Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[C:4]([F:10])[CH:3]=1.CC[O:13][C:14]([CH2:16][CH:17]1[C:22](=O)[CH2:21][CH2:20][CH2:19][CH2:18]1)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:13])[CH2:16][CH:17]3[C:18]([CH2:19][CH2:20][CH2:21][CH2:22]3)=[N:9]2)=[C:4]([F:10])[CH:3]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: NNc1ccc(Cl)cc1F
Solvent: CC(=O)O
Product: O=C1CC2CCCCC2=NN1c1ccc(Cl)cc1F

Procedure:
8.0 Parts of 4-chloro-2-fluorophenylhydrazine and 9.2 parts of ethyl 2-cyclohexanoneacetate [bp 92°-93°, 0.5 mm Hg; prepared by the method described by A. Sergre, et al., J. Amer. Chem. Soc., 79 3503 (1957)] were dissolved in 75 parts of glacial acetic acid, and the resulting solution was refluxed for 16 hours. The reaction solvent was removed under a reduced pressure of 300 mm Hg, and the residual brown oil was dissolved in 150 parts of methylene chloride. The organic solution was washed with saturated aqueous sodium bicarbonate solution, dried with anhydrous magnesium sulfate and the solvent was removed under a reduced pressure of 300 mm Hg to give 2-(4-chloro-2-fluorophenyl)-4,4a,5,6,7,8-hexahydro-3(2H)-cinnolinone as a brown oil that solidified on scratching. Purification was achieved by recrystallization from cyclohexane to yield 5.9 parts of tan solid, mp 110°-112°.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)=[CH:15][C:14]=2[O:32][CH3:33])[N:3]=1.[C:34]([C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39]([NH2:41])=[O:40])#[CH:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:33][O:32][C:14]1[CH:15]=[C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:17]=[CH:18][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([CH2:35][CH2:34][C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([NH2:41])=[O:40])[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][N:5]=1
Reactant: C#Cc1cccc(C(N)=O)c1
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C2CCNCC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2cccc(C(N)=O)c2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)-3-methoxyphenyl)piperidine-1-carboxylate (I34) 0.098 g, 0.20 mmol), 3-ethynylbenzamide (I31) (0.038 g, 0.26 mmol), PdCl2(PPh3)2 (9 mg, 0.01 mmol), triphenylphosphine (0.010 g, 0.04 mmol) and copper(I) iodide (0.009 g, 0.05 mmol) in DMF (2 mL), that had been degassed with nitrogen for 10 minutes, was added triethylamine (0.090 mL, 0.65 mmol). The mixture was degassed with nitrogen then heated to 120° C. for 25 minutes under microwave irradiation. On cooling to room temperature the resulting mixture was left overnight, then an additional portion of 3-ethynylbenzamide (I26) (0.047 g, 0.32 mmol) was added. After degassing with nitrogen the reaction was heated at 120° C. for 25 minutes under microwave irradiation. The volatiles were evaporated under reduced pressure and the residue purified using silica gel column chromatography (20-70% EtOAc/petroleum benzine 40-60° C.) to give the title compound (I35) (0.073 g, 61%) as a yellow solid; 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.35 (d, J=8.3 Hz, 1H), 8.04 (dd, J=1.4, 1.4 Hz, 1H), 8.02 (s, 1H), 7.93 (ddd, J=7.9, 1.8, 1.2 Hz, 1H), 7.80 (m, 1H), 7.53 (m, 1H), 6.88 (dd, J=8.3, 1.6 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 4.27 (m, 2H), 3.91 (s, 3H), 2.81 (m, J=12.2 Hz, 2H), 2.64 (tt, J=12.2, 3.4 Hz, 1H), 1.84 (m, 2H), 1.65 (m, 2H), 1.49 (s, 9H). LCMS Method C: rt 6.59 min; m/z 496.1 [(M-Boc)+H]+, 540.0 [(M-t-Bu)+H]+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[CH3:10][C:11]([Si:14](Cl)([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.O>C(Cl)Cl>[Si:14]([O:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[CH:4][CH:5]=1)([C:11]([CH3:13])([CH3:12])[CH3:10])([CH3:16])[CH3:15]
Reactant: CNc1ccc(O)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CNc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Yield: 43.6 %

