Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si]([S:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])(C(C)C)C(C)C)(C)C.[H-].[Na+].[C:24]([C:26]1([CH2:49][CH:50]2[CH2:52][CH2:51]2)[CH2:31][CH2:30][C:29](OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[CH:28][CH2:27]1)#[N:25]>O1CCCC1.C1(C)C=CC=CC=1>[CH:50]1([CH2:49][C:26]2([C:24]#[N:25])[CH2:31][CH2:30][C:29]([S:11][Si:12]([CH:13]([CH3:14])[CH3:15])([CH:16]([CH3:17])[CH3:18])[CH:19]([CH3:20])[CH3:21])=[CH:28][CH2:27]2)[CH2:52][CH2:51]1
Reactant: N#CC1(CC2CC2)CC=C(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CC1
Reactant: CC(C)[Si](S[Si](C(C)C)(C(C)C)C(C)C)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[Si](SC1=CCC(C#N)(CC2CC2)CC1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
To a degassed, cooled (0° C.) solution of triisopropylsilylsulfide (11.1 g, 58.6 mmol) in tetrahydrofuran (60 ml) was added portionwise over 10 minutes sodium hydride (2.34 g, 60% dispersion in oil) and the mixture stirred until a clear solution formed. 1,1,2,2,3,3,4,4,4-Nonafluorobutane-1-sulfonic acid 4-cyano-4-cyclopropylmethylcyclohex-1-enyl ester (26.9 g, 58.6 mmol) was dissolved in anhydrous toluene (170 ml) and degassed for 30 minutes before addition of TIPS sodium sulfide solution and tetrakis triphenylphosphine palladium (0) (3.38 g, 2.93 mmol). On complete addition the mixture was plunged into an oil bath preheated to 90° C. After 15 min the mixture becomes dark brown in colour. After a further 15 min the mixture was allowed to cool to ambient temperature. The mixture was poured on to ice (200 g) and extracted with diethyl ether (2×200 ml). The combined organic layer was washed with water (200 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give a brown oil. The oil was purified by dry flash column chromatography on silica eluting with isohexane on a gradient of dichloromethane (5-30%). Collecting appropriate fractions followed by evaporation gave a brown oil (20.5 g, 100%). 1H NMR δ (ppm)(CDCl3): 5.92 (1H, s), 2.61-2.54 (2H, m), 2.38-2.28 (1H, m), 2.21-2.10 (3H, m), 1.67-1.44 (2H, m), 1.33-1.23 (3H, m), 1.14 (18H, d, J=7.2 Hz), 0.95-0.85 (1H, m), 0.58-0.55 (2H, m), 0.20-0.18 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH2:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.Cl.[CH2:18](O)[CH3:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][C:9]([CH3:13])([CH3:14])[C:10]([O:12][CH2:18][CH3:19])=[O:11])=[O:7])=[CH:15][CH:16]=1
Reactant: CC(C)(CC(=O)c1ccc(Cl)cc1)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C(C)(C)CC(=O)c1ccc(Cl)cc1

Procedure:
3-(4-Chlorobenzoyl)-2,2-dimethylpropionic acid (13.7 g) was dissolved in ethanol (100 ml) which had been saturated with gaseous hydrogen chloride. The solution as refluxed for eight hours. The solvent was distilled off and replaced by ether. The ethereal solution was washed with saturated sodium bicarbonate solution, then with brine, dried over magnesium sulphate and concentrated in vacuo to yield 14.5 g of ethyl 3-(4-chlorobenzoyl)-2,2-dimethylpropionate as an oil.
Reaction SMILES: [C:1]([S:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([F:11])[CH:5]=1)#[N:2].C([O:14][CH:15]=[C:16]([C:22](OCC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C1CCCCC1.C1(C)C=CC=CC=1>[C:1]([S:3][C:4]1[CH:10]=[C:9]2[C:7](=[C:6]([F:11])[CH:5]=1)[N:8]=[CH:22][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:15]2[OH:14])#[N:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: N#CSc1ccc(N)c(F)c1
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2c(F)cc(SC#N)cc2c1O
Temperature: 130 °C
Yield: 25.6 %

