Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12](=[O:18])(=[O:17])[NH:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=[C:7]([F:19])[C:3]=1[C:4]([OH:6])=O.[NH:20]1[C:24]2=[N:25][CH:26]=[C:27]([NH2:29])[CH:28]=[C:23]2[CH:22]=[CH:21]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:10]([NH:11][S:12](=[O:18])(=[O:17])[NH:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=[C:7]([F:19])[C:3]=1[C:4]([NH:29][C:27]1[CH:28]=[C:23]2[CH:22]=[CH:21][NH:20][C:24]2=[N:25][CH:26]=1)=[O:6]
Reactant: Nc1cnc2[nH]ccc2c1
Reactant: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.9 %

Procedure:
2,6-Difluoro-3-(N-propylsulfamoylamino)benzoic acid (0.095 g, 0.32 mmol), 1H-pyrrolo[2,3-b]pyridin-5-amine (0.043 g, 0.32 mmol), HOBt (0.044 g, 0.32 mmol), and EDCI (0.062 g, 0.32 mmol) were dissolved in DMF (1.6 mL) and stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (30 mL) and washed with a mixture of 1:1:1 water:bicarbonate:brine (3×20 mL). The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via column chromatography eluting with 1:1 then 8:2 EtOAc:hexanes to provide 2,6-difluoro-3-(N-propylsulfamoylamino)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (0.060 g, 0.15 mmol, 45% yield). 1H NMR (400 MHz, CD3OD) δ 8.36-8.40 (m, 2H), 7.64-7.72 (m, 1H), 7.41-7.43 (m, 1H), 7.06-7.13 (m, 1H), 6.50-6.52 (m, 1H), 2.96-3.02 (m, 2H), 1.47-1.57 (m, 2H), 0.87-0.93 (m, 3H); m/z (APCI-pos) M+1=410.2.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].C1(C)C=CC(S(OC[CH2:37][C:38]2[O:42][C:41]([C:43]3[CH:48]=[C:47]([O:49][CH3:50])[C:46]([O:51][CH3:52])=[C:45]([O:53][CH3:54])[CH:44]=3)=[N:40][C:39]=2[CH3:55])(=O)=O)=CC=1.O.[CH3:58]N(C)C=O>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C@@H:11]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:58][CH2:55][C:39]2[N:40]=[C:41]([C:43]3[CH:44]=[C:45]([O:53][CH3:54])[C:46]([O:51][CH3:52])=[C:47]([O:49][CH3:50])[CH:48]=3)[O:42][C:38]=2[CH3:37])=[CH:19][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)Nc1nc2ccccc2o1
Reactant: CN(C)C=O
Reactant: COc1cc(-c2nc(C)c(CCOS(=O)(=O)c3ccc(C)cc3)o2)cc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(OCCc2nc(-c3cc(OC)c(OC)c(OC)c3)oc2C)cc1)Nc1nc2ccccc2o1
Temperature: 25 °C

Procedure:
To the solution of 3.12 g of methyl (2S)-2-(1,3-benzoxazol-2-ylamino)-3-(4-hydroxyphenyl)propionate in 50 ml of dimethylformamide 60% suspension of NaH in mineral oil (0.4 g) was added portionwise with stirring at room temperature under argon atmosphere. When the evolution of the gas ceased, the solution of 2-[4-methyl-2-(3,4,5-trimethoxyphenyl)-1,3-oxazol-5-yl]ethyl 4-toluenesulfonate (4.47 g, 10 mmol) in dimethylformamide was added dropwise. The mixture was heated at 80° C. with stirring. After cooling, the mixture was poured into 1 l of water and extracted several times with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate and the solvent was evaporated, to obtain crude methyl (2S)-2-(1,3-benzoxazol-2-ylamino)-3-[4-(2-[5-methyl-2-(3,4,5-trimethoxy-phenyl)-1,3-oxazol-4-yl]ethoxy)phenyl]propionate.
Reaction SMILES: [C:1]([C:3](=[C:6]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)SC)[C:4]#[N:5])#[N:2].O.[NH2:20][NH2:21]>CO>[NH2:2][C:1]1[NH:21][N:20]=[C:6]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(CNC(SC)=C(C#N)C#N)c1
Reactant: NN
Solvent: O
Solvent: CO
Product: COc1cccc(CNc2n[nH]c(N)c2C#N)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 25.57 g (98.6 mmol) of 2-cyano-3-(3-methoxy-benzylamino)-3-methylmercapto-acrylonitrile, 5.16 ml (104 mmol) of hydrazine hydrate and 140 ml of methanol is stirred at RT for 1 hour, heated under reflux for 2.5 hours and then concentrated by evaporation in vacuo. Recrystallization of the residue from ethanol/hexane yields the title compound; m.p. 151-153° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1.Cl[C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[O:26])[C:16]([C:23]([OH:25])=[O:24])=[CH:17][N:18]2[CH2:21][CH3:22])=[CH:13][C:12]=1[F:27]>N1C=CC=CC=1>[CH2:21]([N:18]1[C:19]2[C:14](=[CH:13][C:12]([F:27])=[C:11]([N:8]3[CH2:7][CH2:6][NH:5][CH:4]([CH2:3][O:2][CH3:1])[CH2:9]3)[CH:20]=2)[C:15](=[O:26])[C:16]([C:23]([OH:25])=[O:24])=[CH:17]1)[CH3:22]
Reactant: COCC1CNCCN1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(COC)C3)cc21

