Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].COP([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])(OC)=O.[CH2:21]([C:23]1[CH2:24][C@H:25]2[C@@H:28]([CH:29]=1)[C:27](=O)[CH2:26]2)[CH3:22]>O1CCCC1.CC(C)([O-])C.[K+].C(OC(=O)CP(OC)(OC)=O)(C)(C)C>[CH2:21]([C:23]1[CH2:29][C@H:28]2[C@@H:25]([CH:24]=1)[C:26](=[CH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:27]2)[CH3:22]
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Reactant: CCC1=C[C@H]2C(=O)C[C@H]2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC1=C[C@H]2C(=CC(=O)OC(C)(C)C)C[C@H]2C1
Temperature: 5 °C
Reaction time: 1 h
Yield: 134.2 %

Procedure:
Potassium t-butoxide (8.66 g) was dissolved in tetrahydrofuran (50 mL) under a nitrogen atmosphere, and the solution was then cooled to approximately 5° C. Tert-butyl (dimethoxyphosphoryl)acetate (17.30 g) was added thereto at 15° C. or lower, and the mixture was stirred at 5 to 15° C. for 1 hour. (1R,5S)-3-Ethylbicyclo[3.2.0]hept-3-en-6-one (10.00 g) and tetrahydrofuran (25 mL) were further added thereto, and the mixture was stirred at 5 to 15° C. for 1.5 hours. Potassium t-butoxide (0.90 g) and tert-butyl(dimethoxyphosphoryl)acetate (1.73 g) were further added thereto, and the mixture was stirred for approximately 1 hour. Then, the reaction mixture was separated into aqueous and organic layers by the addition of toluene (85 mL) and water (40 mL). The organic layer was washed twice with water (20 mL) and then concentrated under reduced pressure to obtain tert-butyl [(1R,5S)-3-ethylbicyclo[3.2.0]hept-3-en-6-ylidene]acetate (23.09 g) as a yellow oil.
Reaction SMILES: CN1[C:11](=[O:12])[C:10]2[C:5](=[N:6][CH:7]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[N:9]=2)[N:4]=C1.C[OH:27]>[OH-].[Na+]>[NH2:4][C:5]1[C:10]([C:11]([OH:27])=[O:12])=[N:9][C:8]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]2)=[CH:7][N:6]=1
Reactant: Cn1cnc2ncc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2c1=O
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Yield: 34 %

Procedure:
Tert-butyl 4-(3-methyl-4-oxo-pteridin-6-yl)piperazine-1-carboxylate (25 g, 72.17 mmol) was stirred in NaOH (250 mL of 10% w/w,) and MeOH (250 mL) overnight at RT. The resulting suspension was concentrated and then acidified with formic acid followed by extraction of the aqueous with DCM. The mixture was treated with water, taken to pH 10 and filtered. The aqueous layer was reacidified and the resulting precipitated product was extracted into DCM and concentrated to give the product as a yellow solid (8 g, 24.74 mmol, 34% Yield).
