Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][N:12]=[C:11]2[C:15]2[S:31][C:18]3[C:19]4[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][C:20]=4[O:21][CH2:22][CH2:23][C:17]=3[CH:16]=2)=[C:6]([Cl:32])[CH:5]=1)(O)=[O:2].CN.[CH3:35][N:36](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C[CH2:60][N:61](C(C)C)C(C)C>C1COCC1>[Cl:32][C:6]1[CH:5]=[C:4]([C:1](=[O:2])[NH:36][CH3:35])[CH:9]=[CH:8][C:7]=1[N:10]1[CH:14]=[N:13][N:12]=[C:11]1[C:15]1[S:31][C:18]2[C:19]3[CH:27]=[CH:26][C:25]([C:28]([NH:61][CH3:60])=[O:29])=[CH:24][C:20]=3[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1
Reactant: O=C(O)c1ccc(-n2cnnc2-c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)c(Cl)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(-n2cnnc2-c2cc3c(s2)-c2ccc(C(=O)NC)cc2OCC3)c(Cl)c1

Procedure:
Following the procedures in Examples 47 and 235, 2-(4-(4-carboxy-2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid was reacted with excess methylamine, HATU and DIPEA in THF to give 329 as a colorless solid after reverse phase HPLC. MS: (ESI+) 494.1
Reaction SMILES: CO.Cl.[C:4]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:31]1[N:32]=[C:33]([NH:36]C=O)[S:34][CH:35]=1)[C:15]([NH:17][CH:18]1[C:29](=[O:30])[N:20]2[C:21]([C:26]([OH:28])=[O:27])=[C:22]([Cl:25])[CH2:23][S:24][C@H:19]12)=[O:16])=[O:10])([CH3:7])([CH3:6])[CH3:5].C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C>[C:4]([O:8][C:9]([CH2:11][O:12][N:13]=[C:14]([C:31]1[N:32]=[C:33]([NH2:36])[S:34][CH:35]=1)[C:15]([NH:17][CH:18]1[C:29](=[O:30])[N:20]2[C:21]([C:26]([OH:28])=[O:27])=[C:22]([Cl:25])[CH2:23][S:24][C@H:19]12)=[O:16])=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82.4 %

Procedure:
Methanol (15 ml) and conc. hydrochloric acid (0.8 g) were added to 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-formamidothiazol-4-yl)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 2.2 g), and stirred at room temperature for 2.5 hours. To the resultant solution were added ethyl acetate (50 ml) and water (50 ml), and then the solution was adjusted to pH 7.5 with a saturated solution of sodium bicarbonate. After separating the aqueous layer, the aqueous solution was saturated with sodium chloride, and adjusted to pH 3.0 with 10% hydrochloric acid. After adding water, the solution was extracted with ethyl acetate. The extract was washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diisopropyl ether and the precipitates were collected by filtration and dried to give 7-[2-(tert-butoxycarbonylmethoxyimino)-2-(2-aminothiazol-4-yl)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.72 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C@@H:14]([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([CH:28]=O)=[N:22][N:23]([CH:25]([F:27])[F:26])[CH:24]=1.[B][B][B][B][B][B][B][B][B][B]>CO>[Cl:19][C:20]1[C:21]([CH2:28][NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]3([CH3:17])[C@@H:14]([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:16])=[N:9]3)[CH:7]=2)=[N:22][N:23]([CH:25]([F:27])[F:26])[CH:24]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COC[C@@H]1F
Reactant: O=Cc1nn(C(F)F)cc1Cl
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Product: C[C@]1(c2cc(NCc3nn(C(F)F)cc3Cl)ccc2F)N=C(N)COC[C@@H]1F
Temperature: 23 °C
Reaction time: 1 h
Yield: 4.5 %

