Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH:3]=[CH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.Cl.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>>[ClH:1].[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:2][CH:3]=[CH:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:17]
Reactant: O=[N+]([O-])c1ccc(CC=CCCl)cc1
Reactant: CCNCC
Agent: Cl
Product: CCN(CC)CC=CCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 250 ml of diethylamine at 0° C. add 30 g (0.14 mole) of 1chloro-4-(4-nitrophenyl)-2-butene over a 30 minute period. Stir for 16 hr at room temperature. Remove the solvent in vacuo. Extract the residue with 200 ml of 10% hydrochloric acid. Extract the resulting solution 2×100 ml ethyl acetate and discard. Adjust the pH of the water layer to about 12 with 10% sodium hydroxide. Extract 3×100 ml methylene chloride. Take the combined organic extracts and dry over Na2SO4. Remove the solvent in vacuo. Dissolve the residue in 100 ml ethanol, and add 1.5 equivalents of concentrated hydrochloric acid. Evaporate off the solvent, and crystallize the residue with acetone to provide the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]1(=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8](=[O:15])[O:7]1.CCN(CC)CC>C1(C)C=CC=CC=1>[OH:5][CH2:4][CH2:3][CH2:2][N:1]1[C:6](=[O:7])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:15]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCO
Yield: 67 %

Procedure:
To a solution of 3-aminopropan-1-ol (1.0 g, 13.1 mmol) and isobenzofuran-1,3-dione (2.0 g, 13.1 mmol) in toluene (25 mL, 3 mL/mmol) was added Et3N (2 mL, 13.1 mmol) and the reaction was heated at reflux for 24 h. Then reaction was quenched with water and extracted with EtOAc (2×40 mL). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford 2-(3-hydroxypropyl)isoindoline-1,3-dione (1.8 g, 87%). Observed mass (M+1): 206.1. This material was taken to the next step without further purification.
Reaction SMILES: [CH2:1]([NH:4][S:5](Cl)(=[O:7])=[O:6])[CH2:2][CH3:3].[NH2:9][C:10]1[C:11]([F:21])=[C:12]([C:17]([F:20])=[CH:18][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]>C(Cl)Cl>[F:21][C:11]1[C:10]([NH:9][S:5](=[O:7])(=[O:6])[NH:4][CH2:1][CH2:2][CH3:3])=[CH:19][CH:18]=[C:17]([F:20])[C:12]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1c(F)ccc(N)c1F
Reactant: CCCNS(=O)(=O)Cl
Solvent: ClCCl
Product: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)OC)c1F
Temperature: 25 °C

Procedure:
Propylsulfamoyl chloride (0.379 mL, 2.40 mmol) was added to methyl 3-amino-2,6-difluorobenzoate (0.150 mL, 0.802 mmol), TEA (0.335 mL, 2.40 mmol) in DCM (1.5 mL) at 0° C. The solution was warmed to room temperature overnight. The solids were filtered, and the supernate was concentrated to provide crude methyl 2,6-difluoro-3-(N-propylsulfamoylamino)benzoate, which was used directly in next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH:12]=O)[CH:5]=1.[CH2:15]([O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[O:29][CH2:28][CH2:27][C:26]2=[O:33])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1CCCC1>CO>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([CH:12]=[C:27]2[C:26](=[O:33])[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([O:22][CH2:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:24]=3)[O:29][CH2:28]2)[CH:5]=1
Reactant: O=C1CCOc2ccc(OCc3ccccc3)cc21
Reactant: COC(=O)c1ccc(OC)c(C=O)c1
Solvent: CO
Solvent: C1CCNC1
Product: COC(=O)c1ccc(OC)c(C=C2COc3ccc(OCc4ccccc4)cc3C2=O)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80 %

