. 1-3-(2), 300 mg, 1.09 mmol) was dissolved in methanol (2 mL), then conc. HCl (5 mL) was added thereto, and then the reaction mixture was refluxed overnight. The solvent was removed under reduced pressure to give the titled reference compound (263 mg) as a yellow solid. (Yield 93%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]4[O:20][CH2:19][O:18][C:13]=4[CH:14]=3)[C:9]2=[O:21])[CH2:2]1.[Cl:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1>>[ClH:22].[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]3[CH2:17][CH2:16][C:15]4[C:10](=[CH:11][C:12]5[O:20][CH2:19][O:18][C:13]=5[CH:14]=4)[C:9]3=[O:21])[CH2:2]2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CCCl)cc1
Reactant: O=C1c2cc3c(cc2CCN1CC1CCCNC1)OCO3
Product: COc1ccc(CCN2CCCC(CN3CCc4cc5c(cc4C3=O)OCO5)C2)cc1
Product: Cl

Procedure:
Prepared from 2-[(piperidin-3-yl)-methyl]-6,7-methylenedioxy- 1-oxo-1,2,3,4-tetrahydro-isoquinoline and 1-chloro-2-(4-methoxy-phenyl)-ethane analogously to Example 1.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.C[O:21][C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=1.CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:4]([C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:29][C:25]2[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=2)[C:22]([OH:30])=[O:21])=[CH:11][CH:12]=1)([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: COC(=O)c1cccc(O)c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2cccc(C(=O)O)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 3-hydroxy-benzoic acid methyl ester via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[CH:13]=[N:12][C:11]([C:14]([F:17])([F:16])[F:15])=[N:10]2)=[CH:4][C:3]=1[S:18](Cl)(=O)=O.C(O)C.Cl.O>[Zn].C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[CH:13]=[N:12][C:11]([C:14]([F:15])([F:16])[F:17])=[N:10]2)=[CH:4][C:3]=1[SH:18]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)cc1-n1cnc(C(F)(F)F)n1
Agent: Cl
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(-n2cnc(C(F)(F)F)n2)cc1S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
In a 50-ml eggplant flask provided with a magnetic stirrer was placed 3.44 g (9.6 mmol) of 2,4-dimethyl-5-(3-trifluoromethyl-1H-1,2,4-triazol-1-yl)benzenesulfonyl chloride, followed by addition of 3.14 g (48 mmol) of zinc, 16 ml of ethanol and 8 ml (80 mmol) of 35% hydrochloric acid. The mixture was stirred at room temperature for 30 minutes and then refluxed with heating, for 4 hours. The mixture was cooled to room temperature. Thereto were added 50 ml of water and 50 ml of ethyl acetate to give rise to phase separation. The aqueous phase was extracted with 50 ml of ethyl acetate. The ethyl acetate phase was washed with water and then with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Vacuum distillation was conducted to distil off ethyl acetate to obtain a title compound as 2.25 g of a crystal. Yield: 86%
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][C:27]([F:30])([CH3:29])[CH3:28])C>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[CH:25]=[C:26]([C:27]([F:30])([CH3:29])[CH3:28])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C#CC(C)(C)F
Solvent: ClC(Cl)Cl
Product: CC(C)(F)c1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2

Procedure:
The title compound was prepared from (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine and 4-fluoro-4-methyl-pent-2-ynoic acid ethyl ester employing the procedure described in Example 105. [α]D25 −21.61 (c 0.56, CHCl3).
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][C:9]#N)=[C:6]([N+:11]([O-])=O)[CH:5]=[CH:4][CH:3]=1.C[OH:15].O>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:11]2
Reactant: N#CCc1c(F)cccc1[N+](=O)[O-]
Reactant: CO
Solvent: O
Product: O=C1Cc2c(F)cccc2N1
Temperature: 25 °C

Procedure:
6-Fluoro-2-nitrobenzyl cyanide (23.10 g, 0.12 mole) (prepared according to A. Kalir et. al., Synthesis, 1987, 514-515) was dissolved in 10:1 MeOH/H2O (250 mL) and the solution was chilled in an ice water bath. HBr gas was bubbled into the cold mixture for 75 min. The solution was allowed to warm up to r.t. and then concentrated to half its volume under reduced pressure. THF (100 mL), water (100 mL) and conc. HCl (6 mL) were successively added at r.t. and stirring was maintained for 75 min. The mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, sat. aq. NaHCO3 and brine, then dried over sodium sulfate and concentrated under reduced pressure. This material (20.9 g) was dissolved in acetic acid (200 mL) and hydrogenated for 2 h in a Parr apparatus at 50 Psi, in the presence of 10% Pd/C (4.33 g). The reaction mixture was filtered through a cake of Celite® (Fisher Scientific), and the cake was washed with acetic acid. The solution was concentrated under reduced pressure and dissolved in MeOH (300 mL) containing 1N NaOH (15 mL). This mixture was poured into 2:1 sat aq. NaCl/H2O (600 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. The crude residue was triturated with ether to yield 5.8 g (first crop) of pure 1,3-dihydro4-fluoro-2H-indol-2-one. The mother liquor was chromatographed on Silica Gel (230-400 mesh, eluted with 40% ethyl acetate in hexane) to yield an additional 1.6 g of product (overall yield from cyanide: 41%).
Reaction SMILES: O/[N:2]=[CH:3]/[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14].N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCOCC1.O>[C:3]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]([O:15][CH3:16])=[O:14])#[N:2]
Reactant: COC(=O)c1[nH]c2ccccc2c1/C=N/O
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1[nH]c2ccccc2c1C#N
Temperature: 60 °C
Yield: 76 %

Procedure:
To a mixture of methyl 3-[(E)-(hydroxyimino)methyl]-1H-indole-2-carboxylate (from Key Organics, 1.0 g, 4.6 mmol) and pyridine (7.4 mL, 92 mmol) in 1,4-dioxane (20 mL) was added methanesulfonyl chloride (1.4 mL, 18 mmol). The reaction was heated at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified on silica gel (eluting with 0-5% MeOH/dichloromethane) to give the desired product (0.7 g, 76%). LCMS calculated for C11H9N2O2(M+H)+: m/z=201.1. Found: 201.1.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([CH3:29])=[C:9]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[C:10]([O:17][CH:18]([F:20])[F:19])=[N:11]2.O1CCCC1.CO.[OH-].[Li+]>O>[F:20][CH:18]([F:19])[O:17][C:10]1[C:9]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[C:8]([CH3:29])[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:30])=[O:2])[N:11]=1
Reactant: COC(=O)COc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(F)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cc2ccc(F)cc2)c(OC(F)F)nc2c(F)ccc(OCC(=O)O)c12
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of [2-difluoromethoxy-8-fluoro-3-(4-fluorobenzyl)-4-methylquinolin-5-yloxy]acetic acid methyl ester (0.20 g), tetrahydrofuran (4.0 mL), methanol (4.0 mL), water (3.0 mL) and lithium hydroxide (0.020 g) was stirred at room temperature for 40 minutes. The mixture was partitioned between ethyl acetate and 1.0 M aqueous hydrochloric acid. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over sodium sulfate and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC using a gradient over 30 minutes of acetonitrile in water gave title compound as a white solid, 0.10 g.