Procedure:
To a solution of (5R,6R)-5-(5-amino-2-fluoro-phenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylamine (intermediate A10B) (20.4 mg, 80 μmol) in methanol (0.3 ml) was added at 23° C. under inert atmosphere 4-chloro-1-difluoromethyl-1H-pyrazole-3-carbaldehyde (15.9 mg, 88 μmol) and the reaction mixture was stirred at 23° C. for 60 min. Then decaborane (19.5 mg, 160 μmol) was added in one portion and the mixture was stirred at 45° C. for 15 h. The solution was quenched with 10% Na2CO3-sol., methanol was removed under reduced pressure and then extracted three times with ethyl acetate. The organic layers were dried with Na2SO4 and evaporated to give the crude product, which was purified by basic preparative HPLC (column: Gemini 5μ C18 110A° AXIA (50×21.2 mm), flow: 40 ml/min; gradient: water (+0.1% TEA)/acetonitrile (90%-10% 1 min plateau; in 4.5 min to 5%-95%); collection: UV-detector 230 nm) and further purified by preparative TLC (Merck Si—NH2 HPTLC-plate with dichloromethane/methanol 9:1) to give the (5R,6R)-5-(5-((4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl)methylamino)-2-fluorophenyl)-6-fluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (1.5 mg, 4.5%) as a colorless oil. MS (ISP): m/z=420.1 [(M+H)+] and 422.1 [(M+2+H)+].
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1)#[N:22]>>[C:21]([C:23]1[CH:31]=[CH:30][C:26]([C:27]([N:20]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH2:18][CH3:19])=[O:28])=[CH:25][CH:24]=1)#[N:22]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc(C#N)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-cyanobenzoyl chloride, there is obtained ethyl N-(p-cyanobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate as a solid, mass spectrum m/e: M+ 395 (5), 366 (24), 194 (100), 165 (18), 130 (20), 102 (14);
Reaction SMILES: CN(C)CCN=C=NCCC.[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Br:22])[C:16]([OH:18])=O.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH2:36][NH2:37])[CH2:26][CH2:25]1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[NH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Br:22])[C:16]([NH:37][CH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[N:27]1[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]1)=[O:18]
Reactant: Nc1cc(C(=O)O)ccc1Br
Reactant: CN1CCN(c2ccccc2CN)CC1
Agent: CCCN=C=NCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN1CCN(c2ccccc2CNC(=O)c2ccc(Br)c(N)c2)CC1

Procedure:
N1,N1-dimethyl-N2-((propylimino)methylene)ethane-1,2-diamine (0.70 ml, 3.99 mmol) was added to a stirred solution/suspension of 3-amino-4-bromobenzoic acid (719 mg, 3.33 mmol), (2-(4-methylpiperazin-1-yl)phenyl)methanamine (820 mg, 3.99 mmol) and HOBt (140 mg, 1.0 mmol) in dry DCM (20 ml) under argon. After 24 hrs the reaction mixture was diluted with DCM and washed several times with water. The solvent was removed in vacuo and the resulting yellow oil was triturated with DCM/diethyl to give a yellow crystalline powder;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH2:35]([N:42]1[CH2:46][CH2:45][C@H:44]([NH2:47])[CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)(Cl)Cl>[CH2:35]([N:42]1[CH2:46][CH2:45][C@H:44]([NH:47][C:27]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)=[CH:17][CH:18]=2)=[O:33])[CH2:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)N[C@H]4CCN(Cc5ccccc5)C4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 59.5 %

