Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.C1COCC1.[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[NH2:26]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:26][N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1ncc[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1nccn1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
Alternative procedure using 1M LiN(TMS)2 as base: A 1M THF solution of LiHMDS (19.62 ml, 19.62 mmol) was added dropwise to a solution of ethyl 1H-imidazole-2-carboxylate (2.5 g, 17.84 mmol) in DMF (119 ml) at 0° C. The reaction was stirred at 0° C. for 10 minutes. A DMF (119 ml) suspension of (aminooxy)diphenylphosphine oxide (4.99 g, 21.41 mmol) was added. After stirring for 10 minutes, the ice bath was removed, and stirring was continued at room temperature. After 3 hrs, the starting material was completely consumed. Water was added portion-wise to the reaction mixture until complete dissolution of the suspension. The clear solution was concentrated to dryness under reduced pressure. Ethyl acetate was added to the solid, forming a yellow suspension. The suspension was stirred for 15 minutes and filtered. The solid was washed with ethyl acetate and dichloromethane, successively. The collected organic wash was concentrated. The crude product was dissolved in 10% MeOH/DCM (10 ml) and was chromatographed on a prepacked silica gel column (Isco prep: 0-5% MeOH-DCM over 20 minutes. The product began eluting around 7 minutes (˜2% MeOH/DCM). The desired ethyl 1-amino-1H-imidazole-2-carboxylate (2.57 g, 16.56 mmol, 93% yield) was obtained as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[CH2:34][C:35]([OH:37])=[O:36]>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[CH2:34][C:35]([OH:37])=[O:36])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)CC1COCCN1
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOCC2CC(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 68.6 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.18 g, 0.39 mmol) was reacted with 2-(morpholin-3-yl)acetic acid hydrochloride (0.07 g, 0.39 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a light yellow solid (0.14 g, 67%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5](Cl)[C:6]([CH3:12])=[N:7]2.[F-:14].[K+]>CS(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([F:14])[C:6]([CH3:12])=[N:7]2
Reactant: [F-]
Reactant: Cc1nc2cccc(Br)c2nc1Cl
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1nc2cccc(Br)c2nc1F
Temperature: 90 °C
Yield: 105 %

Procedure:
A 1-L, three-necked round-bottomed flask equipped with a mechanical stirrer, a nitrogen gas inlet, and a temperature probe was charged 5-bromo-3-chloro-2-methylquinoxaline (21.5 g, 83 mmol), DMSO (215 mL) and KF (4.85 mL, 209 mmol), and the resulting mixture was heated at 90° C. for 2.5 h. The mixture was cooled to RT and ice/water (430 mL) was added. The precipitated solid was collected by vacuum filtration and then washed with water (100 mL) and dried in vacuo to afford 5-bromo-3-fluoro-2-methylquinoxaline (126f; 21 g) as a brown solid, which was used without further purification in the subsequent step: 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (1H, d, J=2.2 Hz), 8.01 (1H, d, J=1.2 Hz), 7.59 (1H, t, J=7.9 Hz), 2.79 (3H, d, J=1.4 Hz). 19F NMR (377 MHz, CDCl3) δ ppm −70.61 (1F, br. s.). m/z (ESI, +ve) 240.9 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O>>[CH3:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: Cc1ccc(C=O)c(C)c1
Product: Cc1ccc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c(C)c1

Procedure:
6-[4-(2,4-Dimethyl-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2,4-dimethylbenzaldehyde. Mass spectrum (ES) MH+=299.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[NH:12][N:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:16]3[CH:17]=[C:18]4[O:23][CH2:22][O:21][C:19]4=[CH:20][C:15]=3[CH2:14][CH:13]([CH3:24])[N:12]([C:25](=[O:27])[CH3:26])[N:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1)OCO3
Reactant: CC(=O)OC(C)=O
Solvent: O
Product: CC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2CC1C)OCO3
Reaction time: 1 h