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55]([OH:57])=O)=[O:40])([CH3:37])([CH3:36])[CH3:35].FC1C(N)CCCN(C2NN=CC=2[N+]([O-])=O)C1.[NH2:75][C:76]1[CH:77]=[N:78][N:79]([CH2:96][CH:97]([F:99])[F:98])[C:80]=1[N:81]1[CH2:87][CH2:86][CH:85]([F:88])[CH:84]([NH:89][C:90](=[O:95])[C:91]([F:94])([F:93])[F:92])[CH2:83][CH2:82]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:99][CH:97]([F:98])[CH2:96][N:79]1[C:80]([N:81]2[CH2:82][CH2:83][CH:84]([NH:89][C:90](=[O:95])[C:91]([F:94])([F:93])[F:92])[CH:85]([F:88])[CH2:86][CH2:87]2)=[C:76]([NH:75][C:55]([C:43]2[N:44]=[C:45]([C:47]3[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=3[F:54])[S:46][C:42]=2[NH:41][C:39](=[O:40])[O:38][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:57])[CH:77]=[N:78]1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: Nc1cnn(CC(F)F)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CCCN(c2[nH]ncc2[N+](=O)[O-])CC1F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)Nc1cnn(CC(F)F)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.4 %

Procedure:
A solution of PyBOP (692 mg, 1.33 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (372 mg, 1.05 mmol) in DCM (40 mL) was stirred at room temperature for 30 min. A solution of Intermediate 51, N-(1-(4-amino-1-(2,2-difluoroethyl)-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide (354 mg, 0.95 mmol) and DIPEA (0.28 mL, 1.62 mmol) in DCM (40 mL) was added and the mixture stirred at room temperature for 16 hr. The mixture was diluted with DCM (50 mL) and washed with water (20 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-5% MeOH/DCM) gave tert-butyl 4-(1-(2,2-difluoroethyl)-5-(4-fluoro-5-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)-2-(2,6-difluorophenyl)thiazol-5-ylcarbamate as an off-white solid (600 mg, 0.84 mmol) which was dissolved in HCl in 1,4-dioxane (4 M, 10 mL, 40.0 mmol) and MeOH (10 mL) and heated in a sealed pressure vessel behind a blast shield at 60° C. for 16 hr. The solvents were removed under reduced pressure and the residue re-dissolved in MeOH and loaded onto an SCX column. The column was washed with MeOH and eluted with 0-10% 7 N ammonia in MeOH/DCM to give 203 as an off-white solid (197 mg, 40% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.00 (s, 1H), 7.37-7.29 (m, 1H), 7.09-6.99 (m, 2H), 6.31-6.01 (m, 3H), 4.56-4.28 (m, 3H), 3.39-3.13 (m, 5H), 2.32-2.17 (m, 1H), 2.14-1.94 (m, 2H), 1.77-1.64 (m, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 516 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[CH2:5][CH:6]([CH2:15][C:16](OCC)=[O:17])[CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Cl:1][C:2]1[C:3]2[C:4]3[CH2:5][CH:6]([CH2:15][CH2:16][OH:17])[CH2:7][CH2:8][C:9]=3[S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCOC(=O)CC1CCc2sc3ncnc(Cl)c3c2C1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCCC1CCc2sc3ncnc(Cl)c3c2C1
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A solution of ethyl 2-[3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]acetate (2.88 g, 9.27 mmol, 1.00 equiv) in 25 mL of distilled THF was added DIBAL-H (25% in hexane, 10.56 g, 2.00 equiv) dropwise at −30° C. under nitrogen. The resulting solution was stirred for 2 h at this temperature and quenched with saturated aqueous NH4Cl, extracted with 3×100 mL of ethyl acetate. The organic layers were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1) to afford 2.20 g (88%) of the desired 2-[3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]ethan-1-ol as a light yellow solid. MS: m/z 269, 270 [M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][CH2:10][P:11](=[O:20])([O:16][CH:17]([CH3:19])[CH3:18])[O:12][CH:13]([CH3:15])[CH3:14]>>[CH:1](=[N:9][CH2:10][P:11](=[O:20])([O:12][CH:13]([CH3:15])[CH3:14])[O:16][CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)OP(=O)(CN)OC(C)C
Product: CC(C)OP(=O)(CN=Cc1ccccc1)OC(C)C

Procedure:
The desired imine is obtained in a quantitative yield by reacting 10.6 g. (0.1 mol) benzaldehyde with 19.5 g. (0.1 mol) diisopropyl aminomethylphosphonate under the conditions described in Example 1.