Procedure:
A mixture of 48 g of 4-(cyanosulfanyl)-2-fluoroaniline and 57.7 g of diethyl ethoxymethylenemalonate is stirred at 130° C. After 1.5 h the mixture is diluted with 200 mL of a 1:1 mixture of cyclohexane and toluene. The mixture is cooled to 0° C. and the precipitate collected by filtration. It is washed with two 75 mL portions of a 1:1 mixture of cyclohexane and toluene, dried in a stream of air, and then it dissolved in 400 mL of diphenyl ether. The mixture is refluxed for 1 h and then cooled to 25° C. It is diluted with 1 L of 1:1 toluene/cyclohexane and the precipitate collected by filtration. The solid is dried in a stream of air to give 20 g of the title compound.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[C:22]([CH3:37])=[N:23][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:25][CH:26]=1.O>CN(C)C=O>[CH3:37][C:22]1[C:21]([CH2:20][O:18][C:15]2[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH2:9][CH2:8][N:3]3[CH:7]=[CH:6][N:5]=[N:4]3)=[CH:17][CH:16]=2)=[CH:26][CH:25]=[C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:36])[F:34])=[CH:29][CH:28]=2)[N:23]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COc1ccc(CCCCn2ccnn2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
14 mg (0.55 mmol) of 95% sodium hydride were added to at 0° C. to a solution of 109 mg (0.50 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 143 mg (0.50 mmol) 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed twice with water, and twice with heptane. The residue was dried at 40° C. in vacuum to give 191 mg (82%) of the title compound as white powder.
Reaction SMILES: C([S:9][CH2:10][CH2:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[C:23]([OH:25])=[O:24])=[O:13])(=O)C1C=CC=CC=1.[NH3:26]>O.C(OCC)(=O)C>[O:13]=[C:12]([N:26]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[C:23]([OH:25])=[O:24])[CH2:11][CH2:10][S:9][S:9][CH2:10][CH2:11][C:12]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH:15]1[C:23]([OH:25])=[O:24])=[O:13]
Reactant: N
Reactant: O=C(SCCC(=O)N1c2ccccc2CC1C(=O)O)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C1Cc2ccccc2N1C(=O)CCSSCCC(=O)N1c2ccccc2CC1C(=O)O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 1-[3-(benzoylthio)-1-oxopropyl]-2,3-dihydro-1H-indole-2-carboxylic acid (3.0 g.) and methanolic ammonia (5.5 N solution, 45 ml.) was stirred at room temperature for 2.5 hours, then evaporated under reduced pressure on a rotary evaporator to give a resinous material. The residue was dissolved in water, and the aqueous solution was washed with ethyl acetate three times. The aqueous phase was acidified to pH ca. 2 by dropwise addition of dilute hydrochloric acid, whereby an oil separated. The oil was extracted with ethyl acetate (two times). The combined extract was washed with water, then with saline, and dried over anhydrous sodium sulfate. The ethyl acetate was evaporated on a rotary evaporator under reduced pressure to give an oily residue which was placed under high vacuum to give a solid material. The crude product was dissolved in a small amount of warm ethyl acetate with warming on a steam bath (there was some insoluble solid material which was removed by filtration). The ethyl acetate solution was kept under mild nitrogen stream until a precipitate started to separate. The mixture was chilled in ice, then kept in a refrigerator. The precipitate was collected on a filter and washed with acetonitrile to give 1,1'-dithiobis[3-oxo-1,3-propanediyl]bis[2,3-dihydro-1H-indole-2-carboxylic acid], m.p. 213°-216°.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:10]2[C:5](=[CH:6][C:7]([CH3:16])=[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=2)[CH2:4][CH2:3]1.O=O.O.C([O:25]C)(C)(C)C>C(O)(=O)C>[CH3:17][C:2]1([CH3:1])[C:10]2[C:5](=[CH:6][C:7]([CH3:16])=[C:8]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=2)[C:4](=[O:25])[CH2:3]1
Reactant: COC(C)(C)C
Reactant: CCCCOc1cc2c(cc1C)CCC2(C)C
Agent: O=O
Solvent: CC(=O)O
Solvent: O
Product: CCCCOc1cc2c(cc1C)C(=O)CC2(C)C
Temperature: 40 °C
Yield: 75.5 %

