Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=3)[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:21]1([N:24]2[C:33]3[C:28](=[CH:29][C:30]([F:48])=[C:31]([Sn](CCCC)(CCCC)CCCC)[C:32]=3[CH3:34])[C:27](=[O:49])[C:26]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:25]2)[CH2:23][CH2:22]1.C(OCC)(=O)C.Cl>CN(C)C=O.[Ag-]=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:21]1([N:24]2[C:33]3[C:28](=[CH:29][C:30]([F:48])=[C:31]([C:15]4[CH:16]=[C:17]5[C:12](=[CH:13][CH:14]=4)[CH2:11][N:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:20])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH2:18]5)[C:32]=3[CH3:34])[C:27](=[O:49])[C:26]([C:50]([O:52][CH2:53][CH3:54])=[O:51])=[CH:25]2)[CH2:22][CH2:23]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cc2c(=O)c(C(=O)OCC)cn(C3CC3)c2c1C
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccc(Br)cc3C2)cc1
Agent: O=[Ag-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(C)c(-c3ccc4c(c3)CN(S(=O)(=O)c3ccc(C)cc3)C4)c(F)cc2c1=O
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
In 25 ml of N,N-dimethylformamide was dissolved 2.30 g of 2-(p-toluenesulfonyl)-5-bromoisoindoline, and 1.51 g of silver (I) oxide and 0.75 g of tetrakis(triphenylphosphine)palladium (0) were added to the solution, after which the resulting mixture was stirred at 100° C. for five minutes under a nitrogen atmosphere. Subsequently, to this reaction mixture was added 1.54 g of ethyl 1-cyclopropyl-6-fluoro-8-methyl-7-tributylstannyl-1,4-dihydro-4-oxoquinoline-3-carboxylate dissolved in 5 ml of N,N-dimethylformamide, and resulting mixture was stirred at 100° C. for 15 minutes. The reaction mixture was added to a mixed solvent of 50 ml of ethyl acetate and 100 ml of water, and the pH was adjusted to 2 with 2N hydrochloric acid, after which insolubles were removed by filtration. The organic layer formed was separated, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. The residue obtained was purified by a column chromatography (eluent: toluene:ethyl acetate=3:1), and diethyl ether was thereafter added thereto, after which the crystals formed were collected by filtration, to obtain 0.55 g of colorless, crystalline ethyl 1-cyclopropyl-6-fluoro-8-methyl-7-[2-(p-toluenesulfonyl)isoindolin-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[C:22]([Cl:34])=[CH:21][N:20]=1>>[Cl:34][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[N:6]([CH2:12][CH3:13])[C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: COc1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)CCCc2cc(N)c(OC)cc21
Product: CCN1C(=O)CCCc2cc(Nc3ncc(Cl)c(Nc4ccccc4OC)n3)c(OC)cc21
Yield: 35.9 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1-ethyl-8-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (51 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-phenyl)-amine (53 mgs) was converted to the title compound (33 mgs, 35%) as a white foam. 1H-NMR (CDCl3): δ 8.42 (d, J=7.9 Hz, 1H), 8.23 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.54 (s, 1H), 7.13-7.09 (1, 2H), 7.01-6.94 (d, 2H), 6.72 (s, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 2.70-2.60 (m, 2H), 2.30-2.19 (m, 4H), 1.17 (t, J=7.3 Hz, 3H). LC/MS: found (M+H)+=468.24; MP: 78-80° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH2:9][C:10]([O:12][C@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:42])[F:43])=[C:36]([O:44][CH2:45][CH:46]2[CH2:47][CH2:48]2)[CH:35]=1)[CH2:31][C:30]1[C:29]([Cl:49])=[CH:28][N+:27]([O-:50])=[CH:26][C:25]=1[Cl:24])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc(CN(CC(=O)O)C(=O)OC(C)(C)C)cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(CN(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)C(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of 