Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([O:9][CH3:10])(=[O:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5].Br[CH2:12][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][C:26]([OH:28])=[O:27].O>CO>[CH3:7][O:6][C:4](=[O:5])[CH:3]([C:2]([O:9][CH3:10])=[O:8])[CH2:12][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][C:26]([OH:28])=[O:27]
Reactant: COC(=O)CC(=O)OC
Reactant: O=C(O)CCCCCCCCCCCCCCBr
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)C(CCCCCCCCCCCCCCC(=O)O)C(=O)OC
Temperature: 50 °C

Procedure:
Sodium (1.11 g, 48.2 mmol) was dissolved in dry methanol (30 ml) and heated to 50° C. Dimethyl malonate (5.87 ml, 51.4 mmol) was added over 15 min. The mixture was heated to reflux and a suspension of 15-bromopentadecanoic acid (5 g, 15.6 mmol) in dry methanol (50 ml) was added over 45 min. The resulting mixture was refluxed for another 30 min. After cooling to RT, water was added and the mixture was concentrated. Water was added to the residue an made alkaline with 1 N NaOH and extracted with ether (1×50 ml). The aqueous layer was acidified with 1N HCl and extracted with ether (3×30 ml). The combined organic layers was dried (Na2SO4) and concentrated to give the title compound in 98% (5.7 g) yield.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](CC2C=CC=CC=2)[CH2:4][C:3]1([CH2:17][CH3:18])[CH2:15][CH3:16]>CO.[H][H].[OH-].[OH-].[Pd+2]>[NH2:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1([CH2:17][CH3:18])[CH2:15][CH3:16]
Reactant: [H][H]
Reactant: CCC1(CC)CN(Cc2ccccc2)CCC1N
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCC1(CC)CNCCC1N

Procedure:
A mixture of 20% Pd(OH)2 on carbon (0.8 g) and 4-amino-1-benzyl-3,3-diethylpiperidine (8.0 g, 32.52 mmol) in methanol (100 ml) was stirred in hydrogen atmosphere (1 atm.) at 30° C. for 6 hr. The catalyst was filtered off, washed with methanol and filtrate was concentrated to dryness to afford 4-amino-3,3-diethylpiperidine. Yield 4.8 g (94.60%), C9H20N2, m/z 157 (M+1), PMR (CDCl3): 0.9 (s, 6H), 1.5 (m, 2H), 1.58 (bs, 2H, D2O exchangeable), 2.26-2.68 (m, 4H), 3.06 (m, 1H), 3.52 (bs, 1H, D2O exchangeable).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>CO.C([O-])(O)=O.[Na+]>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[CH:7]=[N:6][C:5]([C:3]([NH:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCCOCC(=O)O
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(O)COCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 140 °C
Yield: 32.1 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (20 mg, 0.065 mmol), (2-amino-ethoxy)-acetic acid (39 mg, 0.32 mmol), and NaOMe (14 mg, 0.26 mmol) in MeOH (2 mL) was heated at 140° C. in a microwave reactor for 6 h. Solvent was evaporated in vacuo, and the residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH about 1, and the organic layer was dried over MgSO4 and concentrated. The crude product was purified by chromatography (0-2% MeOH/EtOAc+1% AcOH) to give a yellow solid. The solid was then dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 1 with 4 M HCl, and the resulting precipitate was collected by filtration and dried to give 8.3 mg of the title compound as an off-white solid. MS: (+) m/z 398.29 (M+1).
Reaction SMILES: [N:1]([C:4]1[CH:21]=[CH:20][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].O=[C:23]([CH2:30][CH2:31][CH3:32])[CH2:24][C:25]([O:27]CC)=[O:26].[O-]CC.[Na+].O>C(O)C>[C:14]1([CH2:13][CH2:12][CH2:11][NH:10][C:8]([C:7]2[CH:20]=[CH:21][C:4]([N:1]3[C:23]([CH2:30][CH2:31][CH3:32])=[C:24]([C:25]([OH:27])=[O:26])[N:3]=[N:2]3)=[CH:5][CH:6]=2)=[O:9])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc(C(=O)NCCCc2ccccc2)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCc1c(C(=O)O)nnn1-c1ccc(C(=O)NCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
The pale-yellow solid of 4-azido-N-(3-phenylpropyl)benzamide obtained in Example 60a) and ethyl 3-oxohexanoate (1.08 ml, 6.43 mmol, 1.25 eq.) were dissolved in ethanol (20 ml), sodium ethoxide (486 mg, 6.43 mmol, 1.25 eq.) was added, and the mixture was stirred at room temperature for 10 min, and then at 60° C. for 13 hr. Water (20 ml) was added to the reaction mixture, ethanol was evaporated, and the residue was diluted with 2% aqueous sodium carbonate solution (20 ml) and washed with ethyl acetate-hexane (2:1, 50 ml). The organic layer was extracted with 2% aqueous sodium carbonate solution (20 ml). The aqueous layers were combined, washed with ethyl acetate-hexane (1:1, 30 ml), acidified with 6N hydrochloric acid and stood still at 0° C. The precipitate was collected by filtration, washed with ice-cold water and dried to give the title compound as a grayish white powder (1.99 g, 5.07 mmol, 98.7%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([NH:38][C:39](=O)[O-:40])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:39]([NH:38][C:30]2[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=[C:28]([O:27][CH2:26][CH2:25][O:24][CH3:23])[CH:29]=2)=[O:40])[CH:20]=[CH:21][CH:22]=1
Reactant: COCCOc1cc(NC(=O)[O-])cc(C(F)(F)F)c1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Product: COCCOc1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(OC)c(OC)cc34)c2)cc(C(F)(F)F)c1
Yield: 70 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg, 0.3 mmol) and 3-(2-methoxyethoxy)-5-(trifluoromethyl)phenylcarbamate from Example 117A (160 mg, 0.45 mmol) using Example 115C to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea (118 mg, 0.21 mmol, 69%). 1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 1H), 9.04 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.55 (d, 1H), 7.50-7.41 (m, 2H), 7.35 (s, 1H), 7.34 (s, 1H), 7.29-7.23 (m, 2H), 6.87 (s, 1H), 4.19-4.11 (m, 2H), 4.00 (s, 6H), 3.70-3.63 (m, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 575 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9](O)=[O:10])=[CH:4][CH:3]=1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C@@H:12]([CH3:17])[C:13]([F:16])([F:15])[F:14])[C:9]([Cl:26])=[O:10])=[CH:4][CH:3]=1
Reactant: C[C@H]([C@H](C(=O)O)c1ccc(Cl)cc1)C(F)(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@H]([C@H](C(=O)Cl)c1ccc(Cl)cc1)C(F)(F)F
Reaction time: 1 h

