Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([Cl:18])=[N:10][CH:9]=1.C([Sn](CCCC)(CCCC)[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)CCC>CCOC(C)=O>[Cl:18][C:11]1[CH:12]=[C:13]([C:8]([C:24]2[S:25][CH:26]=[CH:27][N:28]=2)=[CH:9][N:10]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: COC(=O)c1cc(Cl)ncc1Br
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)c1cc(Cl)ncc1-c1nccs1
Temperature: 65 °C

Procedure:
To a 100 mL round bottom flask was added bis(tri-tertbutylphosphine)palladium(0) (204 mg, 0.40 mmol, 0.1 equiv). The flask was then flushed with nitrogen and charged with 1,4-dioxane (20 mL), methyl 5-bromo-2-chloroisonicotinate (7-1, 1000 mg, 4.0 mmol, 1 equiv) and 2-(tributylstannyl)-1,3-thiazole (1.5 mL, 4.8 mmol, 1.2 equiv). The reaction mixture was heated for 3 hours at 65° C., diluted with EtOAc (20 mL) and filtered through celite. The filtrate was concentrated and the residue purified by normal phase column chromatography (0-40% EtOAc in hexanes) to afford the title compound (7-2) as a yellow solid. ESI+MS[M+H]+C10H8ClN2O2S=255.0
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[N:2]1.[N:13]1([CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([NH2:32])=[CH:24][CH:23]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[N:13]1([CH2:19][CH2:20][O:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]([NH:32][C:10]([C:8]3[CH:7]=[CH:6][C:5]4[S:1][N:2]=[N:3][C:4]=4[CH:9]=3)=[O:12])=[CH:24][CH:23]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: O=C(O)c1ccc2snnc2c1
Product: O=C(Nc1ccc(OCCN2CCOCC2)c2ccccc12)c1ccc2snnc2c1

Procedure:
Compound is prepared from benzo[1,2,3]thiadiazole-5-carboxylic acid and 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine according to conditions described in general procedure G. Mp: 188-190° C.; 1H NMR (300 MHz, CDCl3) δ 2.70 (t, 4H), 3.00 (t, 2H), 3.78 (t, 4H), 4.30 (t, 2H), 6.82 (d, 1H), 7.58 (m, 2H), 7.65 (d, 1H), 7.88 (d, 1H), 8.15 (d, 1H), 8.25 (d, 2H), 8.40 (s, 1H), 9.18 (s, 1H); MS 435 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[NH2:15])[N:11]=[C:10]([CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[CH:9]=2)=[CH:4][CH:3]=1.C=O.[C:32]([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[NH:15][CH3:32])[N:11]=[C:10]([CH:20]3[CH2:25][C:24]([CH3:27])([CH3:26])[O:23][C:22]([CH3:29])([CH3:28])[CH2:21]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(c2cc(-c3ccc(Cl)cc3)n(-c3ccccc3N)n2)CC(C)(C)O1
Reactant: [BH3-]C#N
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1ccccc1-n1nc(C2CC(C)(C)OC(C)(C)C2)cc1-c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
To a solution of 2-(5-(4-chlorophenyl)-3-(2,2,6,6-tetramethyltetrahydro-2H-pyran-4-yl)-1H-pyrazol-1-yl)aniline (Example 62) (25 mg, 0.06 mmol, 1 eq) in THF (2 mL) was added formaldehyde (13.64 of a 37% aqueous solution, 0.18 mmol, 3 eq). After 15 min, acetic acid (0.1 mL) and sodium cyanoborohydride (12 mg, 0.18 mmol, 3 eq) were added and the solution stirred 5 hrs. Aqueous saturated NaHCO3 was added, the solution extracted with DCM, the organics combined, dried over MgSO4 and concentrated. Purification by RP-HPLC, eluting with a linear gradient of 20%-100% CH3CN in 0.1% TFA/H2O followed by freebasing with aqueous MP-carbonate resin in DCM and concentration gave 8.6 mg (32%) the title compound.
Reaction SMILES: O[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:15])=O>>[Cl:15][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cnc2cc(Cl)ccc2n1
Product: Clc1ccc2nc(Cl)cnc2c1

