Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][CH:38]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]2[CH2:22][C@@H:21]([C:23]3[CH:34]=[CH:33][C:26]4[O:27][C:28]([CH3:32])([CH3:31])[O:29][CH2:30][C:25]=4[CH:24]=3)[O:20][C:19]2=[O:35])=[CH:12][CH:11]=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>N1C=CC=CC=1>[CH3:31][C:28]1([CH3:32])[O:27][C:26]2[CH:33]=[CH:34][C:23]([C@H:21]3[O:20][C:19](=[O:35])[N:18]([CH2:17][CH2:16][C:13]4[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][O:6][CH2:5][C:4]5[CH:3]=[C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])[CH:38]=[CH:37][CH:36]=5)=[CH:15][CH:14]=4)[CH2:22]3)=[CH:24][C:25]=2[CH2:30][O:29]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(N)c5)cc4)C(=O)O3)ccc2O1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(NS(C)(=O)=O)c5)cc4)C(=O)O3)ccc2O1

Procedure:
A solution of (5R)-3-[2-(4-[2-[(3-aminobenzyl)oxy]ethoxy}phenyl)ethyl]-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (Example 1 xii)) (117 mg) in pyridine (10 mL) was stirred with methanesulfonyl chloride (39 mg) at 20° C. for 90 min. The reaction mixture was partitioned between aqueous NaHCO3 and DCM. The organic solution was dried (Na2SO4), and the solvent was removed in vacuo to yield the title compound (138 mg). LCMS RT=3.30 min
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])[C@@H:7]([CH3:17])[CH2:6][NH:5]2.ClC(Cl)C.N1C=CC=CC=1.Cl[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([N:8]([C:12]([CH:14]3[CH2:15][CH2:16]3)=[O:13])[C@@H:7]([CH3:17])[CH2:6][N:5]2[C:29]([O:31][CH:32]([CH3:34])[CH3:33])=[O:30])=[CH:10][CH:11]=1
Reactant: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C1CC1
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CC(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)OC(=O)N1C[C@H](C)N(C(=O)C2CC2)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 100-mL round bottomed flask fitted with a nitrogen inlet and magnetic stir bar was charged with (S)-(6-bromo-2-methyl-3,4-dihydroquinoxalin-1 (2H)-yl)(cyclopropyl)methanone (0.62 g, 2.1 mmol), dichloroethane (25 mL), and pyridine (0.254 mL, 3.15 mmol). The mixture was cooled to 0° C. in an ice bath. A solution of isopropyl chloroformate (1 M in toluene, 2.52 mL, 2.52 mmol) was then added dropwise over several minutes. The reaction mixture was stirred for 30 min in an ice bath before warming to ambient temperature for 1 h. The reaction mixture was diluted with dichloromethane (20 mL) and washed with 1 M aqueous HCl solution (25 mL). The organic layer was separated and concentrated under reduced pressure. The oil was put through a silica pad using 1:1 hexane/ethyl acetate and the eluent was concentrated in vacuo. This afforded (S)-isopropyl 7-bromo-4-(cyclopropanecarbonyl)-3-methyl-3,4-dihydroquinoxalin-1(2H)carboxylate (0.83 g, 100%) as a solid, which was used directly in next step. MS (ESI, pos. ion) m/z 381, 383 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5](Cl)=[N:6][CH:7]=1.[OH-].[K+].[C:12]([CH2:14]C(OCC)=O)#[N:13].Cl.[OH-].[Na+]>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]([Cl:9])[C:5]([CH2:14][C:12]#[N:13])=[N:6][CH:7]=1
Reactant: Clc1cc(Br)cnc1Cl
Reactant: CCOC(=O)CC#N
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#CCc1ncc(Br)cc1Cl
Temperature: 70 °C
Reaction time: 3 h
Yield: 58.9 %