Procedure:
Chloroform (10 ml) and triethylamine (2 ml) were added to 4-[(6,7-dimethoxy-4-quinazolinyl)oxy]aniline (100 mg) to prepare a solution. Triphosgene (110 mg) was added to the solution, and the mixture was stirred at room temperature for 30 min. (3S)-(+)-1-Benzyl-3-aminopyrrolidine (89 mg) was then added thereto, and the mixture was stirred at room temperature for 5 hr. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin-layer chromatography using chloroform/methanol for development. Diethyl ether was added to the purification product, and the precipitated crystal was collected by filtration and was washed to give the title compound (100 mg, yield 60%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([C:11]([O:13]C)=O)=[C:4]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:3]1=[O:21].[NH2:22][CH2:23][CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][N:2]1[C:3](=[O:21])[C:4]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[C:5]2[C:11](=[O:13])[N:22]([CH2:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[C:8](=[O:10])[C:6]2=[CH:7]1
Reactant: COC(=O)c1c(C(=O)O)cn(C)c(=O)c1-c1ccncc1
Reactant: NCCc1ccc2ccccc2n1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1cc2c(c(-c3ccncc3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a mixture of 1-methyl-2-oxo-1,2-dihydro-3-(4-pyridyl)-4-methoxycarbonyl-pyridine-5-carboxylic acid (500 mg, 1.7 mmol, see Example b3)), 2-aminoethyl quinoline (358 mg, 2.0 mmol), PyBOP (1.2 g, 2.2 mmol) and DIPEA (671 mg, 5.2 mmol) in DCM (20 ml) was stirred at r.t. overnight. The solvent was removed, the residue was purified by column chromatography on silica gel (PE:EA=10:1) to give the title compound as a white solid (600 mg, 84%).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:5])[CH3:4].CC(C)([O-])C.[K+].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(OC(=O)C)C>C1COCC1.O>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:2]([CH3:1])[C:3](=[O:5])[CH3:4])=[CH:15][CH:14]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CNC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)N(C)Cc1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 96.3 %

Procedure:
1.316 g N-methylacetamide was dissolved in 60 mL THF. 2.02 g Potassium tert-butoxide was added and the mixture stirred for 20 min at 50° C. Then 3 g of 4-bromobenzylbromide dissolved in 10 mL THF was added and the mixture stirred for 2 h at 50° C. After cooling ethylacetate and water were added and the organic phase extracted with water (1×), dried and the solvent distilled off to yield 2.8 g N-(4-bromobenzyl)-N-methylacetamide as an oil.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2([CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)[NH:5][C:4]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[S:22][C:3]1=2.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1>[N:26]1[CH:27]=[CH:28][C:23]([C:21]2[S:22][C:3]3[C:2](=[O:1])[NH:7][C:6]4([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]4)[NH:5][C:4]=3[CH:20]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)c1sc(-c3ccncc3)cc1N2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC2(CCNCC2)Nc2cc(-c3ccncc3)sc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A mixture of tert-butyl 4′-oxo-6′-(pyridin-4-yl)-3′,4′-dihydro-1′H-spiro[piperidine-4,2′-thieno[3,2-d]pyrimidine]-1-carboxylate (0.154 g, 0.385 mmol) and trifluoroacetic acid (3.0 mL) was stirred for 1 h at room temperature. The mixture was poured into sat. aqueous sodium hydrogen carbonate (100 mL), ethyl acetate (70 mL) and tetrahydrofuran (30 mL). After shaking well, the yellow precipitate was collected by filtration. This solid was suspended in ethyl acetate-dichloromethane (1:2, 10 mL) and the mixture was heated to 60° C. After 10 min, the precipitate was collected by filtration to afford the title compound (0.107 mg, 93%) as a yellow solid:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:20][N:21]([CH3:23])[CH3:22])[N:3]=1.[C:24]([Cu])#[N:25]>CS(C)=O>[CH3:22][N:21]([CH2:20][C:4]1[N:3]=[C:2]([C:24]#[N:25])[C:11]2[C:6]([C:5]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH3:23]
Reactant: N#C[Cu]
Reactant: COc1ccc2c(Cl)nc(CN(C)C)c(-c3ccccc3)c2c1
Solvent: CS(C)=O
Product: COc1ccc2c(C#N)nc(CN(C)C)c(-c3ccccc3)c2c1
Reaction time: 3 h