Procedure:
45 g of 2-hydroxy-6-chloroquinoxaline are treated in a sulphonation flask with 100 ml of phosphorus oxychloride. The mixture is stirred at reflux temperature for 20 minutes. The excess phosphorus oxychloride is thereupon distilled off and the residue is treated with 500 ml of ice-water. The product obtained is filtered off and washed with water until it is neutral. By crystallization from ethanol/water there is obtained 2,6-dichloroquinoxaline of melting point 152° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:29])([F:28])[F:27])=[N:4][N:5]([C:8]2[CH:13]=[C:12]([S:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[C:6]=1[Cl:7].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:22][C:23]([F:32])([F:31])[CH:24]([F:30])[O:25][C:26]([F:27])([F:28])[F:29])=[N:4][N:5]([C:8]2[CH:13]=[C:12]([S:14]([CH2:15][C:16]([F:19])([F:18])[F:17])=[O:41])[C:11]([CH3:20])=[CH:10][C:9]=2[F:21])[C:6]=1[Cl:7]
Reactant: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)c(Cl)c2Cl)cc1SCC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc(F)c(-n2nc(OC(F)(F)C(F)OC(F)(F)F)c(Cl)c2Cl)cc1S(=O)CC(F)(F)F
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
0.35 g of 4,5-dichloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole was dissolved in 10 mL of chloroform, and 0.15 g of m-chloroperbenzoic acid (purity: 75%) was added under cooling with ice. After stirring for 30 minutes under cooling with ice, the solution was washed with an aqueous sodium thiosulfate solution and then washed with an aqueous sodium hydrogen carbonate solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:2) to obtain 0.35 g of 4,5-dichloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylsulfinyl)phenyl}-3-{1,1,2-trifluoro-2-(trifluoromethoxy)ethoxy}pyrazole.
Reaction SMILES: [CH2:1]([N:4]([CH2:29][CH2:30][CH3:31])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]2[CH2:19][CH2:18][CH:17]([CH2:20][NH:21][CH2:22][C:23]3[NH:24][CH:25]=[CH:26][N:27]=3)[CH2:16][N:15]2[CH:28]=1)=[O:11])[CH2:2][CH3:3].[CH3:32][N:33]1[CH:37]=[CH:36][N:35]=[C:34]1[CH:38]=O.C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.C(O)(=O)C>[CH2:29]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]2[CH2:19][CH2:18][CH:17]([CH2:20][N:21]([CH2:22][C:23]3[NH:24][CH:25]=[CH:26][N:27]=3)[CH2:38][C:34]3[N:33]([CH3:32])[CH:37]=[CH:36][N:35]=3)[CH2:16][N:15]2[CH:28]=1)=[O:11])[CH2:30][CH3:31]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCNC(=O)c1cn2c(n1)CCC(CNCc1ncc[nH]1)C2
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCNC(=O)c1cn2c(n1)CCC(CN(Cc1ncc[nH]1)Cc1nccn1C)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
The compound (19.6 mg) obtained in Example 19-4 was dissolved in methanol (2.0 ml) and added with 1-methyl-2-imidazole carboxaldehyde (6.2 mg) and sodium cyanoborohydride (5.9 mg). The solution was adjusted to pH 4 with acetic acid and stirred at room temperature for 3 hours. The resultant was added with a saturated sodium hydrogen carbonate aqueous solution to stop the reaction and subjected to extraction with chloroform. The organic layer was washed with water and a saturated saline solution and dried with anhydrous sodium sulfate. The solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (22.0 mg) of the subject compound as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([C@@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][OH:13])[CH2:8][CH2:7]1)([CH3:5])=[CH2:4].[CH2:14](Br)[CH3:15]>CS(C)=O>[CH2:14]([O:13][CH2:12][C@H:9]1[CH2:10][CH2:11][C@@H:6]([C:3]([CH3:5])=[CH2:4])[CH2:7][CH2:8]1)[CH3:15]
Reactant: CCBr
Reactant: C=C(C)[C@H]1CC[C@@H](CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=C(C)[C@H]1CC[C@@H](COCC)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6 g of sodium hydride -- 50% in mineral oil -- were allowed to react with 100 ml of dimethyl-sulfoxide, at 55° - 60° for 90 min. 7.5 g of cis-4-isopropenyl-cyclohexylmethanol were then added to the resulting solution, followed by a dropwise addition of 20 g of ethyl bromide. The reaction mixture was stirred overnight at room temperature, then poured onto crushed ice and finally extracted with hexane. After the usual treatments of washing, drying and evaporation, the fractional distillation of the obtained residue yielded cis-4-isopropenyl-cyclohexylmethyl ethyl ether, bp 96° - 97°/10 Torr.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[Br:12]Br.Br>C(O)(=O)C.O>[Br:12][CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[C:7]1=[O:11]
Reactant: BrBr
Reactant: O=C1CCc2cc(Cl)ccc21
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2ccc(Cl)cc2CC1Br