Procedure:
To a solution of 5-bromo-2,3-dichloropyridine (10.0 g, 0.044 mol) in N-methyl-2-pyrrolidone (70 mL) at 0° C. was added potassium hydroxide (5.4 g, 0.097 mol), and the resulting mixture was heated to 70° C. Ethyl cyanoacetate (5.65 mL, 0.53 mol) was added via syringe over 15 min, and then heating at 70° C. was continued for 3 h more. The pH of the reaction mixture was adjusted to 2 by careful addition of concentrated aqueous hydrochloric acid, and the resulting mixture was heated at 130° C. for 2 h. The reaction mixture was cooled to 20° C., treated with 1 N aqueous sodium hydroxide (15-16 mL) and extracted with three portions of methyl tert-butyl ether (3×100 mL). The combined organic extracts were washed with water, dried (Na2SO4) and concentrated under reduced pressure to afford the title compound (6.0 g) as a brown colored solid, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH2:13][CH2:14][CH2:15][OH:16].Cl.[O-:18][C:19]#N.[K+]>O>[OH:16][CH2:15][CH2:14][CH2:13][N:12]1[C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:10])([F:11])[F:9])=[CH:7][C:2]=2[NH:1][C:19]1=[O:18]
Reactant: Nc1cc(C(F)(F)F)ccc1NCCCO
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n1CCCO
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a stirred mixture of 21 parts of 3-{[2-amino-4-(trifluoromethyl)phenyl]amino}-1-propanol and 100 parts of water are added 14.4 parts of hydrochloric acid solution. The whole is stirred for 10 minutes at room temperature. After cooling to 0°-10° C., there is added dropwise a solution of 18 parts of potassium cyanate in 50 parts of water. Upon completion, stirring is continued for 2 hours. The precipitated product is filtered off and dried. Then it is melted and the melt is stirred for 10 minutes. After cooling, it is dissolved in trichloromethane while heating. The solution is filtered and the product is allowed to crystallize from the filtrate. It is filtered off and dried, yielding 8 parts (34%) of 1,3-dihydro-1-(3-hydroxypropyl)-5-(trifluoromethyl)-2H-benzimidazol-2-one.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:10](P(=O)(OCC)OCC)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-].[K+]>O1CCCC1>[C:11]1(/[CH:10]=[CH:4]/[C:3]2[C:2]([NH2:1])=[N:9][CH:8]=[CH:7][CH:6]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Reactant: Nc1ncccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ncccc1/C=C/c1ccccc1
Temperature: 80 °C
Yield: 40.4 %

Procedure:
In 35 ml of tetrahydrofuran (THF) was dissolved 1.28 g of 2-aminonicotinaldehyde, followed by addition of 2.50 g of diethyl benzylphosphonate and 2.08 g of potassium hydroxide, and the mixture was refluxed at 80° C. for 4.5 hours. This reaction mixture was filtered to remove insoluble matter and the filtrate was evaporated under reduced pressure. The residue was dissolved in 2N-hydrochloric acid and the solution was washed with ether, made basic bv adding 15% aqueous sodium hydroxide solution, and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated off. The residue was recrystallized from acetonitrile to provide 0.83 g of the title compound as yellow prisms. This product was used as a starting material without further purification.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]([O:19]CC)=[O:18])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C(O)C>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]([OH:19])=[O:18])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnn(C(C)(C)C)c1-c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)n1ncc(C(=O)O)c1-c1ccc(F)cc1
Yield: 100 %

Procedure:
A solution of the compound (18.67 g, 64.31 mmol) obtained in step 1 and 1N aqueous sodium hydroxide solution (70.0 mL, 70 mmol) in ethanol (180 mL) was stirred at 70° C. for 14 hr, and concentrated under reduced pressure. To the residue were added water and 1N hydrochloric acid, and the precipitate was collected by filtration to give 1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazole-4-carboxylic acid (16.87 g, 64.3 mmol, 100%) as a white powder.
Reaction SMILES: C([O:8][C:9](=[O:23])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:14][CH:13]=1)C1C=CC=CC=1>[Pd].C(O)C>[CH3:22][S:19]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C:9]([OH:23])=[O:8])=[CH:17][CH:16]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Nc1ccc(CCC(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(CCC(=O)O)cc1
Reaction time: 0.33 h

Procedure:
3-[4-[(Methanesulfonyl)amino]phenyl]propionic acid benzyl ester from Preparation 26 (5.0 g (0.015 mol) and 0.75 g of 5% Pd/C catalyst in 150 ml of ethanol is hydrogenated on the Parr hydrogenator for 20 min. The mixture is filtered through a pad of Celite. The filtrate is concentrated to give a solid. It is recrystallized from ethanol to give 3-[4-[(methanesulfonyl)amino]phenyl]propionic acid; m.p. 152.5°-154° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.C[N:18](C=O)C>COCCOC.[Cu]Cl>[Br:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[C:10]([NH2:18])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: Cl[Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Product: Nc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To a solution of potassium tert-butoxide (21.92 g, 195 mmol) and copper (I) chloride (2.36 g, 23.8 mmol) in ethyleneglycol dimethylether (170 mL), stirred at 0° C. under nitrogen, a solution of 1-bromo-4-nitrobenzene (141, 8.69 g, 43.0 mmol) in DMF (45 mL) was added drop wise over 50 min. After complete addition the cooling bath was removed and the mixture was allowed to stir at room temperature for 4 h, diluted with DCM, washed with aqueous NH4Cl, dried over MgSO4, filtered and concentrated to give compound 142 (7.85 g, 84% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:21]2[N:20]=[CH:19][N:18]([C:10]3[N:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:22]=2)=[CH:34][CH:33]=1)(=[O:31])=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)cn2)cc1