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH2:37]([O:41][C:42]1[CH:75]=[CH:74][C:45]([C:46]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:63]=[C:62]4[C:58]([CH2:59][N:60]([C@@H:65]([CH:70]([CH3:72])[CH3:71])[C:66]([O:68]C)=[O:67])[C:61]4=[O:64])=[CH:57][CH:56]=3)=[C:51]([Cl:73])[CH:50]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]>>[CH2:37]([O:41][C:42]1[CH:75]=[CH:74][C:45]([C:46]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]3[CH:63]=[C:62]4[C:58]([CH2:59][N:60]([C@@H:65]([CH:70]([CH3:71])[CH3:72])[C:66]([OH:68])=[O:67])[C:61]4=[O:64])=[CH:57][CH:56]=3)=[C:51]([Cl:73])[CH:50]=2)=[O:47])=[CH:44][CH:43]=1)[CH2:38][CH2:39][CH3:40]
Reactant: CCCCOc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)c(Cl)c2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CCCCOc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)c(Cl)c2)cc1
Yield: 93 %

Procedure:
The compound of example 484 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 483.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[S:10])=[C:4]([OH:20])[C:3]=1[S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=C1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[S:10])=[C:4]([O:20][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:3]=1[S:21]([N:24]([CH3:26])[CH3:25])(=[O:23])=[O:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(Cl)c2Cl)c1O
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(NC(=S)Nc2cccc(Cl)c2Cl)c1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
To a solution of N-[4-chloro-2-hydroxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2,3dichlorophenyl)thiourea (440 mg, 1.07 mmol) in THF (20 mL), tert-butyldimethylsilyl chloride (730 mg, 4.85 mmol) and imidazole (132 mg, 1.94 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. Then it was partitioned between ethyl acetate and water. The combined organic phase was dried and concentrated. Chromatography of the residue on silica gel (30% Ethyl acetate/Hexane) gave desired product (270 mg, 50%). EI-MS m/z 570 (M+).
Reaction SMILES: [CH3:1][C:2]([O-:5])([CH3:4])[CH3:3].[K+].OC1[CH:9]=[C:10]([CH:14]=C(O)C=1)[C:11]([O-])=O.[C:18]([C@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:51])[CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH:44]=[C:45]([C:47]([O:49][CH3:50])=[O:48])[CH:46]=1)[O:32][CH2:33][C:34]([N:36]1[CH2:40][CH2:39][CH2:38][C@@H:37]1[C:41]([OH:43])=O)=[O:35])([OH:20])=[O:19]>CN(C)C=O>[C:2]([O:5][C:41]([C@H:37]1[CH2:38][CH2:39][CH2:40][N:36]1[C:34](=[O:35])[CH2:33][O:32][C:31]1[CH:44]=[C:45]([C:47]([O:49][CH3:50])=[O:48])[CH:46]=[C:29]([O:28][CH2:27][C:26]([N:22]2[CH2:23][CH2:24][CH2:25][C@@H:21]2[C:18]([O:20][C:10]([CH3:14])([CH3:11])[CH3:9])=[O:19])=[O:51])[CH:30]=1)=[O:43])([CH3:4])([CH3:3])[CH3:1]
Reactant: COC(=O)c1cc(OCC(=O)N2CCC[C@@H]2C(=O)O)cc(OCC(=O)N2CCC[C@@H]2C(=O)O)c1
Reactant: O=C([O-])c1cc(O)cc(O)c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1
Reaction time: 0.04 h
Yield: 68.4 %

Procedure:
To a solution of 595 mg (5.3 mmol) potassium tert-butylate in 4 ml dimethylformamide at room temperature was added dropwise a solution of 420 mg (2.5 mmol) 3,5-dihydroxybenzoate in 4 ml dimethylformamide. Stirring was continued for 2-3 min and a solution of 1.46 mg (5.0 mmol) (R)- (1)-bromoacetyl-pyrrolidine-2-carboxylic acid tert-butyl ester in 5 ml dimethylformamide was added within 1-2 min. The reaction mixture was stirred for additional 2 h at room temperature. The solvent was removed in vacuo and the residue purified by flash-chromatography to yield 1.01 g (68%) of the title compound as a colorless oil. MS m/e (%): 608 (M+NH4+, 92), 591 (M+H+, 48), 535 (41), 479 (100).