Procedure:
19.1 g (98.3 mmol) of 3-formyl-4-methoxybenzoic acid methyl ester (from Example 37) were added to a room temperature suspension of 25.0 g (98.3 mmol) of 6-benzyloxychroman-4-one and 8.21 mL (98.3 mmol) of pyrrolidine in 350 mL CH3OH. After stirring 20 hours at room temperature, the reaction mixture was filtered, washed two times with CH3OH and the precipitate dried under vacuum to give 33.93 of the title product as a yellow powder. Mp: 167°-169° C. 80% yield. 1H NMR (300 m Hz, CDCl3): δ3.93 (s, 3H); 3.91 (s, 3H); 12 aromatic resonances δ6.8→8.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([CH3:17])[CH:9]=2)[CH2:4][CH2:3]1.[CH3:18]OC(OC)N(C)C.N1CCCC1.C([O-])=O.[NH4+]>CN(C)C=O.[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:11](=[CH:12][CH:13]=2)[NH:14][CH:18]=[CH:17]3)[CH2:4][CH2:3]1
Reactant: Cc1cc(N2CCN(C)CC2)ccc1[N+](=O)[O-]
Reactant: COC(OC)N(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CN1CCN(c2ccc3[nH]ccc3c2)CC1
Temperature: 50 °C

Procedure:
A solution of 1-methyl-4-(3-methyl-4-nitro-phenyl)-piperazine (10a), (2.63 g, 11.2 mmol), N,N-dimethylformamide dimethyl acetal (4.7 mL, 35.84 mmol) and pyrrolidine (1.5 mL, 17.9 mmol) in anhydrous N,N-dimethylformamide (20 mL) was heated at 120° C. for 18 hours. The reaction mixture was concentrated in vacuo, taken up in ethanol (50 mL) containing 2 mL of water and to this was added ammonium formate (3.67 g, 58.2 mmol). Palladium, 10 wt. % on activated carbon (0.84 g) was added and the suspension was stirred and heated at 50° C. for 30 minutes. The reaction mixture was then filtered through a celite pad and the pad rinsed with hot methanol (20 mL). The combined filtrate and washings were concentrated in vacuo and the residue was taken up in ethyl acetate (100 mL), washed with aqueous saturated sodium bicarbonate solution (2×100 mL), brine, dried (MgSO4) and concentrated in vacuo. The resultant crude product was purified by flash chromatography on SiO2 eluting first with hexane and then 15% ethyl acetate/hexane to afford the desired title compound as an off-white solid, 1.44 g, 60%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][C:40](O)=[O:41])[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[C:26]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([CH2:39][C:40](=[O:41])[NH:1][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][S:12]([C:15]4[CH:20]=[CH:19][C:18]([NH:21][CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][CH:16]=4)(=[O:13])=[O:14])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:35][CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)CNc1ccc(S(=O)(=O)Oc2ccc3nc(N)sc3c2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)CC4CCN(C(=O)OC(C)(C)C)CC4)sc3c2)cc1
Reaction time: 0.17 h

Procedure:
1st step: A solution of 4-isobutylaminobenzenesulfonic acid 2-aminobenzo-thiazol-6-yl ester (intermediate 27) (300 mg, 0.495 mmol), 4-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (361 mg, 1.485 mmol), HBTU (563 mg, 1.485 mmol) and N,N-diisopropylethylamine (432 μl, 2.475 mmol) in 4 ml of dimethylformamide is stirred at room temperature overnight. Water is added to the reaction medium, which is extracted with ethyl acetate. The organic phase is washed with water and then with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness. The residue obtained is purified by HPLC on a Dynamax C18, 60 Å, 21×300 mm column with a 95/5 mixture of water/acetonitrile, for 5 minutes, with a gradient of from 5% to 40% in water for 5 minutes, with a gradient of from 40% to 80% of acetonitrile in water for 30 minutes, with a gradient of from 80% to 95% of acetonitrile in water for 5 minutes, and then with a 5/95 mixture of water/acetonitrile for 5 minutes with a flow rate of 20 ml/minute. The solvents each contain 0.07% (v/v) of trifluoroacetic acid. The fractions are collected every 30 seconds and are monitored by analytical HPLC on a Hypersil C18, 4.6×50 mm column, with a gradient of from 0 to 100% of acetonitrile in water, over 10 minutes at a flow rate of 1 ml/minute. The solvents each contain 0.07% (v/v) of trifluoroacetic acid. The fractions containing the expected product are concentrated to dryness to give 4-{[6-(4-isobutylamino-benzenesulfonyloxy)benzothiazol-2-ylcarbamoyl]methyl}piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][CH2:23][OH:24])=[N:12][C:11]=2[CH:25]([CH3:27])[CH3:26])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:30]([N:32]=C=O)=[O:31].O.C(N(CC)CC)C>O1CCCC1>[C:30]([O:24][CH2:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:25]([CH3:27])[CH3:26])[N:12]=1)(=[O:31])[NH2:32]
Reactant: CC(C)c1nc(CCO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1nc(CCOC(N)=O)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: -20 °C
Reaction time: 0.05 h
Yield: 83.3 %

