Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:14]2[CH2:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[S:17](=[O:26])(=[O:25])[CH2:16][CH2:15]2)[CH:3]=1.[C:27]([O:31][CH2:32][CH3:33])(=[O:30])[CH:28]=[CH2:29].C(N(CC)CC)C.CN(C)C=O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.O>[O:25]=[S:17]1(=[O:26])[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[CH2:20][N:14]([C:4]2[CH:3]=[C:2](/[CH:29]=[CH:28]/[C:27]([O:31][CH2:32][CH3:33])=[O:30])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][CH3:13])[CH:10]=3)[N:5]=2)[CH2:15][CH2:16]1
Reactant: C=CC(=O)OCC
Reactant: CCc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(CC)cc12
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
A mixture of 4-(4-chloro-6-ethylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (300 mg, 0.78 mmol), ethyl prop-2-enoate (170 mg, 1.70 mmol), triethylamine (1 mL) and N,N-dimethylformamide (2 mL), bis(tri-tert-butylphosphine)palladium(0) (15 mg, 0.02 mmol) was heated with stirring in a 10 mL of microwave process vial for 30 minutes at 100° C. under microwave irradiation. The reaction mixture was poured into water (5 mL) and extracted with ethyl acetate (10 mL×3). The organic layers were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluting with 20-40% ethyl acetate in petroleum ether) to afford 280 mg of the product as a white solid (yield was 80%). MS obsd. (ESI+) [(M+H)+] 451.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:32][C:33]3[CH:34]=[CH:35][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:37][CH:38]=3)=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OCC1CC1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCc2ccc(S(C)(=O)=O)cc2)c1OCC1CC1
Temperature: 70 °C
Yield: 16.5 %

Procedure:
To a stirring solution of 4-(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.246 mmol) in acetonitrile (15 mL) was added potassium carbonate (102 mg, 0.740 mmol) and 1-bromomethyl-4-methanesulfonyl-benzene (122 mg, 0.493 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-45% ethyl acetate in pet ether) to afford the title compound as a solid (20 mg, 16%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH2:15]1[O:28][C:27]2[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][C:22](O)=O)=[CH:18][C:17]=2[O:16]1>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:22](/[CH:21]=[CH:20]/[C:19]3[CH:25]=[CH:26][C:27]4[O:28][CH2:15][O:16][C:17]=4[CH:18]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc4c(c3)OCO4)nc2n(CC)c1=O
Yield: 37.4 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.0 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.33 g (12.1 mmol) of 3,4methylenedioxycinnamic acid. Then, the resultant crude crystals were recrystallized from dimethylformamide/water to give 1.34 g (yield 38%) of Compound 78 as a yellowish green powder.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>ClCCl>[CH2:16]([O:15][C:13](=[O:14])[NH:4][CH:1]1[CH2:3][CH2:2]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC1CC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CC1)OCc1ccccc1
Reaction time: 2 h
Yield: 587.7 %

Procedure:
To a solution of cyclopropylamine (5.0 g, 87.5 mmol) and triethylamine (30 mL) in dichloromethane (100 mL) at 0° C. was added dropwise benzyl chloroformate (15.0 mL, 10.5 mmol) and the resulting mixture was stirred for 2 h. Additional benzyl chloroformate (1 mL) was added and the resulting reaction mixture was stirred overnight. The reaction was then quenched by addition of a saturated NaHCO3 and the separated aqueous phase was extracted several times with dichloromethane. The combined dichloromethane extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (15% EtOAc to 5% MeOH/EtOAc) to give cyclopropyl-carbamic acid benzyl ester (11.8 g, 71%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH:8]=2)[CH:3]=[CH:2]1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[CH:23]=[CH:24]/[N+:25]([O-:27])=[O:26]>C1(C)C=CC=CC=1>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH:23]([C:3]1[C:4]2[C:9](=[CH:8][C:7]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:24][N+:25]([O-:27])=[O:26]
Reactant: c1cc2ccc(N3CCOCC3)cc2[nH]1
Reactant: O=[N+]([O-])/C=C/c1ccccc1F
Solvent: Cc1ccccc1
Product: O=[N+]([O-])CC(c1ccccc1F)c1c[nH]c2cc(N3CCOCC3)ccc12
Temperature: 150 °C
Yield: 43.6 %

