Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([NH2:10])=[S:9].O.[CH2:12](N)[C:13]#[CH:14]>C(O)C>[CH2:14]([NH:10][C:8](=[S:9])[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[C:13]#[CH:12]
Reactant: C#CCN
Reactant: NC(=S)Cc1ccccn1
Solvent: CCO
Solvent: O
Product: C#CCNC(=S)Cc1ccccn1
Reaction time: 8 h

Procedure:
To 4.0 g. (0.026 mole) of 2-(2-pyridyl)thioacetamide in 20 ml. of water at 0°C. is added 2.9 g. (0.053 mole) of propargylamine with stirring and the resulting suspension is allowed to stand overnight at 5°C. Ethanol (5 ml.) is added and the mixture is stirred for 5 hours, then extracted with dichloromethane. The extracts are dried and concentrated. The residue is chromatographed on a silica gel "dry-column", using 1:10 ethyl acetate/ether as the eluant. The product fraction is treated with charcoal, filtered, concentrated and the residue is recrystallized from benzene/ligroin to give N-propargyl-2-(2-pyridyl)thioacetamide, m.p. 62°-63°C.
Reaction SMILES: Br[C:2]1[C:3]([N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:4][S:5][CH:6]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O.O>[CH3:21][N:18]1[CH2:19][CH2:20][C:8]2[N:7]([C:3]3[C:2]([C:25]4[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=4)=[CH:6][S:5][CH:4]=3)[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]=2[CH2:17]1
Reactant: OB(O)c1ccncc1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cscc2Br)CCN(C)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cscc2-c2ccncc2)CCN(C)C1
Temperature: 95 °C

Procedure:
To a de-aerated solution of 5-(4-bromo-thiophen-3-yl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (160 mg, 0.44 mmol), 4-pyridinylboronic acid (81.9 mg, 0.66 mmol) and K3PO4 (235 mg, 1.11 mmol) in DMF-water (4.5:0.5 mL) was added dichlorobis(triphenylphosphine) palladium (II) (15.5 mg, 5 mol %). The reaction mixture was heated at 95° C. for 30 min under nitrogen atmosphere. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(4-pyridin-4-yl-thiophen-3-yl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as an off white solid (90 mg). 1H NMR (Oxalate salt, CD3OD) d (ppm): 8.4-8.3 (bs, 2H), 8.19 (s, 1H), 7.8 (s, 1H), 7.35 (s, 1H), 7.05-6.9 (m, 4H), 4.7-4.5 (m, 2H), 3.7-3.5 (m, 2H), 3.1 (s, 3H), 3.05-3.0 (m, 1H), 2.7-2.59 (m, 1H), 2.4 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH:16]1[C:28]2[N:27]([CH2:29][CH2:30]O)[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH:25]1[C:26]2[N:27]([CH2:29][CH2:30][O:1][C:2]3[CH:3]=[C:4]([S:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=3)[C:28]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: COC(=O)C(C)(C)Sc1cccc(O)c1
Reactant: OCCn1c2ccccc2c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Sc1cccc(OCCn2c3ccccc3c3ccccc32)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
The title product was prepared according to the procedure described in Method B starting from methyl 2-(3-hydroxyphenylthio)iso-butyrate (prepared as described in example 1) (0.609 g, 2.7 mmol), 9H-carbazol-9-ethanol (0.570 g, 2.7 mmol), DIAD (0.708 g, 3.5 mmol), and triphenylphosphine (0.917 g, 3.5 mmol) added piecemeal in small portions, keeping the temperature below 30° C., in 14 mL of anhydrous THF. The reaction was left under magnetic stirring for 18 hours at room temperature. After this period, the solvent was evaporated and the residue purified by silica gel chromatography using hexane/AcOEt 9/1 as eluent. 0.510 g of product were obtained (yield: 45%); Mp: 101-103° C.; TLC: silica gel, eluent hexane/AcOEt 8/2, Fr: 0.38; 1H NMR (CDCl3, 300 MHz) δ: 8.05 (d, 2H), 7.50 (m, 4H), 7.15 (m, 2H), 7.08 (t, 1H), 7.00 (d, 1H), 6.90 (s, 1H), 6.80 (m, 1H), 4.75 (t, 2H), 4.35 (t, 2H), 3.60 (s, 3H), 1.40 (s, 6H); HPLC: Column: Symmetry—C18, (5 μm) 4.6×150 mm, T: room temperature, mobile phase CH3CN/H2O 65/35 (v/v), pH: as is, flow rate: 0.80 mL/min, 205 nm UV detector, retention time 11.45 min; E.A. conforming for C25H25NO3S.
Reaction SMILES: CC([C:5]1[C:25](=[O:26])[C:24](C(C)(C)C)=[CH:23][C:7](=[C:8]2[CH:14]=[C:13](C(C)(C)C)[C:11](=[O:12])[C:10](C(C)(C)C)=[CH:9]2)[CH:6]=1)(C)C>[Pd]>[C:11]1([OH:12])[CH:10]=[CH:9][C:8]([C:7]2[CH:23]=[CH:24][C:25]([OH:26])=[CH:5][CH:6]=2)=[CH:14][CH:13]=1
Reactant: CC(C)(C)C1=CC(=C2C=C(C(C)(C)C)C(=O)C(C(C)(C)C)=C2)C=C(C(C)(C)C)C1=O
Agent: [Pd]
Product: Oc1ccc(-c2ccc(O)cc2)cc1
Reaction time: 3 h
Yield: 85.4 %