Procedure:
In 10 ml of dry tetrahydrofuran was dissolved 1.0 g (2.4 mmol) of the alcohol compound (123b), and the mixture was cooled to -20° C., followed by addition of 540 mg (2.9 mmol) of trichloroacetylisocyanate. After 3 minutes, the mixture was warmed to 0° C. and stirred for 10 minutes. There were added 4 ml of water and 2 ml of triethylamine, and the mixture was warmed at 50° C. for 2 hours. The mixture was diluted with ice-water, extracted with ethyl acetate, the extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% methanol/ethyl acetate), and recrystallized from ethyl acetate to give 930 mg of Compound I-138 as crystals (yield 85%). mp 189-191° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=O.[CH2:11](Br)[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].O>C(O)C>[C:12]([C:11]1[O:1][C:2]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=2[CH:4]=1)(=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1ccc(O)c(C=O)c1
Solvent: CCO
Solvent: O
Product: Cc1ccc2oc(C(=O)c3ccccc3)cc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To a solution of 2-hydroxy-5-methylbenzaldehyde (1 g) and phenacyl bromide (1.06 g) in ethanol (10 ml) potassium carbonate (2.03 g) was added. The mixture was stirred at 80° C. for 1 h. Then the reaction mixture was poured into water (50 ml) and extracted with dichloromethane (3×20 ml). The combined organic layers were washed with brine (20 ml), dried (MgSO4), and concentrated under reduced pressure. The crude was purified by flash chromatography on silica gel (hexane/ethyl acetate 12:1) to give 2-benzoyl-5-methylbenzofuran (1.1 g) as yellowish solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH:27]1[C:39]2[CH:38]([CH2:40][O:41][C:42]([N:44]=[C:45]=[S:46])=[O:43])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]=2[CH:30]=[CH:29][CH:28]=1>ClCCl>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:45]([NH:44][C:42]([O:41][CH2:40][CH:38]2[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:31]3[C:39]2=[CH:27][CH:28]=[CH:29][CH:30]=3)=[O:43])=[S:46])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCCCCNCCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1
Solvent: ClCCl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=S)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of 2-({4-[2-(heptylamino)ethyl]-1,3-thiazol-2-yl}thio)-2-methylpropionic acid tert-butyl ester (2.5 g) synthesized in Example 303-2 in dichloromethane (20 mL) was added dropwise 9H-fluorene-9-ylmethyloxycarbonylisothiocyanate (2.5 g), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and subjected to silica gel chromatography (elution solvent; hexane:ethyl acetate=4:1) to give the title compound (3.1 g) as a pale-brown solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[NH:27][N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:17]=1)=[O:15])([CH3:12])[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.Cl[CH2:56][CH2:57][N:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Si:1]([O:8][CH2:9][C:10]([NH:13][C:14]([C:16]1[C:20]2=[N:21][C:22]([C:25]3[C:33]4[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=4)[N:27]([CH2:56][CH2:57][N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)[N:26]=3)=[CH:23][N:24]=[C:19]2[N:18]([C:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH:17]=1)=[O:15])([CH3:11])[CH3:12])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)n[nH]c2c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4c(n3)c(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)cn4C(c3ccccc3)(c3ccccc3)c3ccccc3)nn(CCN3CCOCC3)c2c1
Temperature: 90 °C
Yield: 72.3 %