Procedure:
A 2.0 g (6.15 mmol) portion of the product of Example 26 was stirred with 10 ml of acetic anhydride at 25 ° C. for 3 hours then 50 ml of distilled water were added and the stirring was continued for one hour. The yellow precipitate formed was filtered, washed with 3×10 ml of distilled water and dried at 80°-100° C. to obtain 2.6 g of raw product. After recrystallization from 10 ml of ethanol 1.94 g (85.8%) of the aimed product were obtained, m.p.: 140°-142° C.
Reaction SMILES: [OH:1][CH:2]([CH2:17][C:18]1[CH:26]=[C:25]([CH3:27])[C:24]2[C:20](=[CH:21][N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[N:23]=2)[CH:19]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].C(N(C(C)C)CC)(C)C.[NH:45]1[CH2:50][CH2:49][CH:48]([C:51]2[C:52](=[O:61])[NH:53][C:54]3[C:59]([CH:60]=2)=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH2:47][CH2:46]1.O.ClCCl.CN(C)[CH:68]=[O:69]>ClCCl>[O:61]=[C:52]1[C:51]([CH:48]2[CH2:47][CH2:46][N:45]([C:68]([O:1][CH:2]([CH2:17][C:18]3[CH:26]=[C:25]([CH3:27])[C:24]4[C:20](=[CH:21][N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:35])[CH3:34])[N:23]=4)[CH:19]=3)[C:3](=[O:4])[N:5]3[CH2:10][CH2:9][CH:8]([N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]4)[CH2:7][CH2:6]3)=[O:69])[CH2:50][CH2:49]2)=[CH:60][C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[NH:53]1
Reactant: O=c1[nH]c2ccccc2cc1C1CCNCC1
Reactant: CN(C)C=O
Reactant: Cc1cc(CC(O)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(CC(OC(=O)N2CCC(c3cc4ccccc4[nH]c3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 4 h

Procedure:
To a solution of (±)-2-hydroxy-3-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)-1-(4-(piperidin-1-yl)piperidin-1-yl)propan-1-one (130 mg, 0.26 mmol) and diisopropylethylamine (91 μL, 0.52 mmol) in dichloromethane (1 mL) at 0° C. was added 4-nitrophenyl-chloroformate (57.6 mg, 1.10 equiv). The ice bath was removed and stirring continued for 4 h. The reaction was treated with a solution of 3-(piperidin-4-yl)quinolin-2(1H)-one (88.9 mg, 1.50 equiv) and diisopropylethylamine (91 μL, 0.52 mmol) in dimethylformamide (1 mL). The reaction was stirred at room temperature overnight. The reaction was poured into water/dichloromethane. The mixture was extracted with dichloromethane (2×) which was washed with saturated sodium bicarbonate, then water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (5% to 20% methanol/dichloromethane) gave 112 mg (57%) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[C:16](O)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].CCN=C=NCCCN(C)C>C(Cl)Cl>[OH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([NH:1][CH2:2][CH2:3][S:4][S:5][CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:24]
Reactant: CC(C)(C)OC(=O)NCCSSCCN
Reactant: O=C(O)c1ccccc1O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCSSCCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.2 %

Procedure:
tert-Butyl 2-(2-(2-aminoethyl)disulfanyl)ethylcarbamate (500 mg, 1.98 mmol) was taken up in CH2Cl2 (20 mL) along with salicylic acid (273 mg, 1.98 mmol) and EDCI (693 mmol, 2.2 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with CH2Cl2, washed with saturated aqueous NaHCO3, brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by chromatography (40% EtOAc, 60% pentane) afforded tert-butyl 2-(2-(2-(2-hydroxybenzamido)ethyl)disulfanyl)ethylcarbamate (400 mg, 54%). Mass calculated for C16H24N2O4S2: 372.12. found: [M+H]+=373.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[CH:8]=[O:9]>S(=O)(=O)(O)O>[F:5][C:6]1[C:13]([N+:1]([O-:4])=[O:2])=[CH:12][CH:11]=[C:10]([F:14])[C:7]=1[CH:8]=[O:9]
Reactant: O=Cc1c(F)cccc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=Cc1c(F)ccc([N+](=O)[O-])c1F
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 70.4 %

Procedure:
To stirring 69% nitric acid (6.48 ml, 93.59 mmol) cooled to 5° C. was added concentrated sulfuric acid (4.16 ml, 78.11 mmol) dropwise, keeping the internal temperature below 8° C. After complete addition stirring was continued for 15 minutes. This mixture was added to a solution of 2,6-difluorobenzaldehyde (10 g, 70.37 mmol) in concentrated sulfuric acid (50 ml) dropwise keeping the internal temperature below 10° C. After complete addition the mixture was stirred at 5° C. for 15 minutes then allowed to warm to room temperature over 90 minutes. The reaction mixture was poured onto ice-water (400 ml) and the resulting solid stirred for 1 hour. The solid was collected by filtration, washed with water and dried under vacuum to yield the title compound (9.27 g, 70%). 1H NMR (DMSO-d6, 300 MHz): 10.21 (1 H, t, J=1.02 Hz), 8.52 (1 H, ddd, J=9.38, 8.60, 5.51 Hz), 7.51 (1 H, td, J=9.53, 1.76 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:23]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[C:30]([OH:35])[CH:29]=2)#[N:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.ClCCl>[C:23]([C:25]1[CH:26]=[N:27][C:28]2[C:33]([CH:34]=1)=[CH:32][CH:31]=[C:30]([O:35][C:2]1[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=1)[CH:29]=2)#[N:24]
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: N#Cc1cnc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4cc(C#N)cnc4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 95 °C
Yield: 86.4 %