Procedure:
N-tert-Butyl-4-{1-[6-(4-chloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide was prepared from 4-(4-chloro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (example E.70) (0.68 g, 1.5 mmol) and commercially available 4-(tert.-butylsulfamoyl)-phenylboronic acid (0.46 g, 1.8 mmol) according to the general procedure VI. Obtained as a light yellow solid (0.26 g) which was subsequently deprotected.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]2[C:9]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[N:10][N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:4]=2[CH:3]=1.FC1C=CC([C@H]([NH:48][C:49]([NH2:51])=[O:50])[C@H](O)C)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([SiH](CC)CC)C>O1CCOCC1.C(Cl)Cl.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+]>[CH3:8][C:6]1[C:5]2[C:9]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[N:10][NH:11][C:4]=2[CH:3]=[C:2]([NH:48][C:49](=[O:50])[NH2:51])[N:7]=1
Reactant: Cc1nc(Cl)cc2c1c(N1CCOCC1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C[C@@H](O)[C@@H](NC(N)=O)c1ccc(F)cc1
Agent: Cl[Pd+]
Agent: CC[SiH](CC)CC
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1nc(NC(N)=O)cc2[nH]nc(N3CCOCC3)c12
Temperature: 90 °C
Reaction time: 6 h

Procedure:
4-(6-Chloro-4-methyl-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)morpholine (75 mg, 0.152 mmol), 1-((1S,2R)-1-(4-fluorophenyl)-2-hydroxypropyl)urea, (48.2 mg, 0.227 mmol), BrettPhos palladacycle (12.10 mg, 0.015 mmol), cesium carbonate (128 mg, 0.394 mmol) 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl (8.13 mg, 0.015 mmol) were dissolved in dioxane (1 mL) and purged under agron for five minutes. The reaction mixture was heated to 90° C. and stirred for six hrs. The reaction mixture was filtered through celite, rinsed with methanol, and concentrated in vacuo. The crude residue was dissolved in TFA (1 mL) and triethylsilane (0.036 mL, 0.227 mmol) was added. The reaction mixture was stirred at rt for 30 min then diluted with DCM and concentrated in vacuo. The reaction mixture was diluted with DMF (1 mL), filtered, and purified by mass-triggered reverse-phase HPLC. Fractions containing pure compound were filtered through a PS-HCO3 cartridge and the filtrate was concentrated in vacuo to give 1-(1S,2R)-1-(4-fluorophenyl)-2-hydroxypropyl)-3-(4-methyl-3-morpholino-1H-pyrazolo[4,3-c]pyridin-6-yl)urea. MS ESI calc'd. For C21H26FN6O3 [M+H]+ 429. found 429. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 12.17 (s, 1H), 9.11 (s, 1H), 7.31 (dd, J=5.6 Hz, 8.7 Hz, 2H), 7.12 (t, J=8.9 Hz, 2H), 7.06 (s, 1H), 4.91 (s, 1H), 4.69 (dd, J=4.2 Hz, 8.5 Hz, 1H), 3.90 (s, 1H), 3.77-3.73 (m, 5H), 3.08 (d, J=4.2 Hz, 4H), 2.68 (s, 3H), 0.93 (d, J=6.4 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.[Si](N=C=S)(N=C=S)(N=C=S)[N:18]=[C:19]=[S:20].Cl>C1C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:19](=[S:20])[NH2:18])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: S=C=N[Si](N=C=S)(N=C=S)N=C=S
Agent: Cl
Agent: [Li]CCCC
Solvent: c1ccccc1
Solvent: O
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.4 %

Procedure:
A solution of 3-methyl-5,6,7,8-tetrahydroquinoline (1.43 g, 0.01 mole) in benzene (20 ml) was treated with n-butyl-lithium (15% w/w, 4.5 ml, 0.01 mole) and the solution was allowed to stand at room temperature for 0.5 h. The solution was then treated with a suspension of silicon tetraisothiocyanate (1.3 g, 0.005 mole) in benzene (5 ml) at 0° C. After 10 min., water (50 ml) was added and the mixture was stirred for 0.5 h at room temperature and then acidified with conc. HCl. The aqueous layer was separated, washed with ethyl acetate and the pH was adjusted to 10 with solid Na2CO3. The basic mixture was extracted with ethyl acetate (3 × 50 ml) and the combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was triturated with n-hexane to give 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide (0.2 g, 10%).
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].Cl[CH2:12][C@H:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1>CN(C)C=O>[C:1]([O:9][CH2:12][C@H:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OC[C@H](CCl)O1
Reactant: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@H](COC(=O)c2ccccc2)O1
Temperature: 150 °C
Reaction time: 72 h
Yield: 88 %