Procedure:
100 g 3,3,6-trimethyl-5-butoxy-indane are dissolved in 400 g acetic acid and 1 g Co-II acetate is added. The reaction mixture is heated to 40° C., with stirring, and oxygen is passed through this solution for 10 hours. After cooling to room temperature, 500 g water and 500 g methyl tert.-butyl ether are added. After phase separation, the organic phase is rinsed with a further 200 g water and distilled in a 30 cm packed column. 80 g 3,3,6-trimethyl-5-butoxy-indan-1-one is obtained, which corresponds to a yield of 75% of theory. The compound can be recrystallised from heptane and a white solid is obtained, melting point: 59° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:31])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[CH:20]=3)[CH2:14][CH2:13]2)[O:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=O.[NH2:33][NH2:34]>C(O)C>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]([N:15]2[CH2:14][CH2:13][C:12]3([C:3]4[CH:2]=[N:34][NH:33][C:4]=4[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=4[O:11]3)[CH2:17][CH2:16]2)=[O:31])=[CH:20][C:21]=1[C:27]([F:28])([F:29])[F:30]
Reactant: COc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2C(=O)C3=CO)cc1C(F)(F)F
Reactant: NN
Solvent: CCO
Product: COc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2[nH]ncc23)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-(hydroxymethylene)-1′-[4-methoxy-3-(trifluoromethyl)-benzoyl]spiro[chromane-2,4′-piperidine]-4-one (54 mg, 0.12 mmol) and hydrazine (3.8 μL, 0.12 mmol) in ethanol (1.7 mL) was allowed to stir for 1 h at 25° C., then for 2.5 h at 50° C. The mixture was cooled and then concentrated in vacuo. The residue was taken up in DMF and was purified by reverse phase HPLC to give (4-methoxy-3-(trifluoromethyl)phenyl)(1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone. ESI-MS m/z calc. 443.2. found 444.1 (M+1)+; Retention time: 2.40 minutes (4 min run). 1H NMR (400 MHz, CDCl3) δ 9.15-8.90 (m, 1H), 7.73 (s, 1H), 7.67 (d, J=8.3 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J=7.7 Hz, 1H), 7.33-7.18 (m, 1H), 7.04 (dd, J=18.8, 8.3 Hz, 2H), 6.91 (t, J=7.5 Hz, 1H), 6.05-5.60 (m, 1H), 4.50-4.05 (m, 2H), 4.08-3.55 (m, 3H), 3.97 (s, 3H), 2.50-2.32 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:6]=[CH:5][N:4]=1.C([O-])(=O)C.[Na+].[Br:29]Br>C(O)(=O)C.O>[Br:29][C:13]1[CH:12]=[CH:11][C:10]([NH:15][C:16](=[O:21])[C:17]([CH3:19])([CH3:20])[CH3:18])=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:2]([F:1])([F:22])[F:23])[N:8]=2)[CH:14]=1
Reactant: BrBr
Reactant: CC(C)(C)C(=O)Nc1ccccc1-c1ccnc(C(F)(F)F)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(Br)cc1-c1ccnc(C(F)(F)F)n1
Reaction time: 1 h
Yield: 88.4 %