Procedure:
A mixture of 1-(1-chloro-6-methoxy-4-phenylisoquinolin-3-yl)-N,N-dimethylmethanamine (31 mg), 1 mL DMSO, and 16 mg CuCN was stirred at 140 C for 3 h. The solution was cooled and purified directly by reverse-phase HPLC to give the titled compound.
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[K+].[K+].[K+].[OH:9][CH2:10][C:11]([CH2:15][OH:16])([CH2:13][OH:14])[CH3:12]>>[OH:14][CH2:13][C:11]([CH2:15][OH:16])([CH3:12])[CH:10]=[O:9].[OH:9][CH2:10][C:11]([CH2:15][OH:16])([CH3:12])[C:13]([OH:2])=[O:14]
Reactant: O=P([O-])([O-])[O-]
Reactant: CC(CO)(CO)CO
Agent: [K+]
Product: CC(C=O)(CO)CO
Product: CC(CO)(CO)C(=O)O
Temperature: 30 °C
Reaction time: 48 h

Procedure:
One loopful bacterial cells of Rhodococcus erythropolis SD806 strain were inoculated in 200 ml of a culture medium having the same composition as culture medium 1 shown in Table 3 and incubated with shaking at 30° C. for 2 days. After completion of the incubation, the bacterial cells were harvested by centrifugation and 1 liter of a 50 mM potassium phosphate buffer solution containing 5 g of 1,1,1-tris(hydroxymethyl)ethane was added thereto to prepare a resting cell suspension reaction mixture. The reaction mixture had a turbidity in terms of absorbance of 0.8 at 660 nm. This was shaken at 30° C. for 24 hours. A portion of the reaction mixture was analyzed by high performance liquid chromatography and as a result, it was found that 3.3 g of 1,1,1-tris(hydroxymethyl)ethane was oxidized and decomposed to produce 1.1 g of 2,2-bis (hydroxymethyl)propionaldehyde and 2.0 g of 2,2-bis (hydroxymethyl)propionic acid.
Reaction SMILES: [NH2:1][C:2]1([CH2:7][O:8][CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1>>[C:16]1([CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:8][CH2:7][C:2]2([NH:1][CH2:29][CH2:28][C:27]3[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(CCBr)cc1
Reactant: NC1(COC(c2ccccc2)c2ccccc2)CCCC1
Product: COc1ccc(CCNC2(COC(c3ccccc3)c3ccccc3)CCCC2)cc1

Procedure:
The title compound was prepared as described in Example 1 using 1-amino-1-diphenylmethoxymethylcyclopentane (see Preparation 4) and 4-methoxyphenethyl bromide. The title compound was obtained as a pale brown oil which was characterised as a hydrate (0.50 g, 49%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[C:4]([O:12][CH3:13])[CH:3]=1.[Li]CCCC.[B:19](OC)([O:22]C)[O:20]C.C(OCC)(=O)C>C1COCC1.CCCCCC>[CH3:13][O:12][C:4]1[CH:3]=[C:2]([B:19]([OH:22])[OH:20])[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][O:10][CH3:11]
Reactant: COCOc1ccc(Br)cc1OC
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COCOc1ccc(B(O)O)cc1OC
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 76.6 %