Procedure:
A mixture of 4-(1H-indol-6-yl)morpholine (0.300 g, 1.483 mmol) and (E)-1-fluoro-2-(2-nitrovinyl)benzene (0.372 g, 2.225 mmol) in toluene (8 mL) was heated in a pressure tube at 150° C. for 2 days. The solvent was removed under vacuum, and the residue was subjected to ISCO (80 g silica gel, solid loading, 30-60% ethyl acetate/hexane) to provide the desired product (0.239 g, 0.647 mmol, 43.6% yield) as a tan solid.
Reaction SMILES: [CH2:1]([CH:9]([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:10][C:11]1[C:12]([CH2:36][CH:37]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[C:13]([CH2:16][CH:17]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N#N.C([Li])CCC.CCCCCC.Br[CH2:80][CH2:81][C:82]#[N:83]>C(=O)=O.CC(C)=O.C1COCC1>[CH2:1]([CH:9]([CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[CH2:10][C:11]1[CH:15]=[CH:14][C:13]([CH2:16][CH:17]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH2:80][CH2:81][C:82]#[N:83])[C:12]=1[CH2:36][CH:37]([CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH3:55])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCCC(CCCCCCCC)CC1=CCC(CC(CCCCCCCC)CCCCCCCCCC)=C1CC(CCCCCCCC)CCCCCCCCCC
Reactant: N#CCCBr
Agent: N#N
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCCCCCCCCCC(CCCCCCCC)CC1=C(CC(CCCCCCCC)CCCCCCCCCC)C(CCC#N)(CC(CCCCCCCC)CCCCCCCCCC)C=C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
Tris(2-octyldodecyl)cyclopentadiene (18.12 grams, 20 mmol) was placed in a 3-necked round bottom flask equipped with an additional funnel, a gas inlet adapter, and a septum. After flashing with dried N2 for 2 minutes, 50 ml of dried THF (distilled over K) was added. The solution was cooled in dry ice/acetone bath, followed injected 8.4 M n-butyl lithium in hexane solution (2.40 ml; 20 mmol). The dry ice/acetone bath was removed, and the resulting dark red solution was stirred at room temperature for 1 hour, followed by cooling in dry ice/acetone bath. 3-Bromopropionitrile (2.70 grams, 20 mmol) in 10 ml dried THF solution was then dropwise added from the additional funnel. After the addition, the reaction solution was stirred at room temperature for another 3 hours. The reaction was slowly quenched with 10 ml water. The organic layer was separated, and the aqueous layer was extracted with 50 ml hexane. The organic layers were combined, dried over MgSO4, filtered, and rota-vaporized to give 19.6 grams of yellow liquid. The crude reaction product was purified by column chromatography on SiO2 eluting with 5% ethyl acetate/hexane. The unreacted tris(2-octyldodecyl)cyclopentadiene (3.66 grams) was recovered and the title compound (12.83 grams) was isolated. FTIR: 2248 cm−1 (C≡N); 13C NMR (4 isomers): 152.5-129.1 ppm (C═C), 120.8-119.6 ppm (4 peaks; C≡N), 59.5 ppm, 56.9 ppm, 51.3 ppm, 41.1 ppm, 39.5-26.4 ppm, 22.7 ppm, 14.1 ppm
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[CH:8][C:9]([O:14][CH:15]([CH3:17])[CH3:16])=[C:10]([CH:13]=1)[CH:11]=O)([CH3:5])[CH3:4])#[N:2].[NH2:18][C@H:19]1[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:20]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(OC(N1CCC[C@H](NCC2C=C(C(C#N)C)C=CC=2OC)[C@@H]1C1C=CC=CC=1)=O)(C)(C)C>>[C:28]([O:27][C:25]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][CH2:11][C:10]2[CH:13]=[C:6]([C:3]([C:1]#[N:2])([CH3:5])[CH3:4])[CH:7]=[CH:8][C:9]=2[O:14][CH:15]([CH3:17])[CH3:16])[C@@H:20]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)Oc1ccc(C(C)(C)C#N)cc1C=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)[C@@H]1c1ccccc1
Agent: COc1ccc(C(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Product: CC(C)Oc1ccc(C(C)(C)C#N)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 41 and Compound 17 in the same manner of Compound 18.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6](Cl)=[O:7])=[CH:2]1.[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[O:17][CH3:18].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:14]2[CH:13]=[CH:12][C:11]([O:17][CH3:18])=[C:10]([Cl:9])[C:15]=2[Cl:16])=[O:7])=[CH:2]1
Reactant: O=C(Cl)c1ccoc1
Reactant: COc1cccc(Cl)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COc1ccc(C(=O)c2ccoc2)c(Cl)c1Cl