Procedure:
4-Chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (200 mg, 0.62 mmol), (prepared as described for the starting material in Example 10), was suspended in DMF (3 ml) under argon. 3-Cyano-7-hydroxyquinoline (116 mg, 0.68 mmol) and potassium carbonate (129 mg, 0.93 mmol) were added and the reaction mixture was heated at 95° C. for 90 minutes. Upon cooling to ambient temperature the mixture was diluted with dichloromethane and poured on the top of an ISOLUTE silica column. Elution was done using successively dichloromethane, dichloromethane/methanol (95/5) and dichloromethane/methanol saturated with ammonia (95/5). Evaporation of the solvent and trituration of the solid in ether gave 4-(3-cyanoquinolin-7-yloxy)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (244 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:22](=[O:23])[C:11]3=[CH:12][NH:13][C:14]([CH3:21])=[C:15]([CH2:16][CH2:17][CH2:18][C:19]#[N:20])[C:10]3=[N:9]2)=[CH:4][CH:3]=1.CO[CH:26](OC)[CH2:27][NH2:28]>CS(C)=O.[Cu]Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:22](=[O:23])[C:11]3=[CH:12][NH:13][C:14]([CH3:21])=[C:15]([CH2:16][CH2:17][CH2:18][C:19]4[NH:28][CH:27]=[CH:26][N:20]=4)[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(CN)OC
Reactant: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1CCCC#N
Agent: Cl[Cu]
Solvent: CS(C)=O
Product: Cc1[nH]cc2c(=O)n(-c3ccc(Cl)cc3)nc-2c1CCCc1ncc[nH]1
Temperature: 100 °C
Yield: 8.2 %

Procedure:
To a solution of the product of Example 107 (0.131 g, 0.4 mmol) and aminoacetaldehyde dimethylacetal (43 μl, 0.4 mmol) in DMSO (1 ml) was added copper(I) chloride (0.04 g, 0.4 mmol) and the mixture heated at 100° C. for 120 hours. The solvent was removed in vacuo and the residue suspended in formic acid (10 ml) and heated at 70° C. for 18 hours. The reaction was filtered and the solvent evaporated from the filtrate in vacuo. The crude product was purified by flash chromatography (silica gel, 6-10% MeOH/CH2Cl2) to give the title compound as a yellow solid (0.012 g, 8.1%). 1H NMR (360 MHz, CD3OD) δ8.34 (1H, s), 8.02 (2H, d, J 8.7 Hz), 7.42 (2H, d, J8.7 Hz), 7.11 (2H, br s), 2.99 (2H, br s), 2.80 (2H, br s), 2.40 (3H, s), 2.05 (2H, br s); MS (ES+) m/z 368/370 [MH]+.
Reaction SMILES: [F:1][CH2:2][O:3][C:4]1[CH:30]=[CH:29][C:28]([N:31]2[C:35]([C:36]([F:39])([F:38])[F:37])=[N:34][N:33]=[N:32]2)=[CH:27][C:5]=1[CH2:6][NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[C@H:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.FC(F)(F)C(O)=O.CC#N.O.C(Cl)[Cl:52]>>[ClH:52].[ClH:52].[F:1][CH2:2][O:3][C:4]1[CH:30]=[CH:29][C:28]([N:31]2[C:35]([C:36]([F:39])([F:38])[F:37])=[N:34][N:33]=[N:32]2)=[CH:27][C:5]=1[CH2:6][NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][NH:10][C@H:9]1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(-n3nnnc3C(F)(F)F)ccc2OCF)[C@@H]1c1ccccc1
Solvent: CC#N
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: FCOc1ccc(-n2nnnc2C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A room temperature solution of [2-fluoromethoxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzyl]-([2S,3S]-1-t-butoxy carbonyl-2-phenyl-piperidin-3-yl)-amine (113 mg, 0.205 mmol) in methylene chloride (5 mL) was treated with trifluoroacetic acid (2.5 mL) and stirred at room temperature for 50 minutes. HPLC analysis (C18 Vydac protein and peptide column, 4.6×250 mm, 1 mL/min, linear gradient of 10% MeCN:H2O (0.1% TFA) to 95% MeCN over 15 minutes, hold at 95% MeCN for 10 minutes, 254 nm) shows the title compound at 13.5 minutes. The reaction was concentrated in vacuo to give a yellow oil and transferred to a separatory funnel using ethyl acetate/aq. satd'd NaHCO3. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo to give 136 mg of crude title compound as a yellow oil. TLC (5:93:2 methanol:ethyl acetate:triethylamine) shows the title compound at 0.35 Rf. This material was dissolved in chloroform and purified by radial chromatography (5:93:2 methanol:ethyl acetate:triethylamine) to give 41.2 mg of pure product along with 50 mg of product containing small amounts of the corresponding phenol. The pure product was dissolved in diethyl ether, cooled to 0° C. and HCl (g) was bubbled into the ether. Removal of the ether and drying gave 48 mg of the hydrochloride salt as an off white solid.
Reaction SMILES: Br[CH2:2][C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[SH:16]>>[CH3:7][C:3]1([CH3:8])[C:4](=[O:5])[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16][CH2:2]1
Reactant: CC(C)(CBr)C(=O)O
Reactant: Nc1ccccc1S
Product: CC1(C)CSc2ccccc2N(c2ccccc2)C1=O
Yield: 71 %

