Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][C:16]2[C:25]([NH:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=3)=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.O.[OH-].[Li+].O.Cl>C1COCC1>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([NH:26][C:25]2[C:16]([NH:15][S:12]([C:9]3[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:37])=[O:2])=[CH:7][CH:8]=3)(=[O:14])=[O:13])=[N:17][C:18]3[C:23]([N:24]=2)=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=1
Reactant: COC(=O)CCc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Nc2cc(OC)cc(OC)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Nc2nc3ccccc3nc2NS(=O)(=O)c2ccc(CCC(=O)O)cc2)cc(OC)c1
Yield: 74.9 %

Procedure:
Methyl-3-{4-[({3-[(3,5-dimethoxyphenyl)amino]quinoxalin-2-yl}amino)sulfonyl]phenyl}propanoate (50 mg, 0.10 mmol, 1 eq.) and lithium hydroxide monohydrate (20.1 mg, 0.48 mmol, 5 eq.) are dissolved in THF (1 ml) and water (1 ml) and the yellow solution is heated up to 50° C. for 1 h. Aqueous HCl 1N is added until reaching acidic pH and the precipitate formed is filtered off then washed with water until neutral. The solid is dried under vacuum at 40° C. overnight, affording 38.1 mg (78%) of the title compound as a yellow powder. 1H NMR (DMSO-d6) δ 12.30-11.95 (m, 2H), 8.91 (s, 1H), 8.02 (d, J=8.2 Hz, 2H), 7-95-7.82 (br s, 1H), 7.60-7.50 (m, 1H), 7.48-7.23 (m, 6H), 6.23 (s, 1H), 3.75 (s, 6H), 2.88 (t, J=7.2 Hz, 2H), 2.56 (t, J=7.5 Hz, 2H). HPLC (max plot) 100%; Rt 4.10 min. LC/MS: (ES+): 509.4; (ES−): 507.4.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[CH:10][CH:11]=[C:12]([O:14]C(=O)C)[CH3:13])[C:4]([CH3:9])([CH3:8])[CH2:5][CH2:6][CH:7]=1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[CH3:1][C:2]1[C:3](=[CH:10][CH2:11][CH:12]([OH:14])[CH3:13])[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH:7]=1
Reactant: CC(=O)OC(C)=CC=C1C(C)=CCCC1(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC1=CCCC(C)(C)C1=CCC(C)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 107.2 %

Procedure:
The resulting crude acetoxy compound of formula II (108 g) is dissolved in 400 ml of ethanol (96%) and added dropwise within 10 minutes at 20°-30° C with slight cooling to a suspension of 20 g of sodium borohydride in 600 ml of 96% ethanol. The mixture is then heated until a slight reflux occurs and stirred at this temperature for 15 minutes. The end of the reaction can be detected by a spontaneous colour change from dark-yellow to lemon-yellow. After cooling to room temperature, the cloudy mixture is poured on to saturated ammonium chloride solution/ice and the mixture is extracted with hexane. After the usual washing to neutrality with water and drying over anhydrous sodium sulphate, the solvent is evaporated under a vacuum. There are obtained 96 g of crude 4-(2,6,6-trimethyl-2-cyclohexen-1-ylidene)-butan-2-ol (formula III).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]1[S:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([F:19])[C:17]=2[N:18]=1.[OH:20]O>C(Cl)Cl.C[Re](=O)(=O)=O>[Cl:9][C:4]1[CH:5]=[C:6]([I:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[C:10]1[S:11][C:12]2[CH:13]=[N+:14]([O-:20])[CH:15]=[C:16]([F:19])[C:17]=2[N:18]=1
Reactant: OO
Reactant: Fc1cncc2sc(-c3c(Cl)cc(I)cc3Cl)nc12
Agent: C[Re](=O)(=O)=O
Solvent: ClCCl
Product: [O-][n+]1cc(F)c2nc(-c3c(Cl)cc(I)cc3Cl)sc2c1
Yield: 45 %