Procedure:
A solution of 4-(methylamino)phenol (5.0 g, 29 mmol), TBDMSCl (4.8 g, 32 mmol) and imidazole (9.9 g, 0.15 mol) in DCM was stirred at r.t. for 1 h. Water was added, and the mixture was extracted with EtOAc. The organic layer was dried (Na2SO4), concentrated and purified by silica gel chromatography (PE:EtOAc=10:1) to give 3.0 g (43%) of the title compound as a dark green oil. [M+H] Calc'd for C13H23NOSi, 238. Found, 238.
Reaction SMILES: [CH3:1]/[C:2](=[CH:8]\[CH2:9][CH2:10][CH3:11])/[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:12]1(C(C)O)[CH2:14][CH2:13]1>>[CH3:1]/[C:2](=[CH:8]\[CH2:9][CH2:10][CH3:11])/[C:3]([O:5][CH:6]([CH:12]1[CH2:14][CH2:13]1)[CH3:7])=[O:4]
Reactant: CCC/C=C(\C)C(=O)OCC
Reactant: CC(O)C1CC1
Product: CCC/C=C(\C)C(=O)OC(C)C1CC1

Procedure:
Prepared from ethyl (E)-2-methyl-2-hexenoate and cyclopropyl methyl carbinol according to the ester preparation method C described above.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[CH3:35][NH:36][CH2:37][CH2:38]Cl>C(#N)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([CH2:38][CH2:37][NH:36][CH3:35])[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[C@H:14]1[CH2:15][CH2:16][C@H:17]([C:20]2[CH:24]=[C:23]([CH3:25])[O:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: CNCCCl
Reactant: Cc1cc([C@H]2CC[C@H](c3nnc4n3-c3ccc(Cl)cc3CNC4)CC2)no1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CNCCN1Cc2cc(Cl)ccc2-n2c(nnc2[C@H]2CC[C@H](c3cc(C)on3)CC2)C1
Temperature: 70 °C

Procedure:
A mixture of trans-8-chloro-1-[4-(5-methyl-isoxazol-3-yl)-cyclohexyl]-5,6-dihydro-4H-2,3,5,10b-tetraaza-benzo[e]azulene (50.0 mg, 0.130 mmol), cesium carbonate (170 mg, 0.521 mmol) and 2-methylaminoethyl chloride hydrochloride (67.7 mg, 0.521 mmol) in acetonitrile (1.3 ml) was heated at 70° C. for 20 h. After cooling to room temperature the reaction mixture was partitioned between 1 M aqueous sodium hydroxide solution (2 ml) and ethyl acetate (5 ml). The layers were separated. The aqueous layer was extracted with three 5-ml portions of ethyl acetate. The combined organic layers were concentrated in vacuo. Preparative RP-HPLC with water (0.05% formic acid)/methanol as eluent gave the hydroformate salt of the title compound, which was liberated by filtration over aminopropyl modified silica gel (10 g) with methanol (20 ml) as eluent. The filtrate was concentrated to dryness. The residue was redissolved in ethyl acetate, filtrated over cotton wool and concentrated to dryness to give the title compound (38 mg, 66%) as off-white solid. MS m/e: 441 ([M+H]+).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>C(Cl)Cl>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCC2(CC1)OCCO2
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C

Procedure:
A solution of 1,4-dioxa-spiro[4.5]decan-8-ol (prepared according to the procedure of Kayser, Margaret M.; Clouthier, Christopher M. Journal of Organic Chemistry (2006), 71(22), 8424-8430, 11 g, 70 mmol) in DCM (100 mL) was treated with TEA (11 mL, 77 mmol) followed by TsCl (Aldrich, 13.3 g, 70 mmol) slowly at 0° C. The reaction was warmed to room temperature over 2 hours. The solution was partitioned between DCM and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give white solid, which was then purified by silica gel column on a CombiFlash® system (Teledyne Isco, Inc, Lincoln, Neb.) system using hexanes and ethyl acetate (from 10% ethyl acetate to 100% ethyl acetate) to afford the title compound as white solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:20])=[N:4][C:5]2[CH:6]=[CH:7][C:8]3[C:15]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[OH:1][C:2]1[C:3]([OH:20])=[N:4][C:5]2[CH:6]=[C:7]([N+:21]([O-:23])=[O:22])[C:8]3[C:15]([S:16](=[O:18])(=[O:19])[NH2:17])=[CH:14][CH:13]=[CH:12][C:9]=3[C:10]=2[N:11]=1
Reactant: O=[N+]([O-])O
Reactant: NS(=O)(=O)c1cccc2c1ccc1nc(O)c(O)nc12
Agent: O=S(=O)(O)O
Product: NS(=O)(=O)c1cccc2c1c([N+](=O)[O-])cc1nc(O)c(O)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
To a solution of 1,0 g (3,4 mmol) 2,3-dihydroxy-7-sulphamoylbenzo[f]quinoxaline in 25 ml concentrated sulfuric acid was added at 0° C. 0,15 ml 100% nitric acid. Stirring was continued at 0° C. for 30 min, and then the mixture was poured into 100 ml ice-water to give a precipitate. The crude product was recrystallized (dimethylformamide-water) to give 0,7 g (61%) 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline, m.p. 360° C. NMR (DMSO-d6): 12,4 (1H, broad s), 12,3 (1H, broad s), 8.7 (1H, d), 8.5 (1H,d), 8.17 (1H,s), 7.9 (1H,t), 7.4 (2H, broad s).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:16][CH:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]3[N:17]=[C:18]([NH:21][CH2:22][CH3:23])[N:19]=[CH:20][C:9]=3[C:8]2=[O:24])=[CH:4][CH:3]=1.Cl.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:22]([NH:21][C:18]1[N:19]=[CH:20][C:9]2[C:8](=[O:24])[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[N:31][CH:30]=4)=[CH:26][CH:25]=3)[CH2:16][C@H:15]3[N:11]([CH2:12][CH2:13][CH2:14]3)[C:10]=2[N:17]=1)[CH3:23]
Reactant: O=C(Cl)c1cccnc1
Reactant: CCNc1ncc2c(n1)N1CCCC1CN(Cc1ccc(N)cc1)C2=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(Cc1ccc(NC(=O)c3cccnc3)cc1)C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.3 %