Procedure:
3-Furoyl chloride (18.0 g) and 2,3-dichloro anisole (24.7 g) are dissolved in 125 ml of CS2 and treated with AlCl3 (18.7 g), first at 5° C. and then at room temperature. After five hours the reaction is quenched with ice/HCl and extracted with CH2Cl2. Drying and evaporation gives a crystalline product that is triturated with hexane to yield 4-(3-furoyl)-2,3-dichloroanisole, mp 118°-122° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1>>[ClH:1].[ClH:1].[CH:14]1([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[N:4]=[N:3][C:2]([C:22]4[CH:21]=[C:20]5[C:25](=[CH:24][CH:23]=4)[NH:17][CH:18]=[CH:19]5)=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)[CH2:16][CH2:15]1
Reactant: Clc1ccc(N2CCN(C3CC3)CC2)nn1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Product: Cl
Product: c1cc2cc(-c3ccc(N4CCN(C5CC5)CC4)nn3)ccc2[nH]1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 68, starting from 3-chloro-6-(4-cyclopropyl-piperazin-1-yl)-pyridazine and 5-indoleboronic acid.
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH3:8])[CH2:3]/[CH:4]=[CH:5]/[CH2:6][OH:7].[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][N:12]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C)C=O>[OH:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:7][CH2:6]/[CH:5]=[CH:4]/[CH2:3][Si:2]([CH3:9])([CH3:8])[CH3:1])=[O:16])=[CH:13][N:12]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: C[Si](C)(C)C/C=C/CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: C[Si](C)(C)C/C=C/COC(=O)c1ccc(O)nc1
Yield: 38 %

Procedure:
1.3 g of 4-trimethylsilyl-(E)-but-2-en-1-ol (synthesis described in J. Org. Chem. 1984, 49, 4092), 1.08 g of 6-hydroxy-nicotinic acid and 178 mg of 4-dimethylaminopyridine were placed in succession in 30 ml of abs. dimethylformamide. 1.77 g (1.1 eq.) of dicyclohexylcarbodiimide were added thereto at 0° and the mixture was left to react at room temperature overnight. The separated urea was filtered off, the filtrate was extracted with ethyl acetate, washed twice with H2O, dried over Na2SO4 and the solvent was removed under reduced pressure. Flash chromatography on SiO2 (hexane/ethyl acetate=1/1) yielded 782 mg of 4-trimethylsilanyl-(E)-but-2-enyl 6-hydroxy-nicotinate as white crystals of m.p. 107-110° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH2:19]([NH2:23])[CH:20]([CH3:22])[CH3:21].Cl>C(Cl)Cl>[CH2:19]([NH:23][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CN
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCC(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
To a solution of 4-methoxybenzenesulfonylchloride (1 g, 4.8 mmol) in DCM (20 mL) was added pyridine (1.17 mL, 14.5 mmol) followed by isobutylamine (961 μL, 9.7 mmol) and the reaction was stirred at room temperature for 16 hours. 1 M aqueous HCl was added, extracted with DCM, filtered through a phase separator, concentrated then purified by silica gel column chromatography (100% DCM) to give N-isobutyl-4-methoxy-benzenesulfonamide (1.03 g, 88%). LCMS (m/z, Method A) ES− 242 [M−1]−.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:18][N:6]2[C:7](=[O:17])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][N:12]=3)[N:10]=[C:5]2[NH:4][CH2:3]1.[H-].[Na+].[N:22]1[C:27]2[CH2:28][CH:29]([CH2:31]OS(C)(=O)=O)[CH2:30][C:26]=2[N:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[N:22]1[C:27]2[CH2:28][CH:29]([CH2:31][N:4]3[C:5]4=[N:10][C:9]([C:11]5[CH:16]=[CH:15][N:14]=[CH:13][N:12]=5)=[CH:8][C:7](=[O:17])[N:6]4[CH2:18][C:2]([CH3:19])([CH3:1])[CH2:3]3)[CH2:30][C:26]=2[N:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCC1Cc2nccnc2C1
Reactant: CC1(C)CNc2nc(-c3ccncn3)cc(=O)n2C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CN(CC2Cc3nccnc3C2)c2nc(-c3ccncn3)cc(=O)n2C1
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 10.6 %