Procedure:
3 g N-[2-[2-(trifluoromethyl)4-pyrimidinyl]phenyl]-2,2-dimethylpropanamide was dissolved in 30 mL glacial acetic acid, 5 g anhydrous sodium acetate was added, and a solution of 2.8 g bromine in 5 mL acetic acid was added dropwise with stirring over 1 h. The reaction mixture was stirred at room temperature overnight, after which it was diluted with water. The precipitate was collected by filtration, washed well with water, then with hexane, and was dried in a vacuum oven overnight to yield 3.3 g of the title compound melting at 153°-157° C. 1H NMR (CDCl3): δ 1.28 (s,9H), 7.40-8.4 (6H), 10.6 (s,1H,NH).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[C:29](O)(=[O:32])[CH2:30][CH3:31]>>[NH2:13][C:9]1[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]2[CH:27]=[CH:28][C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])=[CH:3][CH:4]=2)[C:8]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)cc1
Reactant: CCC(=O)O
Product: C=CC(=O)Nc1ccc(Oc2ncnc(N)c2-c2ccc(Oc3ccccc3)cc2)cc1
Yield: 51 %

Procedure:
N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide was prepared from 6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine and propionic acid using Method E (51% yield). HPLC: 96%, RT=4.165 min. MS: m/z=427 [M+H]+, RT=4.11 min. 1H-NMR (DMSO-d6) δ 9.78 (s, 1H), 7.94 (s, 1H), 7.48 (d, 2H), 7.36-7.32 (m, 4H), 7.09 (t, 1H), 7.02 (t, 4H), 6.91 (d, 2H), 6.39 (broad s, 2H), 2.24 (q, 2H), 1.01 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]([F:22])([F:21])[F:20])=[N:17][CH:18]=3)[CH:15]=2)=[CH:6][CH:5]=1.C1C(=O)N([Br:32])C(=O)C1>C(Cl)Cl>[Br:32][C:18]1[N:17]=[C:16]([C:19]([F:20])([F:21])[F:22])[N:14]2[CH:15]=[C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:23])[F:24])=[CH:9][CH:8]=3)[CH:11]=[CH:12][C:13]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: FC(F)(F)Oc1ccc(-c2ccc3cnc(C(F)(F)F)n3c2)cc1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(-c2ccc3c(Br)nc(C(F)(F)F)n3c2)cc1

Procedure:
6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)imidazo[1,5-a]pyridine (1.2001 g, 3.466 mmol) was dissolved in CH2Cl2 (20 mL) in a 250 mL round bottomed flask. The solution was treated with NBS (925.4 mg, 5.199 mmol, 1.5 equiv.) at 0° C. for 30 min. And then the solvent was removed by rota-yap to give a crude mixture. Obtained crude mixture was purified by a column chromatography (SiO2=80 g, EtOAc/hexane=1:7 Rf=0.5) to give 1-bromo-6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)imidazo[1,5-a]pyridine as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:4].F[C:17]1[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][C:18]=1[CH2:19][N:20]([CH3:31])[C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CS(C)=O>[CH2:23]([O:22][C:21]([N:20]([CH2:19][C:18]1[CH:32]=[C:33]([N+:36]([O-:38])=[O:37])[CH:34]=[CH:35][C:17]=1[C:5]([CH2:3][CH3:4])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH3:31])=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OCc1ccccc1
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(CC)(C(=O)OCC)c1ccc([N+](=O)[O-])cc1CN(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 97.5 %

