Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.I[C:60]1[CH:65]=[CH:64][C:63]([O:66][C:67]([F:70])([F:69])[F:68])=[CH:62][CH:61]=1>>[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[C:58][C:60]2[CH:61]=[CH:62][C:63]([O:66][C:67]([F:68])([F:69])[F:70])=[CH:64][CH:65]=2)=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: FC(F)(F)Oc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-iodo-4-(trifluoromethoxy)benzene.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=3)[CH2:18][CH2:17]2)=[O:15])=[N:12][CH:13]=1>>[CH3:28][C:27]1[C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:14]([C:11]3[N:12]=[CH:13][C:8]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[CH:9][CH:10]=3)=[O:15])[CH2:17][CH2:18]2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: O=C1CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cn3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cn3)CC2)c(C)c1
Yield: 71.7 %

Procedure:
Using pyrrolidin-2-one (94 mg) and (5-bromopyridin-2-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (375 mg) described in Preparation Example 134 and by the reaction and treatment in the same manner as in Example 1, the title compound (272 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:30])=[C:6]([C:8]([CH3:29])([CH3:28])[CH2:9][C:10]([OH:27])([C:23]([F:26])([F:25])[F:24])[CH2:11][NH:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[C:18](=[O:19])[O:17][CH2:16]3)[CH:7]=1.[Br:31]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:31][C:14]1[C:13]([NH:12][CH2:11][C:10]([OH:27])([C:23]([F:24])([F:26])[F:25])[CH2:9][C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[OH:30])([CH3:28])[CH3:29])=[CH:22][CH:21]=[C:20]2[C:15]=1[CH2:16][O:17][C:18]2=[O:19]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(CC(O)(CNc1ccc2c(c1)COC2=O)C(F)(F)F)c1cc(F)ccc1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(CC(O)(CNc1ccc2c(c1Br)COC2=O)C(F)(F)F)c1cc(F)ccc1O

