Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)=[O:12])[N:7]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29]3)=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.CCOC(C)=O>CCOC(C)=O.CCOCC>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)=[O:12])[N:7]([C:22]2[CH:31]=[C:30]3[C:25]([CH2:26][CH2:27][NH:28][CH2:29]3)=[CH:24][CH:23]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(C#N)c3)cc2C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(C#N)c2)n(-c2ccc3c(c2)CNCC3)n1
Temperature: 22.5 °C
Reaction time: 6.5 h
Yield: 50.3 %

Procedure:
To t-butyl 7-(3-t-butyl-5-(3-(3-cyanophenyl)ureido)-1H-pyrazol-1-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (0.34 g, 0.66 mmol) in EtOAc (5.0 ml) was added 3M HCl/EtOAc (1.1 mL, 3.3 mmol). The resulting mixture was stirred at 20-25° C. for 6.5 h. The suspension was diluted with Et2O to fully precipitate the solids. These were collected by filtration, rinsed with Et2O and dried to yield 1-(3-t-butyl-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1H-pyrazol-5-yl)-3-(3-cyanophenyl)urea (0.1377 g, 46% yield) of as an off-white solid. 1H NMR (400 MHz, DMSO-d6): 10.1 (s, 1H), 9.47 (brs, 2H), 8.97 (s, 1H), 7.94-7.93 (m, 1H), 7.63-7.60 (m, 1H), 7.49-7.33 (m, 5H), 6.37 (s, 1H), 4.36 (brs, 2H), 3.37 (brs, 2H), 3.06-3.03 (m, 2H), 1.28 (s, 9H); MS (ESI) m/z: 415.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([OH:23])=O)[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[N:37]1([CH2:43][CH2:44][N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21]([N:40]3[CH2:39][CH2:38][N:37]([CH2:43][CH2:44][N:45]4[CH2:46][CH2:47][O:48][CH2:49][CH2:50]4)[CH2:42][CH2:41]3)=[O:23])[CH:17]=2)(=[O:11])=[O:12])=[C:7]([CH3:9])[CH:8]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: C1CN(CCN2CCOCC2)CCN1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)N3CCN(CCN4CCOCC4)CC3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (63 mg, 0.18 mmol), CDI (58 mg, 0.36 mmol) and 4-[2-(piperazin-1-yl)ethyl]morpholine (60 mg, 0.30 mmol) in DCE (4.5 mL).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[C:13]([F:30])[CH:12]=2)[CH2:6]1)=[N+]=[N-].N1C=CC=CC=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>C(OCC)(=O)C.[Pd]>[C:37]([NH:1][CH2:4][C@@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)=[C:13]([F:30])[CH:12]=2)[CH2:6]1)(=[O:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3C[C@@H](CN=[N+]=[N-])OC3=O)cc2F)CC1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 82 %

Procedure:
A solution of 14.92 g (35.5 mmol) of the azide 4 in 2000 mL of ethyl acetate was treated with 2 g of 10% palladium on carbon followed by hydrogenation at one atmosphere for 24 h. The flask was flushed with nitrogen, followed by sequential addition of 14.0 g (14.4 ml, 177.5 mmol) of pyridine and 9.1 g (8.4 mL, 88.8 mmol) of acetic anhydride. The mixture was stirred at ambient temperature for 72 h, followed by filtration through celite. The filtrate was extracted with water, 1N copper sulfate solution, dried and concentrated in vacuo to afford a tan solid. This material was purified by silica gel chromatography to afford 12.7 g (82%) of the product 5 as a powdery white solid, mp 153°-159° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:11]2[S:12][C:13]([CH2:16][N:17]3[C:21]4=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]4[N:19]=[C:18]3[CH2:28][CH3:29])=[CH:14][CH:15]=2)[CH2:10][CH:9]=[CH:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH2:28]([C:18]1[N:17]([CH2:16][C:13]2[S:12][C:11]([C:6]3([C:4]([OH:5])=[O:3])[CH2:10][CH:9]=[CH:8][CH2:7]3)=[CH:15][CH:14]=2)[C:21]2=[N:22][C:23]([CH3:27])=[CH:24][C:25]([CH3:26])=[C:20]2[N:19]=1)[CH3:29]
Reactant: CCOC(=O)C1(c2ccc(Cn3c(CC)nc4c(C)cc(C)nc43)s2)CC=CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2(C(=O)O)CC=CC2)s1
Temperature: 80 °C