Procedure:
10 g (24.5 mmole) of 3,3',5,5',-terta-tert-butyl-diphenoquinone in 40 ml of ethylbenzene was hydrogenated as in Example 9. The filtered reaction mixture containing 4,4'-bis(2,6-di-tert-butylphenol) was transferred to a heavy walled bottle containing a magnetic stirring bar and as strong solid acid 9 g of Nafion® 117, which was obtained from the Du Pont Company as a film, which was cut into small pieces, treated with conc. HCl at 70° C. for one hour, washed with water and acetone and dried in an oven at 70° C. over night. The reactor was placed in an oil bath at 170° C. with stirring. The dealkylation was completed within 30 minutes. 3.8 g (20.4 mmol) of 4,4'-biphenol was obtained in the same way as described in Example 9 (83.3% yield). The filtrate containing 14.3 g p- and m-tert-butyl-ethylbenzene was placed in a popbottle containing 0.2 g 5% Pd/C, 10 g 3,3',5,5'-tetra-tert-butyl-diphenoquinone, and magnetic stirring bar. The hydrogenation was completed after 3 hours at 130° C. under 25 psi H2 pressure. The removal and washing of the catalyst was done as described above. The filtrate was transferred to a popbottle containing a magnetic stirring bar and the catalyst from the previous dealkylation, which had been treated with conc. HNO3, washed with acetone and water and dried at 70° C. overnight. The reaction mixture was kept at 170° C. for 45 minutes, cooled and worked up in the same way as above. 3.9 g (20.9 mmole) of 4,4'-biphenol was obtained (85.5% yield). The filtrate contained 22.2 g of p- and m-tert-butyl-ethylbenzene (69.9% yield).
Reaction SMILES: [CH3:1][C:2]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][C:3]=1[NH:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].C(O)(=[O:24])C.OO>O>[OH:24][C:11]1[CH:12]=[N:13][C:5]([NH:4][C:3]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([F:19])([F:21])[F:20])[C:2]=2[CH3:1])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1c(Nc2ncccc2C(=O)O)cccc1C(F)(F)F
Reactant: CC(=O)O
Agent: OO
Solvent: O
Product: Cc1c(Nc2ncc(O)cc2C(=O)O)cccc1C(F)(F)F

Procedure:
To a suspension of 10 g. of 2-(2-methyl-3-trifluoromethylanilino) nicotinic acid and 160 ml. of glacial acetic acid, add 9 ml. of 30% hydrogen peroxide solution at room temperature. Warm the reaction mixture on a steam bath for one hour and add an additional 5 ml. of 30% hydrogen peroxide. Heat the resulting mixture for three hours on a steam bath, dilute with water and filter. After recrystallization from acetic acid, the product, 5-hydroxy-2-(2-methyl-3-trifluoromethylanilino) nicotinic acid melts at 305°-308° (dec.)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1.C([O-])(=O)C.[Na+]>C(O)C.C(OCC)(=O)C>[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:18][CH:17]=1
Reactant: Nc1ccc(S)cc1
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(Sc2ccc(N)cc2)c([N+](=O)[O-])c1
Yield: 96.4 %

