Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.S(=O)(=O)(O)O.[Cl:8][C:9]1[CH:31]=[CH:30][C:12]2[C:13]3[C:14](=[CH:25][NH:26][C:27]=3[CH2:28][CH3:29])[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[CH:10]=1.S(=O)(O)[O-:33].[Na+]>C(O)(=O)C>[Cl:8][C:9]1[CH:31]=[CH:30][C:12]2[C:13]3[CH:27]([CH2:28][CH3:29])[NH:26][C:25](=[O:33])[C:14]=3[CH2:15][N:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:11]=2[CH:10]=1
Reactant: O=S([O-])O
Reactant: CCc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC1NC(=O)C2=C1c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 1 h

Procedure:
In one portion, 0.9 ml (7.9 mmol) of 30% hydrogen peroxide was added to 40 ml of a 1% solution of concentrated sulfuric acid in acetic acid. After stirring for 1 hour, 2.0 g (5.6 mmol) of 8-chloro-6-(2-chlorophenyl)-1-ethyl-2H,4H-pyrrolo[3,4-d][2]benzazepine were added, and the resulting mixture was stirred for 20 minutes. The excess peracid was discharged by the addition of saturated aqueous sodium bisulfite solution, and the mixture was concentrated at reduced pressure. The residue was partitioned between methylene chloride and water and neutralized with concentrated ammonium hydroxide solution. The methylene chloride solution was washed with brine, dried over anhydrous sodium sulfate, and concentrated at reduced pressure. The resulting oil was crystallized from ether to give 8-chloro-6-(2-chlorophenyl)-1-ethyl-1,4-dihydropyrrolo[3,4-d][2]benzazepin-3(2H)-one as yellow prisms, mp 233°-235° C. Recrystallization from a mixture of ethyl acetate and methanol gave colorless prims, mp 236°-237° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]([CH:22]=1)=[N:20][CH:19]=[C:18]1[C:13]=2[CH:14]([OH:23])[CH2:15][CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])(=O)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]([CH:22]=1)=[N:20][CH:19]=[C:18]1[C:13]=2[CH:14]([O:23][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:15][CH2:16][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: OC1CCCc2cnc3cc(OCc4ccccc4)ccc3c21
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1CCCc2cnc3cc(OCc4ccccc4)ccc3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.6 %

Procedure:
To a suspension of Compound 224 (1.10 g, 3.60 mmol) in dry CH2Cl2 (10 mL) under ice-cooling was added successively 2,6-lutidine (0.59 mL, 5.07 mmol) and tert-butyldimethylsilyl trifluromethanesulfonate (0.99 mL, 4.31 mmol), the resultant homogeneous solution was then stirred at 25° C. for 30 minutes. The reaction mixture was diluted with CH2Cl2 (20 mL), washed with brine, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, ethyl ether-petroleum ether-benzene=1:2:2) to give Compound 225 (1.475 g, 98 percent): white solid; mp 123°-125° C.; Rf =0.50 (silica, 33 percent ethyl ether in benzene); IR (CHCl3) νmax 2952, 2933, 1621, 1506, 1336, 1295, 1256, 1240, 1174, 1151, 1090, 1025, 838 cm-1 ; 1H NMR (300 MHz, CDCl3) δ 8.61 (s, 1 H, H6), 7.98 (d, J=9.2 Hz, 1 H, H1), 7.55-7.48 (m, 3 H, H4 and aromatic), 7.46-7.34 (m, 3 H, aromatic), 7.27 (dd, J=9.2, 2.7 Hz, 1 H, H2), 5.42 (t, J=2.6 Hz, 1 H, H10), 5.20 (s, 2 H, benzylic), 3.04-2.93 (m, 1 H, H7), 2.87-2.72 (m, 1 H, H7), 2.26-2.05 (m, 2 H, H8 or H9), 1.92-1.76 (m, 2 H, H8 or H9), 0.84 (s, 9 H, SiC(CH3)3), 0.22 (s, 6 H, Si(CH3)2); MS (FAB+) m/e (rel intensity) 420 (M+H, 100), 362 (23), 330 (3), 288 (9); HRMS for C26H34NO2Si (M+H), calcd 420.2359, found 420.2360.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([CH:29]([OH:40])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[C:27]([CH:41]([CH3:43])[CH3:42])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:46])[CH2:22][C:23]([CH3:45])([CH3:44])[O:24]3)=[CH:15][CH:14]=1.CO>O1CCCC1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([C@H:29]([OH:40])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:39])[F:37])=[CH:32][CH:31]=3)=[C:27]([CH:41]([CH3:42])[CH3:43])[CH:26]=[C:25]3[C:20]=2[C@@H:21]([OH:46])[CH2:22][C:23]([CH3:44])([CH3:45])[O:24]3)=[CH:15][CH:14]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1[C@H](O)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Reaction time: 0.5 h

