Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH3:31])[C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:29])[C:22](OC(C)(C)C)=[O:23])[C:17]1=[O:30])(=[O:14])=[O:13])[CH:6]=[CH:5]2.FC(F)(F)C(O)=O.Cl.CN(C)CCCN=C=NCC.C1C=CC2N(O)N=NC=2C=1.[NH:61]1[CH2:66][CH2:65][CH2:64][CH:63]([NH:67][C:68](=[O:75])[C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[CH2:62]1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:9](=[CH:4][CH:3]=1)[CH:8]=[C:7]([S:12]([N:15]([CH3:31])[C@H:16]1[CH2:20][CH2:19][N:18]([C@H:21]([CH3:29])[C:22]([N:61]3[CH2:66][CH2:65][CH2:64][CH:63]([NH:67][C:68](=[O:75])[C:69]4[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=4)[CH2:62]3)=[O:23])[C:17]1=[O:30])(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(NC1CCCNC1)c1ccccc1
Reactant: C[C@H](C(=O)OC(C)(C)C)N1CC[C@H](N(C)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](C(=O)N1CCCC(NC(=O)c2ccccc2)C1)N1CC[C@H](N(C)S(=O)(=O)c2ccc3cc(Cl)ccc3c2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.2 %

Procedure:
A solution of tert-butyl (2R)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](methyl)amino]-2-oxopyrrolidin-1-yl}propanoate (0.017 g) in DCM (0.5 ml) was treated with trifluoroacetic acid (0.5 ml) and stirred at room temperature for 2 h. The mixture was then concentrated under reduced pressure to give an oil which was subsequently treated with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.01 g), HOBT (0.007 g) and triethylamine (0.020 ml). After stirring at room temperature for 1 h, N-piperidin-3-ylbenzamide (0.010 g) was added and stirring was continued for 16 h. The reaction mixture was partitioned between DCM and water. The organic extract was concentrated under reduced pressure and the residue purified using SPE (silica, eluting with cyclohexane:ethyl acetate 3:1, 1:1, 1:3, ethyl acetate) to give the title compound (0.012 g) as a pale yellow gum.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[N:2]1.S1([C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)C(=O)N1)(=O)=O.[Br-]>O1CCCC1>[C:4]1([C:3]2([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[S:1](=[O:10])(=[O:11])[NH:2]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=S1(=O)N=Cc2ccccc21
Reactant: O=C1NS(=O)(=O)c2ccccc21
Agent: [Br-]
Solvent: C1CCOC1
Product: O=S1(=O)NC(c2ccccc2)(c2ccccc2)c2ccccc21

Procedure:
Various procedures have been reported for synthesizing 3-substituted-benz[d]isothiazole-1,1-dioxides and 3,3-disubstituted-2,3-dihydrobenz[d]isothiazole-1,1-dioxides from saccharin (3-oxo-2,3-dihydrobenz[d]isothiazole-1,1-dioxide) and from saccharin pseudo-chloride (3-chlorobenz[d]isothiazole-1,1-dioxide). As reported by A. Mustafa et al, J. Chem. Soc., 1952, p. 1339, the treatment of saccharin pseudo-chloride with excess phenylmagnesium bromide gave the corresponding 3,3-diphenyl-2,3-dihydrobenz[d]isothiazole-1,1-dioxide in almost quantitative yield. Methyl-, ethyl-, n-propyl- and n-butylmagnesium halides were reported by these authors to react analogously. R. A. Abramovitch et al, J. Chem. Soc., Perkin Trans I, 1974(22), p. 2589, reviewed and reinvestigated the reactions of saccharins with alkyl and aryl Grignard reagents and found that either the 3-alkyl (or 3-aryl) -benz[d]-isothiazole-1,1-dioxide and/or the open-chain tertiary alcohol, o-CH2OH benzenesulfonamide wherein R is alkyl (or aryl) were obtained with one exception. When saccharin was treated with an excess of phenylmagensium bromide in boiling tetrahydrofuran, 3,3-diphenyl-2,3-dihydrobenz[d]isothiazole-1,1-dioxide was obtained as the minor product together with the open-chain tertiary alcohol.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=3)[C:10]([S:21][CH3:22])=[CH:9]2)=[N:6][CH:7]=1.Cl[C:24]1[CH:29]=[C:28]([CH:30]2[CH2:32][CH2:31]2)[CH:27]=[CH:26][N:25]=1>>[CH:30]1([C:28]2[CH:27]=[CH:26][N:25]=[C:24]([C:2]3[CH:3]=[N:4][C:5]([N:8]4[C:16]5[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=5)[C:10]([S:21][CH3:22])=[CH:9]4)=[N:6][CH:7]=3)[CH:29]=2)[CH2:32][CH2:31]1
Reactant: Clc1cc(C2CC2)ccn1
Reactant: COC(=O)c1ccc2c(SC)cn(-c3ncc(Br)cn3)c2c1
Product: COC(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C5CC5)ccn4)cn3)c2c1