Procedure:
Compound 6 (80.0 mg, 0.227 mmol) obtained in Example 6 was dissolved in dichloromethane (5 mL), and the mixture was stirred at room temperature for 1.5 hours after adding nicotinoyl chloride.hydrochloride (61.0 mg, 0.340 mmol) and triethylamine (0.095 mL, 0.340 mmol). Thereafter, an aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was purified by silica gel column chromatography to give the title compound (Compound 7) (54.3 mg, 52%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH3:5].[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=4)=[CH:23][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)#[N:7]>>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][CH2:18][NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][N:30]=[C:29]([N:4]([CH2:3][CH2:2][OH:1])[CH3:5])[N:28]=4)=[CH:23][CH:22]=3)[CH:15]=2)[NH:10][CH:9]=1)#[N:7]
Reactant: CNCCO
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: CN(CCO)c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using (2-hydroxy-ethyl)-N-methylamine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 441 (M+H)+.
Reaction SMILES: CC#N.[OH2:4].[C:5]1(/[CH:11]=[CH:12]/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(Cl)Cl>CC#N>[C:5]1([C@H:11]2[C@H:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[O:4]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O
Reactant: C(=C/c1ccccc1)\c1ccccc1
Solvent: ClCCl
Solvent: CC#N
Product: c1ccc([C@@H]2O[C@H]2c2ccccc2)cc1
Yield: 99 %

Procedure:
Under a flow of F2 (10% in N2) of 20.0 ml min−1 (3.33 mmol h−1) passed through first conduit 12, MeCN:H2O (4:1, 4.95 ml) was added to conduit 16 at a rate of 9.90 ml h−1 (110.0 mmol h−1) and trans-stilbene 24 (0.36 g, 2.0 mmol) (in a 1:1 mixture of DCM:MeCN) was added to conduit 38 at a rate of 9.90 ml h−1. All reaction fluids were collected in a pot 22 containing sodium bicarbonate solution 25 (50 ml). The reaction mixture was then added to another 25 ml of sodium bicarbonate solution, washed with DCM (3×75 ml), dried over MgSO4 and filtered. The solvent was removed under reduced pressure to yield trans-2,3-diphenyloxirane (0.39 g, 1.99 mmol, 99%) as a yellow solid, with no purification required;
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]1(=[O:15])[O:10][C:8](=[O:9])[C:7]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:6]12.[CH:16]1[C:24]2[C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[S:21][C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl>ClCCl.O>[C:8]([C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[C:5]([C:26]1[CH:27]=[CH:28][C:22]2[S:21][C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:24]=3[C:23]=2[CH:25]=1)=[O:15])([OH:10])=[O:9]
Reactant: c1ccc2c(c1)sc1ccccc12
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1ccccc1C(=O)c1ccc2sc3ccccc3c2c1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
To a mixture of aluminum chloride (40.0 g, 300 mmol) in anhydrous dichloromethane (1000 cm3) is added a suspension of phthalic anhydride (14.8 g, 100 mmol) in anhydrous dichloromethane (200 cm3). The suspension is stirred for 30 minutes, cooled to 5° C. and then a solution of dibenzothiophene (20.0 g, 110 mmol) in anhydrous dichloromethane (200 cm3) added drop wise under cooling with ice. After addition, the mixture is allowed to stir at 23° C. for 4 hours. The reaction mixture poured into a solution of water (1000 cm3) and concentrated hydrochloric acid (400 cm3). The product extracted with dichloromethane (2 200 cm3) and the organic extracted with aqueous sodium hydroxide (5%, 500 cm3). The basic layer acidified and the oily precipitate is isolated by decanting away the acidic solution. Water (200 cm3) is added, which solidified the oil and the solid collected by filtration, washed with water (500 cm3) and dried under vacuum to give 2-(o-carboxybenzoyl)dibenzothiophene as a pale yellow solid (35.64 g, 99%). 1H NMR (300 MHz, CDCl3) 8.47-8.52 (m, 1H), 7.99-8.15 (m, 2H), 7.60-7.86 (m, 4H), 7.35-7.57 (m, 4H).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][CH2:8][C:9]([OH:11])=O)=[O:6])[CH:2]=[CH2:3].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:37][CH2:38][C:39]1[N:40]2[CH:46]=[N:45][CH:44]=[C:41]2[S:42][CH:43]=1>CN(C=O)C.ClCCl>[CH2:1]([O:4][C:5]([NH:7][CH2:8][C:9]([NH:37][CH2:38][C:39]1[N:40]2[CH:46]=[N:45][CH:44]=[C:41]2[S:42][CH:43]=1)=[O:11])=[O:6])[CH:2]=[CH2:3]
Reactant: NCc1csc2cncn12
Reactant: C=CCOC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C=CCOC(=O)NCC(=O)NCc1csc2cncn12