Procedure:
A suspension of 0.5 g (1.94 mmol) of 7,7-dimethyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 10 ml of anhydrous dimethylformamide was treated with 155 mg (3.89 mmol) of sodium hydride (50% suspension in mineral oil) and the resulting mixture was stirred for 40 min at 50° C. 0.888 g (3.89 mmol) of methanesulfonic acid 6,7-dihydro-5H-cyclopentapyrazin-6-ylmethyl ester in 2 ml of anhydrous dimethylformamide was added and the reaction mixture stirred at room temperature for 18 h. The solution was treated with water and extracted with ethyl acetate. The organic phase was dried and evaporated to give crude product, which was purified by silica gel chromatography, eluting with dichloromethane/methanol in the proportions 100/1 to 95/5 to give 80 mg of pure product obtained in the form of free base which was transformed into the hydrochloride salt. Mp: 193–195° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)[N+:5]([O-])=[CH:6][CH:7]=1.C[Si]([C:20]#[N:21])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:20]([C:11]1[N:10]=[C:9]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=2)[CH:14]=[C:13]([CH3:15])[CH:12]=1)#[N:21]
Reactant: Cc1ccnc(-c2cc(C)cc[n+]2[O-])c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: Cc1ccnc(-c2cc(C)cc(C#N)n2)c1
Temperature: 25 °C
Reaction time: 36 h
Yield: 90.3 %

Procedure:
4,4′-Dimethyl-2,2′-bipyridyl N-oxide (3.7 g, 18 mmol) was dissolved in nitroethane (50 ml), and trimethylsilyl cyanide (5.5 g, 55 mmol) and N,N-dimethylcarbamoyl chloride (2.9 g, 27 mmol) were added thereto. The mixture was stirred at room temperature for 36 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (5:1, v/v) were collected, concentrated and recrystallized from hexane-ethyl acetate to give the titled compound (3.4 g, 87%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1>>[C:22]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:23]=[CH:24][CH:25]=[C:20]([CH2:19][N:16]2[CH:11]([C:4]3[C:5]([O:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])[CH:21]=1
Reactant: COc1cccc(OC)c1C1CCCC(=O)N1
Reactant: BrCc1cccc(-c2ccccc2)c1
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 4 (GP4) by reaction of 6-(2,6-dimethoxyphenyl)piperidin-2-one with commercially available 3-(bromomethyl)-1,1′-biphenyl. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.95 min.; [M+H]+: 402.16 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12][CH3:13])[C:3]=1[C:4](O)=[O:5].CN(C1C=CC=CN=1)C.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12][CH3:13])[C:3]=1[C:4]([Cl:25])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(Cl)cc(Cl)c1C(=O)O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COc1cc(Cl)cc(Cl)c1C(=O)Cl
Reaction time: 15 h
Yield: 55 %

Procedure:
26.0 g. (0.117 mol) 2,4-Dichloro-6-methoxybenzoic acid were dissolved in 50 ml. anhydrous methylene chloride and, after the addition of 0.1 g. dimethylaminopyridine, 50 ml. thionyl chloride were added dropwise thereto at ambient temperature. After stirring for 15 hours, the reaction mixture was evaporated and the residue distilled. Yield: 55% of theory; b.p. 118-124° C./0.1 mm.Hg.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([OH:30])=O)[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[OH:31][N:32]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.NO>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2([C:28]([NH:32][OH:31])=[O:30])[CH2:20][CH2:19][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:17][CH2:16]2)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(C(=O)c3cccs3)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)NO)CCN(C(=O)c3cccs3)CC2)cc1