Procedure:
To a solution of 2-(2,6-dichloro-4-iodophenyl)-7-fluorothiazolo[5,4-c]pyridine (5.3 g, 12.6 mmol) in DCM (100 mL) under a nitrogen atmosphere was added methyltrioxorhenium(VII) (313 mg, 1.3 mmol) followed by 30% aqueous hydrogen peroxide (2.6 mL, 25.1 mmol). The reaction mixture was stirred at room temperature for 48 hours with a further two additions of methyltrioxorhenium(VII) (313 mg, 1.3 mmol) and 30% aqueous hydrogen peroxide (2.6 mL, 25.1 mmol) added over this period. The precipitate obtained was collected by filtration and the filtrate was partitioned between water. The aqueous layer was extracted with DCM (×2). The combined organic phases were washed with a saturated solution of NaHCO3, dried (MgSO4) and concentrated under reduced pressure. The resultant residue was combined with the previously filtered solid and was purified by column chromatography on silica gel eluting with 0-90% EtOAc in petroleum ether (40-60° C.), followed by 0-10% MeOH in DCM to afford the title compound as a white solid (2.5 g, 45% yield). LCMS (Method D): RT=3.36 min, m/z: 441 [M+H+].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:17]1[CH:18]=[CH:19][C:20]2[N:24]=[C:23]([CH2:25][CH3:26])[N:22]([CH3:27])[C:21]=2[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC.N>[Cu]I.CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([CH2:25][CH3:26])[N:22]([CH3:27])[C:21]=3[CH:28]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1nc2ccc(Br)cc2n1C
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: CCc1nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cc2n1C
Temperature: 150 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
A mixture of 4-(benzyloxy)pyridin-2(1H)-one (1.0 g), 6-bromo-2-ethyl-1-methyl-1H-benzimidazole (1.19 g), potassium carbonate (2.06 g), N,N′-dimethylethylenediamine (0.53 ml), CuI (0.95 g) and DMSO (20 ml) was stirred at 150° C. for 2 h. After cooling to 0° C., 28% NH3 solution (56.0 ml) was added. The precipitate was collected by filtration. The collected material was dissolved in THF, passed through a plug of NH silica gel (EtOAc) and concentrated in vacuo. The resulting solid was collected to give the title compound (1.03 g) as a pink solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[NH2:11][N:12]1[C:17]2[C:18]([CH2:29]O)=[CH:19][CH:20]=[C:21]([C:22]3[C:23]([CH3:28])=[N:24][O:25][C:26]=3[CH3:27])[C:16]=2[O:15][CH2:14][CH:13]1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:28][C:23]1[C:22]([C:21]2[C:16]3[O:15][CH2:14][CH:13]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:12]4[C:17]=3[C:18]([CH:29]=[N:11]4)=[CH:19][CH:20]=2)=[C:26]([CH3:27])[O:25][N:24]=1
Reactant: Cc1noc(C)c1-c1ccc(CO)c2c1OCC(c1ccccc1)N2N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1noc(C)c1-c1ccc2cnn3c2c1OCC3c1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 31.9 %