Procedure:
To a solution of the product of Step 5, above (6), in methanol was added an excess of 2N NaOH. The reaction mixture was heated to 80° C. for 1 hour, cooled to room temperature and the solvent evaporated. Water was added to the residue and the solution was extracted 2 times with EtOAc. The aqueous layer was acidified with 10% HCl and the resultant white suspension was extracted 2 times with EtOAc. The organics were dried over MgSO4, filtered and concentrated to a solid. The solid was crystallized from EtOAc to yield the title compound (8).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=CC=CC=1CN1CCNCC1.[C:16](=[O:19])([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]1[O:2][CH2:3][CH2:15][O:19][CH2:16][CH2:1][O:2][CH2:3][CH2:15][O:19][CH2:16][CH2:1][O:2][CH2:3][CH2:15][O:19][CH2:16]1
Reactant: COc1ccccc1CN1CCNCC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C1COCCOCCOCCOCCOCCO1

Procedure:
3.0 g of intermediate compound 8a were reacted in 70 ml of DMF with 2.9 g of N-(2-methoxybenzyl)piperazine analogously to Example 8b in the presence of 5.7 g of potassium carbonate and a spatula tipful of 18-crown-6, 1.3 g (27%) of the product being obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>C1COCC1.O>[OH:9][C:4]1[CH:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[C:6]([OH:8])[CH:5]=1
Reactant: Nc1cc(O)cc(O)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1cc(O)cc(O)c1)OCc1ccccc1
Reaction time: 3 h

Procedure:
To a mixture of 5-aminobenzene-1,3-diol (0.60 g, 3.7 mmole) and sodium hydrogencarbonate (1.4 g, 16 mmole) in THF/water (15 mL, 1:1 v/v) was added dropwise benzyl chloroformate 1.6 mL, 11 mmole). After 3 h at rt, THF was removed under vacuum and the remaining aqueous layer was extracted with ethyl acetate. Purification by column chromatograpy over silica gel provided benzyl N-(3,5-dihydroxyphenyl)carbamate. 1H NMR (CD3OD): δ 7.42-7.25 (m, 5H), 6.46 (d, 2H, J=2.4 Hz), 5.97-5.94 (m, 1H), 5.14 (s, 2H).
Reaction SMILES: [NH:1]([C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([C:27]([NH:29][C@H:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[CH:33]=4)[CH3:31])=[O:28])=[CH:24][CH:25]=3)[C:20]([CH3:41])=[C:19]2[CH3:42])=[CH:13][CH:12]=1)=[O:4])[NH2:2].CCN(C(C)C)C(C)C.CN([CH:55]=[O:56])C>>[CH:38]([C:34]1[CH:33]=[C:32]([C@@H:30]([NH:29][C:27]([C:23]2[CH:22]=[C:21]3[C:26](=[CH:25][CH:24]=2)[N:18]([CH2:17][C:14]2[CH:13]=[CH:12][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[C:3]4[O:4][C:55](=[O:56])[NH:2][N:1]=4)=[CH:16][CH:15]=2)[C:19]([CH3:42])=[C:20]3[CH3:41])=[O:28])[CH3:31])[CH:37]=[CH:36][CH:35]=1)([CH3:39])[CH3:40]
Reactant: CN(C)C=O
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)NN)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3-c3n[nH]c(=O)o3)cc2)c2ccc(C(=O)N[C@@H](C)c3cccc(C(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture of (S)-1-((2′-(hydrazinocarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-N-(1-(3-isopropylphenyl)ethyl)-2,3-dimethyl-1H-indole-5-carboxamide (0.062 g, 0.11 mmol), N,N′-carbonyldiimidazole (0.027 g, 0.16 mmol) and DIEA (0.03 mL, 0.16 mmol) in DMF was stirred at room temperature for 1 h, and then stirred at 50° C. for 1 h. The reaction mixture was poured on to ice-water, and then extracted with ethyl acetate. The combined organic layers were washed with water and brine. The solvent was remove and the residue was purified with preparative-HPLC to obtain the title compound. ESI-MS (m/z): 585 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][N:14]=1)[C:10]#[N:11].[C:21]([C:23]1[CH:24]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:26]=[CH:27][C:28]=1[F:29])#[N:22]>>[C:21]([C:23]1[CH:24]=[C:25]([S:30]([N:6]([C:7]2[CH:8]=[C:9]([C:10]#[N:11])[CH:12]=[CH:13][N:14]=2)[CH2:5][C:4]2[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:3]=2[O:2][CH3:1])(=[O:32])=[O:31])[CH:26]=[CH:27][C:28]=1[F:29])#[N:22]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: COc1ccc(CNc2cc(C#N)ccn2)c(OC)c1
Product: COc1ccc(CN(c2cc(C#N)ccn2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1