Procedure:
Sodium benzoate (40.64 g, 0.282 mol) was added to a mixture of (R)-4-chloromethyl-2,2-dimethyl-1,3-dioxolane (42.38 g, 0.282 mol) prepared by the same manner as example 3 and N,N-dimethylformamide (400 ml) and the resulting mixture was stirred for 3 days at 150° C. After cooling the salt was filtered off and N,N-dimethylformamide was removed in vacuo and water was added to the residue and extracted with toluene. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and condensed in vacuo to give 58.63 g of crude (R)-4-benzoyloxymethyl-2,2-dimethyl-1,3-dioxolane (yield 88%).
Reaction SMILES: [CH3:1]C(=C)C[Mg]Cl.[Cl:7][C:8]1[CH:31]=[CH:30][C:11]([CH2:12][N:13]2[C:17]3([CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C:18]3=[O:28])[CH2:16][C:15](=[O:29])[CH2:14]2)=[CH:10][CH:9]=1>C1COCC1>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:12][N:13]2[C:17]3([CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C:18]3=[O:28])[CH2:16][C:15]([OH:29])([CH3:1])[CH2:14]2)=[CH:30][CH:31]=1
Reactant: C=C(C)C[Mg]Cl
Reactant: O=C1CN(Cc2ccc(Cl)cc2)C2(CCN(C3CCCCC3)C2=O)C1
Solvent: C1CCOC1
Product: CC1(O)CN(Cc2ccc(Cl)cc2)C2(CCN(C3CCCCC3)C2=O)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
2-Methylallylmagnesium chloride in THF (3.0 M, 0.074 mL) was added to a solution of 1-(4-chlorobenzyl)-7-cyclohexyl-1,7-diazaspiro[4.4]nonane-3,6-dione (0.040 g, 0.00011 mol) in THF (1.0 mL, 0.012 mol) and the resulting mixture was stirred at 50° C. for 1 h. The reaction mixture was then allowed to cool to RT and was then quenched by the addition of saturated NH4Cl. The crude reaction mixture was purified by prep. HPLC to afford the desired product. LC/MS: 377.2 (M+1H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-:10].[Cs+]>ClCCl.CCCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(I)c1
Reactant: [OH-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cc1cc(C)cc(O)c1
Yield: 96 %

Procedure:
Following general operating mode A, 3,5-dimethyliodobenzene (145 μL, 1.0 mmol) was reacted with cesium hydroxide to give the expected product in the form of a white solid with a yield of 96% (eluent: dichloromethane/heptane 20:80).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:18][C@@H:19]([OH:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:24]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])([CH3:26])[CH3:25].[Na+].[I-]>C1COCC1.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[N:14][N:15]2[CH2:18][C@@H:19]([O:21][Si:28]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:30])[CH3:29])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](O)Cn1ncc2ccc(OCc3ccccc3)cc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc(OCc3ccccc3)cc21)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
To a mixture of (S)-1-(6-benzyloxyindazol-1-yl)-propan-2-ol (2.03 g, 7.20 mmol) in anhydrous THF/DMF (100 mL/35 mL) under nitrogen was added sodium hydride (60% in mineral oil, 0.40 g, 10.0 mmol). After 30 min tert-butyl-chloro-dimethyl-silane (1.52 g, 10 mmol) and a catalytic amount of NaI were added and the mixture was stirred overnight at ambient temperature. Additional NaH (5 mmol) and tert-butyl-chloro-dimethyl-silane (5 mmol) were added to the reaction mixture, which was stirred for 6 h. The reaction mixture was evaporated to a residue that was mixed with a saturated aqueous solution of sodium bicarbonate and extracted with ethyl acetate (2×200 mL). Purification by chromatography (silica, EtOAc/hexane) gave an oil (2.81 g, 99%).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[C:5]([CH3:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.[C:36]([O:41][CH3:42])(=[O:40])[C:37]([CH3:39])=O>CCCCCC.CCOCC.C1C=CC=CC=1>[CH3:39][C:37](=[CH:2][CH2:3][CH:4]=[C:5]([CH3:11])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:36]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)C(C)=O
Reactant: CCCCCC(C)=CCCBr
Agent: [Li]CCCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: CCCCCC
Product: CCCCCC(C)=CCC=C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 5.0 g. of 1-bromo-4-metyl-3-nonene and 6.35 g. of triphenylphosphine in 25 ml. of dry benzene is heated under reflux for 12 hrs., then the mixture is allowed to cool to 25°C. and 50 ml. of dry ether and 11 ml. of 15% n-butyl lithium in hexane are added. The resulting mixture is stirred for 2 hrs. at 25°C., giving a red solution, then 2.5 g. (2.15 ml.) of methyl pyruvate in 10 ml. of ether is added and the mixture is stirred at room temperature (about 25°C.) for 18 hrs. The solvents are then removed by evaporation under reduced pressure and the resulting residue is dissolved in methylene chloride and chromatographed over silica gel. Elution with 5,10 and 20% ethyl acetate in cyclohexane and evaporation of the eluate fractions gives a residue comprising methyl 2,6-dimethyl-2,5-undecadienoate.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH2:15][CH3:16])([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:19]([N:23]=[C:24]=[O:25])[CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:15][CH3:16])([OH:14])[C:7]2[CH:12]=[CH:11][C:10]([O:13][C:24](=[O:25])[NH:23][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=2)=[CH:17][CH:18]=1
Reactant: CCC(O)(c1ccc(O)cc1)c1ccc(Cl)cc1
Reactant: CCCCN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCNC(=O)Oc1ccc(C(O)(CC)c2ccc(Cl)cc2)cc1
Reaction time: 20 h