Procedure:
A solution of 2.0 M oxalyl chloride in methylene chloride (0.132 mL) at −78° C. was treated with methylene chloride (0.363 mL) followed by dimethyl sulfoxide (0.025 mL, 0.353 mmol) dropwise. The reaction mixture was stirred at −78° C. for 20 min and treated with a solution of [4-amino-8-(3,5-dimethylisoxazol-4-yl)-3-phenyl-3,4-dihydro-2H-1,4-benzoxazin-5-yl]methanol (0.062 g, 0.18 mmol) in methylene chloride (1.50 mL) dropwise. The reaction mixture was stirred at −78° C. for 1 h and treated with triethylamine (0.0984 mL, 0.706 mmol) dropwise. The reaction mixture was stirred at −78° C. for 1 h and warmed to 25° C. The reaction mixture was quenched with water (2 mL) and diluted with methylene chloride (30 mL) and saturated ammonium chloride solution (10 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated to give a tan foam. Purification via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% trifluoroacetic acid, at flow rate of 60 mL/min) gave the desired product (19 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.43 (d, J=8.3 Hz, 1H), 7.39-7.30 (m, 3H), 7.13-7.06 (m, 2H), 7.03 (d, J=8.3 Hz, 1H), 5.90 (dd, J=3.9 Hz, 1H), 4.79 (dd, J=11.6, 3.4 Hz, 1H), 4.69 (dd, J=11.6, 4.6 Hz, 1H), 2.32 (s, 3H), 2.16 (s, 3H). LCMS calculated for C20H18N3O2 (M+H)+: m/z=332.1. found: 332.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[C:17]([Cl:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[Cl:20])=[N:6][CH:7]=1.[Li]CCCC.[CH2:26]([O:28][C:29]([C:31]1[C@@H:32]2[N:47]([CH3:48])[C@H:36]([CH2:37][C:38]=1OS(C(F)(F)F)(=O)=O)[CH2:35][N:34]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:33]2)=[O:30])[CH3:27].[NH4+].[Cl-]>C1COCC1.[Cl-].[Cl-].[Zn+2].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>[CH2:26]([O:28][C:29]([C:31]1[C@@H:32]2[N:47]([CH3:48])[C@H:36]([CH2:37][C:38]=1[C:2]1[CH:7]=[N:6][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]3[C:17]([Cl:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[Cl:20])=[CH:4][CH:3]=1)[CH2:35][N:34]([C:49]([O:51][C:52]([CH3:53])([CH3:55])[CH3:54])=[O:50])[CH2:33]2)=[O:30])[CH3:27]
Reactant: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
Reactant: Cc1cc(Cl)c(OCCOc2ccc(Br)cn2)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C1=C(c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)nc2)C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]1N2C
Temperature: -78 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A sol. of 5-bromo-2-[2-(2,6-dichloro-4-methyl-phenoxy)-ethoxy]-pyridine (790 mg, 2.10 mmol) in THF (18 mL) was cooled to −78° C. BuLi (1.6M in hexane, 2.65 mL, 4.20 mmol) was added. The mixture was stirred at −78° C. for 1 h, and ZnCl2 (1M in THF, 6.30 mL, 6.30 mmol) was added. The mixture was allowed to warm to rt. A sol. of (rac.)-(1R*,5S*)-9-methyl-7-trifluoromethanesulfonyloxy-3,9-diaza-bicyclo[3.3.1]non-6-ene-3,6-dicarboxylic acid 3-tert-butyl ester 6-ethyl ester (WO 2003/093267; 641 mg, 1.40 mmol) in THF (3.00 mL), and then Pd(PPh3)4 (40 mg, 0.035 mmol) were added. The mixture was rapidly heated to 55° C., and was stirred at this temperature for 20 min. The mixture was allowed to cool to rt, and aq. sat. NH4Cl was added. The solvents were partially removed under reduced pressure, and the rest was diluted with EtOAc. This mixture was washed with water. The aq. layer was extracted back with EtOAc (3×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 1:3→EtOAc) yielded the title compound (444 mg, 52%). LC-MS: tR=0.94 min; ES+: 606.28.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[C:13]([C:18](=[N:20][NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=3)=[O:23])[CH3:19])[C:12]=2[OH:34])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH2:16][CH3:17])[N:14]=[C:13]([C:18](=[N:20][NH:21][C:22]([C:24]3[CH:33]=[CH:32][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)=[O:23])[CH3:19])[C:12]=2[OH:34])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc(C(C)=NNC(=O)c2ccc(C(=O)OC)cc2)c(O)c1-c1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1nc(C(C)=NNC(=O)c2ccc(C(=O)O)cc2)c(O)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 44.6 %