Procedure:
340 μl (1.89 mmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 10.58 mg (70 μmol) of (1R,2S)-1-aminoindan-2-ol in ±1 ml of tetrahydrofuran, and the mixture is stirred for another 30 min. A solution of 230 mg (0.47 mmol) of rac-5-(4-fluorophenyl)-6-{hydroxy[4-(trifluoromethyl)phenyl]methyl}-7-isopropyl-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (Example 21A) in 11 ml of tetrahydrofuran are then very slowly added dropwise, and the mixture is stirred overnight. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: gradient cyclohexane/dichloromethane/ethyl acetate 40:40:1→2:2:1) gives the diastereomerically pure target compounds.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O.CO.C([O-])(O)=O.[Na+]>CN(C=O)C>[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1
Reactant: Nc1nc(Br)cs1
Reactant: OB(O)c1ccco1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1nc(-c2ccco2)cs1
Temperature: 70 °C

Procedure:
4-Bromo-thiazol-2-ylamine (100 mg, 0.34 mmol) was combined with 57 mg (0.51 mmol) of 2-furan boronic acid. To this mixture was added 5 mL of MeOH, 1 mL of sat. NaHCO3 (aq), and 0.8 mL of DMF. Reaction mixture was degassed and Pd[P(Ph)3]4 (25 mg) was added. Reaction mixture was heated at 70° C. for 7 hours. The reaction mixture was brought to room temperature and filtered. The filtrate was evaporated and purified using reverse phase HPLC.
Reaction SMILES: C([O:3][CH2:4][CH3:5])=O.[CH3:6][Si:7]([CH2:10][Mg]Cl)([CH3:9])[CH3:8].Cl.[NH4+]>C(OCC)C>[CH3:6][Si:7]([CH3:10])([CH3:9])[CH2:8][CH:4]([OH:3])[CH2:5][Si:7]([CH3:9])([CH3:8])[CH3:6]
Reactant: CCOC=O
Reactant: C[Si](C)(C)C[Mg]Cl
Agent: Cl
Agent: [NH4+]
Solvent: CCOCC
Product: C[Si](C)(C)CC(O)C[Si](C)(C)C
Yield: 70 %