Procedure:
Synthesized from methyl 1-(5-bromopyrimidin-2-yl)-3-(methylthio)-1H-indole-6-carboxylate (1.7 g, 4.49 mmol) and 2-chloro-4-cyclopropylpyridine (1.03 g, 6.73 mmol) in analogy to the procedures 141a) and b). White solid. Yield: 1.2 g (64% of theory)
Reaction SMILES: N[C:2]1[C:3]([Cl:12])=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[N:9][CH:8]=[CH:7]2.N([O-])=O.[Na+].N(O)=O.[H+].[B-](F)(F)(F)[F:22]>>[Cl:12][C:3]1[C:2]([F:22])=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: F[B-](F)(F)F
Reactant: Nc1c(Cl)ccc2ccncc12
Agent: O=NO
Agent: O=N[O-]
Agent: [H+]
Product: Fc1c(Cl)ccc2ccncc12
Reaction time: 0.5 h

Procedure:
8-Amino-7-chloroisoquinoline (0.005 mole), prepared as in Example 12, in 40% fluoboric acid (30 ml.) is cooled to -10° C. and diazotized with finely powdered sodium nitrite (3.5 g.). After 30 minutes, the reaction mixture is tested for nitrous acid with starch/iodide paper as described in Example 15. When a positive reaction is obtained, the reaction mixture is washed with small portions of ether and then agitated with a mixture of ethanol and ether (20 ml. each). The diazonium tetrafluoroborate is filtered, washed with ether, dried in vacuo and decomposed on an oil bath at approximately 150° C. The residue is partitioned between ether and 5% aqueous sodium hydroxide solution. The ether phase and extracts are combined, washed with water, dried over sodium sulfate and evaporated to yield 7-chloro-8-fluoroisoquinoline.
Reaction SMILES: [N:1]1([CH2:6][CH:7]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-]>CO>[N:1]1([CH2:6][CH:7]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)c1ccc(OC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(OC(Cn2ccnc2)c2ccc(F)cc2)cc1-c1ccc(F)cc1

Procedure:
4-[2-(imidazol-1-yl)-1-(4-fluorophenyl)ethoxy]-2-(4-fluorophenyl) benzoic acid was prepared from methyl 4-[2-(imidazol-1-yl)-1-(4-fluorophenyl)ethoxy]-2-(4-fluorophenyl)benzoate by treatment with aqueous hydroxide in methanol and used without further purification.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.O[CH2:13][CH:14]1[N:19]([S:20]([CH3:23])(=[O:22])=[O:21])[C:18]2[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=2[O:16][CH2:15]1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>CN1CCCC1=O>[N:28]1([CH2:13][CH:14]2[N:19]([S:20]([CH3:23])(=[O:22])=[O:21])[C:18]3[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=3[O:16][CH2:15]2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)N1c2ccccc2OCC1CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)N1c2ccccc2OCC1CN1CCOCC1

Procedure:
In the same manner, the isomeric 3-hydroxymethyl-4-methanesulfonyl-3,4-dihydro-2H-1,4-benzoxazine p-toluenesulfonate obtained above (40.8 g, 0.10 mole) was reacted with 60 ml of morpholine in 100 ml of N-methylpyrrolidone to give 22.5 g of 3-(4-morpholinylmethyl)-4-methanesulfonyl-3,4-dihydro-2H-1,4-benzoxazine.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:15][C:16]([OH:18])=O)[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].[CH3:19][CH:20]([CH3:36])[CH2:21][C@H:22]([NH2:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:15][C:16]([NH:35][C@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:21][CH:20]([CH3:36])[CH3:19])=[O:18])[CH:7]=[CH:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2]
Reactant: CC(C)C[C@H](N)c1ccccc1N1CCCCC1
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CC(=O)N[C@@H](CC(C)C)c2ccccc2N2CCCCC2)cc1OCC