Procedure:
To a flask with sodium hydride (207 mg, 8.64 mmol) was added DMSO (5 mL). The mixture was stirred at rt for 5 min. Diethyl 2-ethylmalonate (1626 mg, 8.64 mmol) in DMSO (5 mL) was added. After 20 min stirring, 13A (550 mg, 1.728 mmol) in DMSO (5 mL) was added. The reaction mixture was heated at 65° C. over night. The reaction was quenched with water, extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by flash chromatography to give 13B (820 mg, 98% yield). MS (ESI) m/z: 486.9 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ ppm 8.00-8.12 (m, 2H) 7.49 (d, J=8.79 Hz, 1H) 7.24-7.45 (m, 5H) 5.11-5.32 (m, 2H) 4.57 (d, J=16.26 Hz, 2H) 4.10-4.33 (m, 4H) 2.89 (d, J=3.95 Hz, 3H) 2.44 (t, J=7.25 Hz, 2H) 1.15-1.34 (m, 6H) 0.81-1.05 (m, 3H).
Reaction SMILES: Cl.[CH2:2]([NH2:6])[C:3](=[CH2:5])[CH3:4].[C:7](=O)([O:13]C(C)(C)C)[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>ClCCl>[C:9]([O:8][C:7]([NH:6][CH:2]=[C:3]([CH3:4])[CH3:5])=[O:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: C=C(C)CN
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)=CNC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
A solution of 13.44 g of methallylamine hydrochloride and 27.3 g of di-tert.-butyl carbonate in 250 ml of dichloromethane at 20° is treated with 25.2 g of triethylamine. The solution is stirred for 1 hour at 20° washed with water and the organic phase is dried and the solvent is removed to give a colourless oil. Flash-chromatography on silica-gel affords pure 3-(N-tert.-butoxycarbonylamino)-2-methyl-prop-2-ene as a colourless oil; 1H-NMR (CDCl3): δ (ppm)=4.83 (2H, m, 2×CH=C), 4.70-4.60 (1H, broad s, exch. D2O, NH), 3.67 (2H, s, CH2N), 1.73 (3H, s, CH3), 1.45 (9H, s, tBu).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.S(Cl)(Cl)=O.[CH3:19]O>>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([O:14][CH3:19])=[O:13])=[CH:7][CH:6]=[CH:5]2
Reactant: CO
Reactant: O=C(O)c1cccc2cc(O)ccc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2cc(O)ccc12
Temperature: 22.5 °C

Procedure:
To a cooled solution of 6-hydroxy-1-napthoic acid (TCI America) (50 g, 0.27 mmol) in methanol (500 mL), thionyl chloride (29 mL, 0.40 mmol) was added slowly. The temperature was maintained at 15 to 30° C. The reaction mixture was allowed to warm to RT and stirred O/N. The solvent was concentrated in-vacuo and the residue azeotroped with benzene. The title compound was obtained as a pink solid.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=1.[CH2:8]([N:12]1[N:16]=[C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[C:14]2=[N:13]1)[CH2:9][C:10]#[CH:11]>>[Cl:21][C:20]1[C:14]2[C:15](=[N:16][N:12]([CH2:8][CH2:9][C:10]#[C:11][C:2]3[CH:6]=[CH:5][N:4]([CH3:7])[N:3]=3)[N:13]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: C#CCCn1nc2cccc(Cl)c2n1
Reactant: Cn1ccc(Br)n1
Product: Cn1ccc(C#CCCn2nc3cccc(Cl)c3n2)n1
Yield: 10 %

Procedure:
The title compound was prepared in accordance with the general method of Example 108(C), from 3-bromo-1-methyl-1H-pyrazole (70 mg, 0.43 mmol) and 2-but-3-ynyl-4-chloro-2H-benzo[d][1,2,3]triazole (89-0.43 mmol, Example 146(B)). Microwave conditions. The crude residue was purified by flash, chromatography (cyclohexane/AcOEt 7:3) to yield 12 mg (42 μmol, 10%) of 4-chloro-2-(4-(1-methyl-1H-pyrazol-3-yl)but-3-ynyl)-2H-benzo[d][1,2,3]triazole as a brown semi-solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[O:21][C:22]=1[CH3:23]>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[N:19]=[C:20]([C:24]4[S:25][CH:26]=[CH:27][CH:28]=4)[O:21][C:22]=3[CH3:23])=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Cc1oc(-c2cccs2)nc1CCl
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: Cc1oc(-c2cccs2)nc1COc1ccc(CCCn2ccnc2)cc1
Yield: 84 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-5-methyl-2-(2-thienyl)oxazole to give 4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-5-methyl-2-(2-thienyl)oxazole. The yield was 84%. Recrystallization from acetone-isopropyl ether gave colorless prisms, mp 102-103° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:10])[CH2:5][CH:6]([OH:9])CO.O>ClCCl>[OH:10][C:4]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH2:3][O:2][CH3:1])[CH2:5][CH:6]=[O:9]
Reactant: COCC(O)(CC(O)CO)c1ccccc1
Solvent: ClCCl
Solvent: O
Product: COCC(O)(CC=O)c1ccccc1
Temperature: 25 °C