Procedure:
55 mg of (−)-5-[4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylamino]-phthalide is mixed under nitrogen in 1 ml of dimethylformamide at 2° C. with 18 mg of N-bromosuccinimide. After 2 hours at this temperature, it is diluted with 20 ml of ethyl acetate, extracted with water, and the organic phase is dried (Na2SO4) and concentrated by evaporation. With chromatography on silica gel, the title compound in crystalline form is eluted with hexane/ethyl acetate (4:1), flash point 228-232° C.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]([CH2:14][CH:15]([O:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:16])[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C.Cl>ClCCl>[C:1]([O:9][CH2:10][CH:11]([CH2:14][CH:15]([O:17][C:18](=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH3:16])[CH2:12][O:13][S:27]([CH3:26])(=[O:29])=[O:28])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(CC(CO)COC(=O)c1ccccc1)OC(=O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(CC(COC(=O)c1ccccc1)COS(C)(=O)=O)OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cooled solution of 1.85 g (5.60 mM) of 2-(2-benzoyloxypropan-1-yl)-3-hydroxy-propyl benzoate m5 in 40 ml of dichloromethane are added 0.607 ml (7.84 mM) of methanesulfonyl chloride and 1.34 ml (9.52 mM) of triethylamine. After stirring at 0° C. for 30 minutes, the mixture is poured into an ice cooled 2N aqueous hydrochloric acid and the product is isolated by dichloromethane extraction. The dichloromethane layer is washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate. Evaporation of the solvent gives the crude product of the titled compound m11'.
Reaction SMILES: [CH2:1]([S:7][CH2:8][CH:9]1[CH:14]2[O:15][CH:11]([CH2:12][CH2:13]2)[CH:10]1[CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][C:21]([CH3:34])([CH3:33])[C:22](=[N:31]O)[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].I([O-])(=O)(=O)=[O:36].[Na+].O1CCCC1>CO>[CH2:1]([S:7]([CH2:8][CH:9]1[CH:14]2[O:15][CH:11]([CH2:12][CH2:13]2)[CH:10]1[CH2:16][CH:17]=[CH:18][CH2:19][CH2:20][C:21]([CH3:34])([CH3:33])[C:22](=[NH:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCCCCSCC1C2CCC(O2)C1CC=CCCC(C)(C)C(=NO)OCc1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCS(=O)CC1C2CCC(O2)C1CC=CCCC(C)(C)C(=N)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 634 mg (1.72 mmol) of [1α,2β(5Z),3β,4α]-7-[3-([hexylthio)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-2,2-dimethyl-5-heptenimidic acid, phenylmethyl ester (prepared as described in Example 17) in 6.78 ml of methanol at 0° C. is added dropwise over 4 minutes 4.8 ml of 0.5M aqueous sodium periodate solution. Tetrahydrofuran (2 ml) is then added and the resulting reaction mixture is stirred at room temperature for 15 hours. A precipitate is removed by filtration and washed with ether (3×50 ml). The filtrate is washed with 60 ml of saturated aqueous NaHCO3 solution and dried over anhydrous magnesium sulfate. Concentration in vacuo affords an oily crude product. This is chromatographed on silica gel 60 using 0.5-1.0% CH3OH in CH2Cl2 as eluant. This gives [1α,2β(5Z),3β,4α]- 7-[3-[(hexylsulfinyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-2,2-dimethyl-5-heptenimidic acid, phenylmethyl ester and [1α,2β(5Z),3β,4α]-7-[3-[(hexylsulfonyl)methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-2,2-dimethyl-5-heptenimidic acid, phenylmethyl ester.
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]1=[O:4].[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]([Cl:18])=[CH:13][N:12]=1.C([O-])(O)=O.[Na+]>CO.O>[Cl:10][C:11]1[N:16]=[C:15]([NH:1][CH:2]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:3]2=[O:4])[C:14]([Cl:18])=[CH:13][N:12]=1
Reactant: NC1CCCCNC1=O
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1NCCCCC1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of (±)-α-amino-ε-caprolactam (256 mg, 2.0 mmol), 2,4,5-trichloropyrimidine (366 mg, 2.0 mmol, 1 equiv.) and NaHCO3 (168 mg, 2 mmol, 1 equiv.) in a mixture of MeOH (12 mL) and H2O (6 mL) was stirred at room temperature for 15 h. The resulting precipitate was collected by vacuum filtration and washed with small amounts of MeOH and water, providing the product 3-(2,5-dichloropyrimidin-4-ylamino)azepan-2-one; ESMS m/z 275.0 (M+H+).
Reaction SMILES: C([O:3][C:4](=[O:29])[C@H:5]([CH3:28])[CH2:6][C@H:7]([N:21]1[C:25](=[O:26])[CH2:24][CH2:23][C:22]1=[O:27])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)C.[OH-].[Na+].C1C[O:35]CC1.C(O)C>O>[C:12]1([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=[CH:14][C:9]([CH2:8][C@@H:7]([NH:21][C:25](=[O:26])[CH2:24][CH2:23][C:22]([OH:27])=[O:35])[CH2:6][C@@H:5]([CH3:28])[C:4]([OH:3])=[O:29])=[CH:10][CH:11]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)[C@H](C)C[C@@H](Cc1ccc(-c2ccccc2)cc1)N1C(=O)CCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@H](C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)O)C(=O)O
Reaction time: 16 h

Procedure:
(2R,4S)-5-Biphenyl-4-yl-4-(2,5-dioxopyrrolidin-1-yl)-2-methylpentanoic acid ethyl ester (590 mg) is added to a mixture of 1 M NaOH (2.75 ml), THF (9 ml) and ethanol (9 ml). The mixture is stirred for 16 h. The mixture is diluted with water (20 ml) and extracted with isopropyl acetate. The water phase is acidified with 1 M HCl (5 ml) and extracted with isopropyl acetate. The combined organic phases are dried (MgSO4) and concentrated in vacuo to give (2R,4S)-5-Biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methyl-pentanoic acid (3-a, R1=4-oxo-pentanoic acid, R2=H, R3=H). 1H NMR (DMSO): 1.05 (2H), 1.35 (1H), 1.79 (1H), 2.29 (2H), 2.39 (3H), 2.70 (2H), 3.97 (1H), 7.25 (2H), 7.34 (1H), 7.44 (2H), 7.56 (2H), 7.63 (2H), 7.74 (1H), 12.01 (2H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]([CH2:6][CH2:7][OH:8])[CH2:2]1.[CH2:9]([N:18]=[C:19]=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]=[C:16]=[O:17]>C1(C)C(C)=CC=CC=1>[O:1]1[CH2:5][CH2:4][N:3]([CH2:6][CH2:7][O:8][C:16]([NH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:18][C:19]([O:8][CH2:7][CH2:6][N:3]2[CH2:4][CH2:5][O:1][CH2:2]2)=[O:20])=[O:17])[CH2:2]1
Reactant: O=C=NCCCCCCN=C=O
Reactant: OCCN1CCOC1
Solvent: Cc1ccccc1C
Product: O=C(NCCCCCCNC(=O)OCCN1CCOC1)OCCN1CCOC1