2-(tert-butoxycarbonyl(3,4-dimethoxybenzyl)amino)acetic acid (0.209 g, 0.642 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.150 g, 0.357 mmol), EDC (0.205 g, 1.071 mmol), and DMAP (0.087 g, 0.714 mmol) in DCM (5 ml) was stirred at RT overnight. The reaction mixture was diluted with DCM (20 ml) and washed with HCl 1M and with NaHCO3 5%. The organic layer was dried over Na2SO4, and the solvent was removed under vacuum. The crude was purified by chromatography on silica gel column (DCM:EtOAc=70:30) affording (S)-4-(2-(2-(tert-butoxycarbonyl(3,4-dimethoxybenzyl)amino) acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.258 g, 0.355 mmol, 99% yield, MS/ESI+ 727.3 [MH]+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24]CC)=[O:15])[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[N:29]1([C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:27])[NH:20][C:19](=[O:28])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:6]=[N:7][N:8]([CH:11]([CH3:12])[CH3:13])[C:9]=2[CH:10]=[C:2]([C:38]2[CH:37]=[CH:36][C:35]([N:29]3[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]3)=[CH:40][CH:39]=2)[CH:3]=1)=[O:15]
Reactant: OB(O)c1ccc(N2CCNCC2)cc1
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)cc2c1cnn2C(C)C
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(N4CCNCC4)cc3)cc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in a similar manner as described for example 8 from 6-bromo-1-(1-methylethyl)-N-[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]-1H-indazole-4-carboxamide (80 mg, 0.192 mmol) and [4-(1-piperazinyl)phenyl]boronic acid (59 mg, 0.288 mmol). The product was collected as a white solid (34 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.53 (br. s., 1H) 8.66 (br. s., 1H) 8.33 (s, 1H) 8.00 (s, 1H) 7.82 (s, 1H) 7.73-7.76 (m, 1H) 7.72 (s, 1H) 7.01-7.09 (m, 2H) 5.89 (s, 1H) 5.14 (dt, J=13.33, 6.60 Hz, 1H) 4.39 (br. s., 1H) 4.38 (br. s., 1H) 3.38-3.52 (m, 4H) 3.09-3.14 (m, 1H) 3.00-3.09 (m, 3H) 2.81-2.90 (m, 1H) 2.21 (s, 3H) 2.13 (s, 3H) 1.50 (s, 3H) 1.48 (s, 3H). LC-MS (ES) m/z=499.4 [M+H]+
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[N:28]1[C:37]2[C:32](=[C:33]([NH:38][NH2:39])[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1>>[N:28]1[C:37]2[C:32](=[C:33]([N:38]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:19]=[CH:18][C:17]([S:20]([C:23]([F:26])([F:24])[F:25])(=[O:22])=[O:21])=[CH:16][CH:15]=5)[N:8]=4)=[CH:4][CH:3]=[N:39]3)[CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)ccc1=O
Reactant: NNc1cccc2ncccc12
Product: O=c1ccn(-c2ccc(S(=O)(=O)C(F)(F)F)cc2)nc1-c1ccnn1-c1cccc2ncccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethansulfonyl-phenyl)-1H-pyridazin-4-one (A-27) and quinolin-5-yl-hydrazine according to the method described for example 43. MS: M=498.1 (M+H)+
Reaction SMILES: Cl.[CH:2]1([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C:16]([CH3:31])([S:27]([CH3:30])(=[O:29])=[O:28])[C:17]([NH:19][O:20]C3CCCCO3)=[O:18])[C:10](=[O:32])[CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.CO>O1CCOCC1.ClCCl>[CH:2]1([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C:16]([CH3:31])([S:27]([CH3:30])(=[O:29])=[O:28])[C:17]([NH:19][OH:20])=[O:18])[C:10](=[O:32])[CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(CCn1ccc(C2CCCCC2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(CCn1ccc(C2CCCCC2)cc1=O)(C(=O)NO)S(C)(=O)=O
Yield: 202.4 %