Procedure:
A solution of methyl 4-chloro-3-nitrobenzoate (1.00 g, 4.638 mmol) in anhydrous ethanol (40 mL) was treated with 4-aminothiophenol (0.813 g, 6.494 mmol) and anhydrous sodium acetate (1.90 g, 23.19 mmol) at room temperature under a nitrogen atmosphere, at reflux for 2 hours. The reaction was cooled, diluted with ethyl acetate (100 mL), and washed with water (3×50 mL) and brine (50 mL). The organic phase was dried over magnesium sulfate, filtered, and concentrated by rotary evaporation. The resulting orange solid was triturated with ethyl ether/hexanes (1:1 v/v, 3×30 mL), and dried in vacuo to afford the title compound (1.36 g, 4.469 mmol, 96%). 1H NMR (300 MHz, DMSO-D6) δ ppm 3.87 (s, 3 H) 5.80 (s, 2 H) 6.70 (d, J=8.46 Hz, 2 H) 7.00 (d, J=8.46 Hz, 1 H) 7.23 (d, J=8.46 Hz, 2 H) 8.05 (dd, J=8.46, 1.84 Hz, 1 H) 8.64 (d, J=1.84 Hz, 1 H). MS (ESI+) m/z 305 (M+H)+.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[C:9]2[C:28](=[O:29])[N:27]([C:30]3[CH:35]=[C:34]([Cl:36])[C:33](=[O:37])[N:32]([CH3:38])[CH:31]=3)[CH:26]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)[C:10]=2[N:11]([CH:23]([CH3:25])[CH3:24])[C:12]=1[C:13]1[C:14]([O:21][CH3:22])=[N:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=1)=[O:7])C>C1COCC1.CO>[Cl:36][C:34]1[C:33](=[O:37])[N:32]([CH3:38])[CH:31]=[C:30]([N:27]2[C:28](=[O:29])[C:9]3[C:8]([C:6]([OH:7])=[O:5])=[C:12]([C:13]4[C:14]([O:21][CH3:22])=[N:15][C:16]([O:19][CH3:20])=[N:17][CH:18]=4)[N:11]([CH:23]([CH3:25])[CH3:24])[C:10]=3[CH:26]2[C:39]2[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=2)[CH:35]=1
Reactant: CCOC(=O)c1c2c(n(C(C)C)c1-c1cnc(OC)nc1OC)C(c1ccc(Cl)cc1)N(c1cc(Cl)c(=O)n(C)c1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ncc(-c2c(C(=O)O)c3c(n2C(C)C)C(c2ccc(Cl)cc2)N(c2cc(Cl)c(=O)n(C)c2)C3=O)c(OC)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2N Aqueous NaOH (0.208 mmol) was added to a solution of 5-(5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-6-(4-chloro-phenyl)-2-(2,4-dimethoxy-pyrimidin-5-yl)-1-isopropyl-4-oxo-1,4,5,6-tetrahydro-pyrrolo[3,4-b]pyrrole-3-carboxylic acid ethyl ester (Example 220) (0.104 mmol) in 1:1 THF/MeOH (2 mL) and the mixture was stirred at 80° C. for 1 h. After evaporation of MeOH, the pH was adjusted to 5 with addition of 10% w/w aqueous citric acid and extracted with EtOAc (3×). The combined organic phases were successively washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was purified by SFC to afford the title compound as a white solid. tR: 1.10 min (HPLC 3); ESI-MS: tR=0.97 min, [M+H]+ 598/600/602 (LC-MS 1); TLC: Rf=0.31 (9:1 CH2Cl2/MeOH).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][N:12]([S:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)(=[O:17])=[O:16])[CH2:11][CH2:10]1)(C)(C)C.Cl>O1CCOCC1.C(Cl)(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][S:15]([N:12]2[CH2:11][CH2:10][CH:9]([CH2:8][NH2:7])[CH2:14][CH2:13]2)(=[O:16])=[O:17])=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(S(=O)(=O)CCc2ccc(F)cc2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: NCC1CCN(S(=O)(=O)CCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 0.4 g of {1-[2-(4-fluoro-phenyl)-ethanesulfonyl]-piperidin-4-ylmethyl}-carbamic acid tert-butyl ester and 5 mL of 4N HCl in dioxane was stirred at room temperature for 3 h, then diluted with 50 mL of chloroform, washed with 50 mL of saturated sodium carbonate, dried over magnesium sulfate and concentrated to dryness under reduced pressure. The product was a white solid:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)[CH2:13][CH2:12]2)=[O:10])=[C:4]([CH3:24])[CH:3]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1>>[CH3:24][C:4]1[CH:3]=[C:2]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([C:26]([F:37])([F:36])[F:25])[CH:32]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)cc(C)c1C(=O)N1CCC(N2CCC(O)CC2)CC1