Procedure:
Bromopivalic acid (Example 10(a)) (59.4 g, 328 mmol) was reacted with 2-aminothiophenol (41 g, 328 mmol, freshly distilled) according to the procedure for Example 1(d). Column chromatography yielded the title compound (52.3 g, 232 mmol, 71%). 1H NMR (DMSO-d6) δ 12.44 (br s, 1H); 7.22 (d, 1H); 6.99 (t, 1H); 6.63 (d, 1H); 6.47 (t, 1H); 5.27 (br s, 2H); 2.88 (s, 2H); 1.14 (s, 6H). MS Da/e=226 (MH+), 208 (M-H2O), 180 (M-CO2). Calcd for C11H15NSO2 : C, 58.64; H, 6.71; N, 6.22; S, 14.23. Found: C, 58.41; H, 6.78; N, 6.13; S, 14.29.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[OH2:7].[F:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH2:28][C:29]([OH:31])=[O:30])=[C:14]([CH3:27])[C:15]2=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=2)=[CH:11][C:10]=1[O:32][CH3:33].CO>CC(C)=O>[F:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH2:28][C:29]([OH:31])=[O:30])=[C:14]([CH3:27])[C:15]2=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:26])=[O:7])=[CH:21][CH:20]=2)=[CH:11][C:10]=1[O:32][CH3:33]
Reactant: O
Reactant: COc1cc2c(cc1F)C(=Cc1ccc(SC)cc1)C(C)=C2CC(=O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CC(C)=O
Product: COc1cc2c(cc1F)C(=Cc1ccc(S(C)=O)cc1)C(C)=C2CC(=O)O
Temperature: 25 °C

Procedure:
A solution of sodium periodate, 4.28 g. (20 mole) in 40 ml. of water is added dropwise to 6-fluoro-5-methoxy-2-methyl-1-(ρ-methylthiobenzylidene)-3-indenyl acetic acid, 3.70 g. (10 mole) in 300 ml. methanol and enough acetone to cause solution. This solution is stirred over night at room temperature and filtered. The filtrate is evaporated at 30° to a small volume which causes the product to precipitate. The suspension is diluted with several volumes of water, cooled and collected. After rinsing with water and cold methanol-water (1:1), the product is dried in vacuo over potassium hydroxide pellets, and then in a vacuum oven at 70° C. The crude product is recrystallized from methylene chloride-petroleum ether to give 6-fluoro-5-methoxy-2-methyl-1-(ρ-methylsulfinylbenzylidene)-3-indenyl acetic acid (M.P. 190-193°).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-:12].[K+]>C(O)C>[N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:2])=[O:12])=[CH:5][CH:6]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Agent: [K+]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1
Yield: 83 %