Procedure:
117 g (1 mol) of 2-(1,3-oxazolidin-3-yl)-ethanol are reacted with 84 g (0.5 mol) of hexamethylene diisocyanate in 20 g of xylene by the method described in Example 1. This reaction is catalyzed by the addition of 0.05 g of Sn(II) octoate and is carried out first at 30° C and later at 50° C. The product obtained, which is about 90% pure, is solid at room temperature, but a pourable liquid at 50° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9](C#N)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([CH3:33])=[CH:27]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:33][C:28]1[NH:29][C:30]2[C:26]([CH:27]=1)=[CH:25][C:24]([O:23][C:4]1[CH:3]=[CH:2][C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:19][CH2:20][CH2:21][CH2:22]4)=[CH:9][CH:10]=3)[N:5]=1)=[CH:32][CH:31]=2
Reactant: Cc1cc2cc(O)ccc2[nH]1
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc2cc(Oc3ccc4ccc(OCCCN5CCCC5)cc4n3)ccc2[nH]1
Temperature: 95 °C
Yield: 58.1 %

Procedure:
A suspension of 4-chloro-6-cyano-7-(3-(pyrrolidin-1-yl)propoxy)quinoline (150 mg, 0.48 mmol), (prepared as described for the starting material in Example 11), 5-hydroxy-2-methylindole (84 mg, 0.57 mmol) and cesium carbonate (200 mg, 0.72 mmol) in DMF (6 ml) was heated at 95° C. for 2 hours. After cooling, the mixture was filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography eluting with methylene chloride, followed by ethyl acetate, followed by methanol/methylene chloride (1/9) followed by methylene chloride/methanol saturated with ammonia (9/1 followed by 85/15) to give 6-cyano-((2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline (112 mg, 46%).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:12][C:13]([C:15]2[CH:16]=[C:17]([C:24]([N:26]3[CH2:30][CH2:29][CH2:28][C@@H:27]3[CH3:31])=[O:25])[N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]=23)=[O:14])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[Br:34]N1C(=O)CCC1=O.ClCCl>C(Cl)(Cl)Cl>[F:33][C:2]([F:1])([F:32])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:12][C:13]([C:15]2[C:16]([Br:34])=[C:17]([C:24]([N:26]3[CH2:30][CH2:29][CH2:28][C@@H:27]3[CH3:31])=[O:25])[N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]=23)=[O:14])[CH2:10][CH3:11])=[CH:5][CH:4]=1
Reactant: CC[C@@H](NC(=O)c1cc(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC[C@@H](NC(=O)c1c(Br)c(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a solution of 6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide (Comp. No. 16e) (200 mg, 0.43 mmol) in chloroform (5 ml) was added N-bromo-succinimide (76 mg, 0.43 mmol) and the mixture was stirred for 18 h at 25° C. Then excess dichloromethane was added and the mixture was washed consecutively with water, aqueous sodium hydrogencarbonate and brine. The organic layer was evaporated to dryness. The crude product was purified by reverse phase HPLC to give 200 mg (86%) of 7-bromo-6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide. LC/MS (method 3): Rt=1.81 min; m/z=543.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]2=[N:6][S:7][N:8]=[C:4]2[C:3]=1[N+:12]([O-])=O.C(O)C.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:12][C:3]1[C:4]2[C:5](=[N:6][S:7][N:8]=2)[C:9]([CH3:11])=[CH:10][C:2]=1[CH3:1]
Reactant: Cc1cc(C)c2nsnc2c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2nsnc2c1N