Procedure:
Ethyl formate (0.1 mol) was slowly added to 0.3 mol of trimethylsilylmethyl magnesium chloride solution dissolved in diethyl ether which was contained in a 500 ml flask. The mixture was allowed to react under reflux for about 24 hours. After hydrolyzing the reactant using ammonium hydrochloride solution, the obtained reaction product was separated and purified by a vacuum distillation and a 70 percent yield was obtained. The structure of the obtained distillates was analyzed using NMR and a spectroscopic method of FT-IR spectroscopy.
Reaction SMILES: [OH-].[Na+].Cl.Cl[CH2:5][C:6]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:9]=[CH:8][N:7]=1.[SH:18][C:19]1[NH:20][C:21]2[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:22]=2[N:23]=1>>[CH3:29][O:28][C:26]1[CH:25]=[CH:24][C:22]2[NH:23][C:19]([S:18][CH2:5][C:6]3[N:11]=[C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)[CH:9]=[CH:8][N:7]=3)=[N:20][C:21]=2[CH:27]=1
Reactant: ClCc1nccc(N2CCOCC2)n1
Reactant: COc1ccc2nc(S)[nH]c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2[nH]c(SCc3nccc(N4CCOCC4)n3)nc2c1
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
5N sodium hydroxide (6.42 ml) was added dropwise to a stirred mixture of 2-chloromethyl-4-morpholinopyrimidine hydrochloride (3.65 g) and 2-mercapto-5-methoxybenzimidazole (2.63 g). Stirring was continued for 1.5 hours and the mixture was allowed to stand for a further 16 hours. After stripping, the solid residue was washed with water and recrystallised from acetonitrile to give 5-methoxy-2-(4-morpholino-2-pyrimidinylmethylthio)-(1H)-benzimidazole (4.09 g), m.p. 188°-92°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([NH:14][C:15]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:26][CH2:25]3)=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])=[CH:10][N:9]=1.[CH:27]1(B(O)O)[CH2:29][CH2:28]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.O>[CH:24]1([C:21]2[CH:22]=[CH:23][C:15]([NH:14][C:11]3[CH:10]=[N:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH:27]4[CH2:29][CH2:28]4)=[N:13][CH:12]=3)=[C:16]([CH:20]=2)[C:17]([OH:19])=[O:18])[CH2:26][CH2:25]1
Reactant: O=C(O)c1cc(C2CC2)ccc1Nc1cnc(-c2ccccc2Cl)nc1
Reactant: OB(O)C1CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)c1cc(C2CC2)ccc1Nc1cnc(-c2ccccc2C2CC2)nc1
Temperature: 110 °C

Procedure:
In a schlenck tube, a mixture of 2-(2-(2-chlorophenyl)pyrimidin-5-ylamino)-5-cyclopropylbenzoic acid (0.55 mmol, 0.200 g), cyclopropylboronic acid (0.71 mmol, 0.061 g), K3PO4 (1.86 mmol, 0.395 g), PCy3 (0.05 mmol, 0.015 g) and Pd(AcO)2 (0.03 mmol, 0.006 g) in a mixture of toluene/water 6:1 (6 ml) was heated at 110° C. for 72 hours, under argon atmosphere. The crude mixture was poured into water and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and the solvent removed. The crude mixture was purified by reverse phase chromatography eluting with a gradient of 100% water to 100% MeOH/AcN 1:1 affording 0.016 g (71% of yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[C:19](=[C:21]([CH2:28][CH3:29])[N:22]([CH2:24][CH2:25][O:26][CH3:27])[N:23]=3)[N:20]=2)[C:7](OCCCC)=[N:8][CH:9]=1)(=[O:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH3:41][O:42][CH2:43][CH:44]([OH:46])[CH3:45]>>[C:1]([C:4]1[CH:5]=[C:6]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[C:19](=[C:21]([CH2:28][CH3:29])[N:22]([CH2:24][CH2:25][O:26][CH3:27])[N:23]=3)[N:20]=2)[C:7]([O:46][CH:44]([CH3:45])[CH2:43][O:42][CH3:41])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: COCC(C)O
Reactant: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(CCOC)nc2c(=O)[nH]1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCc1c2nc(-c3cc(C(C)=O)cnc3OC(C)COC)[nH]c(=O)c2nn1CCOC
Yield: 29 %