Procedure:
To methyl 4-[(2-{1-[5-(4-t-butylphenyl)-1-ethyl-4-hydroxy-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.032 mmol, 15.0 mg), methanol (1.5 mL) was added, and 1 M aqueous sodium hydroxide (0.162 mmol, 0.162 mL) was added at room temperature. After 30 minutes of stirring at room temperature and 1.25 hours of stirring at 60° C., the reactor was cooled to 0° C., and 1 M hydrochloric acid (0.162 mmol, 0.162 mL) and water were added. The precipitated solid was recovered by filtration, washed with water, dried by means of a vacuum pump and purified by silica gel thin layer chromatography (chloroform/methanol=10/1) to give the desired product as a yellow solid (6.4 mg, yield 44%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([OH:9])=O)=[N+:2]=[N-:3].C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[C:22]([O:36][CH3:37])=[C:23]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:24]=[C:25]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:26]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C1COCC1.CN(C=O)C>[N:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:7]([NH:20][C:21]1[CH:26]=[C:25]([C:27]([CH3:29])([CH3:30])[CH3:28])[CH:24]=[C:23]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:22]=1[O:36][CH3:37])=[O:9])=[N+:2]=[N-:3]
Reactant: Cc1ccc(C(=O)O)cc1N=[N+]=[N-]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reaction time: 1 h
Yield: 94.2 %

Procedure:
3-Azido-4-methyl benzoic acid (240 mg, 1.24 mmoL) was suspeneded in 3 mL of CH2Cl2 and 3 mL of THF. Oxalyl choride (0.14 mL, 1.5 mmol) was added, followed by 1 drop of 10% DMF in THF. The mixture was stirred for 1 h and then concentrated. The residue was redissolved in dry CH2Cl2 (5 mL) and 391 mg (1.27 mmol) of N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide was added followed by 0.4 ml (2.5 mmol) of DIPEA. The mixture became homogeneous, and was stirred for 4 h, and then was washed with 1M NaHSO4 and saturated NaHCO3. The washes were extracted once with CH2Cl2 and the extracts were combined, dried with Na2SO4, filtered, and concentrated to provide 516 mg (93%) of 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide as a tan powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CCO>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1CCNC1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(N2CCCC2)nc1
Temperature: 70 °C
Yield: 78.1 %

Procedure:
To a slurry of 2-chloro-5-nitropyridine (10 g, 63.1 mmol) in EtOH (100 mL) at room temperature was added pyrrolidine (15.72 mL, 189 mmol) and the mixture was heated at 70° C. for 18 h. The cooled solution was concentrated in vacuo and the residue partitioned between CH2Cl2 and 1M NaOH. The organic layer was dried (Na2SO4), filtered and solvent removed in vacuo to give title compound (9.52 g, 78%). MS (ESI) m/z 194 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([O:15][C@@H:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[CH3:21])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([O:15][C@@H:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[CH3:21])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: C[C@@H]1CCC[C@H]1Oc1cc(Cl)ncn1
Reactant: CC#CCO
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(O[C@@H]2CCC[C@H]2C)ncn1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
In 3.6 ml of tetrahydrofuran was suspended 0.09 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.14 g of 2-butyn-1-ol was slowly added dropwise under stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, and 0.6 ml of a tetrahydrofuran solution containing 0.38 g of 4-chloro-6-(trans-2-methylcyclopentyloxy)pyrimidine was slowly added dropwise, followed by stirring at room temperature for 3 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.36 g of 4-(2-butynyloxy)-6-(trans-2-methylcyclopentyloxy)pyrimidine (the present compound (169)).
Reaction SMILES: [C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:17][N:18](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:19].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNC>C(Cl)(Cl)Cl.CN(C=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](=[O:13])[N:18]([CH3:19])[CH3:17])[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 70.8 %