Procedure:
5-Chloroindan-1-one is reacted with bromine in glacial acetic acid using a catalytic amount of 48% strength HBr solution in water at room temperature. 2-Bromo-5-chloroindan-1-one is obtained with a melting point of 94-96° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1[OH:10])[CH:5]=O.[N+:12]([CH3:15])([O-:14])=[O:13].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:15][N+:12]([O-:14])=[O:13])[CH:7]=[C:8]([F:11])[C:9]=1[OH:10]
Reactant: O=Cc1cc(F)c(O)c(F)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1cc(F)c(O)c(F)c1
Temperature: 110 °C
Yield: 70.8 %

Procedure:
3,5-Difluoro-4-hydroxybenzaldehyde (2.27 g, 14.4 mmol), nitromethane (4.7 mL, 86.4 mmol) and ammonium acetate (4.4 g, 57.6 mmol) were dissolved in acetic acid (22 mL) and the reaction mixture was heated at 110° C. for 1 hour 30 min. The reaction was concentrated under reduced pressure and the residue partitioned between ether and water. The layers were separated and the organic layer was dried with Na2SO4. The organic mixture was filtered and the filtrate concentrated under reduced pressure to afford a crude product. The crude product was purified by flash column chromatography (eluent: EtOAc/hexane 22/78) to afford the title compound (2.05 g, yield: 71%). Electrospray MS M−1 ion=200. 1H-NMR (CDCl3, 200 MHz): 7.84 (d, 1H, J=13.7 Hz), 7.45 (d, 1H, J=13.7 Hz), 7.19-6.99 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]#[N:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]21[CH2:20][CH2:19][CH2:18][CH2:17]2.[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+]>CN(C)C=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]3[NH:23][N:22]=[N:21][N:16]=3)=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]21[CH2:20][CH2:19][CH2:18][CH2:17]2
Reactant: N#CCOc1cc2c(c(Cl)c1Cl)C(=O)C1(CCCC1)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2c(cc(OCc3nnn[nH]3)c(Cl)c2Cl)CC12CCCC2

Procedure:
The title compound is prepared following substantially the same procedure described in Example 38, Step B, using the following substances: [1'-oxo-6',7'-dichlorospiro(cyclopentane-1,2'-indan)-5'-yloxy]acetonitrile (5.3 g.), sodium azide (1.44 g.), ammonium chloride (1.14 g.) and dimethylformamide (35 ml.). This procedure affords 5.0 g. (83%) of 5-[1'-oxo-6',7'-dichlorospiro(cyclopentane-1,2'-indan)5'-yloxymethyl]tetrazole which after recrystallization from acetonitrile melts at 191° C.
Reaction SMILES: [O:1]=[C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:15](O)[CH2:16][OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[C:9]1([C:2]2([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[O:17][CH2:16][CH2:15][O:1]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCO
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1(c2ccccc2)OCCO1

Procedure:
A solution of ethyl 3-oxo-3-phenylpropanoate (23.74 g) in toluene, ethyleneglycol (23.04 g), and p-toluenesulfonic acid (200 mg) in toluene (300 mL) was stirred under reflux with a Dean-Stark trap for 15 hours. The cooled mixture was poured onto saturated aqueous sodium bicarbonate (100 mL) and the organic layer was washed with water, brine and dried over Na2SO4. Filtration and evaporation of solvent provided the title compound which was used in the next reaction without further purification.
Reaction SMILES: [Na+].[CH3:2][S:3]([CH2-:5])=[O:4].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2C(=O)O[C:17](=[O:18])[C:16]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:15]23)=[CH:10][CH:9]=1.Cl.C(Cl)Cl>CS(C)=O>[CH3:2][S:3]([CH2:5][C:17]([C:16]1[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=1[NH:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1)=[O:18])=[O:4]
Reactant: COc1ccc(-n2c(=O)oc(=O)c3ccccc32)cc1
Reactant: [CH2-]S(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ccc(Nc2ccccc2C(=O)CS(C)=O)cc1
Reaction time: 1 h