Procedure:
19.5 g (73.13 mmol) of (2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoic acid were dissolved in 860 ml of dichloromethane, and 0.5 ml of DMF was added. At from −5° C. to −10° C. (ice/acetone cooling bath), 73 ml (146.26 mmol) of a 2 M solution of oxalyl chloride in dichloromethane were then slowly added dropwise, and the mixture was stirred at this temperature for 1 h. After the reaction had gone to completion, the reaction solution was evaporated under reduced pressure and the residue obtained was taken up in 200 ml dichloromethane and then once more concentrated to dryness. This gave 20.1 g (70.5 mmol, 96% of theory) of the title compound as a colourless oil. Without further purification and without further spectroscopic characterization, the product obtained in this manner was used for subsequent reactions.
Reaction SMILES: C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@H:29]12)[CH3:27].[OH:51][CH2:52][CH2:53][N:54]1[CH2:59][CH2:58][N:57]([C:60]([C@@H:62]2[CH2:66][C@H:65]([SH:67])[CH2:64][N:63]2[C:68]([O:70][CH2:71][C:72]2[CH:77]=[CH:76][C:75]([N+:78]([O-:80])=[O:79])=[CH:74][CH:73]=2)=[O:69])=[O:61])[CH2:56][CH2:55]1>C(#N)C>[OH:51][CH2:52][CH2:53][N:54]1[CH2:55][CH2:56][N:57]([C:60]([C@@H:62]2[CH2:66][C@H:65]([S:67][C:32]3[C@H:33]([CH3:34])[C@@H:29]4[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]4[C:31]=3[C:36]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=3)=[O:37])[CH2:64][N:63]2[C:68]([O:70][CH2:71][C:72]2[CH:73]=[CH:74][C:75]([N+:78]([O-:80])=[O:79])=[CH:76][CH:77]=2)=[O:69])=[O:61])[CH2:58][CH2:59]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CCN(CCO)CC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(CCO)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 52.5 %