Procedure:
A 4.0 M solution of HCl in 1,4-dioxane (3.3 mL) was added slowly to a solution of the 4-(4-cyclohexyl-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (220 mg, 0.14 mmol) in dichloromethane (5 mL) followed by methanol (1 mL) at room temperature. The reaction was concentrated in vacuo and the title compound was purified using reverse phase chromatography (Gradient used with formic acid modifier(0.05%), 95:5 water:acetonitrile to 5:95 water:acetonitrile). Gradient time 6 minutes. Furnished a white solid (105 mg, 58.6%) MS (LC/MS) m/z 371.6 (M+1)
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][S:24]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[CH2:33][OH:34])(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[CH:33]=[O:34])(=[O:26])=[O:25]
Reactant: CS(=O)(=O)N1CCCCC1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CS(=O)(=O)N1CCCCC1C=O
Reaction time: 24 h
Yield: 22.6 %

Procedure:
Dess-Martin periodinane (21 g, 50 mmol) was added to a solution of (1-(methylsulfonyl)piperidin-2-yl)methanol (4.9 g, 25.4 mmol) in anhydrous methylene chloride (125 mL). The reaction was stirred for 24 hours, filtered, and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (25-75% ethyl acetate in hexanes) to provide a white waxy solid (1.1 g, 24% yield). 1H NMR (CDCl3, 300 MHz) δ 9.56 (s, 1H), 4.61-4.58 (br d, 1H, J=6.3 Hz), 3.75-3.68 (m, 1H), 3.13-3.04 (td, 1H, J=12.0, 3.2 Hz), 2.97 (s, 3H), 2.33-2.22 (m, 1H), 1.89-1.55 (m, 4H), 1.27-1.21 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:18].[H-].[Na+].[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25]Br)[CH3:22]>CN(C)C=O>[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25][O:18][C:3]1[CH:4]=[CH:5][C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])=[N:8][O:9][C:10]=2[C:2]=1[Cl:1])[CH3:22]
Reactant: Oc1ccc2c(-c3ccccc3F)noc2c1Cl
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc2c(-c3ccccc3F)noc2c1Cl)OCC
Temperature: 80 °C

Procedure:
A solution of 5.0 g of 7-chloro-6-hydroxy-3-(2-fluorophenyl)-1,2-benzisoxazole in 30 ml dimethylformamide is added to a suspension of 1 g (50% suspension in oil) sodium hydride in 30 ml of dimethylformamide with stirring. Bromoacetaldehyde diethylacetal (6.2 ml) is added and the reaction mixture is heated at 80° C. for 24 hrs. The resulting dark solution is poured onto ice/water and extracted with four-100 ml portions of ether. The combined ether extracts are washed with dilute sodium hydroxide solution, saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Removal of the solvent followed by recrystallization from ether/petroleum ether affords {[7-chloro-3(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetaldehyde diethyl acetal as white needles, mp 59° C.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5][CH:4]=1.Cl>CO>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1=C(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Mg]
Solvent: CO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1c1ccc(F)cc1
Reaction time: 8 h
Yield: 85 %

Procedure:
Magnesium metal (0.525 g, 21.8 mmol) was added in three portions over approximately 0.3 h to a stirred solution of the product of step D (0.762 g, 2.18 mmol) in methanol at ambient temperature. After stirring overnight, the reaction mixture was poured into 1 N hydrochloric acid (100 mL) and extracted three times with ethyl acetate. The combined organic extracts were washed with saturated sodium bicarbonate, brine, dried (MgSO4) and concentrated in vacuo. Purification of the residue by medium pressure liquid chromatography on silica gel (gradient elution; 0–25% ethyl acetate/hexanes as eluent) furnished the title compound (3:1 mixture of cis/trans diastereoisomers) as a colorless oil (0.651 g).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH3:20][CH:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH3:22]>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:26]3[CH2:27][CH2:28][N:23]([CH:21]([CH3:22])[CH3:20])[CH2:24][CH2:25]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: CC(C)N1CCNCC1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: CC(C)N1CCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1
Yield: 89.2 %

Procedure:
The title compound of Example 2 (1.0 g, 3.4 mmol) was combined with 1-(1-methylethyl)piperazine (0.48 g, 3.7 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic purification, 1.17 g of the title product was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH2:20][CH2:21][CH3:22])[N:5]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)[C:6](=[O:8])[CH:7]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C(O)(=O)C1C=CC=CC=1.N1CCCCC1>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[N:3]=[C:4]([CH2:20][CH2:21][CH3:22])[N:5]([CH2:9][CH2:10][O:11][C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[C:27]3[S:23][C:24](=[O:29])[NH:25][C:26]3=[O:28])=[CH:14][CH:13]=2)[C:6](=[O:8])[CH:7]=1
Reactant: CCCc1nc(C)cc(=O)n1CCOc1ccc(C=O)cc1
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCc1nc(C)cc(=O)n1CCOc1ccc(C=C2SC(=O)NC2=O)cc1
Temperature: 25 °C
Yield: 125.7 %