Procedure:
3.5 mol p-nitrobenzylchloride are dissolved in the hot in 2300 ml of ethanol and a solution of 3.8 mol potassium hydroxide in 1100 ml of aqueous ethanol (70:30) is added thereto drop by drop. After completion of the addition, cooling takes place in an ice bath to 0° C., the precipitate is filtered off and washed in hot water and warm aqueous alcohol (50:50). Drying is then carried out in a vacuum at 75° C. (yield: 83%).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:20])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[CH3:30][O:31][CH2:32]Cl>CN(C)C=O.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20][CH2:30][O:31][CH3:32])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(C)=C1c1ccc(O)cc1C2
Reactant: COCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCC12CCC(=O)C(C)=C1c1ccc(OCOC)cc1C2
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 75.4 %

Procedure:
A solution of 9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (5.30 g, 21 mmol) in anhydrous dimethylformamide (50 mL) was cooled in an ice bath, stirred under a nitrogen atmosphere, and treated successively with N,N-diisopropyl-ethylamine (10.5 mL, 60 mmol) and chloromethyl methyl ether (3.45 mL, 41 mmol). The resulting mixture was stirred while gradually warming to room temperature over 5 hours. After 5.5 hours, additional N,N-diisopropyl-ethylamine (3 mL) and chloromethyl methyl ether (1 mL) were added. After stirring an additional 25 minutes at room temperature, the reaction mixture was diluted with EtOAc (1 L) and washed with 1.3N HCl (1 L). The aqueous phase was separated and extracted with EtOAc (200 mL). The combined organics were washed with 5% NaHCO3 (500 ml) and brine, dried over MgSO4, filtered, and concentrated under vacuum to an orange oil (6.5 g). This material was divided into three portions and each purified by flash chromatography on silica gel using Biotage FLASH 40M columns and 10:1 hexanes-EtOAc as eluting solvent. The product containing fractions were combined and evaporated under vacuum to afford 9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (4.98 g) as an oil.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)([Cl:8])=O.O=[C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1.C([O-])(=O)C.[Na+]>ClCCl>[Cl:8][C:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C:13]=1[CH:3]=[O:4]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Cl)=C(C=O)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To N,N-dimethylformamide (3.87 mL) at 0° C., phosphorus oxychloride (3.73 mL) was added dropwise, maintaining the temperature below 5° C. The resulting mixture was diluted with dichloromethane (15 mL) and stirred at room temperature for 1.5 hours. The reaction was then cooled in an ice bath. tert-Butyl 4-oxopiperidine-1-carboxylate (4.98 g) was added as a solution in dichloromethane (20 mL) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was poured over ice and solid sodium acetate, stirred for 15 minutes, and extracted with dichloromethane. The extracts were washed thoroughly with water and with brine, dried over MgSO4, filtered, and concentrated to obtain the title compound.
Reaction SMILES: I(O)(=O)(=O)=O.[F:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([NH:13][CH:14]([CH2:17][OH:18])[CH:15]=[CH2:16])=[O:12])=[C:9]([C:21]([F:24])([F:23])[F:22])[CH:8]=1.C1(C)C=CC=CC=1.C(OCC)(=[O:34])C>C(#N)C.O>[F:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([NH:13][CH:14]([CH:15]=[CH2:16])[C:17]([OH:34])=[O:18])=[O:12])=[C:9]([C:21]([F:22])([F:23])[F:24])[CH:8]=1
Reactant: C=CC(CO)NC(=O)c1ccc(F)cc1C(F)(F)F
Reactant: CCOC(C)=O
Agent: [O-][I+3]([O-])([O-])O
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: O
Product: C=CC(NC(=O)c1ccc(F)cc1C(F)(F)F)C(=O)O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
At RT, 51.5 g (226 mmol) of periodic acid and 9.9 g (99 mmol) of CrO3 were dissolved in acetonitrile/water. Furthermore, 25 g (90.3 mmol) of 4-fluoro-N-(1-hydroxymethylallyl)-2-trifluoromethylbenzamide were dissolved in acetonitrile/water and the NalO4/CrO3 solution which had been prepared earlier was added dropwise at 0-5° C. over a period of 3 h. The mixture was then stirred at RT for 15 h. 400 ml of 6% strength Na2HPO4 solution were then added dropwise, toluene and ethyl acetate were added and the phases were separated. The aqueous phase was re-extracted with ethyl acetate. The combined organic phases were washed, dried and concentrated. This gave 24.1 g (92% of theory) of the title compound.