Procedure:
A 1.7 g portion of 2-(methoxymethyl)piperazine was dissolved in 8 ml of pyridine. A 0.88 g portion of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and the mixture was heated in a pressure bottle, under argon, at 120°-130° C. for 18 hours. The solvents were removed and the resulting gum evaporated three times from toluene. The residue was purified by column chromatography, eluting with chloroform:methanol saturated with water (90:10). The appropriate fractions were combined and evaporated, giving 550 mg of the desired product, mp 169°-170° C.
Reaction SMILES: [CH3:1][C:2]([CH3:27])=[CH:3][CH2:4][C@@H:5]1[O:7][C@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([O:17]C(NC(CCl)=O)=O)[C@H:10]1[O:25][CH3:26])[CH3:8].[Na].CN(C)CCN1C(S)=NN=N1>>[CH3:1][C:2]([CH3:27])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:25][CH3:26])[CH3:8]
Reactant: CO[C@@H]1[C@H](OC(=O)NC(=O)CCl)CC[C@]2(CO2)[C@H]1[C@]1(C)O[C@H]1CC=C(C)C
Agent: CN(C)CCn1nnnc1S
Agent: [Na]
Product: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 158.4 %

Procedure:
In the same manner as in Example 42, O-chloroacetylcarbamoylfumagillol (195 mg) was reacted with 1-(2-dimethylaminoethyl)-5-mercaptotetrazole sodium (113 mg) with stirring at room temperature for 1 hour. Purification by silica gel column chromatography (eluent: ethyl acetate) gave colorless, powdery O-[[1-(2-dimethylaminoethyl)tetrazol]-5-yl)thioacetylcarbamoyl]fumagillol (217 mg) (83% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]2[CH2:16][C@H:15]([CH3:17])[C@@H:14]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C@H:13]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:12]2)=[C:4]2[CH2:10][CH2:9][O:8][C:5]2=[N:6][CH:7]=1.[F:34][C:35]1[CH:40]=[C:39]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][O:44][CH2:43]2)[CH:38]=[C:37]([F:48])[C:36]=1[C:49]1[N:54]=[C:53]([C:55](O)=[O:56])[CH:52]=[CH:51][C:50]=1[F:58].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:26][C@H:13]1[C@H:14]([OH:18])[C@@H:15]([CH3:17])[CH2:16][N:11]([C:3]2[C:2]([NH:1][C:55]([C:53]3[CH:52]=[CH:51][C:50]([F:58])=[C:49]([C:36]4[C:35]([F:34])=[CH:40][C:39]([O:41][CH:42]5[CH2:47][CH2:46][CH2:45][O:44][CH2:43]5)=[CH:38][C:37]=4[F:48])[N:54]=3)=[O:56])=[CH:7][N:6]=[C:5]3[O:8][CH2:9][CH2:10][C:4]=23)[CH2:12]1.[Si:19]([O:18][C@@H:14]1[C@@H:15]([CH3:17])[CH2:16][N:11]([C:3]2[C:2]([NH:1][C:55]([C:53]3[CH:52]=[CH:51][C:50]([F:58])=[C:49]([C:36]4[C:35]([F:34])=[CH:40][C:39]([O:41][CH:42]5[CH2:47][CH2:46][CH2:45][O:44][CH2:43]5)=[CH:38][C:37]=4[F:48])[N:54]=3)=[O:56])=[CH:7][N:6]=[C:5]3[O:8][CH2:9][CH2:10][C:4]=23)[CH2:12][C@H:13]1[NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])([C:22]([CH3:23])([CH3:25])[CH3:24])([CH3:20])[CH3:21]
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cc(OC3CCCOC3)cc2F)n1
Reactant: C[C@H]1CN(c2c(N)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cc(OC5CCCOC5)cc4F)n3)cnc3c2CCO3)C[C@@H](N)[C@@H]1O
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cc(OC5CCCOC5)cc4F)n3)cnc3c2CCO3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl ((3R,4R,5S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-methylpiperidin-3-yl)carbamate (20 mg, 0.042 mmol), 6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridine-2-carboxylic acid (18 mg, 0.050 mmol) and HATU (32 mg, 0.084 mmol) in DMF (0.10 mL) and DIPEA (22 μL, 0.13 mmol) was stirred at room temperature for 2 h. The reaction was quenched with water and the mixture was extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to yield the amide intermediate, tert-butyl ((3R,4R,5S)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-{5-[({6-[2,6-difluoro-4-(tetrahydro-2H-pyran-3-yloxy)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-2,3-dihydrofuro[2,3-b]pyridin-4-yl}-5-methylpiperidin-3-yl)carbamate.
Reaction SMILES: [CH3:1][S:2]([N:5](S(C)(=O)=O)[C:6]1[CH:35]=[CH:34][C:9]([C:10]([N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]([N:22]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:23](=[O:25])[CH3:24])[CH2:14][C@@H:13]2[CH3:33])=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[OH-].[Na+].O.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([N:22]([C@H:15]2[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:12]([C:10](=[O:11])[C:9]3[CH:34]=[CH:35][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][CH:8]=3)[C@@H:13]([CH3:33])[CH2:14]2)[C:23](=[O:25])[CH3:24])=[CH:27][CH:28]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc2)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(NS(C)(=O)=O)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 84.3 %