Procedure:
7.9 g. of 4-chloro-4'-hydroxy-α-ethyl-benzhydrol, 3.3 g. of n-butyl-isocyanate and 0.3 ml. of triethyl amine are dissolved in 40 ml. of dry tetrahydrofurane under stirring at 25° C., and the solution is allowed to stand at this temperature for 20 hours. When the reaction is complete, tetrahydrofurane is distilled off under reduced pressure, the residue is taken up in ether, the ethereal solution is shaken with a 5% aqueous sodium hydroxide solution and washed to neutral with water. The organic phase is dried over anhydrous magnesium sulfate, filtered and ether is distilled off in vacuo. Crystallization of the residue from a mixture of n-hexane and ethyl acetate yields 9.3 g. of the named compound, which melts at 78° to 79° C.
Reaction SMILES: [CH:1]([S:4][C:5]1[N:10]=[C:9]([C:11]2[S:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=[O:17])[N:16]=2)[CH:8]=[CH:7][CH:6]=1)([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)(Cl)Cl>[CH:1]([S:4]([C:5]1[N:10]=[C:9]([C:11]2[S:12][C:13]3[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](=[O:17])[N:16]=2)[CH:8]=[CH:7][CH:6]=1)=[O:30])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)Sc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: ClC(Cl)Cl
Product: CC(C)S(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.4 %

Procedure:
2-[6-(Isopropylthio)-2-pyridyl]-4H-1,3-benzothiazine-4-one (0.09 g, 0.29 mmol) was dissolved in chloroform (50 ml). A solution of 3-chloroperbenzoic acid (ca. 77%, 0.064 g, 0.29 mmol) in chloroform (10 ml) was added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated and the residue was recrystallized from ethanol to give the titled compound (0.056 g, 59%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]2[CH2:18][CH:19]([F:22])[CH:20]([F:21])[C:15]2=[N:14]1.C(O)(=[O:25])C>[O-2].[Cr+6].[O-2].[O-2]>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[CH:17]=[C:16]2[C:18](=[O:25])[CH:19]([F:22])[CH:20]([F:21])[C:15]2=[N:14]1
Reactant: CC(=O)O
Reactant: FC1Cc2cn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)nc2C1F
Agent: [Cr+6]
Agent: [O-2]
Product: O=C1c2cn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)nc2C(F)C1F
Temperature: 50 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
To a solution of (86) (20.2 mg, 56.6 mmol) in 500 mL acetic acid was added chromium(VI) oxide (30 mg, 283 mmol). The mixture was stirred at 50° C. for 12 h. The solvent was removed under reduced pressure. The mixture was then chromatographed on a silica gel TLC plate using hexane/ethyl acetate (9:1) to give (87): Yield 76%): 1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.81 (s, 2H), 6.23 (dd, 1H, J=4.97, 55.81 Hz), 5.37 (ddd, 1H, J=4.97, 12.36, 47.15 Hz).