Procedure:
General procedure A was followed using N-Boc-isonipecotic acid (0.20 g, 0.86 mmol), HATU (0.43 g, 1.1 mmol), DIPEA (0.76 mL, 4.4 mmol), dimethylamine hydrochloride (92 mg, 1.1 mmol) and DMF (4 mL) to furnish the title compound as a pale brown oil (156 mg, 70%), umax (CHCl3)/cm−1 3020, 2861, 1684, 1631, 1417, 1367, 1151, 1030; m/z (ESI) C13H24N2NaO3 requires 279.1679, found [M+Na]+ 279.1677.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC[N:16]([CH:20]([CH3:22])C)[CH:17]([CH3:19])C.N1CCCC1>C(#N)C>[C:8]1([CH:2]([N:16]2[CH2:17][CH2:19][CH2:22][CH2:20]2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C(Br)c1ccccc1
Solvent: C1CCNC1
Solvent: CC#N
Product: CCOC(=O)C(c1ccccc1)N1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 109.8 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) was dissolved in acetonitrile (4.0 ml). DIPEA (0.26 ml, 1.48 mmol) and pyrrolidine (0.12 ml, 1.48 mmol) were sequentially added and the solution was stirred at room temperature for 1.5 hours. Acetonitrile was evaporated and the residue was purified by flash chromatography (petroleum ether/EtOAc=9/1) to obtain ethyl 2-phenyl-2-(pyrrolidin-1-yl)acetate (315 mg, quantitative yield) as a colorless oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH2:9][C:8](=[O:12])[C:7]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:6]1.F[B-](F)(F)F.[CH3:24][S:25][C:26](=[S+]C)[S:27][CH3:28].O1CCOCC1.N1C=CC=CC=1>C(OCC)(=O)C>[CH3:24][S:25][C:26]([S:27][CH3:28])=[C:9]1[C:8](=[O:12])[C:7]([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[N:6][N:5]([CH2:4][CH2:3][CH:2]([CH3:18])[CH3:1])[C:10]1=[O:11]
Reactant: CC(C)CCN1N=C(c2cccs2)C(=O)CC1=O
Reactant: CSC(SC)=[S+]C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CSC(SC)=C1C(=O)C(c2cccs2)=NN(CCC(C)C)C1=O
Temperature: 100 °C
Yield: 20 %

Procedure:
2-(3-Methyl-butyl)-6-thiophen-2-yl-2H-pyridazine-3,5-dione (0.215 g, 0.814 mmol) and (bis-methylsulfanyl-methylene)-methyl-sulfonium tetrafluoro borate salt (prepared as described in WO 2008/011337; 0.79 g, 3.26 mmol) were combined. 1,4-Dioxane (1.06 mL) and pyridine (0.15 mL) were added. The mixture was heated at 100° C. for 1 h while stirring. Upon cooling, the mixture was diluted with ethyl acetate (30 mL) and washed with water (15 mL), saturated aqueous brine solution (15 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was passed through a plug of silica gel (Merck silica gel 60, 40-63 μm; eluting with 25% ethyl acetate in hexanes). Upon concentrating, 4-(bis-methylsulfanyl-methylene)-2-(3-methyl-butyl)-6-thiophen-2-yl-2H-pyridazine-3,5-dione (0.06 g, 0.163 mmol) was obtained as an orange solid. The solid was combined with 2-amino-4-(methanesulfonylamino-methyl)-thiophene-3-sulfonic acid amide (0.07 g, 0.245 mmol). Toluene (5 mL) and 1,4-dioxane (10 mL) were added and the mixture stirred at 100° C. in a sealed vial for 2 h. Upon cooling, the mixture was concentrated in vacuo to afford a thick oil. Purification by flash column chromatography (Teledyne Isco RediSep column; 5-100% ethyl acetate in hexanes) afford the desired product, N-{3-[5-hydroxy-2-(3-methyl-butyl)-3-oxo-6-thiophen-2-yl-2,3-dihydro-pyridazin-4-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.018 g, 0.032 mmol, 10%) as a light orange powder. 1H NMR (400 MHz, DMSO-d6) δ: 0.95 (6H, d, J=6.2 Hz), 1.57-1.69 (3H, m), 2.97 (3H, s), 4.13 (2H, t, J=7.1 Hz), 4.27 (2H, d, J=5.5 Hz), 7.13-7.16 (1H, m), 7.31 (1H, s), 7.64-7.69 (2H, m), 7.89 (1H, d, J=4.0 Hz). LC-MS (ESI) calculated for C20H23N5O6S4 557.05. found 558.0 [M+H+].
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([F:7])([F:6])[F:5].[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]([NH2:18])=[S:17])[CH2:12][CH2:11]1>C(O)C>[CH3:9][N:10]1[CH2:15][CH2:14][N:13]([C:16]2[S:17][CH:2]=[C:3]([C:4]([F:7])([F:6])[F:5])[N:18]=2)[CH2:12][CH2:11]1
Reactant: CN1CCN(C(N)=S)CC1
Reactant: O=C(CBr)C(F)(F)F
Solvent: CCO
Product: CN1CCN(c2nc(C(F)(F)F)cs2)CC1