Procedure:
2.77 g (11 mMol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid are added at ambient temperature to a solution of 2.71 g (11 mMol) of anhydrous (S)-3-methyl-1-(2-piperidino-phenyl)-1-butylamine (ee=98.5%) in 30 ml of absolute toluene and the mixture is stirred until dissolved. Then 2.38 g (11.55 mMol) of N,N'-dicyclohexyl-carbodiimide are added and the mixture is stirred at ambient temperature. After 24 hours a further 0.54 g (2.14 mMol) of 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid and 0.48 g (2.33 mMol) of N,N'-dicyclohexylcarbodiimide are added and the mixture is stirred overnight. It is then cooled to an internal temperature of +5° C. and suction filtered to separate the precipitate, which is washed once with 5 ml of toluene. The combined toluene filtrates are evaporated down in vacuo to a volume of about 10 ml. The resulting solution is heated over the steam bath and petroleum ether is added in batches thereto (total of 55 ml) until the turbidity remains. It is cooled in ice, whereupon crystallisation takes place. It is suction filtered and dried at 75° C./4 torr. The product obtained (4.57 g; melting point 111-112° C.; ee=98.9%) is suspended in 50 ml of petroleum ether. The mixture is heated over the steam bath and sufficient toluene is added in batches (8 ml in total) until a solution is obtained. This is then cooled in ice and suction filtered to separate the crystals, which are dried at 75° C./4 torr.
Reaction SMILES: Cl.[O:2]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[C:12]#N)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH2:17]>CCOCC>[O:2]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:17])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O
Reactant: N#Cc1cccc(Oc2ccccc2)c1
Agent: Cl
Solvent: CCOCC
Product: O=Cc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Hydrogen chloride was introduced until saturation into a solution of 37.9 g of anhydrous stannous chloride (0.2 mole) in 200 ml of anhydrous ether. To the resulting solution, was added 19.5 g of 3-phenoxybenzonitrile (0.1 mole) and the mixture was stirred for 10 hours at room temperature. After addition of 200 ml of water and thorough stirring, the insoluble matter was removed by filtration. The filtrate was separated and the ether layer was further washed three times with 50 ml of water. After removal of the ether by distillation, the residue was distilled to obtain 8.5 g of crude 3-phenoxybenzaldehyde boiling at 100° to 115° C./0.45 mmHg which contained 71.4% of 3-phenoxybenzaldehyde.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]5[NH:39][C:38](=[O:40])[O:37][N:36]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=[C:16]3[CH3:44])=[CH:11][CH:10]=2)[CH2:4][C:3]1([CH3:46])[CH3:45].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl.O>[CH3:45][C:3]1([CH3:46])[C:2](=[O:1])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[C:20](=[O:21])[C:19]([CH2:22][C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:35]5[NH:39][C:38](=[O:40])[O:37][N:36]=5)=[CH:25][CH:24]=4)=[C:18]([CH2:41][CH2:42][CH3:43])[N:17]=[C:16]3[CH3:44])=[CH:11][CH:10]=2)[CH2:4]1
Reactant: CCCc1nc(C)n(-c2ccc(OC3CCC(O)C(C)(C)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC3CCC(=O)C(C)(C)C3)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a solution of 3-{4-[(4-hydroxy-3,3-dimethylcyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one (0.33 g) in methylene chloride (3 mL) was added 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.34 g), and the mixture was stirred for 1 hr. Ethyl acetate, water and sodium thiosulfate were added to the reaction mixture, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.20 g, 61%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[C@:10]([CH2:23][CH:24]([OH:27])[CH2:25][OH:26])([CH3:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CO[C:30](OC)([CH3:32])[CH3:31].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[C@:10]([CH2:23][CH:24]3[CH2:25][O:26][C:30]([CH3:32])([CH3:31])[O:27]3)([CH3:22])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@]1(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Reactant: COC(C)(C)OC
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CN(C)C=O
Product: CC1(C)OCC(C[C@@]2(C)C[C@H](c3cccc(Cl)c3)[C@@H](c3ccc(Cl)cc3)NC2=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methylpiperidin-2-one (Example 102, Step A) (4.900 g, 12.00 mmol) and 2,2-dimethoxypropane (14.76 mL, 120 mmol) in N,N-dimethylformamide (34 mL) at room temperature was added CSA (0.279 g, 1.200 mmol) and the reaction mixture was allowed to stir for 1 hr at room temperature. The reaction was quenched with sodium bicarbonate (100 mL) and EtOAc (100 mL). The layers were separated and the organic layer was washed three times with sat. sodium carbonate (100 mL). The aqueous layers were combined and were extracted with EtOAc (200 mL). The organic layers were combined, washed with sat. aq. NaCl solution, dried with sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:10]1[CH2:15][CH2:14][S:13][CH2:12][CH2:11]1>>[S:13]1[CH2:14][CH2:15][N:10]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:11][CH2:12]1
Reactant: C1CSCCN1
Reactant: N#Cc1ccccc1F
Product: N#Cc1ccccc1N1CCSCC1