Procedure:
A mixture of N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (200 mg, 0.277 mmol), 4-(2-chloroethyl)morpholine hydrochloride (62 mg, 0.333 mmol) and K2CO3 (191 mg, 1.385 mmol) in dry DMF (20 mL) was heated to 90° C. for 3 hours. Reaction mixture was extracted with ethyl acetate (100 mL), organic phase washed with water (3×10 mL) and brine (2×10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to afford N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1-(2-morpholinoethyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (167 mg, crude) as a yellow oil. LCMS: (M+H)+=834.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@@H:40]2[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]2)=[O:37])=[O:30])[CH2:3]1.[CH2:46]=O>>[OH:1][C@H:2]1[CH2:6][N:5]([C:7](=[O:28])[CH2:8][C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:4]([C:29]([N:31]2[CH2:35][CH2:34][CH2:33][C@@H:32]2[C:36]([NH:38][CH2:39][C@@H:40]2[CH2:45][CH2:44][CH2:43][N:42]([CH3:46])[CH2:41]2)=[O:37])=[O:30])[CH2:3]1
Reactant: O=C(NC[C@@H]1CCCNC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=O
Product: CN1CCC[C@@H](CNC(=O)[C@H]2CCCN2C(=O)[C@@H]2C[C@@H](O)CN2C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1

Procedure:
The title compound was prepared by a method similar to Step 3 of Example 17, using (2R)-1-{(2S,4R)-4-hydroxy-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-N-((3R)-3-piperidylmethyl)pyrrolidine-2-carboxamide and 37% aqueous formaldehyde solution. The compound was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Br:14]N1C(=O)CCC1=O>>[Br:14][CH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1cc(C)cc(C)c1
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)c1cc(C)cc(CBr)c1

Procedure:
The subtitle compound was prepared from ethyl 3,5-dimethylbenzoate (2 g) and N-bromosuccinimide (2 g) by the method of example 5 step (i). Purification was by chromatography eluting with 5% ethyl acetate in isohexane Yield 1.85 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:29])[CH2:17][C:16]3[C:11](=[C:12]([Cl:27])[C:13]([Cl:26])=[C:14]([O:18]CC4C=CC=CC=4)[CH:15]=3)[C:10]2=[O:28])=[CH:5][CH:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH3:29])[CH2:17][C:16]3[C:11](=[C:12]([Cl:27])[C:13]([Cl:26])=[C:14]([OH:18])[CH:15]=3)[C:10]2=[O:28])=[CH:5][CH:4]=1
Reactant: COc1ccc(C2(C)Cc3cc(OCc4ccccc4)c(Cl)c(Cl)c3C2=O)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2(C)Cc3cc(O)c(Cl)c(Cl)c3C2=O)cc1

Procedure:
2-(4-Methoxyphenyl)-2-methyl-5-benzyloxy-6,7-dichloro-1-indanone (3.44 g., 0.008 mole) is catalytically hydrogenated in absolute ethanol (300 ml.) over 5% palladium on carbon (500 mg.) in a Parr apparatus at 25° C. for 4 hrs. The reaction mixture is filtered and concentrated in vacuo to give 2.6 g. of 2-(4-methoxyphenyl)-2-methyl-5-hydroxy-6,7-dichloro-1-indanone which melts at 149°-156° C. and is used without further purification.
Reaction SMILES: [F:1][CH:2]([F:8])[CH:3]([OH:7])[C:4]([NH2:6])=[O:5].[C:9]([Si:13]([CH3:16])([CH3:15])Cl)([CH3:12])([CH3:11])[CH3:10].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[Si:13]([O:7][CH:3]([CH:2]([F:8])[F:1])[C:4]([NH2:6])=[O:5])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NC(=O)C(O)C(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC(C(N)=O)C(F)F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3,3-difluoro-2-hydroxypropanamide (700 mg, 5.6 mmol) in DMF (5.6 mL) was added tert-butyldimethylchlorosilane (1.10 g, 7.28 mmol) and triethylamine (1.17 mL, 8.40 mmol). The mixture was stirred at room temperature for 3 h, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate (2×) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to provide Intermediate 10 that was used without further purification. MS: m/z=240.3 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:16])([CH3:15])[CH:3](O)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][C:2]([CH3:16])([CH3:15])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(C)(C)C(O)Cc1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)(C)C=Cc1ccccc1[N+](=O)[O-]