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:15][C:14](=[O:16])[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])(C)(C)C.[C:17]1([CH:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)C(Cl)=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[C:33]1([CH2:43][NH2:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1>>[C:27]1([CH:23]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:6]([N:8]2[CH2:15][C:14](=[O:16])[CH2:13][C@H:9]2[C:10]([NH:44][CH2:43][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]=[CH:35][CH:34]=2)=[O:12])=[O:7])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NCc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)O
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: O=C1C[C@@H](C(=O)NCc2cccc3ccccc23)N(C(=O)C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from 1-(tert-butoxycarbonyl)-4-oxoproline, diphenylacetyl chloride, and 1-naphthylmethylamine the title com-pound was obtained in 60% purity by LC/MS. MS(ESI+): m/z=463.4.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([C:8]1[C:12](=[O:13])[O:11][N:10]([C:14](Cl)=[O:15])[C:9]=1[CH2:17][CH2:18][CH3:19])[CH3:7]>ClCCl>[CH2:6]([C:8]1[C:12](=[O:13])[O:11][N:10]([C:14]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:15])[C:9]=1[CH2:17][CH2:18][CH3:19])[CH3:7]
Reactant: C1CCNC1
Reactant: CCCc1c(CC)c(=O)on1C(=O)Cl
Solvent: ClCCl
Product: CCCc1c(CC)c(=O)on1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0°C., a solution of 0.43 g (6 mmol) of pyrrolidine in 35 ml of dichloromethane are added dropwise to a solution of 0.44 g (2 mmol) of 4-ethyl-3-propyl-2-(chlorocarbonyl)-5(2H)-isoxazolone in 10 ml of dichloromethane, and the mixture is stirred at room temperature overnight. For work-up, the residue were chromatographed over silica gel using petroleum ether:ethyl acetate (4:1). MS (DCI): 253 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH2:10].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:21][CH3:22])[CH:20]=1)[CH:16]=O.CO[CH:25](OC)[N:26]([CH3:28])[CH3:27]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:16][C:15]2[CH:14]=[C:13]([O:12][CH3:11])[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=2)[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]=[CH:25][N:26]([CH3:28])[CH3:27]
Reactant: COC(OC)N(C)C
Reactant: Nc1cc(Cl)c(N)c(Cl)c1
Reactant: COc1cc(C=O)cc(OC)c1
Solvent: CCO
Product: COc1cc(CNc2cc(Cl)c(N=CN(C)C)c(Cl)c2)cc(OC)c1
Temperature: 5 °C
Reaction time: 16 h

Procedure:
A mixture of 5.3 g. of 2,6-dichloro-p-phenylenediamine and 4.98 g. of 3,5-dimethoxybenzaldehyde in 100 ml. of ethanol is heated on a steam bath, solution occurs, followed by crystallization. Warming is continued on the steam bath for 16 hours. The reaction mixture is cooled, 50 ml. of glacial acetic acid and 500 mg. of platinum oxide are added and the mixture is hydrogenated in a Parr apparatus at 40 p.s.i. for 15 minutes. The mixture is filtered and washed with ethanol, then the combined filtrate and washings are evaporated to dryness. The residue is treated with 200 ml. of saturated sodium carbonate then is extracted twice with 200 ml. of ethyl acetate. The combined extract is evaporated to dryness. The residue is dissolved in methanol and the solution is cooled at 5° C. to provide crystals. The crystals are collected by filtration and washed with methanol to give 7.8 g. of product. This product is heated at reflux with 20 ml. of N,N-dimethylformamide dimethylacetal for 18 hours. The resulting solution is evaporated to an amber syrup. The syrup is treated with ether/hexane