Procedure:
According to a similar manner to that in Reference Example 12, the title compound was synthesized from 2-fluorobenzonitrile and thiomorpholine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([CH:18]=[N:19][OH:20])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[N:29]1C(=O)CC[C:30]1=O.CN.C(N(CC)CC)C>CN(C=O)C.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:25])([F:27])[F:26])[O:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:19][OH:20])=[N:29][CH3:30])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C=NO
Agent: CN
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN=C(NO)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 75 °C
Yield: 39 %

Procedure:
To a solution of 4-[5-(3,5-Dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzaldehyde oxime (i.e. the product of Step 2, 500 mg) in DMF (25 mL) was added N-chloro succinimide (168 mg) and heated to 75° C. for 1 h. After cooling, the reaction mixture was poured onto water and extracted with MTBE. The combined organic layers were dried (Na2SO4) and concentrated in vacuo to ¼ of the original volume to obtain the crude hydroxamic acid chloride. This mixture was added to a solution of methylamine (0.66 mL, 41 mg) and triethylamine (0.18 mL, 0.13 g) in THF and stirred at room temperature over night. After concentration in vacuo, the mixture was purified by chromatography on silica gel to obtain the title compound (270 mg, 39%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:3]=1.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.[N+:35]([O-])([OH:37])=[O:36].CO>C(O)(C(F)(F)F)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([N+:35]([O-:37])=[O:36])[C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cc1-c1ncccc1F
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: CC(C)(C)C(=O)Nc1c(-c2ncccc2F)cc(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h
Yield: 83.7 %

Procedure:
To a suspension of N-[4-bromo-2-(3-fluoro-pyridin-2-yl)-phenyl]-2,2-dimethyl-propionamide (6.45 grams, 18.4 mmoles) in TFA (100 mL) and TFAA (25.5 mL, 183.6 mmole), at 0° C., was added a TFA solution (30 mL) of 90% fuming nitric acid (2.46 mL, 55.1 mmoles) over a 45 minute period. The mixture was then stirred at 0° C. for a total of 4 hours. The crude reaction (now homogenous) was poured into ice producing a pasty mass. The mixture was diluted to 500 mL total volume with water, treated with 50 mL of methanol, and vigorously stirred for 12 hours. The resulting solids were filtered, washed with copious amounts of water, then dried in vacuo at 50° C. to afford the title compound (6.1 grams, 82% yield) as a tan powder.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH2:24][C:23]([CH3:26])([CH3:25])[CH2:22][C:21]([CH3:28])([CH3:27])[CH:20]=2)=[CH:15][C:14]=1[CH3:29].OP([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]23[O:9][CH:20]2[C:21]([CH3:28])([CH3:27])[CH2:22][C:23]([CH3:25])([CH3:26])[CH2:24]3)=[CH:15][C:14]=1[CH3:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C2=CC(C)(C)CC(C)(C)C2)ccc1F
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: ClCCl
Product: Cc1cc(C23CC(C)(C)CC(C)(C)C2O3)ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 87.5 %

Procedure:
A solution of meta-chloroperbenzoic acid (20 g, 90 mmol) in 250 ml of CH2Cl2 is added dropwise to a cooled (0° C.) solution of 1-fluoro-2-methyl-4-(3,3,5,5-tetramethylcyclohex-1-en-1-yl)benzene (15 g, 61 mmol) and K2HPO4 (21 g, 90 mmol) in dry CH2Cl2 (100 ml). The resulting milky solution is stirred at room temperature for 14 hours, filtered and washed successively with 5% cold NaOH (2×50 ml), H2O (2×50 ml) and brine (75 ml). The CH2Cl2 fraction is dried (MgSO4), and the solvent is removed under reduced pressure to provide 14 g (88%) of 2-(4-fluoro-3-methylphenyl)-4,4,6,6-tetramethyl-1-epoxycyclohexane: 1H NMR δ=0.9 (s,6), 0.95 (s,3), 1.1 (s,3), 1.15 (q,2), 1.85 (AB-q, 2), 2.1 (s,3), 2.55 (s,1), 6.85 (t,1), 7.1 (t,1), 7.25 (dd,1).
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:14])[C:4]([O:6][C:7]1([CH2:12][CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5].[CH3:15]I>[Ag-]=O.CN(C)C=O>[CH3:15][O:1][CH2:2][C:3](=[CH2:14])[C:4]([O:6][C:7]1([CH2:12][CH3:13])[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:5]
Reactant: CI
Reactant: C=C(CO)C(=O)OC1(CC)CCCC1
Agent: O=[Ag-]
Solvent: CN(C)C=O
Product: C=C(COC)C(=O)OC1(CC)CCCC1
Temperature: 50 °C
Reaction time: 30 h
Yield: 62 %