Procedure:
To a 2 molar solution of dimsyl sodium in dimethylsulfoxide (365 ml.), cooled to 10° C., was added a solution of 65 g. of N-(4-methoxyphenyl)isatoic anhydride in 150 ml. dimethylsulfoxide with stirring and stirring was continued 30 minutes at room temperature and 1 hour at 50° C. The reaction mixture was poured onto 1200 g. of ice, 70 ml. of concentrated hydrochloric acid was added, and the mixture was extrated with methylene dichloride. The extract was washed with water, dried (MgSO4), and concentrated under reduced pressure to give, after recrystallization from benzenecyclohexane 45 g. 2-(methylsulfinyl)-2'-(4-methoxyanilino)acetophenone; m.p. 115°-116° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14]Cl)=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39].[NH:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[CH2:45][OH:46].O>CN(C)C(=O)C>[Cl:1][C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][N:40]2[CH2:44][CH2:43][CH2:42][C@H:41]2[CH2:45][OH:46])=[CH:9][C:8]([C:16]2[N:17]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([CH2:25][N:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[CH:20][CH:19]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:39]
Reactant: OC[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(OCCCCl)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCCCN3CCC[C@H]3CO)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 68.7 %

Procedure:
In a similar manner to Step 2 of Example 440, 4-chloro-5-(3-chloropropoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (119 mg, 0.208 mmol) was dissolved in N,N-dimethylacetoamide (1.2 mL), and the solution was treated with (S)-(+)-2-pyrrolidinemethanol (0.205 mL, 2.08 mmol). The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain (S)-4-chloro-5-[3-(2-hydroxymethylpyrrolidin-1-yl)propoxy]-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (91.0 mg, yield 69%).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)=[CH:7][C:5]=1[NH2:6])([O-])=O.C1N=CN([C:25](N2C=NC=C2)=[O:26])C=1>C(OCC)(=O)C.C(Cl)Cl.[Pt](=O)=O>[CH3:18][C:13]1([CH3:19])[C:14]([CH3:17])([CH3:16])[O:15][B:11]([C:8]2[CH:9]=[CH:10][C:4]3[NH:1][C:25](=[O:26])[NH:6][C:5]=3[CH:7]=2)[O:12]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])c(N)c2)OC1(C)C
Agent: O=[Pt]=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Reaction time: 0.5 h

Procedure:
A solution of 2-nitro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.35 g, 8.9 mmol) in ethyl acetate (100 mL) was treated with platinum(IV) oxide (0.2 g) and stirred vigorously under a hydrogen atmosphere for 30 minutes. The reaction mixture was degassed with nitrogen and filtered through celite washing with ethyl acetate. This solution was then treated with CDI (1.8 g, 11.1 mmol) and stirred overnight at ambient temperature. The solution was diluted with methylene chloride (100 mL) and the precipate was filtered and washed with cold methanol. The solids were dried in vacuo to yield 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydro-2H-benzimidazol-2-one as a white solid.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH3:13][C:14](=[O:19])[CH2:15][C:16](=[O:18])[CH3:17]>>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:15]([C:14](=[O:19])[CH3:13])[C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: CC(=O)C(=Cc1ccc(C(F)(F)F)cc1)C(C)=O

Procedure:
4-Trifluoromethylbenzaldehyde (8,7 g) was condensed with 2,4-pentanedione (5,01 g) in a similar manner as described above. The crude product was crystallized from a mixture of ether-petroleum ether (1:1), mp 46°-48° C., yield 3.8 g (30%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH:24]([F:26])[F:25])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH+:7]([O-:35])[C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:23][CH:24]([F:25])[F:26])=[CH:12][CH:11]=2)=[O:9])[CH:2]=1
Reactant: O=C(Nc1cccnc1)c1ccc(OC(F)F)c2oc3ccccc3c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(OC(F)F)c2oc3ccccc3c12)[NH+]([O-])c1cccnc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A suspension of N-(pyrid-3-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide (50 mg, 0.14 mmol) (example 23) and m-chloroperbenzoic acid (50-55%) (120 mg, 0.704 mmol) in chloroform (10 ml) was stirred at room temperature for 12 h. Chloroform was evaporated and the resulting solid was stirred in saturated sodium bicarbonate solution, filtered, dried and purified by column chromatography using 40% acetone-chloroform as the eluent to give 25 mg of of N-(pyrid-3-yl)-4-difluoromethoxy-dibenzo[b,d]furan-1-carboxamide-N1-oxide as white solid; mp: 252° C. (dec)
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:9][C:10]([C:13]2[CH2:18][CH2:17][O:16][CH2:15][CH:14]=2)=[CH:11][CH:12]=1)(=O)=O.[C:28]([C:30]1([OH:38])[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1)#[CH:29].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH2:19]([C:8]1[C:7]([C:29]#[C:28][C:30]2([OH:38])[CH:35]3[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]3)[CH2:31]2)=[CH:12][CH:11]=[C:10]([C:13]2[CH2:18][CH2:17][O:16][CH2:15][CH:14]=2)[N:9]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Oc1ccc(C2=CCOCC2)nc1Cc1ccccc1)C(F)(F)F
Reactant: C#CC1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: OC1(C#Cc2ccc(C3=CCOCC3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 66.8 %