Procedure:
A mixture of 4-[2-[4-methyl-2-propyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]benzaldehyde (10 g, 24.5 mmol) (obtained from preparation 1), thiazolidine-2,4-dione (3.5 g, 30 mmol), benzoic acid (388 mg, 3.18 mmol) and piperidine (352 μl, 303 mg, 3.68 mmol) in toluene (50 ml) was refluxed for 1 h with continuous removal of water. The reaction mixture was cooled to room temperature and the resultant crystalline compound was filtered and washed with water and dried to afford the title compound (12.3 g, 99%), mp 240-242° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)=[CH:10][C:9]([NH2:21])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]([O:26][C:27]([NH:29][C@H:30]([CH2:34][NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[C:39]([O:38][C:36](=[O:37])[NH:35][CH2:34][C@@H:30]([NH:29][C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:28])[C:31](=[O:32])[NH:21][C:9]1[CH:10]=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=2)[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)([CH3:42])([CH3:41])[CH3:40]
Reactant: CCCc1cccc(-c2cc(N)nn2-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)NC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1cccc(-c2cc(NC(=O)[C@@H](CNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)nn2-c2ccccc2)c1
Yield: 91.5 %

Procedure:
To a solution of 1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-ylamine (177 mg) prepared according to the same procedures as Preparation 8 in DMF (1.8 ml) were added (R)-2,3-bis-tert-butoxycarbonylaminopropionic acid (292 mg), HOBt.H2O (147 mg) and WSC.HCl (184 mg), and the mixture was stirred at room temperature for 2 hours. To this reaction solution were added water and a saturated aqueous solution of sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The separated organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1) to give the titled compound (329 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:58])[CH2:7][N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:13][N:14]([CH2:44][C:45]1[N:46]([CH2:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH:47]=[CH:48][N:49]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([NH:27][C:28](=[O:43])[NH:29][C@H:30]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31][CH2:32][C:33](O)=[O:34])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:4])([CH3:3])[CH3:2].[NH2:59][CH2:60][CH2:61][C:62]1[CH:67]=[CH:66][C:65]([S:68]([NH2:71])(=[O:70])=[O:69])=[CH:64][CH:63]=1.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>[C:53]([O:52][C:51](=[O:57])[CH2:50][N:46]1[CH:47]=[CH:48][N:49]=[C:45]1[CH2:44][N:14]([CH2:13][C:9]1[N:8]([CH2:7][C:6](=[O:58])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=[CH:11][N:10]=1)[CH2:15][CH2:16][CH2:17][CH2:18][C@H:19]([NH:27][C:28]([NH:29][C@@H:30]([CH2:31][CH2:32][C:33](=[O:34])[NH:59][CH2:60][CH2:61][C:62]1[CH:63]=[CH:64][C:65]([S:68](=[O:69])(=[O:70])[NH2:71])=[CH:66][CH:67]=1)[C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[O:43])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:54])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)Cn1ccnc1CN(CCCC[C@H](NC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Cn1ccnc1CN(CCCC[C@H](NC(=O)N[C@@H](CCC(=O)NCCc1ccc(S(N)(=O)=O)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc1nccn1CC(=O)OC(C)(C)C
Yield: 101.8 %

Procedure:
A solution of (S)-4-(3-((S)-6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)-1-tert-butoxy-1-oxohexan-2-yl)ureido)-5-tert-butoxy-5-oxopentanoic acid (80 mg, 0.098 mmol), 4-(2-aminoethyl)benzenesulfonamide (30 mg, 0.15 mmol), HATU (50 mg, 0.17 mmol), and DIPEA (0.50 mL) in DMF (5 mL) was stirred at 40° C. overnight. The solvents were evaporated under reduced pressure to give a residue, which was purified by Biotage SP4 using a gradient of 0-20% MeOH in DCM to give (S)-tert-butyl 6-(bis((1-(2-tert-butoxy-2-oxoethyl)-1H-imidazol-2-yl)methyl)amino)-2-(3-((S)-1-tert-butoxy-1,5-dioxo-5-(4-sulfamoylphenethylamino)pentan-2-yl)ureido)hexanoate (100 mg, 100%). ESMS m/z: 501.9 (M/2+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH2:9][C:10]2=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C1CCc2ccc(Br)cc21