Procedure:
A mixture of 19.8 g of 1-ethylcyclopentyl α-(hydroxymethyl)acrylate, 40.0 g of methyl iodide, 30.0 g of silver (I) oxide and 50 g of N,N-dimethylformamide was stirred at 50° C. for 30 hours. The solids were filtered off, followed by conventional aqueous workup. The solvent was distilled off in vacuo. Purification by distillation (boiling point 53° C./16 Pa) gave 1-ethylcyclopentyl α-(methoxymethyl)acrylate represented by formula (10). The yield was 62%.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.[Br:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[C:17]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>ClCCl>[Br:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[C:17]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21]
Reactant: CC(=O)OCc1c(Br)cccc1Br
Reactant: CN(C)c1ccc2c(c1)CCNC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)OCc1c(Br)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Temperature: 150 °C
Yield: 27.9 %

Procedure:
6-Dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (150 mg, 0.789 mmol), Acetic acid 2,6-dibromo-benzyl ester (487 mg, 1.58 mmol), cuprous iodide (30 mg, 0.16 mmol) and potassium carbonate (109 mg, 0.789 mmol) were deposited in a sealed vessel. 3 mL DMSO was added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 24 hours. Cuprous iodide (30 mg, 0.16 mmol) was added and the mixture was heated at 150° C. for an additional 24 hours. This was diluted with dichoromethane and filtered through a pad of celite. The filtrate was partitioned between dichloromethane and 5% aq. ammonium hydroxide. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 50% ethyl acetate/hexanes) to yield Acetic acid 2-bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl ester (93 mg, 0.22 mmol). MS (ESI) 417.1 (M+H)+.
Reaction SMILES: [CH3:1][S:2](O)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][C:8]=1[S:14]([NH2:17])(=[O:16])=[O:15].N1C=CC=CC=1.CS(Cl)(=O)=O>C(#N)C>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:9][C:8]=1[S:14]([NH2:17])(=[O:15])=[O:16]
Reactant: CS(=O)(=O)O
Reactant: Nc1ccc(N)c(S(N)(=O)=O)c1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Temperature: 23 °C
Reaction time: 20 h
Yield: 86.3 %

Procedure:
2,5-Diamino-benzenesulfonamide methanesulfonate (1.80 kg, 6.35 mol) was suspended in acetonitrile (24 L). Pyridine (1.55 L, 19.1 mol) was added, followed by the careful slow addition of methanesulfonyl chloride (517 mL, 6.68 mol). After stirring at 23° C. for 20 h, the mixture was partially concentrated in vacuo at 55° C. Water (18 L) was added to the concentrate, and the resulting suspension was stirred at 23° C. for 2 h. The solid was filtered and was then washed with water (4 L) and air dried on the filter. The solid was suspended in absolute ethanol (9 L), stirred at 23° C. for 9 h, and was then filtered. The solid was washed with absolute ethanol (2×2 L), and was then further dried in vacuo at 50° C. to afford the desired product, 2-amino-5-methanesulfonylamino-benzenesulfonamide (1.45 kg, 5.48 mol, 86%), as a purple solid.
Reaction SMILES: C(OC1N=C2C(N=C(OC)N2CCCC2CCCCN2)=C(N)N=1)CCC.[NH2:27][C:28]1[N:36]=[C:35]([O:37][CH2:38][CH2:39][CH2:40][CH3:41])[N:34]=[C:33]2[C:29]=1[N:30]=[C:31]([O:60][CH3:61])[N:32]2[CH2:42][CH2:43][CH:44]1[CH2:49][CH2:48][N:47](C(OCC2C=CC=CC=2)=O)[CH2:46][CH2:45]1>>[CH2:38]([O:37][C:35]1[N:34]=[C:33]2[C:29]([N:30]=[C:31]([O:60][CH3:61])[N:32]2[CH2:42][CH2:43][CH:44]2[CH2:45][CH2:46][NH:47][CH2:48][CH2:49]2)=[C:28]([NH2:27])[N:36]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 4-{2-[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]ethyl}-1-piperidinecarboxylate.