Procedure:
5,7-Dimethyl-4-nitro-2,1,3-benzothiadiazole (20 g) is warmed to ebullition in water (2.2 l) and ethanol (2.2 l) and sodium dithionite is added portionwise (strongly exothermic reaction). The reaction mixture is immediately cooled in an ice bath and extracted with ethyl acetate. The organic phase is concentrated by evaporation and the residue recrystallised in water to give 4-amino-5,7-dimethyl-2,1,3-benzothiadiazole. Mp=113-114°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][NH:11][C:10](=[O:13])[CH2:9]2)=[CH:4][C:3]=1[I:14].C(N(CC)CC)C.[C:22](=O)([O:28]C(C)(C)C)[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:24]([O:23][C:22]([N:11]1[CH2:12][C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([I:14])[CH:4]=2)[CH2:9][C:10]1=[O:13])=[O:28])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=C1C[C@H](c2ccc(Cl)c(I)c2)CN1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(Cl)c(I)c2)CC1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To (4R)-4-(4-chloro-3-iodophenyl)pyrrolidin-2-one (17.4 g, 54.4 mmol) was added 50 mL DCM. The solution was cooled to 0° C. Triethylamine (9.1 mL, 65.25 mmol) was added followed by di-tert butyl carbonate (13.1 g, 59.04 mmol) in 60 mL of DCM. A catalytic amount of DMAP was added, the mixture warmed to room temperature, and then stirred overnight at room temperature. A 5% solution of HCl (50 mL) was added and the organic phase separated. The DCM layers were then washed with brine and evaporated to give the title compound (43a) as a yellowish solid (18.3 g, 80% yield). 1H-NMR (400 MHz, CD3OD): δ 7.83-7.84 d, J=2 Hz, 1H), 7.35-7.46 (m, 1H), 7.31-7.33 (m, 1H), 4.11-4.15 (m, 1H), 3.62-3.67 (m, 2H), 3.45-3.61 (m, 1H), 2.80-2.84 (m, 1H), 2.69-2.74 (m, 1H) 1.52 (s, 9H); MS (ESI) m/z 443.86 (M+Na)+.
Reaction SMILES: Cl.[C:2](=N)([NH2:4])[CH3:3].[NH:6]([C:8]([C:10]1[C:14]([CH3:15])=[CH:13][S:12][C:11]=1[NH:16][C:17](=[O:30])[CH2:18][N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][C:20]1=[O:29])=O)[NH2:7]>>[CH3:15][C:14]1[C:10]([C:8]2[NH:6][N:7]=[C:2]([CH3:3])[N:4]=2)=[C:11]([NH:16][C:17](=[O:30])[CH2:18][N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][C:20]2=[O:29])[S:12][CH:13]=1
Reactant: CC(=N)N
Reactant: Cc1csc(NC(=O)CN2C(=O)CCc3ccccc32)c1C(=O)NN
Agent: Cl
Product: Cc1n[nH]c(-c2c(C)csc2NC(=O)CN2C(=O)CCc3ccccc32)n1

Procedure:
The title compound was prepared from acetimidamide hydrochloride (55 mg, 0.590 mmol) and N-(3-(hydrazinecarbonyl)-4-methylthiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide (141 mg, 0.393 mmol) according to the procedure of Example 1.11.2, above. Retention time (min)=4.106, method [7], MS(ESI) 382.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 12.07 (s, 1H), 7.23-7.31 (m, 2H), 7.05-7.23 (m, 2H), 6.57 (s, 1H), 4.86 (s, 2H), 3.02-3.07 (m, 2H), 2.84-2.87 (m, 2H), 2.41 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@@H:13]2[CH3:25])=[N:4][N:3]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[C:26]([C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][C@@H:13]3[CH3:25])=[N:4][N:3]=2)=[CH:30][CH:29]=1)#[N:27]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(Cl)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1nnc(-c2ccc(C#N)cc2)c2ccccc12
Yield: 94.4 %

Procedure:
Heat a mixture of (S)-tert-butyl 4-(4-chlorophthalazin-1-yl)-3-methylpiperazine-1-carboxylate (4.0 g, 11.0 mmol), 4-cyanophenylboronic acid (2.43 g, 16.5 mmol), cesium carbonate (14.4 g, 44.1 mmol), and (SP-4-1)-bis[bis(1,1-dimethylethyl)(4-methoxyphenyl)phosphine-κP]dichloro-palladium (J. Org. Chem. 2007, 72, 5104-5112) (75.4 mg, 0.11 mmol) in 1,4-dioxane (80 mL) and water (20 mL) at 90° C. overnight. Partition the reaction mixture between water and CH2Cl2. Extract the aqueous layer with CH2Cl2. Dry the combined organic layer over Na2SO4 and concentrate under reduced pressure. Purify the resulting residue by flash silica gel chromatography (gradient of 0 to 20% EtOAc in CH2Cl2) to provide the title compound as a light orange foam (4.46 g, 94%). ES/MS m/z 430.2 (M+1).
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[C:16]([NH2:20])([CH3:19])([CH3:18])[CH3:17].C(OCC)(=O)C>C(Cl)Cl>[C:16]([NH:20][S:12]([C:7]1[C:6]2[CH:5]=[CH:4][N:3]=[CH:2][C:11]=2[CH:10]=[CH:9][CH:8]=1)(=[O:14])=[O:13])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(C)(C)N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)NS(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Powdered isoquinoline-5-sulfonyl chloride hydrochloride (1.00 g, 3.79 mmol) is added in small portions to a stirred solution of tert-butylamine (2.00 mL, 18.9 mmol) in CH2Cl2 (10 mL) at 0° C. under nitrogen. The resultant mixture is allowed to stir at ambient temperature for 1 hour. Ethyl acetate (50 mL) is added to the mixture and the mixture is washed with saturated aqueous NaHCO3 (20 mL). The organic layer is dried over MgSO4, filtered and concentrated. The crude product is chromatographed on silica (gradient 0-2% CH3OH in CH2Cl2) to give 857 mg (3.24 mmol, 86% yield) of the title compound as a white solid. ESIMS: m/z 265 (M+H)+. Analysis for C13H16N2O2S: calcd: C, 59.07; H, 6.10; N, 10.60; found: C, 59.21; H, 6.01; N, 10.67.
Reaction SMILES: [CH:1]1([S:7]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:31])C=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[CH:1]1([S:7]([C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[NH:18][S:19]([CH3:22])(=[O:20])=[O:21])(=[O:31])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1S(=O)C1CCCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1S(=O)(=O)C1CCCCC1
Temperature: 0 °C
Yield: 87.6 %