Procedure:
To a solution of N-((2S,4R)-1-{4-[bis(methylsulfonyl)amino]benzoyl}-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-N-(4-chlorophenyl)acetamide (259 mg, 0.44 mmol) in tetrahydrofuran (5.0 mL) at room temperature was added 1.0 M sodium hydroxide (0.880 mL, 0.88 mmol). The reaction was stirred at room temperature for 2 days. The resulting reaction mixture was poured into a 1:1 mixture of water and saturated sodium bicarbonate (25 mL) and extracted with ethyl acetate (1×25 mL). The aqueous layer was neutralized via addition of 1N HCl to pH ˜8 and extracted with ethyl acetate (2×25 mL). The combined organic layers were washed once with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to afford N-(4-chlorophenyl)-N-((2S,4R)-2-methyl-1-{4-[(methylsulfonyl)amino]benzoyl}-1,2,3,4-tetrahydroquinolin-4-yl)acetamide (190 mg, 76%) as a light-yellow, foamy solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([CH3:22])[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.C(O)(=O)C>C(Cl)Cl.[Zn]>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([CH3:22])[N:19]=[CH:18][C:7]=3[CH2:8][NH:9][CH:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)NC2
Product: Cl
Reaction time: 0.5 h

Procedure:
A mixture of 3.7 g (10.5 mmole) of 9-chloro-7-(2-chlorophenyl)-2-methyl-5H-pyrimido[5,4-d][2]benzazepine, 1.3 g of zinc dust, and 40 ml of acetic acid in 90 ml of methylene chloride was stirred at -15° C. to -20° C. for 30 min. The mixture was filtered over hyflo, and the filtrate was basified with cold dilute aqueous sodium hydroxide and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil. The yellow oil was crystallized from an excess of 6% methanolic hydrogen chloride to give the title compound as a white solid, m.p. 272°-274° C. Recrystallization from methanol gave colorless rods, m.p. 272°-274° C.
Reaction SMILES: [C:1]1([CH:7]([NH:9][CH2:10][CH2:11][OH:12])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>ClCCl>[Si:22]([O:12][CH2:11][CH2:10][NH:9][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(NCCO)c1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(NCCO[Si](C)(C)C(C)(C)C)c1ccccc1
Reaction time: 16 h
Yield: 81.7 %