Procedure:
5-(5-Acetyl-2-butoxy-3-pyridinyl)-3-ethyl-2-(2-methoxyethyl)-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Example 16) (150 mg, 0.36 mmol) was dissolved in 1-methoxypropan-2-ol (3 mL) and the solution heated at reflux for 5 minutes to degas the solution. After cooling potassium hexamethyldisilazide (360 mg, 1.80 mmol) was added and the solution reheated to reflux for 8 h. The cooled reaction mixture was evaporated to dryness and partitioned between ethyl acetate and water after 1N hydrochloric acid had been used to adjust the pH to 8. The organic phase was separated and washed with brine, dried (MgSO4) and evaporated. The crude product was purified by flash column chromatography (gradient elution from 100% dichloromethane 0.5% ammonia to 99% dichloromethane:1% methanol:0.5% ammonia) to give the title compound (45 mg, 29%).
Reaction SMILES: C([NH:8][S:9]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=[O:11])=[O:10])(OC(C)(C)C)=O.[Na+].[I-].C[Si](Cl)(C)C.O>CC#N>[NH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([S:9]([NH2:8])(=[O:11])=[O:10])=[CH:13]1
Reactant: CC(C)(C)OC(=O)NS(=O)(=O)c1c[nH]c2ccccc12
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
N-Boc 1H-indole-3-sulfonamide (1.47 g, 4.96 mmol) was dissolved in CH3CN (75 mL), and NaI (3.72 g, 24.80 mmol) added. The mixture was cooled to 0° C. under N2, and tri-methylsilyl chloride (TMS-Cl, 2.69 g, 24.80 mmol) added dropwise, the mixture stirred for 15 min at 0° C., then stirred at RT overnight. The mixture was poured into water, the resulting off-white precipitate filtered, washed with water and hexane, and air dried to provide 1H-indole-3-sulfonic acid amide (947 mg, 97% yield), which was used without further purification.
Reaction SMILES: Br[C:2]1[NH:21][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:20]=[CH:19][C:14]4[NH:15][C:16](=[O:18])[S:17][C:13]=4[CH:12]=3)[C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.[Na+].CN(C)CCN>CS(C)=O>[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([C:2]2[NH:21][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]4[CH:20]=[CH:19][C:14]5[NH:15][C:16](=[O:18])[S:17][C:13]=5[CH:12]=4)[C:4]=3[CH:3]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: O=c1[nH]c2ccc(Nc3ncnc4[nH]c(Br)cc34)cc2s1
Reactant: O=S([O-])c1ccc(Cl)cc1
Agent: CN(C)CCN
Agent: [Na+]
Solvent: CS(C)=O
Product: O=c1[nH]c2ccc(Nc3ncnc4[nH]c(S(=O)(=O)c5ccc(Cl)cc5)cc34)cc2s1
Yield: 3.5 %