Procedure:
To 40 g (179 mmol) of 3,3-dimethyl-1-(2-nitrophenyl)butan-2-ol in 400 ml of toluene at room temperature are added 23.44 g (197 mmol) of thionyl chloride, and the mixture is boiled under reflux for 2 h. After washing with 100 ml of saturated sodium bicarbonate solution and distilling the organic phase at 116° C./12 mbar, 20 g (48% of theory) of 1-[(1E)-3,3-dimethylbut-1-en-1-yl]-2-nitrobenzene are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:30]1[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([O:18][C:30]4[CH:35]=[CH:34][N:33]=[C:32]([C:36]([NH:38][CH3:39])=[O:37])[CH:31]=4)=[CH:14][C:12]=3[N:13]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Reactant: CNC(=O)c1cc(Cl)ccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3oc(Nc4ccc(Br)cc4)nc3c2)ccn1

Procedure:
The mixture containing 2-[(4-bromophenyl)amino]benzoxazol-5-ol (1 eq), potassium bis(trimethylsilyl)amide (4 eq), was stirred in dimethylformamide for 30 min at room temperature. To this mixture was added (4-chloro(2-pyridyl)-N-methyl-carboxamide (1 eq) and Potassium carbonate (1.2 eq) and microwaved for 6 mins at 150° C. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered and concentrated. Purification on Prep LC yielded the desired product. MS: MH+=439.
Reaction SMILES: [CH3:1][N:2]([C:13]1[N:14]=[N:15][C:16](N2CCOCC2)=[CH:17][CH:18]=1)[N:3]=[C:4]1[CH2:9][CH:8]2[C:10]([CH3:12])([CH3:11])[CH:5]1[CH2:6][CH2:7]2.[ClH:25]>C(Cl)(Cl)Cl>[CH3:1][N:2]([C:13]1[N:14]=[N:15][C:16]([Cl:25])=[CH:17][CH:18]=1)[N:3]=[C:4]1[CH2:9][CH:8]2[C:10]([CH3:12])([CH3:11])[CH:5]1[CH2:6][CH2:7]2
Reactant: Cl
Reactant: CN(N=C1CC2CCC1C2(C)C)c1ccc(N2CCOCC2)nn1
Solvent: ClC(Cl)Cl
Product: CN(N=C1CC2CCC1C2(C)C)c1ccc(Cl)nn1
Yield: 65 %

Procedure:
A mixture of 32.9 g (0.1 moles) of 1,7,7-trimethyl-2-bicyclo(2,2,1)heptylidene-(6-morpholino-3-pyridazinyl)-hydrazine (prepared by the process of Example 8, Step b), 660 ml of chloroform and 660 ml of concentrated hydrochloric acid is heated at 60° while stirring under a nitrogen atmosphere for 6 hours in such a way that the chloroform layer is separated from the reaction mixture every hour and replaced by fresh solvent (660 ml). The camphor recovered can be condensed with 6-chloro-3-pyridazinylhydrazine to give pure 1,7,7-trimethyl-2-bicyclo(2,2,1)heptylidene-(6-chloro-3-pyridazinyl)-hydrazine in 65-72% yield.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][N:4]=1.[S:12]([O-:15])([O-:14])=[O:13].[Na+:16].[Na+]>CO.O>[O:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:3]([CH2:2][S:12]([O-:15])(=[O:14])=[O:13])=[N:4]1.[Na+:16]
Reactant: O=S([O-])[O-]
Reactant: BrCc1noc2ccccc12
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=S(=O)([O-])Cc1noc2ccccc12
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 8.0 of 3-bromomethyl-1,2-benzisoxazole (m.p. 64°-66° C.) in 130 ml of methanol was added a solution of 8.1 g of sodium sulfite in 130 ml of water. The mixture was heated with stirring at 50° C. for 4 hours and concentrated under reduced pressure. The crystalline residue was dissolved in 250 ml of methanol with warming and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the crystalline residue was washed with diethyl ether to give crude sodium 1,2-benzisoxazole-3-methanesulfonate (10.5 g).