Procedure:
A mixture of 60.7 g of 2-benzyl-6-(5,6-dihydro-2H-pyran-4-yl)-3-pyridyl trifluoromethane sulfonate, 23.0 mg of 3-ethynyl-3-quinuclidinol, 17.6 mg of tetrakis(triphenylphosphine)palladium(0), 2.9 mg of cuprous iodide, 63.6 μl of triethylamine and 1 ml of N,N-dimethylformamide was stirred at 60° C. for 1.5 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution, and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 40.7 mg of the target compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:20]2[N:11]([C:12](=[O:30])[C:13]3[CH:14]=[CH:15][C:16]([O:28][CH3:29])=[CH:17][C:18]=3[C:19]=2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=2)[CH2:10][CH2:9][CH:8]=1)(=O)=O>CCO.CCOC(C)=O.O=[Pt]=O>[F:27][C:23]1[CH:22]=[C:21]([C:19]2[C:18]3[CH:17]=[C:16]([O:28][CH3:29])[CH:15]=[CH:14][C:13]=3[C:12](=[O:30])[N:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:20]=23)[CH:26]=[CH:25][CH:24]=1
Reactant: COc1ccc2c(=O)n3c(c(-c4cccc(F)c4)c2c1)C(OS(=O)(=O)C(F)(F)F)=CCC3
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2c(=O)n3c(c(-c4cccc(F)c4)c2c1)CCCC3
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 11-(3-fluorophenyl)-9-methoxy-6-oxo-3,6-dihydro-4H-pyrido[1,2-b]isoquinolin-1-yl trifluoromethanesulfonate in EtOH (4 ml) and EtOAc (2 mL) was added PtO2 as a slurry in EtOH. The reaction was stirred at room temp under an H2 balloon for 16 h. The mixture was filtered through celite and concentrated. Flash chromatography (40 g silica, 30-80% EtOAc/hexanes) gave the titled compound.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]([O:17]C)=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:19]>CO.C1COCC1>[C:1]([NH:9][C:10]1[CH:14]=[CH:13][S:12][C:11]=1[C:15]([NH2:19])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)c1sccc1NC(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: NC(=O)c1sccc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 89 %

Procedure:
To a stirred solution of 14.21 g (54.4 mmol) of crude methyl 3-(benzoylamino)-2-thiophenecarboxylate in 100 mL of methanol and 100 mL of THF was added 100 mL of concentrated aqueous ammonia. The mixture was stirred at room temperature for 5 days and an additional 100 mL of concentrated aqueous ammonia was added. After stirring for 5 more days the mixture was rotovapped to remove the bulk of the organic solvents and the residue was extracted with two 125 mL portions of ethyl acetate. The insoluble material was collected by filtration and combined with the residue from evaporating the ethyl acetate extracts to dryness to furnish 11.96 g (89%) of crude 3-(benzoylamino)-2-thiophenecarboxamide as a tan solid. 1H-NMR (d6-DMSO)δ7.55(3H,m), 7.7(1H, d), 7.95(2H,m), 8.18(1H,d).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][C:14]([CH3:19])([CH3:18])[C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:20][CH3:21].[Cl:22]Cl.O>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][C:14]([CH3:18])([CH3:19])[C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH2:20][CH3:21])[Cl:22]
Reactant: ClCl
Reactant: CCC1Cc2cc(OC(C)(C)C(=O)O)c(Cl)c(Cl)c2C1=O
Solvent: O
Solvent: CC(=O)O
Product: CCC1(Cl)Cc2cc(OC(C)(C)C(=O)O)c(Cl)c(Cl)c2C1=O
Reaction time: 1 h

Procedure:
2-(1-Oxo-2-ethyl-6,7-dichloro-5-indanyloxy)-2-methylpropionic acid (4.7 g., 0.0014 mole) is dissolved in warm acetic acid (170 ml.) and treated with a solution of chlorine (1.06 g., 0.015 mole) in acetic acid (20 ml.) at 20° C. with stirring. The reaction mixture is kept at 20° C. for one hour and then at 80°0 C. for one hour. The reaction mixture is cooled and added to water (1 1.) with stirring. The white powder that separates is recrystallized from acetic acid-water (4:3) to obtain 3.0 g. of 2-(1-oxo-2-ethyl-2,67-trichloro-5-indanyloxy)-2-methylpropionic acid, m.p. 164.5°-165° C.