Procedure:
To a solution of 33.9 g 1-bromo-3,3,3-trifluoro-2-propanone in 300 ml of absolute ethanol are added 28.6 g 4-methyl-1-piperazinylthiocarboxamide. The mixture is refluxed for 4 hours, evaporated to dryness and the residue partitioned between ethyl ether and aqueous NaOH. The ether phase is washed, dried and evaporated, whereby the title compound is obtained, m.p. 62° (ethyl acetate/hexane).
Reaction SMILES: CCS.[Li]CCCC.Cl.C[O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:26][CH:25]=1)=[O:23])=[C:17]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=1)[CH2:16][CH2:15]2.C(Cl)(Cl)Cl>C(OCC)C.CN(C=O)C.CO>[OH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:26][CH:25]=1)=[O:23])=[C:17]([C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([O:45][CH3:46])[CH:40]=1)[CH2:16][CH2:15]2
Reactant: COc1cccc(C2=C(C(=O)c3ccc(OCCN4CCCCC4)cc3)c3ccc(OC)cc3CC2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCS
Solvent: CN(C)C=O
Product: COc1cccc(C2=C(C(=O)c3ccc(OCCN4CCCCC4)cc3)c3ccc(O)cc3CC2)c1
Temperature: 105 °C

Procedure:
To EtSH (1.86 g, 2.21 mL. 0.03 mol) in anhydrous ethyl ether (30 mL) at -70° C. under a dry nitrogen atmosphere in a 200 mL single neck RB flask was added slowly via syringe 1.6M n-BuLi (12.5 mL, 0.02 mol). After addition was complete, the ether was removed under vacuum and a solution of [3,4-dihydro-6-methoxy-2-(3-methoxyphenyl)-1-naphthalenyl][4-[2-(1-piperdinyl)ethoxy]phenylmethanone]hydrochloride (1.07 g, 0.002 mol) in anhydrous DMF (30 mL) was added. The reaction mixture was heated in a 105° C. oil bath for 3 hours. TLC analysis (SiO2, chloroform:methanol, 9:1) showed the starting material to be nearly gone. Numerous spots were present at higher, as well as lower Rf. The spots lower than starting material were attributed to the desired product and the corresponding monophenolic species. The reaction mixture was allowed to cool somewhat and most of the DMF was removed under reduced pressure. The residue was distributed between brine (300 mL) which contained 5 g ammonium chloride and ethyl acetate (100 mL). The aqueous phase was separated and extracted with 3 25 mL portions of ethyl acetate. The combined ethyl acetate extracts were washed with 4 10 mL portions of brine, dried over anhydrous magnesium sulfate, and concentrated to provide 1.31 g. of a brown foul-smelling oil. The oil was purified (in two portions) by radial chromatography over silica gel with an elution gradient consisting of 2.5% methanol in chloroform and changing gradually to 40% of methanol. The product eluted slightly slower than the starting material. Following combination and concentration of the appropriate fractions, 338 mg (35%) of the desired material was obtained. In order to improve the purity, the material was re-chromatographed, which provided 272 mg (28%) of essentially pure material.