Procedure:
The title compound was prepared according to the method described for Preparation 18 using 2-((2,4-dimethoxybenzyl)amino)isonicotinonitrile (Preparation 35) and 3-cyano-4-fluorobenzene-1-sulfonyl chloride. The residue was purified by reverse phase chromatography eluting with 0-100% MeCN in water/0.1% formic acid.
Reaction SMILES: [N+](C1C=CC(S(O[CH2:14][C@@H:15]2[CH2:19][C@@H:18]([CH2:20][CH2:21][CH2:22][Cl:23])[C:17](=[O:24])[NH:16]2)(=O)=O)=CC=1)([O-])=O.[N-:25]=[N+:26]=[N-:27].[Na+].[N-]=[N+]=[N-]>CN(C=O)C>[N:25]([CH2:14][C@H:15]1[NH:16][C:17](=[O:24])[C@H:18]([CH2:20][CH2:21][CH2:22][Cl:23])[CH2:19]1)=[N+:26]=[N-:27]
Reactant: O=C1N[C@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C[C@H]1CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1C[C@@H](CCCCl)C(=O)N1

Procedure:
The ((2S,4R)-4-(3-chloropropyl)-5-oxopyrrolidin-2-yl)methyl 4-nitrobenzenesulfonate (18.05 g, 45.2 mmol) and NaN3 (3.23 g, 49.7 mmol, 1.1 equiv) were stirred in 100 mL of DMF for 19 h. After this time a white solid had formed and LC/MS analysis showed formation of the desired azide. The DMF was removed in vacuo and the residue partitioned between EtOAc/H2O (100+100 mL). The mixture was transferred to a separatory funnel and the layers separated. The aqueous layer was extracted with 100 mL additional EtOAc and the combined organic extracts washed with brine, dried over Na2SO4, filtered and evaporated. The (3R,5S)-5-(azidomethyl)-3-(3-chloropropyl)pyrrolidin-2-one was isolated as a pale yellow syrup (9.08 g, 94% yield).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:42])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH2:38][CH:39]([CH3:41])[CH3:40])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:38]([C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:42])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:18])([F:20])[F:19])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[CH:36][N:35]=1)[CH:39]([CH3:40])[CH3:41]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(CC(C)C)c3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(CC(C)C)c3)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2-isobutyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M257) (0.30 g, 0.50 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (210 mg, 87%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[NH:7][C:6](=O)[C:5]=1[N+:14]([O-:16])=[O:15])[CH3:2].O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:6]1[C:5]([N+:14]([O-:16])=[O:15])=[C:4]([NH:3][CH2:1][CH3:2])[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCNc1cc(C(C)C)[nH]c(=O)c1[N+](=O)[O-]
Product: CCNc1cc(C(C)C)nc(Cl)c1[N+](=O)[O-]

Procedure:
A mixture of 4-ethylamino-6-isopropyl-3-nitro-1H-pyridin-2-one (520 mg, 2.31 mmol) in POCl3 is stirred at reflux for 1.5 h. After cooling, the solution is concentrated in vacuo. The reaction flask is then placed in an ice bath and crushed ice is added to the residue. The mixture is swirled vigorously for a few minutes and then stirred at 0° C. for 1 h. The mixture is then extracted with EtOAc. The extract is washed with additional H2O (20 mL) and brine (20 mL). The extract is dried over Na2SO4 and concentrated to afford (2-chloro-6-isopropyl-3-nitro-pyridin-4-yl)-ethyl-amine as a yellow solid. The material is sufficiently pure to be used without further purification. 1H NMR (CDCl3, 400 MHz) δ 6.62 (br, 1H), 6.44 (s, 1H), 3.31 (m, 2H), 2.91 (sept, J=6.8 Hz, 1H), 1.33 (t, J=7.4 Hz, 3H), 1.26 (d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[N:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:13](=[O:19])[NH:14]3)=[CH:4][CH:3]=1>[Pd].CO.C1COCC1>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[C:12](=[N:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=2)[C:13](=[O:19])[NH:14]3)=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cccc(C=Cc4ccc(O)cc4)c32)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3cccc(CCc4ccc(O)cc4)c32)cc1
Reaction time: 1 h
Yield: 9.3 %