Procedure:
3-Methoxy-4-(methoxymethoxy)benzeneboronic acid was prepared as follows: In a 100 mL flask a mixture of 50% KOH in water (20 g KOH, 7 equiv, 20 g ice) was prepared under argon. To this rapidly stirring mixture at 0° C. (maintained with an ice bath) was added dichloromethane (50 mL) followed by 4-bromo-2-methoxyphenol (10.1 g, 50 mmol, 1.00 equiv), methoxymethylchloride (MOMCl) (4.00 mL, 42.5 mmol, 1.05 equiv) and tetrabutylammonium bromide (322 mg, 1 mmol, 0.02 equiv). The bath was removed and the mixture was slowly allowed to warm to 23° C. with rapid stirring for 2 h. The mixture is transferred to a separatory funnel and diluted with dichloromethane (350 mL) and water (300 mL) which are used to aid the transfer. The organic material (now the bottom layer) are separated, dried over sodium sulfate, decanted and concentrated under reduced pressure to give 4-bromo-2-methoxy-1-(methoxymethoxy)benzene as a yellow liquid which is pure by 1H NMR (11.9 g, 97%): 1H NMR (CDCl3) δ 7.0 (s, 3H), 5.13 (s, 2H), 3.84 (s, 3H), 3.47 (s, 3H). MS (EI) [m+H]/z Calc'd 235, found 235. In a 50 mL round-bottom flask, 4-bromo-2-methoxy-1-(methoxymethoxy)benzene (4.80 g, 19.4 mmol, 1.00 equiv) was taken up in THF (35 mL) and was cooled to −78° C. (20 min for this volume). To this was added n-BuLi (12.75 mL, 1.6 M in hexane, 20.4 mmol, 1.05 equiv) and the mixture was allowed to stir at −78° C. for 40 min. This was then added via cannula to a second flask containing B(OMe)3 (22 mL, 194 mmol, 10 equiv) in THF (50 mL) at −78° C. After 20 min, the cold bath was removed. After 15 min of warming (˜0° C., ice on the side of the flask begins to melt) water (50 mL) was added to the reaction mixture which was stirred for 45 min. The mixture was concentrated under reduced pressure to remove most THF and was then partitioned between ethyl acetate (300 mL) and water (150 mL) which was made acidic by addition of a small amount of 20% citric acid (−10 mL). The organic material was dried over sodium sulfate and concentrated under reduced pressure to give a solid. Trituration with ethyl acetate (10 mL) and hexane (5 mL) followed by filtering gave 3-methoxy-4-(methoxymethoxy)benzene-boronic acid as a white solid (3.15 g, 77%): Rfsm 0.59, p 0.18 (ethyl acetate-hexane 1:1); 1H NMR (CDCl3) δ 7.85 (d, 1H, J=8 Hz), 7.72 (s, 1H), 7.22 (d, 1H, J=8 Hz), 5.30 (s, 2H), 4.00 (s, 3H), 3.55 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]#[N:8])[S:5][CH:6]=1.[C:9](OC)(=[O:17])[C:10]1[C:11](=[CH:13][CH:14]=[CH:15][CH:16]=1)[SH:12].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([C:7]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9](=[O:17])[N:8]=2)[S:5][CH:6]=1
Reactant: COC(=O)c1ccccc1S
Reactant: Cc1csc(C#N)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1csc(-c2nc(=O)c3ccccc3s2)n1
Yield: 48.9 %

Procedure:
4-Methyl-1,3-thiazole-2-carbonitrile (0.27 g, 2.2 mmol) and methyl thiosalicylate (0.75 g, 4.4 mmol) were dissolved in toluene (4 ml), and triethylamine (2.0 ml, 14.3 mmol) was added thereto. The reaction mixture was refluxed for 6 hrs. After cooling, the precipitates were collected by filtration and recrystallized from ethanol to give the titled compound (0.28 g, 49%) as yellow crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17].C(=O)([O-])[O-].[K+].[K+].N1C2C(=CC=CC=2)C=CC=1>[Cu]=O.N1C=CC=CC=1>[CH3:17][C:11]1[CH:10]=[C:15]([CH:14]=[CH:13][CH:12]=1)[O:16][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(Br)c1
Reactant: Cc1cccc(O)c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: c1ccc2ncccc2c1
Product: Cc1cccc(Oc2cccc(C=O)c2)c1
Temperature: 170 °C
Reaction time: 24 h
Yield: 72.1 %