Procedure:
4-(4-but-2-ynyloxybenzenesulfonyl)-N-hydroxy-1-(2-thienylcarbonyl)-4-piperidinecarboxamide was prepared following the procedure Example 64 (step 6). Starting from 4-(4-but-2-ynyloxybenzenesulfonyl)-1-(2-thienylcarbonyl)-4-piperidinecarboxylic acid (335 mg, 0.75 mmol) in dimethylformamide (7 ml), 1-hydroxybenzotriazole(121 mg, 0.90 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (201 mg, 1.05 mmol), N-methylmorpholine (0.124 ml, 1.13 mmol), and hydroxylamine (0.229 ml, 3.75 mmol), 216 mg (62%) of the product was isolated as a solid. HR—MS: m/z Calculated for C21H22N2O6S2 463.0992; Found 463.0988.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[N:4][N:3]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19].[BH4-].[Na+]>ClCCl.CO>[OH:1][CH:2]1[CH2:7][O:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[N:4][N:3]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=1)=[O:19]
Reactant: O=C1COC(c2cccc(C(F)(F)F)c2)=NN1C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccc(C(F)(F)F)cc1)N1N=C(c2cccc(C(F)(F)F)c2)OCC1O
Temperature: 0 °C

Procedure:
To an ice-cooled suspension of 26.0 g 5,6-dihydro-5-oxo-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)-phenyl]-4H-1,3,4-oxadiazine-4-carboxamide (prepared in B above) in 300 ml dichloromethane and 300 ml methanol was added 2.3 g sodium borohydride in portions. The resultant mixture was stirred for 45 min and then quenched with 200 ml 1M HCl and diluted with 1 l dichloromethane. The phases were separated and the organic phase was washed with 200 ml 1 M HCl and 100 ml saturated sodium bicarbonate, dried over sodium sulfate and concentrated under vacuum to give 5,6-dihydro-5-hydroxy-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoro-methyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide. The structure was confirmed by 1H NMR.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([C:7]1[CH:23]=[CH:22][C:10]([O:11][CH2:12][CH:13]2[O:17][CH:16]([C:18](OC)=O)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[C:4]([CH3:6])=[O:5].C([OH:26])C>>[CH3:18][C:16]1([C:1]([NH2:2])=[O:26])[CH2:15][CH2:14][CH:13]([CH2:12][O:11][C:10]2[CH:22]=[CH:23][C:7]([CH2:3][C:4]([CH3:6])=[O:5])=[CH:8][CH:9]=2)[O:17]1
Reactant: COC(=O)C1CCC(COc2ccc(CC(C)=O)cc2)O1
Reactant: CCO
Reactant: CN
Product: CC(=O)Cc1ccc(OCC2CCC(C)(C(N)=O)O2)cc1

Procedure:
Methylamine (15 ml of a 33% solution in ethanol) was added, dropwise, to a stirred solution of methyl 5-[4-acetonylphenoxymethyl]tetrahydrofuran-2-carboxylate, ethylene ketal (4.1 g) in ethanol (80 ml). The reaction mixture was stirred and heated under reflux for 4 hr, cooled and evaporated to an oil which was dissolved in a mixture of methanol (40 ml) and 2N hydrochloric acid (40 ml) and stirred at ambient temperature for 3 hr. The methanol was evaporated and the aqueous residue was extracted into dichloromethane. The organic extract was dried (MgSO4) and evaporated to an oil which was purified by column chromatography on silica gel. Elution with methanol in chloroform (2:98) gave methyl 5-[4-acetonylphenoxymethyl]tetrahydrofuran-2-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[S:9]1[CH:13]=[CH:12][N:11]=[C:10]1[S:14](Cl)(=[O:16])=[O:15]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:14]([C:10]1[S:9][CH:13]=[CH:12][N:11]=1)(=[O:16])=[O:15]
Reactant: O=S(=O)(Cl)c1nccs1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2nccs2)c1Br
Yield: 57 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)thiazole-2-sulfonamide was prepared in the same manner as described in Example 2 from 5-amino-4-bromo-3-methylisoxazole and thiazole-2-sulfonyl chloride in 57% yield. This was purified by HPLC (5% CH3CN to 100% CH3CN over 30 min.) to give a solid., m.p. 175-177° C.