Procedure:
1.82 ml of diphenylphosphoryl chloride and 1.54 ml of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 3.0 g of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 38 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. 1.54 ml of diisopropylethylamine and a solution of 3.63 g of (2S,4S)-2-[4-(2-hydroxyethyl)-1-piperazinylcarbonyl]-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 54) in 30 ml of dry acetonitrile were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 3 hours, after which it was allowed to stand overnight in a refrigerator. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 49(b). The crude product was then purified by column chromatography through silica gel, using a 2:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 3.4 g of the title compound, as a powder. The infrared absorption spectrum and nuclear magnetic resonance spectrum of the product were identical with those of the compound prepared as described in step 54(i), above.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.C[Sn](C)(C)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>C1(C)C=CC=CC=1>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1ccc(Br)cc1
Reactant: C[Sn](C)(C)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccc(-c2ccccn2)cc1

Procedure:
7.85 g (34.3 mmol) of methyl 4-bromophenylacetate are introduced under argon into 95 ml of toluene and, at room temperature, 7.97 g (61.7 mmol) of diisopropylethylamine, 9.50 g (37.7 mmol) of 2-trimethylstannylpyridine and 0.4 g (0.3 mmol) of tetrakis(triphenylphosphane)palladium(0) are added. The mixture is then heated under reflux for 18 h. Cooling is followed by washing with 100 ml each of 1N hydrochloric acid and saturated sodium bicarbonate solution. The organic phase was discarded. The acidic and the basic aqueous phase were neutralized and each extracted with 100 ml of dichloromethane, and the combined organic phases were dried over magnesium sulfate and freed of solvent in vacuo. Example VII is obtained after silica gel chromatography (toluene/ethyl acetate gradient 5: 1-1:1) as a colorless oil.
Reaction SMILES: C(O[C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[SH:12])C.C[O-].[Na+].[CH3:17][O:18][C:19](=[O:28])[C:20]([NH:23][C:24](=[O:27])[CH2:25]Cl)([CH3:22])[CH3:21]>CO>[CH3:17][O:18][C:19](=[O:28])[C:20]([NH:23][C:24]([C:25]1[S:12][C:6]2[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:5]=2[C:4]=1[OH:13])=[O:27])([CH3:22])[CH3:21]
Reactant: COC(=O)C(C)(C)NC(=O)CCl
Reactant: CCOC(=O)c1cc(F)ccc1S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C)NC(=O)c1sc2ccc(F)cc2c1O
Yield: 70.7 %

Procedure:
To a solution of 1.00 g 5-fluoro-2-mercaptobenzoic acid ethyl ester in 10 ml methanol 0.81 g of sodium methoxide were added portionwise, followed by addition of 0.97 g 2-(2-chloro-acetylamino)-2-methyl-propionic acid methyl ester. After refluxing the reaction under argon-atmosphere for 0.5 h the resulting mixture was filtrated, 20 ml water and 1.25 ml of acetic acid were added and the precipitated product was collected by filtration, washed with water, dissolved in ethyl acetate and THF, dried over sodium sulphate, filtrated and concentrated in vacuo. The resulting crude product was crystallized from diethylether to yield 1.10 g 2-[(5-fluoro-3-hydroxy-benzo[b]thiophene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][CH2:10]2)[CH:4]=[C:5]([C:7]#[N:8])[CH:6]=1.[C:18]([CH2:21][C:22](=O)[CH3:23])(=O)[CH3:19].Cl>C(O)C>[CH:9]1([N:3]2[C:2]3=[N:1][C:18]([CH3:19])=[CH:21][C:22]([CH3:23])=[C:6]3[C:5]([C:7]#[N:8])=[CH:4]2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: N#Cc1cc(N)n(C2CCc3ccccc32)c1
Reactant: CC(=O)CC(C)=O
Agent: Cl
Solvent: CCO
Product: Cc1cc(C)c2c(C#N)cn(C3CCc4ccccc43)c2n1
Yield: 45.7 %