to crystallize 7.1 g. of the product of the Example as colorless needles, m.p. 124°-125° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[CH:14]([C:16]1[N:17]([CH2:21]C(OC(C)(C)C)=O)[CH:18]=[CH:19][N:20]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[C:43]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])(=[O:46])[CH:44]=O>ClCCCl.CC(O)=O>[CH3:21][N:17]1[CH:18]=[CH:19][N:20]=[C:16]1[CH2:14][N:1]([CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([S:10](=[O:11])(=[O:12])[NH2:13])=[CH:8][CH:9]=1)[CH2:44][C:43]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)C=O
Reactant: CC(C)(C)OC(=O)Cn1ccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cn1ccnc1CN(CCc1ccc(S(N)(=O)=O)cc1)CC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
A solution of 4-(2-aminoethyl)benzenesulfonamide (0.70 g, 3.5 mmol), AcOH (0.20 mL) and tert-butyl 2-(2-formyl-1H-imidazol-1-yl)acetate (0.735 g, 3.5 mmol) in DCE (20 mL) was heated at 80° C. for 30 min under nitrogen. The reaction mixture was cooled to 0° C., and treated sequentially with NaBH(OAc)3 (2.25 g, 10.5 mmol) and tert-butyl glyoxalate (1.80 g). The reaction mixture was stirred at room temperature overnight and quenched with water. The reaction mixture was extracted with DCM and the organic layer was dried and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel to afford tert-butyl 2-(((1-methyl-1H-imidazol-2-yl)methyl)(4-sulfamoylphenethyl)amino)acetate (0.63 g, 35%). 1H NMR (400 MHz, DMSO-d6) δ 7.67 (d, J=8.4 Hz, 2H), 7.25 (s, 2H), 7.23 (d, J=8.4 Hz, 2H), 7.04 (d, J=1.2 Hz, 1H), 6.76 (d, J=1.2 Hz, 1H), 4.82 (s, 2H), 3.74 (s, 2H), 3.24 (s, 2H), 2.69-2.66 (m, 4H), 1.41 (s, 9H), 1.40 (s, 9H); ESMS m/z: 509 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4](Cl)[N:3]=1.[C:9]1([CH2:19][OH:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>O1CCOCC1.C(#N)C>[C:9]1([CH2:19][O:20][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[N:3]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCc1cccc2ccccc12
Reactant: C1CNCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1COCCO1
Product: c1ccc2c(COc3cncc(N4CCNCC4)n3)cccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of 2,6-dichloropyrazine (298 mg, 2.00 mmol) and 1-naphthylmethanol (348 mg, 2.20 mmol) in dioxane (5 mL) was added NaH (55% in mineral oil, 96 mg, 2.2 mmol) at room temperature. The reaction was stirred at room temperature and monitored by GC. After 3 h, piperazine (189 mg, 2.20 mmol) and NaH (55% in oil, 96 mg, 2.2 mmol) was added into the reaction flask at room temperature. The reaction mixture was stirred at room temperature for 24 h. The solvent was evaporated off. To the residue was added piperazine (671 mg, 7.80 mmol) and acetonitrile (5 mL) and the solution was heated under reflux for 5 h. The reaction mixture was directly loaded on a short column of silica gel for flash column chromatography. Elution with MeOH/dichloromethane (1:9) furnished 0.41 g (64%) of the title compound. HRMS m/z calcd for C19H20N4O (M)+ 321.1715, found 321.1721. Anal. (C19H20N4O.0.1 H2O) C, H, N.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]4)[CH2:13][N:12](CC4C=CC(OC)=CC=4)[C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[O:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH:41]=[C:40]1B(O)O>>[O:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[CH:41]=[C:40]1[C:2]1[N:7]=[C:6]([C:8]2[NH:16][C:15]3[C:14]4([O:21][CH2:20][CH2:19][NH:18][CH2:17]4)[CH2:13][NH:12][C:11](=[O:38])[C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccc(CN2CC3(CN(C(=O)OC(C)(C)C)CCO3)c3[nH]c(-c4ccnc(Cl)n4)cc3C2=O)cc1