Procedure:
A mixture of 3-bromobenzaldehyde (7.01 g, 37.9 mmol), m-cresol (4.51 g, 41.7 mmol), copper oxide (II) (4.53 g, 56.9 mmol), potassium carbonate (7.86 g, 56.9 mmol), pyridine (50 mL) and quinoline (25 mL) was stirred under a nitrogen atmosphere at 170° C. for 24 hrs. The reaction mixture was cooled and pyridine was evaporated under reduced pressure. Ethyl acetate was added to the residue, the insoluble material was filtered off, and the filtrate was washed with 1 M hydrochloric acid and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-10% ethyl acetate/hexane) to give the title compound (5.80 g, 72%) as a pale-brown oil.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[N:13]1[CH:14]=[C:15]2[N:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=13)[S:18][C:17]([C:25]([OH:27])=O)=[CH:16]2.ON1C(=O)CCC1=O.[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][C:41]1=[O:53].C(N(CC)CC)C>C(#N)C>[C:49]([O:48][C:46]([N:43]1[CH2:44][CH2:45][N:40]([CH2:39][CH2:38][CH2:37][NH:36][C:25]([C:17]2[S:18][C:19]3[N:24]4[C:15](=[CH:14][N:13]=[C:23]4[CH:22]=[CH:21][CH:20]=3)[CH:16]=2)=[O:27])[C:41](=[O:53])[CH2:42]1)=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN)C(=O)C1
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCCNC(=O)C2=Cc3cnc4cccc(n34)S2)C(=O)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.4 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.22 g, 22.0 mmol) was added to a stirred suspension of 5-thia-1,8b-diazaacenaphtylene-4-carboxylic acid (2.40 g, 11.0 mmol) and N-hydroxysuccinimide (2.53 g, 22.0 mmol) in acetonotrile (30 ml) at room temperature and the mixture was stirred at room temperature for 1.5 hours. A solution of 1-(3-aminopropan-1-yl)-4-tert-butoxycarbonyl-2-oxopiperazine (3.67 g, 14.3 mmol) and triethylamine (4.45 g, 44.0 mmol) in acetonitrile (15 ml) was added to the mixture. After stirring at room temperature for 19 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in water and extracted with chloroform. The extract was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel (50 g) with Ethyl acetate-Methanol (10:1) to give N-[3-(4-tert-butoxycarbonyl-2-oxopiperazin-1-yl)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide as a purple amorphous powder(1.53 g, 30%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)[C:8]2[C:13]([C:14]=1[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)=[C:6]2[C:4]([OH:3])=[O:5])=[CH:26][CH:25]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1c(-c2cccs2)c2ccccc2n1Cc1ccc(N)cc1
Reactant: OB(O)c1ccccc1
Product: O=C(O)c1c(-c2cccs2)c2ccccc2n1Cc1ccc(Nc2ccccc2)cc1

Procedure:
The title compound was prepared from 1-(4-amino-benzyl)-3-thiophene-2-yl-1H-indole-2-carboxylic acid ethyl ester and phenylboronic acid followed the procedure of Example 16 as a light green solid: 1H NMR (DMSO-d6) δ 5.70 (s, 2H), 6.78 (td, J=7.4, 1.0 Hz, 1H), 6.98 (d, J=8.7 Hz, 2H), 7.01 (dd, J=8.5, 1.0 Hz, 2H), 7.04 (d, J=8.7 Hz, 2H), 7.16 (t, J=3.5 Hz, 1H), 7.17 (dd, J=5.2, 1.6 Hz, 2H), 7.21 (dd, J=6.9, 2.1 Hz, 2H), 7.33-7.37 (m, 1H), 7.61 (dd, J=5.1, 1.3 Hz, 1H), 7.66 (t, J=8.7 Hz, 2H), 8.12 (br s, 1H), 13.34 (br s, 1H); MS (ESI) m/z 425 (MH+); MS (ESI) m/z 423 ([M−H]−); HRMS calcd for C26H21N2O2S: 425.1321; found (ESI+): 425.1319.