Procedure:
A mixture comprising 50 mg (138 μmol) 6-[(6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-1,3-benzothiazol-2(3H)-one (prepared according to example 8), 0.6 mL dimethyl sulfoxide, 109.7 mg sodium 4-chlorobenzenesulfinate, 7.7 mg (mu-benzene-1,2,3,4-tetrayl-1 kappa2C1,C2:2kappa2C3,C4)[bis(trifluoromethanesulfonatato-kappaO)]dicopper, 2.97 μL N,N-dimethylethane-1,2-diamine was heated at 120° C. for 2 hours to give after chromatography 2.2 mg (3%) of the title compound.
Reaction SMILES: C(#N)C.Cl.[CH3:5][N:6]([CH3:10])[CH2:7][CH2:8][SH:9].C[O-].[Na+].Cl[CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CO>[CH3:5][N:6]([CH3:10])[CH2:7][CH2:8][S:9][CH2:15][C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CN(C)CCS
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: CCOC(=O)CC(=O)CSCCN(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
200 ml of acetonitrile was added to 28.3 g of 2-dimethylaminoethanethiol hydrochloride, and after 80 ml of sodium methoxide-containing 28% methyl alcohol solution was added thereto with cooling in an ice bath, 32.9 g of ethyl 4-chloroacetoacetate was dropwise added thereto with cooling in an ice bath. After the dropwise addition, the whole was stirred for 2 hours at 40° C., and then the inorganic salt was separated by filtration and the resulting filtrate was dried under reduced pressure. The oily substance obtained was purified by silica gel column chromatography (with moving phase solvent of chloroform/methyl alcohol, 10/1) to obtain 41.8 g of ethyl 4-(2-dimethylaminoethylthio)acetoacetate. To 23.3 g of the ethyl 4-(2-dimethylaminoethylthio)acetoacetate thus-obtained were added 8.4 g of 3-amino-1,2,4-triazole and 4.0 ml of acetic acid, and the whole was heated under reflux for 4 hours. After the reaction, 100 ml of methyl alcohol was added to the reaction solution and stirred with cooling in an ice bath, and the crystal precipitate was taken out by filtration and recrystallized from 300 ml of methyl alcohol to obtain 10.2 g of the desired product. M.P.: 109°-110° C.
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2([CH2:19][Cl:20])CC[N+](F)(CC2)C1.[Cl-].[Na+].[CH3:24][O:25][C:26]1[CH:27]=[C:28]([C:32](=[O:34])[CH3:33])C=[CH:30][CH:31]=1>C(#N)C>[Cl:20][C:19]1[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][C:28]=1[C:32](=[O:34])[CH3:33]
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: COc1cccc(C(C)=O)c1
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(Cl)c(C(C)=O)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of SELECTFLUOR™(5.0 g, 14.1 mmol) and sodium chloride (825 mg, 14.1 mmol) in acetonitrile (200 ml), under nitrogen, was added 1-(3-methoxyphenyl)ethanone (1.94 ml, 14.1 mmol) and the reaction mixture was stirred at room temperature for 5 days. To the mixture was added distilled water (200 ml) and the solution was extracted with dichloromethane (2×100 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (silica) with gradient elution, ethyl acetate:cyclohexane [5:95 to 10:90]. The appropriate fractions were combined and concentrated to give the title compound (1.12 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([Br:15])[CH:5]=[CH:4][C:3]=1[OH:16].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25](Br)=[O:26]>C(#N)C.O>[Br:15][C:6]1[CH:5]=[CH:4][C:3]2[O:16][CH2:24][C:25](=[O:26])[NH:1][C:2]=2[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1c(O)ccc(Br)c1Oc1ccccc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C1COc2ccc(Br)c(Oc3ccccc3)c2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A solution of 2-amino-4-bromo-3-phenoxyphenol (0.060 g, 0.214 mmol) in acetonitrile (3.88 mL) and water (1.21 mL) was treated with potassium carbonate (0.118 g, 0.857 mmol), followed by the addition of bromoacetyl bromide (0.0279 mL, 0.321 mmol), and the resultant reaction mixture was stirred at RT for 30 min, after which time additional bromoacetyl bromide (0.0186 mL, 0.214 mmol) was added dropwise and the reaction mixture was stirred at RT for 1 h, then warmed to 75° C. and stirred at that temperature for 30 min. The reaction mixture was concentrated and diluted with ethyl acetate and water. Layers were separated and the organic layer was washed with brine, dried with sodium sulfate, filtered, and concentrated in vacuo the yield a crude product. Purification by flash column chromatography (100% hexanes to 50% EtOAc/hexanes) gave the desired product (59.5 mg, 87%) as a white solid. LCMS calculated for C14H11BrNO3 (M+H)+: m/z=320.0, 322.0. found: 319.9, 321.9.
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH:10]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:23][OH:24])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1.[C:25]1([CH2:31]Br)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1>[O:3]1[C:7]2([CH2:8][CH2:9][CH:10]([C:13]3[C:18]([C:19]([F:21])([F:20])[F:22])=[CH:17][CH:16]=[CH:15][C:14]=3[CH2:23][O:24][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:11][CH2:12]2)[O:6][CH2:5][CH2:4]1
Reactant: BrCc1ccccc1
Reactant: OCc1cccc(C(F)(F)F)c1C1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)c1cccc(COCc2ccccc2)c1C1CCC2(CC1)OCCO2