Procedure:
In analogy to the procedures described for intermediates 3B, 3C, 1, 4B and for example 1, the title compound has been prepared by the following reaction sequence: i) 4-hydroxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester [Lawrence, L.; Rigby, A.; Sanganee, H.; Springthorpe, B. PCT Int. Appl. (2001), WO 2001077101 A1] was reacted with benzoyl chloride to give 4-benzoyloxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester; ii) 4-benzoyloxy-[1,4′]bipiperidinyl-1′-carboxylic acid tert-butyl ester was reacted with trifluoroacetic acid to give benzoic acid [1,4′]bipiperidinyl-4-yl ester; iii) 4-bromo-2,6-dimethyl-benzoic acid was converted into its acid chloride and reacted with benzoic acid [1,4′]bipiperidinyl-4-yl ester to give benzoic acid 1′-(4-bromo-2,6-dimethyl-benzoyl)-[1,4′]bipiperidinyl-4-yl ester; iv) benzoic acid 1′-(4-bromo-2,6-dimethyl-benzoyl)-[1,4′]bipiperidinyl-4-yl ester was saponified to give (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone; v) Suzuki reaction of (4-bromo-2,6-dimethyl-phenyl)-(4-hydroxy-[1,4′]bipiperidinyl-1′-yl)-methanone with 3-trifluoromethyl-phenyl boronic acid gave the title compound as light brown solid. MS: 461.3 (MH+).
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)[OH:2].[CH2:11]([N:13]=[C:14]=[O:15])[CH3:12]>>[CH2:11]([NH:13][C:14]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:10])([CH3:9])[S:4]1)=[O:15])[CH3:12]
Reactant: CC1=NC(=NO)SC1(C)C
Reactant: CCN=C=O
Product: CCNC(=O)ON=C1N=C(C)C(C)(C)S1