Procedure:
To a solution of 2-amino-1-(indan-1-yl)pyrrole-4-carbonitrile (19.4 g), acetylacetone (9.6 g) and ethanol (375 ml) was added concentrated hydrochloric acid (3 ml), and the mixture was heated under reflux for 3 hours. The reaction solution was concentrated under reduced pressure and an aqueous sodium hydrogen carbonate solution was added to the residue, which was extracted with ethyl acetate. After the organic layer was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure and the crystal was collected by filtration to give 1-(indan-1-yl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (11.4 g, 46%).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.CCOCC.[C:30]([CH2:32][CH2:33][OH:34])#[N:31].C(=O)(O)[O-].[Na+]>B(F)(F)F.CCOCC.C(OCC)(=O)C>[C:30]([CH2:32][CH2:33][O:34][C@H:2]1[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4][C@@H:3]1[OH:1])#[N:31]
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: N#CCCO
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCCC#N)C[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (2 g), dry ether (50 ml) and 2-cyanoethanol (10 ml.) were sirred at room temperature until the solid had dissolved. Boron trifluoride diethyl etherate (10 drops) was added. After 2 hours at room temperature a further quantity of etherate (10 drops) was added. After 1 hour further etherate (10 drops) was added and after a further hour, the mixture was neutralised with saturated sodium bicarbonate solution, ethyl acetate (50 ml.) added and the organic layer washed with water (3 × 200 ml.). The washed solution was dried over anhydrous sodium sulphate and evaporated to a white foam which was purified by preparative T.L.C. using ethyl acetate. The main band (Rf 0.4) gave the title compound (740 mg;) m.p. 194°-196°C. [α]D + 85° .
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH:16]1[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(OCC)(=O)C>[O:21]=[S:18]1(=[O:22])[CH2:19][CH2:20][CH:16]([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:17]1
Reactant: O=S1(=O)CCC(Br)C1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2cnn(C3CCS(=O)(=O)C3)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), 3-bromotetrahydrothiophene 1,1-dioxide (56 mg, 0.28 mmole; ChemBridge, Cat. No. 4011807), cesium carbonate (0.25 g, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. overnight. After cooling it was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4. After filtration the filtrate was concentrated to yield 74 mg of the product. LCMS (M+H)+: m/z=313.1
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21].[CH3:22][C:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:28])[CH2:24][C:25](O)=[O:26]>>[CH3:28][C:23]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([CH3:22])[CH2:24][C:25]([NH:1][N:2]1[N:11]=[C:10]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:21])=[O:26]
Reactant: CC(C)(CC(=O)O)c1ccccc1
Reactant: Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O
Product: CC(C)(CC(=O)Nn1nc(S(=O)(=O)c2ccccc2)c2ccccc2c1=O)c1ccccc1

Procedure:
The product from Example 68B and 3-methyl-3-phenylbutanoic acid were processed using a method similar to that described in Example 10C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ 11.45 (s, 1H), 8.56 (d, J=8.2, 1H), 8.41-8.34 (m, 1H), 8.14-8.08 (m, 1H), 8.04-7.96 (m, 3H), 7.84-7.77 (m, 1H), 7.68 (dd, J=10.8, 5.0, 2H), 7.38 (dd, J=8.4, 1.1, 2H), 7.33-7.27 (m, 2H), 7.20-7.14 (m, 1H), 2.54 (s, 2H), 1.32 (s, 6H); MS (DCI+) M/Z 479 (M+NH4)+.
Reaction SMILES: [S:1]1[C:5]([CH2:6][CH2:7][OH:8])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+].CCOCC>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:8][CH2:7][CH2:6][C:5]1[S:1][C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[CH:4]=1
Reactant: BrCCCCCCBr
Reactant: OCCc1cc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: BrCCCCCCOCCc1cc2ccccc2s1

Procedure:
2-Benzo[b]thiopheneethanol (2.20 g), 1,6-dibromohexane (2.59 ml), TAB (0.25 g), aqueous 12.5M sodium hydroxide (9 ml), and ether (20 ml) were stirred overnight at room temperature. The mixture was diluted with water (50 ml), extracted with ether (3×50 ml), and the combined, dried extracts were evaporated. The residual oil was purified by FCC eluting with cyclohexane-diethyl ether (100:0→98:2) to give the title compound as a colourless oil (2.73 g).
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6].C(=O)([O-])[O-].[K+].[K+].[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1>CC(C)=O>[C:20]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:19]=[CH:18][C:17]([O:16][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6])=[CH:22][CH:21]=1
Reactant: C=CC(C)(C)C(=O)CCl
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CC(C)(C)C(=O)COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
196.5 g (1.34 mol) of 5-chloro-3,3-dimethylpent-1-en-4-one were added dropwise to a mixture of 184.9 g (1.34 mol) of potassium carbonate and 227.8 g (1.34 mol) of 4-hydroxybiphenyl in 1,000 ml of boiling acetone, in the course of one hour. The mixture was heated to the boil after 5 hours, allowed to cool to room temperature, and filtered off from the precipitated potassium chloride. The oil which remained after the filtrate had been concentrated was taken up in 1,000 ml of ethyl acetate. The solution was washed twice with 150 ml each of 10% strength sodium carbonate solution and water, and dried over anhydrous sodium sulphate, and the solvent was distilled off. Residual amounts of solvent were stripped off at 0.13 mbar (bath temperature: 180° C.). 357.2 (95% of theory) of 5-(biphenyl-4-yloxy)-3,3-dimethylpent-1-en-4-one of melting point 42° to 44° C. were obtained in this manner.
Reaction SMILES: C([C:3](=[C:9]([O:15][CH2:16][CH3:17])[CH:10]=[CH:11][N:12](C)[CH3:13])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#N.CC(O)=[O:20]>>[CH2:16]([O:15][C:9]1[CH:10]=[CH:11][NH:12][C:13](=[O:20])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:17]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(C#N)=C(C=CN(C)C)OCC
Product: CCOC(=O)c1c(OCC)cc[nH]c1=O
Yield: 66.6 %