Procedure:
To a stirred solution of 2-(1-phenylethylamino)ethanol (33) (2.71 g, 16.4 mmol, Eq: 1.00) in dichloromethane (60 ml) were added diisopropylethylamine (2.97 g, 4.01 ml, 23.0 mmol, Eq: 1.4) followed by tert-butyldimethylsilyl chloride (2.72 g, 18.0 mmol, Eq: 1.1) at room temperature under nitrogen atmosphere. The resulting solution was stirred for 16 hrs and then it was poured into water (200 ml). The organic layer was separated, washed with brine, and dried with MgSO4, concentrated, and chromatographed (silica gel, gradient 0 to 10% ethyl acetate-hexane) to obtain 2-(tert-butyldimethylsilyloxy)-N-(1-phenylethyl)ethanamine (34) (oil, 3.75 g, 13.4 mmol, 81.8% yield).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][NH:41]2)=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:35])([CH3:34])[CH3:33].[C:52]([O:56][C:57](=[O:66])[CH2:58][C@@H:59]1[CH2:62][C@H:61]([C:63](O)=[O:64])[CH2:60]1)([CH3:55])([CH3:54])[CH3:53].CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:25][C:26]1[CH:27]=[C:28]([NH:37][C:38]([C@H:40]2[C:49]3[C:44](=[CH:45][C:46]([O:50][CH3:51])=[CH:47][CH:48]=3)[CH2:43][CH2:42][N:41]2[C:63]([C@@H:61]2[CH2:60][C@H:59]([CH2:58][C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:66])[CH2:62]2)=[O:64])=[O:39])[CH:29]=[C:30]([F:36])[C:31]=1[Si:32]([CH3:33])([CH3:35])[CH3:34]
Reactant: COc1ccc2c(c1)CCN[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c([Si](C)(C)C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
HATU (92 mg, 0.24 mmol) was added to a solution of (R)—N-(3,5-difluoro-4-(trimethylsilyl)phenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-1-carboxamide (86 mg, 0.22 mmol), cis-3-(2-(tert-butoxy)-2-oxoethyl)cyclobutanecarboxylic acid (51.9 mg, 0.24 mmol) and DIEA (0.043 mL, 0.24 mmol) in DMF (2 mL) at room temperature, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 3→50% ethyl acetate/hexane) to give tert-butyl 2-(cis-3-((R)-1-((3,5-difluoro-4-(trimethylsilyl)phenyl)carbamoyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (86 mg, 0.22 mmol) as a colorless oil.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=NC2N(O)N=NC=2C=1.[S:56]([C:60]1[CH:61]=[C:62]([CH:64]=[CH:65][CH:66]=1)[NH2:63])([OH:59])(=[O:58])=[O:57]>CN(C=O)C.C(N(CC)CC)C>[S:56]([C:60]1[CH:61]=[C:62]([NH:63][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])[CH:64]=[CH:65][CH:66]=1)([OH:59])(=[O:58])=[O:57]
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N[C@@H](CCC(=O)Nc1cccc(S(=O)(=O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41 %

Procedure:
Boc-Glu-OtBu (75 mg, 0.247 mmol), HATU (112 mg, 0.296 mmol) and HOAt (41 mg, 0.296 mmol) were dissolved in 1 ml of DMF, and triethylamine (52 μl) was added to the solution, followed by stirring at room temperature for 10 minutes. 3-Sulfoaniline (43 mg, 0.247 mmol) was added thereto and stirred at room temperature overnight. After the solvent was removed by distillation, the mixture was purified according to the purification step A. The resulting intermediate was dissolved in 2 ml of trifluoroacetic acid. After stirring for 3 hours at room temperature, the solvent was removed by distillation. The product was purified according to the purification step A to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=O)[CH3:9])[CH:7]=1.Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:8]([CH3:9])[C:6]=2[CH:7]=1
Reactant: COC(=O)CBr
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1oc2ccc(Br)cc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a solution (100 mL) of 1-(5-bromo-2-hydroxyphenyl)ethanone (10.0 g) in N,N-dimethylformamide were added methyl bromoacetate (4.85 mL) and potassium carbonate (12.9 g), and the mixture was stirred overnight at room temperature. The insoluble material was filtered off, 1,8-diazabicyclo[5.4.0]undec-7-ene (6.95 mL) was added to the filtrate, and the mixture was stirred at 120° C. for 2 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to give the title object compound (6.06 g, 48%) as a pale-brown solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][CH2:12][CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:20][C:21]1[C:30]([O:31][CH3:32])=[CH:29][C:24]2[NH:25][C:26](=[O:28])[S:27][C:23]=2[CH:22]=1>>[CH3:32][O:31][C:30]1[C:21]([NH:20][C:2]2[C:3]3[C:10]4[CH2:11][CH2:12][CH:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:14][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:22][C:23]2[S:27][C:26](=[O:28])[NH:25][C:24]=2[CH:29]=1
Reactant: CCOC(=O)C1CCc2c(sc3ncnc(Cl)c23)C1
Reactant: COc1cc2[nH]c(=O)sc2cc1N
Product: CCOC(=O)C1CCc2c(sc3ncnc(Nc4cc5sc(=O)[nH]c5cc4OC)c23)C1