Procedure:
A 5 ml portion of a dichloromethane solution containing 307 mg of N-allyloxycarbonyl glycine was cooled on ice, and 287 mg of 1-hydroxybenzotriazole and 438 mg of 1,3-dicyclohexylcarbodiimide were further added to the cooled mixture, followed by stirring under ice-cooling for 2 hours. Further, 5 ml of dichloromethane containing 3-aminomethylimidazo[5,1-b]thiazole and 10 ml of DMF were added thereto, and dichloromethane was then evaporated under reduced pressure, followed by stirring at room temperature for 1.5 hours. To the reaction solution, a saline solution was added, and extraction was then carried out three times with ethyl acetate. Afterward, the resulting organic layer was dried over anhydrous magnesium sulfate, and after the removal of the drying agent by filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 387 mg of the title compound.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl.[NH2:16][C@H:17]([CH:25]([CH3:27])[CH3:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[F:28][C:29]1[C:30]([CH:51]=O)=[C:31]2[C:37]([C:38]([O-:40])=[O:39])=[CH:36][N:35]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[C:32]2=[N:33][CH:34]=1>C(Cl)Cl>[C:21]([O:20][C:18](=[O:19])[C@H:17]([NH:16][CH2:51][C:30]1[C:29]([F:28])=[CH:34][N:33]=[C:32]2[N:35]([S:41]([C:44]3[CH:50]=[CH:49][C:47]([CH3:48])=[CH:46][CH:45]=3)(=[O:43])=[O:42])[CH:36]=[C:37]([C:38]([OH:40])=[O:39])[C:31]=12)[CH:25]([CH3:27])[CH3:26])([CH3:22])([CH3:24])[CH3:23]
Reactant: CC(C)[C@@H](N)C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)n2cc(C(=O)[O-])c3c(C=O)c(F)cnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@@H](C(=O)OC(C)(C)C)C(C)C)c(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of sodium triacetoxyborohydride (1.143 g, 5.39 mmol), (R)-tert-butyl 2-amino-3-methylbutanoate hydrochloride (1.131 g, 5.39 mmol) and DCM (20 mL) was stirred at room temperature for 10 min. The reaction mixture was cooled to 0° C. 5-fluoro-4-formyl-1-tosyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (1.299 g, 3.60 mmol) was added and the reaction was stirred at 0° C. for 20 min to afford the title compound. [M+H] calc'd for C25H30FN3O6S, 520; found, 520.2.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.[NH3:12]>C(O)(C)C>[Br:1][C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH2:12])[C:5]=2[S:4][CH:3]=1
Reactant: N
Reactant: Clc1ncnc2c(Br)csc12
Solvent: CC(C)O
Product: Nc1ncnc2c(Br)csc12
Temperature: 100 °C
Reaction time: 12 h
Yield: 83 %