Procedure:
To 20 ml of a chloroform solution containing 1.2 g of N-(2-cyclohexylsulfinyl-4-nitrophenyl)methanesulfonamide obtained in Example 3 was added dropwise 60 ml of a chloroform solution containing 3.9 g of m-chloroperbenzoic acid under ice cooling with stirring. The mixture was stirred for 3 hours. The reaction solution was poured into ice water, neutralized with a dilute aqueous sodium hydroxide solution and extracted with chloroform. The chloroform layer was washed, in turn, with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated to give the crude crystals, which were washed with ethyl ether and then recrystallized from ethyl acetate-n-hexane to give 1.1 g of N-(2-cyclohexylsulfonyl-4-nitrophenyl)methanesulfonamide as pale yellow crystals.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:27][CH3:28])=[O:26])[CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37]>CN(C=O)C>[C:36]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25]([NH:27][CH3:28])=[O:26])[CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1)(=[O:38])[CH3:37]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4N)sc3c2)ccn1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4NC(C)=O)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.5 %

Procedure:
To the solution of 4-(2-((1R,2R)-2-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (9 mg, 22 μmole) and triethylamine (11 μL, 80 μmole) in 300 μL of DMF was added acetic anhydride (5 μL, 50 μmole). The reaction solution was stirred at room temperature for 1.5 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give 4-(2-((1R,2R)-2-acetamidocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (5.1 mg, 12 μmole) as white powder. ES/MS m/z 440.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.C[Al](C)C.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C@H:28]2[O:32][C:31](=[O:33])[CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([NH:13][C:31](=[O:33])[CH2:30][CH2:29][C@H:28]([OH:32])[C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)=[N:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc([C@@H]2CCC(=O)O2)c1
Reactant: Nc1cnc(Oc2ccc(Cl)cc2)cn1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cccc([C@@H](O)CCC(=O)Nc2cnc(Oc3ccc(Cl)cc3)cn2)c1
Reaction time: 0.25 h
Yield: 100.1 %

Procedure:
To a stirred solution of 5-(4-chlorophenoxy)pyrazin-2-amine (149 mg, 0.67 mmol) in dry CH2Cl2 (1.5 mL) at room temperature, under argon, is added trimethylaluminum (0.335 mL of a 2.0 N solution in toluene, 0.67 mmol) dropwise. The resulting mixture is stirred for 15 min, then (S)-dihydro-5-(3-methoxyphenyl)furan-2(3H)-one (107 mg, 0.555 mmol) in CH2Cl2 (1.5 mL) is added slowly and stirring is continued at ambient temperature for 3 days. The reaction is quenched carefully with 10% aqueous citric acid (0.5 mL) at 0° C. The mixture is then partitioned between saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (10 mL). The aqueous layer is extracted further with CH2Cl2 (3×10 mL). The combined organic extracts are dried over Na2SO4, filtered, and concentrated in vacuo. The residue is then purified on silica gel (0-75% ethyl acetate in hexane) to give (S)—N-[5-(4-chlorophenoxy)pyrazin-2-yl]-4-hydroxy-4-(3-methoxyphenyl)butanamide (230 mg, 100%) as a white solid.