Procedure:
130 mg (438 μmol) (RS)-ethyl 4-chloro-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-7-carboxylate (prepared according to intermediate example 1a) were transformed in analogy to example 1 using 6-amino-5-methoxy-1,3-benzothiazol-2(3H)-one to give after working up and purification 98.1 mg (47%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:19]=[C:20]([NH:26][C:27]4[CH:32]=[CH:31][C:30]([CH:33]=O)=[CH:29][CH:28]=4)[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=3)[C:13]=2[CH3:35])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH2:39][CH2:40][NH:41][CH2:42][CH2:43][OH:44].C(O)(=O)C.[BH4-].[Na+]>CO>[OH:38][CH2:39][CH2:40][N:41]([CH2:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:20]2[C:21](=[O:25])[N:22]([CH3:24])[CH:23]=[C:18]([C:14]3[C:13]([CH3:35])=[C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:37][CH:36]=4)[CH:17]=[CH:16][CH:15]=3)[N:19]=2)=[CH:28][CH:29]=1)[CH2:42][CH2:43][OH:44]
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(C=O)cc2)n1
Reactant: OCCNCCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CN(CCO)CCO)cc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-tert-butyl-N-{3-[6-(4-formyl-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-benzamide (4) (110 mg; 0.22 mmol) was dissolved in methanol (10 mL) and 1 mL 2-(2-hydroxy-ethylamino)-ethanol was added. To the stirring reaction solution was then added 0.25 mL glacial acetic acid, followed by 0.25 g powdered molecular sieves (4 Å; activated) and the resulting slurry allowed to stir at rt for 4 hr under N2, then heated to 50° C. After 3 hr at 50° C., the reaction was cooled to rt and excess NaBH4 powder (0.5 g) was added portionwise to the stirring slurry. After gas evolution ceased, the reaction slurry was then adsorbed directly onto silica gel and was chromatographed using methanol/CH2Cl2 (1:9) as eluent to provide N-{3-[6-(4-{[bis-(2-hydroxy-ethyl)-amino]-methyl}-phenylamino)-4-methyl-5-oxo-4,5-dihydro-pyrazin-2-yl]-2-methyl-phenyl}-4-tert-butyl-benzamide (5) (75 mg) as an off-white solid. MS 584.24 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5]O.[C:11]1(=[O:18])[NH:16][C:15](=[O:17])[CH2:14][CH2:13][CH2:12]1.BrC1C=CC=CC=1CCN1C(=O)CN(C)C1=O>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][CH2:5][N:16]1[C:11](=[O:18])[CH2:12][CH2:13][CH2:14][C:15]1=[O:17]
Reactant: O=C1CCCC(=O)N1
Reactant: OCCc1ccccc1Br
Agent: CN1CC(=O)N(CCc2ccccc2Br)C1=O
Product: O=C1CCCC(=O)N1CCc1ccccc1Br

Procedure:
2-Bromophenethyl alcohol (402 mg, 2 mmol) and glutarimide (317 mg, 2.8 mmol) were treated as described in the preparation of compound 436. Purification was done by flash chromatography (petroleum ether/ethyl acetate 2:1) to provide the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1.C(Cl)CCl.Cl.[CH3:39][NH:40][CH3:41]>CN(C1C=CN=CC=1)C.C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([N:40]([CH3:41])[CH3:39])=[O:13])=[C:4]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([C:30]([F:33])([F:32])[F:31])[CH:24]=2)(=[O:22])=[O:21])[CH:3]=1
Reactant: O=C(O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNC
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)c1ccccc1CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A mixture of 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (304 mg, 0.57 mmol), DMAP (138 mg, 1.13 mmol), EDC (217 mg, 1.13 mmol), and dimethylamine hydrochloride (93 mg, 1.13 mmol) in CH2Cl2 (3 ml) was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0˜30% EtOAc in hexane) to yield the title compound (122 mg, 38%).