Reactant: OB(O)c1cc2ccccc2o1
Product: O=C1NCC2(CNCCO2)c2[nH]c(-c3ccnc(-c4cc5ccccc5o4)n3)cc21

Procedure:
The title compound was prepared following the general procedure reported for Example 1—1 using E8 and 2-benzofuraneboronic acid. The crude was purified by semi-preparative HPLC (method A) and isolated as a TFA-salt. MS (ES) C22H19N5O3 requires: 401. found: 402.1[M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=O)=[C:4]([CH3:14])[CH:3]=1.[CH2:15]([SH:18])[CH2:16][SH:17].B(F)(F)F.CCOCC.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]32[S:18][CH2:15][CH2:16][S:17]3)=[C:4]([CH3:14])[CH:3]=1
Reactant: Cc1cc(Br)c(C)c2c1CCCC2=O
Reactant: SCCS
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1cc(Br)c(C)c2c1CCCC21SCCS1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 20.0 g of the title compound of Step A in 500 mL of methylene chloride was added 11.2 mL of 1,2-ethanedithiol (purchased from Aldrich Chemical Co.) and 17.0 mL of boron trifluoride diethyl etherate (purchased from Janssen Chimica). The mixture was stirred at room temperature for 3 h. To this reaction mixture was added 15% aqueous sodium hydroxide and the resulting mixture was extracted with methylene chloride. The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to afford 20.2 g of the title compound of Step B as a white solid melting at 164°-165° C. 1H NMR (CDCl3): δ 1.98 (m, 2H), 2.15 (s, 3H), 2.38 (m, 2H), 2.58 (t, 2H), 2.78 (s, 3H), 3.40-3.60 (m, 4H), 7.35 (s, 1H).
Reaction SMILES: C(O[C:6](=O)[N:7]([C@H:9]([CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1)[C:10]([N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1)=[O:11])C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[C:10](=[O:11])[C@H:9]([NH:7][CH3:6])[CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N1CCc2ccccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N1CCc2ccccc2C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 46.3 %

Procedure:
N-((1R)-2-(1,2,3,4-Tetrahydroisoquinolin-2-yl)-1-((2-naphthyl)methyl)-2-oxoethyl)-N-methylcarbamic acid tert-butyl ester (6.12 g, 13.8 mmol) was dissolved in dichloromethane (40 ml). The solution was cooled to 0° C. Trifluoroacetic acid (40 ml) was added. The reaction mixture was stirred for 90 min at 0° C. Dichloromethane (110 ml) and a saturated aqueous solution of sodium hydrogen carbonate (150 ml) were added successively. Solid sodium hydrogen carbonate was added until pH 7 was obtained The phases were separated. The aqueous phase was extracted with dichloromethane (3×60 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (130 g), using dichloromethane/methanol/25% aqueous ammonia 100:10:1 as eluent, to give 2.20 g of (2R)-1-(1,2,3,4 -tetrahydroisoquinolin-2-yl)-2-(methylamino)-3-(2-naphthyl)1-propanone.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1.[SH:20][CH:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23].C(N(CC)CC)C>CN(C=O)C>[Br:1][C:2]1[C:3]([S:20][CH:21]([CH2:25][CH3:26])[C:22](=[O:24])[CH3:23])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(Nc2ncc(Br)c(Cl)n2)cn1
Reactant: CCC(S)C(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(Sc1nc(Nc2ccc(S(N)(=O)=O)nc2)ncc1Br)C(C)=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
73 mg (0.2 mmol) of 5-(5-bromo-4-chloro-pyrimidin-2-ylamino)-pyridine-2-sulfonic acid amide and 32 mg (0.27 mmol) of 3-mercapto-2-pentanone are dissolved in 4 ml of DMF p.a. After 0.038 ml (0.27 mmol) of triethylamine is added, it is allowed to stir for 2 hours at room temperature and for 3 hours at 50° C. After concentration by evaporation, it is flashed with dichloromethane/MeOH (9:1).