Procedure:
7-Bromo-4-chlorothieno[3,2-d]pyrimidine (5 g, 20.17 mmol) obtained in Step 3 of Preparation Example 1 and 2.0M NH3 dissolved in isopropanol solution (50 mL) were added to a sealed reaction vessel and stirred at 100° C. for 12 hours. The reaction mixture was cooled to room temperature and filtered to obtain a solid. The solid was washed with water and dried with N2 gas to obtain the title compound (3.8 g, 83%) without further purification.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:8]=[C:9]([CH:14]([O:17]C)OC)[CH:10]=[C:11](Br)[CH:12]=1.[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C.Cl>CCOCC>[Br:6][C:7]1[CH:12]=[C:11]([B:19]([OH:24])[OH:20])[CH:10]=[C:9]([CH:14]=[O:17])[CH:8]=1
Reactant: COC(OC)c1cc(Br)cc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1cc(Br)cc(B(O)O)c1
Reaction time: 0.13 h

Procedure:
4.2 mL (10.5 mmoles) of 2.5 m n-butyllithium was added to a solution of 3.1 g (10.5 mmoles) of 3,5-dibromo(dimethoxymethyl)benzene in 50 mL of ether at -78° under nitrogen over a period of 2 minutes. The reaction mixture was stirred 8 minutes and 2.415 mL (10.5 mmoles) of triisopropyl borate was added. The reaction was stirred 5.5 hrs at room temperature after cooling to 0°, 21 mL of 2N hydrochloric acid was added. After stirring 1 hour at room temperature, ether layer was separated and washed with saturated sodium chloride solution. After drying over anhydrous MgSO4, solvent was removed to give a solid, which was triturated with petroleum ether. The resulting solid was dried in vacuo to give the desired boronic acid.
Reaction SMILES: C(O)C.Cl.[NH2:5][OH:6].[C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)#[N:8].C[O-].[Na+]>O>[NH2:8][C:7](=[N:5][OH:6])[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: NO
Reactant: CCOC(=O)N1CCC(C#N)CC1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1CCC(C(N)=NO)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Ethanol (150 ml) was added to a solution of hydroxylamine hydrochloride (17.25 g) in water (48 ml). Ethyl 4-cyano-1-piperidinecarboxylate (45 g) was added and the mixture was cooled. Sodium methoxide (44.4 g) was added dropwise at RT and the reaction mixture was stirred for 30 minutes at 60° C. The reaction mixture was cooled, filtered and the filtrate evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent evaporated, yielding 25 g (40%) of ethyl 4-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate. This fraction was redissolved in 2-propanone and converted into the hydrochloric acid salt (1:1) with HCl/2-propanol. The precipitate was filtered off and dried, yielding 22 g (35%) of ethyl 4-[amino(hydroxyimino)methyl]-1-piperidine-carboxylate hydrochloride (intermediate 2).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][Si:52]([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:60])[CH2:6][CH2:5][C:4]1=[O:61])[CH3:2].[N+](=[CH2:64])=[N-].B(F)(F)F>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH3:64])[CH:46]([O:51][Si:52]([C:55]([CH3:57])([CH3:56])[CH3:58])([CH3:54])[CH3:53])[CH2:45]2)[CH:7]([CH3:60])[CH2:6][CH2:5][C:4]1=[O:61])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O[Si](C)(C)C(C)(C)C)C3)C(C)CCC1=O)C(C)CC2OC
Agent: FB(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC)C(O[Si](C)(C)C(C)(C)C)C3)C(C)CCC1=O)C(C)CC2OC

Procedure:
An ethereal solution of 17-ethyl-1-hydroxy-12-[2'-(3"-t-butyldimethylsilyloxy-4"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone is treated with diazomethane and BF3 etherate as in Example 67 to yield 17-ethyl-1-hydroxy-12-[2'-(3"-t-butyldimethylsilyloxy-4"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: B.CSC.[C:5]1([CH2:15][C:16](O)=[O:17])[CH:10]=[CH:9][C:8]([CH2:11][C:12](O)=[O:13])=[CH:7][CH:6]=1>O1CCCC1>[C:8]1([CH2:11][CH2:12][OH:13])[CH:7]=[CH:6][C:5]([CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1
Reactant: O=C(O)Cc1ccc(CC(=O)O)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCc1ccc(CCO)cc1
Reaction time: 16 h

Procedure:
Borane-methyl sulfide complex (2M solution in tetrahydrofuran, 80 mL) was added over 20 min to a stirred solution of 2,2′-(1,4-phenylene)diacetic acid (10.20 g) in tetrahydrofuran (100 mL) cooled in an ice bath. After 16 h, the reaction mixture was carefully quenched with methanol (40 mL). The solution was evaporated in vacuo and the resulting gum was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The ethyl acetate solution was separated, dried over magnesium sulphate, filtered and evaporated in vacuo to give the subtitled compound as gum. Yield 8.64 g.