Procedure:
A mixture of 0.028 g (0.64 mmol) of 4-(N′-{4-[2-(4-hydroxyphenyl)-vinyl]-2-oxo-1,2-dihydro-indol-3-ylidene}-hydrazino)-benzenesulfonamide (Z isomer) and 0.015 g of 10% palladium on charcoal in 60 mL of MeOH:THF (4:1) was subjected to hydrogenation on a Parr apparatus at 50 psi for 1 h. The mixture was filtered through celite, and the filtrate was concentrated to give 0.026 g (93%) of the title compound as a yellow solid: 1H NMR (DMSO-d6): δ 2.82 (t, J=8.0 Hz, 2H), 3.23 (t, J=8.0 Hz, 2H), 6.69 (d, J=8.4 Hz, 2H), 6.78 (d, J=7.7 Hz, 1H), 6.89 (d, J=7.7 Hz, 1H), 7.07 (d, J=8.4 Hz, 2H), 7.18 (t, J=7.7 Hz, 1H), 7.26 (s, 2H), 7.45 (d, J=8.8 Hz, 2H), 7.71 (d, J=8.8 Hz, 2H), 9.20 (bs, 1H), 11.12 (s, 1H), 13.02 (s, 1H); APCI-MS m/z 435 (M−1)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]3)[CH:15]=[CH:14][C:13]=2[O:26][CH3:27])(=[O:10])=[O:9])=[C:4]([Cl:28])[CH:3]=1.[CH3:29][C:30]1[CH:31]=[C:32](B(O)O)[S:33][CH:34]=1.CC(C)([O-])C.[K+]>COCCOC.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>[Cl:28][C:4]1[CH:3]=[C:2]([C:32]2[S:33][CH:34]=[C:30]([CH3:29])[CH:31]=2)[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:23][C@H:22]([CH3:24])[NH:21][C@H:20]([CH3:25])[CH2:19]2)[CH:15]=[CH:14][C:13]=1[O:26][CH3:27])(=[O:10])=[O:9]
Reactant: Cc1csc(B(O)O)c1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2cc(C)cs2)cc1Cl
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-bromo-2-chloro-N-[5-(cis-3,5-dimethyl-1-piperazinyl)-2-(methyloxy)phenyl]benzenesulfonamide (E104) (70 mg, 0.14 mmol) and (4-methyl-2-thienyl)boronic acid (40 mg, 0.28 mmol) in DME (3 ml) was added potassium tert-butoxide (142 mg, 1.26 mmol) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) in water (1 ml) and the resulting mixture stirred in a microwave (set at high absorbance) at 100° C. for 30 minutes. Additional (4-methyl-2-thienyl)boronic acid (20 mg, 0.14 mmol) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) were then added and the mixture stirred in a microwave (set at high absorbance) at 100° C. for a further 30 minutes. The solvent was evaporated after transfer to a new flask with methanol and a few drops of toluene and the residue passed through an SCX column eluting with methanol followed by 2M ammonia in methanol. The appropriate fractions were collected and evaporated in vacuo and the residue purified further by mass directed autoprep HPLC to afford the title compound (E113). MS (ES+) m/e 506/508 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[N:10]=[CH:9][C:8]1=[O:19])=[O:5])[CH3:2].[OH:20]O.O>C(O)(=O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:16]2[C:11](=[CH:12][C:13]([Cl:18])=[CH:14][C:15]=2[Cl:17])[NH:10][C:9](=[O:20])[C:8]1=[O:19])=[O:5])[CH3:2]
Reactant: OO
Reactant: CCOC(=O)Cn1c(=O)cnc2cc(Cl)cc(Cl)c21
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(Cl)cc(Cl)c21
Yield: 48 %