Procedure:
A mixture of ethyl 2-cyano-5-(dimethylamino)-3-ethoxypenta-2,4-dienoate (150 g, 0.63 mol) and HOAc (600 mL) was refluxed overnight. The mixture was concentrated to dryness under high vacuum and the residue treated with water (300 mL). The mixture was extracted with EtOAc (2×250 mL) to remove the impurities. The pH of the aqueous was adjusted with NaHCO3 to pH ˜9-10. The mixture was extracted with CH2Cl2 (3×300 mL). The combined organics were washed with brine, dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography to afford ethyl 4-ethoxy-2-oxo-1,2-dihydropyridine-3-carboxylate (90 g, 66.6% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.C([O-])(O)=O.[Na+].[C:16]([C:18]1[CH:19]=[N:20][C:21]([NH2:25])=[CH:22][C:23]=1[NH2:24])#[N:17].O>CO>[NH2:24][C:23]1[C:18]([C:16]#[N:17])=[CH:19][N:20]2[CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:25]=[C:21]2[CH:22]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: N#Cc1cnc(N)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1cn2cc(-c3ccccc3)nc2cc1N

Procedure:
2-Bromoacetophenone (1.11 g, 5.6 mmol) and NaHCO3 (470 mg) were added to a solution of 3-cyano-4,6-diaminopyridine (500 mg, 3.7 mmol) in methanol (7.5 ml), and the mixture was heated to reflux overnight. The mixture was cooled, water (4 ml) was added, and the precipitate was filtered to give a first crop of the desired product. The filtrate was evaporated, taken up in ethyl acetate and washed (water, brine). The organic layer was dried (Na2SO4), evaporated, and the residue was purified by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40) to yield a second crop of product. The combined isolates were dried to give the title compound (350 mg, 40%). MS (m/e)=235.1 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([OH:9])=O)[CH2:4][O:3]1.[N+]([O-])(O)=O.[N+:14]([O:17][CH2:18][CH2:19][NH2:20])([O-:16])=[O:15]>>[N+:14]([O:17][CH2:18][CH2:19][NH:20][C:7]([C@H:5]1[CH2:4][O:3][C:2](=[O:1])[NH:6]1)=[O:9])([O-:16])=[O:15]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C1N[C@@H](C(=O)O)CO1
Solvent: O=[N+]([O-])O
Product: O=C1N[C@@H](C(=O)NCCO[N+](=O)[O-])CO1
Yield: 41.6 %

Procedure:
Following a procedure similar to that described in Example 1, but using 0.23 g of (4R)-2-oxooxazolidine-4-carboxylic acid and 0.36 g of N-(2-nitrooxyethyl)amine nitrate, 0.16 g of the title compound was obtained as colorless needles, melting at 110°-112° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[C:12]#[N:13])=[CH:9][C:8]([O:14][CH3:15])=[CH:7][C:6]=2[O:16][CH3:17].NC(N)=[O:20].OO>>[CH3:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([C:11]=1[C:12]([NH2:13])=[O:20])=[CH:9][C:8]([O:14][CH3:15])=[CH:7][C:6]=2[O:16][CH3:17]
Reactant: COc1cc(OC)c2cnc(C)c(C#N)c2c1
Reactant: NC(N)=O
Agent: OO
Product: COc1cc(OC)c2cnc(C)c(C(N)=O)c2c1
Reaction time: 2 h

Procedure:
3-methyl-4-cyano-6,8-dimethoxyisoquinoline (2.28 g, 20 mmol) reported in Tetrahedron Letters, 1968, 44, 1160-1163 is added to a finely powdered urea-hydrogen peroxide adduct (1.88 g, 20 mmol) in a glass tube, and the reaction mixture is placed in an oil bath at 85° C. for 2 hours. After completion of the reaction, the reaction mixture is extracted with ethyl acetate and the combined extracts are washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford the title compound.