Procedure:
A suspension of 3.3 grams (0.084 mole) of sodium hydride (60% in mineral oil) in 20 mL of toluene is stirred, and a solution of 24.3 grams (0.080 mole) of [(1,4-dioxaspiro[4.5]decan-8-yl)(3-trifluoromethylphenyl)]methanol in 65 mL of toluene is added dropwise. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about one hour. After this time a solution of 13.7 grams (0.080 mole) of phenylmethyl bromide in 45 mL of toluene is added dropwise. Upon completion of addition, the reaction mixture is heated to reflux where it is stirred for about 4 hours. The reaction mixture is then cooled and shaken with water. The organic layer is separated and dried with magnesium sulfate. The mixture is filtered and the filtrate is concentrated under reduced pressure, yielding phenylmethyl [(1,4-dioxaspiro[4.5]decan-8-yl)(3-trifluoromethylphenyl)]methyl ether.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:12][CH3:13])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH:20]1([C:26](Cl)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>CC(C)=O.O>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[C:26]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:27])=[N:5][N:4]=[N:3]1
Reactant: CCNCCCSc1nnnn1C
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCN(CCCSc1nnnn1C)C(=O)C1CCCCC1
Reaction time: 2 h
Yield: 58.2 %

Procedure:
1-Methyl-5-[3-(N-ethylamino)propylthio]-1,2,3,4-tetrazole (1 g) is dissolved in a mixture of acetone (50 ml) and water (10 ml). To the mixture is added potassium carbonate (0.7 g) and thereto is added dropwise with stirring cyclohexanecarboxylic acid chloride (0.9 g) under ice-cooling. Stirring is continued for 2 hours under ice-cooling. After acetone is distilled off, water is added to the resulting residue and the mixture is extracted with chloroform. The chloroform solution is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride and dried over sodium sulfate. Chloroform is distilled off and then the residue is purified by column chromatography (Wakogel C-200), followed by eluting with chloroform to give 1-methyl-5-[3-(N-ethyl-N-cyclohexylcarbonylamino)propylthio]-1,2,3,4-tetrazole (0.9 g), colorless liquid, nD23.5 =1.5267.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4](=[O:12])(=[O:11])[N:3]=1.C(N(C(C)C)CC)(C)C.[C:22]([O:26][C:27]([C:29]1[C:37]2[CH2:36][CH2:35][N:34]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[CH:33]([CH2:47][NH2:48])[C:32]=2[S:31][C:30]=1[NH2:49])=[O:28])([CH3:25])([CH3:24])[CH3:23]>ClCCl>[C:22]([O:26][C:27]([C:29]1[C:37]2[CH2:36][CH2:35][N:34]([CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)[CH:33]([CH2:47][NH:48][C:2]3[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[S:4](=[O:12])(=[O:11])[N:3]=3)[C:32]=2[S:31][C:30]=1[NH2:49])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CN)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(CN2CCc3c(sc(N)c3C(=O)OC(C)(C)C)C2CNC2=NS(=O)(=O)c3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 77.6 %

Procedure:
3-Chloro-benzo[d]isothiazole-1,1-dioxide (160 mg, 0.79 mmol) and diisopropylethylamine (150 μl, 0.86 mmol) were dissolved in dichloromethane (7 ml) at 0° C. 2-Amino-7-aminomethyl-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester (284 mg, 0.70 mmol) was added and the mixture was stirred for 15 minutes at 0° C., diluted with dichloromethane (10 ml) and washed with water (20 ml) and brine (20 ml). The organic phase was dried (MgSO4), filtered, and the solvent evaporated in vacuo. The residue was purified by silica gel chromatography using a gradient of hexanes/ethyl acetate (1:1) to pure ethyl acetate as eluent, which afforded 309 mg (77%) of 2-amino-7-((1,1-dioxo-1H-benzo[d]isothiazol-3-ylamino)methyl)-6-(4-methoxy-benzyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester as an foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(N2CCCCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCCCC2)c2sc(NC(=O)c3ccnc(N4CCN(C)CC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-piperidin-1-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and N-methylpiperazine. ES-MS m/e (%): 467 (M+H+, 100).