Procedure:
NalO4 (5.20 g) was added to a mixture of 5-methoxy-4-phenyl-pentane-1,2,4-triol (1.10 g), dichloromethane (10 mL), and water (5 mL) chilled in an ice bath. The mixture was stirred vigorously while warming to ambient temperature in the cooling bath and further stirred at this temperature overnight. Then, water (20 mL) and dichloromethane (50 mL) were added, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (2×25 mL). The combined organic phases were washed with water and dried (MgSO4). After removal of the solvent, the title compound was yielded which was directly submitted to the next reaction step (glycol cleavage).
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][CH:16]=[N:15][C:14]=1[CH3:18].C([O-])([O-])=O.[Na+].[Na+].[CH3:26][O:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOC>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([C:3]2[C:2]([F:1])=[CH:10][CH:9]=[C:8]3[C:4]=2/[C:5](=[CH:12]/[C:13]2[NH:17][CH:16]=[N:15][C:14]=2[CH3:18])/[C:6](=[O:11])[NH:7]3)[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: COc1ccc(-c2c(F)ccc3c2/C(=C/c2[nH]cnc2C)C(=O)N3)cc1OC

Procedure:
A solution of (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (50 mg, 0.135 mmol) (Starting Material 11), 2M aqueous Na2CO3 solution (0.14 mL), (Ph3P)2PdCl2 (11 mg, 0.0135 mmol) and 3,4-dimethoxyphenylboronic acid (61.7 mg, 0.339 mmol) (Lancaster) in a 1:4 mixture of DMF:1,2-dimethoxyethane (5 mL) was heated at 104° C. for 2 days. The reaction mixture was concentrated and the crude material was purified by C18 reverse phase chromatography to give (Z)-1,3-Dihydro-4-(3,4-dimethoxyphenyl)-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 19 mg, 37%).
Reaction SMILES: O=[C:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:13][O:14][NH3+:15].[Cl-].N1C=CC=CC=1>C(O)C>[CH3:13][O:14][N:15]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: CO[NH3+]
Agent: [Cl-]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)C(=NOC)C(=O)OCC
Yield: 93221.8 %

Procedure:
A solution of diethyl ketomalonate 1 (51.0 g, 0.293 mmol), o-methylhydroxylamine hydrochloride (24.46 g, 0.293 mmol) and pyridine (23.2 g, 0.293 mmol) in ethanol (250 ml) is heated to reflux for 3 hr. The solvent is removed under reduced pressure. The residue is dissolved in ethyl acetate and washed with water, dilute hydrogen chloride, aqueous sodium hydrogencarbonate solution, and water successively. After drying over sodium sulfate, the solvent is removed under reduced pressure. The resultant residue is distilled under reduced pressure at 80°-85° C./0.5 mmHg to obtain Compound 2 (55.5 g, 93.2%). NNMR (CDCl3)δ: 1.35 (3H, t, J=7.1 Hz), 1.35 (3H, t, J=7.1 Hz), 4.11 (3H, s), 4.36 (2H, q, J=7.1 Hz), 4.37 (2H, q, J=7.1 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[CH:31]1([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32]1>CN(C=O)C>[CH:31]1([N:36]2[CH2:37][CH2:38][N:39]([C:14]([CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]3)=[O:16])[CH2:40][CH2:41]2)[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: C1CCC(N2CCNCC2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCN(C3CCCC3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57 %

Procedure:
1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (2.2 g) in dry DMF (40 ml) was treated with EDC (3.71 g) followed by HOAT (0.1 g). After 5 min, N-cyclopentylpiperazine (1.5 g) in dry DMF (5 ml) was added and the reaction mixture was stirred at rt for 18 h. Excess DMF was removed by evaporation and the resulting residue was re-dissolved in DCM, adsorbed onto silica gel (10 g) and purified by chromatography [silica gel 0-10% MeOH (containing 10% 0.88 ammonia solution/DCM)]. The pure fractions were combined and the solvent removed by evaporation to give the subtitled compound (2 g). LCMS electrospray(+ve) 366(MH+).