Procedure:
2-oxo-4,5,5-trimethyl-3-thiazoline-oxime was reacted with ethyl isocyanate as described in Example 4 to yield 2-oxo-4,5,5-trimethyl-3-thiazoline-O-(ethylcarbamoyl)-oxime, m.p. 84°-86° C.
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[C:17]([C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18]>>[C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:27]([NH:16][C:10]2[CH:11]=[CH:12][C:13]([O:14][CH3:15])=[C:8]([C:3]3[N:4]([CH3:7])[N:5]=[CH:6][C:2]=3[F:1])[CH:9]=2)=[O:28])[CH:23]=[CH:24][CH:25]=1)(=[O:19])[CH3:18]
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Reactant: CC(=O)c1cccc(N=C=O)c1
Product: COc1ccc(NC(=O)Nc2cccc(C(C)=O)c2)cc1-c1c(F)cnn1C
Yield: 53 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-acetylphenylisocyanate, in a similar manner as described in Example 1.68. An additional purification by flash chromatography (SiO2, Hexanes/EtOAc gradient elution) was necessary, providing 36 mg (53% yield) of Compound 88: LCMS m/z (%)=383 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.31 (s, 1H), 8.17 (s, 1H), 8.13 (s, 1H), 7.79 (dd, J1=9.0 Hz, J2=2.2 Hz, 1H), 7.63 (d, J1=15.5 Hz, J2=8.3 Hz, J3=2.7 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.41 (m, 3H), 7.14 (d, J=9.2 Hz, 1H), 3.84 (s, 3H), 3.65 (s, 3H), 2.56 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −177.39 (d, JH,F=4.1 Hz, 1F).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:25]([OH:29])[CH2:26][C:27]#[CH:28]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:28]#[C:27][CH2:26][CH2:25][OH:29])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(Br)cc3)nsc2c1)C(F)(F)F
Product: OCCC#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 13.1, Trifluoro-methanesulfonic acid 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl ester and 3-butyn-1-ol were converted to yield 4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-but-3-yn-1-ol as orange solid, MS: 357 (M, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][C:4]=1[CH3:16].[OH-].[Na+].[CH2:19](O)[CH3:20]>OS(O)(=O)=O.O>[CH2:19]([O:13][C:12](=[O:14])[CH2:11][CH2:10][C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:16])[CH:5]=1)=[O:15])[CH3:20]
Reactant: CCO
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)CCC(=O)c1ccc(OC)c(C)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
To a solution of 4-(4-methoxy-3-methylphenyl)-4-oxobutyric acid (Compound 2, 21.75 g, 98.0 mmol) in absolute ethanol (200 mL) was added 10 drops of concentrated H2SO4. The resulting solution was refluxed for 3 days, then cooled to room temperature, treated with 30 mL of NaOH 2N, diluted with 50 mL of water, and extracted 3 times with EtOAc. The combined organic layers were washed with brine, and dried over MgSO4, and filtered. The solvent was removed to afford 20.6 g (84%) of the title compound as a yellow solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH:15]([CH2:18][OH:19])[O:14][C:13]=2[CH:20]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([NH:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][CH2:16][CH:15]([CH2:18][OH:19])[O:14][C:13]=2[CH:20]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc2c(c1)OC(CO)CO2
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2c(c1)OC(CO)CO2
Temperature: 25 °C
Reaction time: 15 h
Yield: 46 %

Procedure:
Acetic anhydride (0.24 g, 2.4 mmol) was added to a stirred mixture of the title compound from Step 1 above (0.30 g, 1.66 mmol) and Et3N (0.70 g, 6.9 mmol) in CH2Cl2 (30 mL). The reaction was stirred at room temperature for 15 h. More acetic anhydride (0.10 g, 1.0 mmol) was added and the mixture was stirred for a further 5 h at room temperature. The mixture was concentrated and the residue purified by chromatography on silica gel using EtOAc/isohexane (1:3 to 2:3) as eluent to give 170 mg (46%) of the title product as an oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][C:16]#[N:17])[N:14]=2)=[CH:6][CH:5]=1.[CH3:18]I>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH:15]([CH3:18])[C:16]#[N:17])[N:14]=2)=[CH:8][CH:9]=1
Reactant: N#CCc1coc(-c2ccc(F)cc2)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C#N)c1coc(-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
NaH (360 mg, 60% dispersion in oil) was added portionwise over 5 min to a solution of 2-(2-(4-fluorophenyl)oxazol-4-yl)acetonitrile (1.5 g, 7.42 mmol) in dry THF (60 mL) at 0° C. The resulting reaction mixture was slowly allowed to warm up to room temperature and stirred for 1 h. The reaction mixture was again cooled to 0° C. and a solution of methyl iodide (0.5 mL, 7.4 mmol) in dry THF (10 mL) was added dropwise at 0° C. over 30 min. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for another 1 h. The reaction mixture was quenched with saturated NH4Cl solution, diluted with EtOAc and further extracted with EtOAc. The combined extracts were washed with H2O and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluant 10% EtOAc in petroleum ether) to get 2-(2-(4-fluorophenyl)oxazol-4-yl)propanenitrile (360 mg, yield 23%). 1H NMR (400 MHz, CDCl3) δ 8.05-8.02 (m, 2H), 7.71-7.70 (d, J=1.1 Hz, 1H), 7.19-7.14 (t, J=8.7 Hz, 2H), 3.97-3.92 (m, 1H), 1.73-1.72 (d, J=7.2 Hz, 3H). MS (ESI) m/z: Calculated for C12H19FN2O: 216.07. found: 216.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][C@H:8]1[CH2:11][NH:10][C:9]1=[O:12])=[O:6])[CH3:3].C([Li])(CC)C.[CH3:19][S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21]>O1CCCC1.C1CCCCC1>[CH3:3][C:2]([CH3:13])([O:4][C:5]([NH:7][C@H:8]1[CH2:11][N:10]([C:24]([NH:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:25])[C:9]1=[O:12])=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@H]1CNC1=O
Reactant: CS(=O)(=O)N=C=O
Agent: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CN(C(=O)NS(C)(=O)=O)C1=O
Temperature: -75 °C