Procedure:
The above ester, (70 mg, 0.23 mmol) was reacted with 30% H2O2 (0.345 ml) in glacial acetic acid (0.92 ml) at 55° C. for 4.5 h. The mixture was cooled in an icebath and H2O (0.40 ml) was added. The precipitate was filtered off, washed with water and dried to give 35 mg (48%) of the title compound. 1H-NMR (DMSO-d6):δ1.23 (t, 3H), 4.20 (q, 2H), 5.02 (s, 2H), 7.21 (d, 1H), 7.42 (d, 1H), 12.3 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH:21]1([Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:21]1([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: Br[Mg]C1CCCCC1
Product: COc1ccc2c(C3CCCCC3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 416 was used, staring from (1-Chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and cyclohexylmagnesium bromide to give (1-Cyclohexyl-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 337 (MH+).
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([N:24](CC3C=CC(OC)=CC=3)[C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]1=2)([CH3:4])[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:3]=[C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][O:14][C:13]2[CH:17]=[C:18]([S:21]([NH:24][C:25]3[S:26][CH:27]=[CH:28][N:29]=3)(=[O:23])=[O:22])[CH:19]=[CH:20][C:12]1=2)[CH3:4]
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccccc2C(C)(C)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=C(C)c1ccccc1N1CCOc2cc(S(=O)(=O)Nc3nccs3)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of 4-(2-(2-hydroxypropan-2-yl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (300 mg, 0.543 mmol) in DCM (5 mL) was added TFA (0.4 mL, Spectrochem) at 0° C. The reaction mixture was stirred at ambient temperature for 2 h. After completion, the reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL) and extracted with DCM (2×10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude material (47% by LCMS) that was purified by prep HPLC to obtain 4-(2-(prop-1-en-2-yl)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a white solid (45 mg, 20.0%). MS (ESI, positive ion) m/z; 414.1 (M+1). 1H NMR (400 MHz, DMSO) δ 12.51 (s, 1H), 7.50-7.26 (m, 4H), 7.21 (d, J=4.6 Hz, 1H), 7.16-6.94 (m, 1H), 6.77 (d, J=4.5 Hz, 1H), 6.23 (d, J=8.4 Hz, 1H), 5.10 (s, 1H), 4.96 (s, 1H), 4.41-4.08 (m, 2H), 3.52 (d, J=11.7 Hz, 2H), 1.96 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[OH:14][C@@H:15]1[C@@H:20]([CH3:21])[CH2:19][NH:18][CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>C(O)(C)C>[OH:14][C@@H:15]1[C@@H:20]([CH3:21])[CH2:19][N:18]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH2:11][CH2:12][CH2:13][C:3]=23)[CH2:17][C@H:16]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]
Reactant: C[C@H]1CNC[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2c([N+](=O)[O-])cnc3c2CCC3)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture containing 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (410 mg, 2.1 mmol), tert-butyl [(3R,4R,5S)-4-hydroxy-5-methylpiperidin-3-yl]carbamate (240 mg, 1.0 mmol) and triethylamine (0.5 mL, 4 mmol) in isopropyl alcohol (3.0 mL) was stirred at 100° C. for 2 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a CombiFlash® apparatus (eluting with 0 to 80% EtOAc in hexanes) to give the sub-title compound as pale yellow powder (200 mg, 50%). LCMS calc. for C19H29N4O5 (M+H)+: m/z=393.2. Found: 393.2.
Reaction SMILES: [CH2:1]([C@@H:3]1[O:5][CH2:4]1)Cl.[C:6]1([S:12]([C:15]2[CH:16]=[CH:17][C:18]([OH:24])=[C:19]([C:21](=[O:23])[CH3:22])[CH:20]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:6]1([S:12]([C:15]2[CH:16]=[CH:17][C:18]([O:24][CH2:1][C@@H:3]3[CH2:4][O:5]3)=[C:19]([C:21](=[O:23])[CH3:22])[CH:20]=2)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: ClC[C@H]1CO1
Reactant: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1OC[C@@H]1CO1
Temperature: 25 °C

Procedure:
(R)-(−)Epichlorhydrin (1.93 g; 0.021 mol) was added to a suspension of 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone (1.92 g; 0.007 mol) and potassium carbonate (1.44 g; 0.011 mol) in acetonitrile (5 mL). The mixture was heated under reflux for 18 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate, filtered, washed with water and saturated sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (hexane-ethyl acetate; 7:3) to give 1-(5-benzene sulfonyl-2-(S)-oxiranylmethoxy-phenyl)-ethanone as a white solid (1.456 g; 63%). A sample was recrystallized from diethyl ether-hexane: M. p. 115.1-116.8° C. Similarly, but replacing (R)-(−)epichlorhydrin with (S)-(+)epichlorhydrin, 1-(5-benzene sulfonyl-2-(R)-oxiranylmethoxy-phenyl)-ethanone was prepared. M. p. 111.9-113.5° C. Similarly, but replacing 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone with 1-[5-(3-fluoro-benzenesulfonyl)-2-hydroxy-phenyl]-ethanone, the above procedure gave 1-[5-(3-fluoro-benzenesulfonyl)-2-(S)-oxiranylmethoxy-phenyl]-ethanone: M. p. 112.7-114.9° C. Replacing 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone with 1-[5-(3-Fluoro-benzenesulfonyl)-2-hydroxy-phenyl]-ethanone and replacing (R)-(−)epichlorhydrin with (S)-(+)epichlorhydrin gave 1-[5-(3-Fluoro-benzenesulfonyl)-2-(R)-oxiranylmethoxy-phenyl]-ethanone. M. p. 118.3-120.5° C.