Procedure:
3-(4-Bromophenyl)propionic acid (162 g, 706 mmol) and thionyl chloride (155 mL, 2120 mmol) were refluxed for 90 minutes. The thionyl chloride was then removed under vacuum to yield an amber oil. This oil, aluminum chloride (109 g, 816 mmol), and dichloromethane (1000 mL) were refluxed for 90 minutes and then poured onto ice. Dilute hydrochloric acid was added and the mixture was extracted with diethyl ether. The organic layer was washed with 2N hydrochloric acid, water, aqueous sodium bicarbonate, water, and brine. The product was flash chromatographed on a 25×7 cm silica gel column and eluted with ethyl acetate/dichloromethane (5:95) to obtain a pale brown solid after removing solvent under vacuum, (142 g, 95%), 107-109° C. m.p.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1)=[O:4].C(=O)(O)[O-].[Na+].[Br-].[Na+].Cl[O-].[Na+]>ClCCl.O>[CH3:1][O:2][C:3]([N:5]1[CH2:6][CH2:7][CH:8]([CH:11]=[O:12])[CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)N1CCC(CO)CC1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)N1CCC(C=O)CC1
Temperature: 5 °C
Yield: 90 %

Procedure:
4-Hydroxymethylpiperidine-1-carboxylic acid methyl ester (34.7 g, 1.0 eq) was dissolved in dichloromethane and cooled to 0-10° C. A solution of sodium bicarbonate (2.35 g, 0.14 eq) and sodium bromide (2.40 g, 0.10 eq) in water (100 mL) was added over 15 min while maintaining the temperature at 0-10° C. 2,2,6,6-Tetramethyl-1-piperidinyloxy free radical (TEMPO) (0.32 g, 0.01 eq) was added to the mixture, followed by 10-13% w/v sodium hypochlorite solution (135 mL, 1.1 eq) over 1 h with good agitation while maintaining the temperature at 0-10° C. After the reaction was complete, the layers were separated and the organic layer washed with water (150 mL) and dried over sodium sulfate (30 g, 1 w/w eq). The solvent was removed by distillation to provide the title intermediate. (31.0 g, 90% yield)
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1=[O:21].Br[C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[C@H:34]([C:35]([CH3:43])([CH3:42])[O:36][SiH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:33][CH2:32][C:31]2=[O:44])[CH:26]=[N:27][CH:28]=1>>[C:38]([SiH2:37][O:36][C:35]([CH3:43])([CH3:42])[C@@H:34]1[CH2:33][CH2:32][C:31](=[O:44])[N:30]1[CH2:29][C:25]1[CH:24]=[C:23]([C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][CH:9]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][CH2:5]3)[CH:28]=[N:27][CH:26]=1)([CH3:41])([CH3:39])[CH3:40]
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CC(C)(C)[SiH2]OC(C)(C)[C@@H]1CCC(=O)N1Cc1cncc(Br)c1
Product: CN1C(=O)CCc2cc(-c3cncc(CN4C(=O)CC[C@H]4C(C)(C)O[SiH2]C(C)(C)C)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of intermediate A-3 [C], 1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-1) has been coupled to (S)-1-(5-bromo-pyridin-3-ylmethyl)-5-(tert-butyl-dimethyl-silanyloxymethyl)-pyrrolidin-2-one to give the title compound as a brown foam. MS: 480.3 (M+H+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:22]=[CH:21][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:7][CH:6]=1)(=[NH:4])=[O:3].[CH2:23]=O>C(O)(=O)C>[CH3:23][N:4]=[S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:21][CH:22]=1)([CH3:1])=[O:3]
Reactant: CS(=N)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Reactant: C=O
Solvent: CC(=O)O
Product: CN=S(C)(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 100 °C

Procedure:
A mixture of 2-(4-(S-methylsulfonimidoyl)benzyl)isoindoline-1,3-dione (preparation 17b, 200 mg, 63.6 mmol) and paraformaldehyde (115 mg, 1.27 mmol) in acetic acid (2 mL) is heated in a microwave at 100° C. for 4 h. The mixture is concentrated under reduced pressure, and the residue is purified by flash chromatography on silica (gradient dichloromethane to dichloromethane/methanol 95:5). Yield: 189 mg (90% of theory); ESI mass spectrum: [M+H]+=329; r.t. HPLC: 0.45 min (X011_S03).