Procedure:
(S)-3-[[(1,1-Dimethylethoxy)carbonyl]amino]-2-azetidinone (1.12 g) was dissolved in dry tetrahydrofuran (120 ml) and stirred at -75° C. under dry nitrogen. sec-Butyl lithium (4.44 ml of a 1.35 M solution in cyclohexane) was added and followed in two minutes by methylsulfonyl isocyanate (0.72 ml). After stirring for 25 minutes at -75° C., the reaction was quenched by the addition of 0.5 M pH 5.5 monobasic potassium phosphate buffer (60 ml), diluted with ethyl acetate-water, acidified to pH 2.5 with 3N hydrochloric acid, and (60 ml), diluted with ethyl acetate-water, acidified to pH 2.5 with 3N hydrochloric acid, and extracted with ethyl acetate (three times). The extract was washed with water, dried over anhydrous sodium sulfate, and evaporated to dryness in vacuo to yield the desired product as a foam (1.73 g).
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Cl:13][C:14]1[N:19]=[C:18]([F:20])[C:17]([O:21][CH2:22][O:23][CH3:24])=[CH:16][CH:15]=1.[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=1)[CH:31]=[O:32]>C1COCC1>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:31]([C:16]2[CH:15]=[C:14]([Cl:13])[N:19]=[C:18]([F:20])[C:17]=2[O:21][CH2:22][O:23][CH3:24])[OH:32])[CH:33]=1
Reactant: COCOc1ccc(Cl)nc1F
Reactant: O=Cc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COCOc1c(C(O)c2cc(Br)ccc2F)cc(Cl)nc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 76.8 %

Procedure:
A solution of i-Pr2NH (1100 mL, 7.72 mol) in anhydrous THF (3.5 L) was cooled to −10° C. n-BuLi (2.5 M in hexanes, 3087 mL, 7.72 mol) was added drop wise and the solution was stirred for 10 min at 0° C. The reaction mixture was cooled to −78° C. and a solution of 6-chloro-2-fluoro-3-(methoxymethoxy)pyridine (1344 g, 7.02 mol) in anhydrous THF (2 L) was added slowly, keeping the internal temperature below −60° C. The resulting solution was stirred at −75° C. for 1 hr. A solution of 5-bromo-2-fluorobenzaldehyde (1430 g, 7.02 mol) in THF (1.7 L) was added drowise. After the addition was complete, the reaction mixture was stirred at −75° C. for 30 min. The reaction mixture was warmed to RT and quenched with saturated aqueous NH4Cl solution (3 L). EtOAc (5 L) was added and the mixture was stirred vigorously. After phase separation, the aqueous layer was extracted with EtOAc (3 L×2). The combined organics were washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (0-10% EtOAc/hexanes) to provide 2128 g of (5-bromo-2-fluorophenyl)(6-chloro-2-fluoro-3-(methoxymethoxy)pyridin-4-yl)methanol as a light yellow solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C:9]=2[CH:10]=1.S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[O:7][C:8]2[CH:14]=[C:13]([C:15]([O:17][CH2:23][CH3:24])=[O:16])[CH:12]=[CH:11][C:9]=2[CH:10]=1
Reactant: CCO
Reactant: O=C(O)c1ccc2cc(CCCCBr)oc2c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2cc(CCCCBr)oc2c1

Procedure:
A solution of 2-(4-bromobutyl)benzofuran-6-carboxylic acid (29.7 g., 0.1 mole) and sulfuric acid (0.5 ml.) in ethanol (200 ml.) is boiled under reflux. The solution is concentrated to 7/8 volume at reduced pressure. The residue is poured into water. The oily ester is extracted with ether. Evaporation of the solvent provides ethyl 2-(4-bromobutyl)benzofuran-6-carboxylate.