Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]([F:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].[OH-].[Na+]>[C].[Pd].O>[F:10][C:7]1[CH:8]=[CH:9][CH:2]=[C:3]([F:11])[C:4]=1[C:5]#[N:6]
Reactant: N#Cc1c(F)ccc(Cl)c1F
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1c(F)cccc1F
Reaction time: 2.5 h
Yield: 70.2 %

Procedure:
In the same manner as in the process of the reduction step of Example 1, the reaction was carried out at 40° C. for 2.5 hours by using 10 g of 3-chloro-2,6-difluorobenzonitrile, 60 g of water, 0.25 g of palladium-carbon catalyst and 3 g of sodium hydroxide, and refinement was carried out to obtain 5.63 g of 2,6-difluorobenzonitrile.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:32](=O)([O-])[O-:33].[Cs+].[Cs+]>[Cu]I.C(O)C>[CH3:32][O:33][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[N:8]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1cc2ccc(Br)cc2cn1)C1CC1
Agent: [Cu]I
Agent: [Cs+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: CCO
Product: COc1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 210 °C
Reaction time: 5 h
Yield: 5.7 %

Procedure:
N-(7-bromoisoquinolin-3-yl)cyclopropanecarboxamide (150 mg, 0.52 mmol), copper(I) iodide (90 mg, 0.52 mmol), 1,10-phenanthroline (93 mg, 0.52 mmol) and cesium carbonate (219 mg, 0.67 mmol) were added to ethanol (5 mL) in a stainless container. The resulting mixture was stirred at 210° C. for 5 hours under nitrogen. The reaction mixture was concentrated and purified by prep-HPLC and TLC to give the product (7.2 mg, 5.7%). LCMS (ESI): RT (Min)=0.79, M+H+=243.0, method=A. 1H NMR (400 MHz, DMSO-d6): δ 10.76 (s, 1H), 8.99 (s, 1H), 8.35 (s, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.42 (s, 1H), 7.32 (d, J=9.2 Hz, 1H), 3.96 (s, 3H), 2.01 (s, 1H), 0.81-0.79 (m, 4H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[N:19]1([C:24]([NH2:26])=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:18][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:26][C:24]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:25])[CH:7]=2)=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[N:11]=1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Reactant: NC(=O)N1CCCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Temperature: 100 °C
Yield: 100.3 %

Procedure:
A mixture of Example A3 (0.500 g, 1.882 mmol), pyrrolidine-1-carboxamide (1.074 g, 9.41 mmol), Cs2CO3 (1.226 g, 3.76 mmol) and Xantphos (0.218 g, 0.376 mmol) in dioxane (100 mL) was sparged with Ar, treated with Pd2(dba)3 (0.172 g, 0.188 mmol), sparged again with Ar and heated at 100° C. overnight. The mixture was cooled to RT, diluted with THF, the solids removed via filtration and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/DCM) to afford N-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide (648 mg, 100%). MS (ESI) m/z: 344.1 (M+H+).
Reaction SMILES: [NH2:1][C@H:2]([C:6]([O-:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[K+].F[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].S1(CCCC1)(=O)=O>>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([NH:1][CH:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])=[CH:12][CH:13]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CC(C)[C@H](N)C(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1)C(=O)O
Temperature: 100 °C
Yield: 7 %

Procedure:
A mixture of 30 parts of potassium valinate, 15 parts of p-fluoro-benzotrifluoride, 7 parts of dichlorohexano-18-crown-6 ether catalyst, 10 parts of potassium carbonate and 126 parts of sulfolane was placed in a pressure reactor. The reactor was degassed, placed under an argon atmosphere and sealed. The reaction mixture was then heated and maintained at about 100° C. for about 15 hours. Analysis of the reaction product indicated a 7.0% yield of 2-(4-trifluoromethylphenylamino)-3-methylbutanoic acid based on p-fluorobenzotrifluoride starting material.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[N:5]([CH:12]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[C:22]([O:34][CH3:35])[CH:21]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][CH:7](OC)OC)[CH3:2].Cl.[OH-].[Na+].[C:40](OCC)(=[O:42])C.CCCCCC>CC(C)=O>[CH2:1]([O:3][C:4]([N:5]1[CH:6]=[CH:7][C:25]2[C:20](=[CH:21][C:22]([O:34][CH3:35])=[C:23]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:24]=2)[CH:12]1[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([O:42][CH3:40])[CH:19]=1)=[O:36])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)N(CC(OC)OC)C(Cc1ccccc1)c1ccc(OCc2ccccc2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)N1C=Cc2cc(OCc3ccccc3)c(OC)cc2C1Cc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a stirred solution of [1-(4-benzyloxy-3-methoxy-phenyl)-2-phenyl-ethyl]-(2,2-dimethoxy-ethyl)-carbamic acid ethyl ester (100 mg, 0.19 mmol) in acetone (5 mL) was added 6N hydrochloric acid (1 mL) at 0° C. The reaction mixture was stirred at room temperature for 18 hrs and neutralized by addition of 6N aqueous sodium hydroxide solution. The solvent was evaporated and the aqueous phase was extracted with dichloromethane (3×25 μL). The combined extracts were washed with saturated aqueous sodium chloride solution (10 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) afforded 6-benzyloxy-7-methoxy-1-(3-methoxy-benzyl)-1H-isoquinoline-2-carboxylic acid ethyl ester (60 g, 85% yield) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH:17](OC)[O:18]C)[NH:14][C:13]1=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CSC.O>C(O)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C@@H:15]([CH2:16][CH:17]=[O:18])[NH:14][C:13]1=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(C[C@H]1NC(=O)[C@@H]1NC(=O)OCc1ccccc1)OC
Solvent: CC(=O)O
Solvent: O
Solvent: CSC
Product: O=CC[C@H]1NC(=O)[C@@H]1NC(=O)OCc1ccccc1
Temperature: 50 °C
Yield: 47.2 %

Procedure:
To a solution of (3R,4R)-3-benzyloxycarbonylamino-4-(2,2-dimethoxyethyl)azetidin-2-one (2.15 g) in acetic acid (35.2 ml) were added dimethylsulfide (2 ml) and water (8.8 ml) at ambient temperature and the mixture was heated at 50° C. for 4.5 hours. The reaction mixture was evaporated in vacuo and the residue was dissolved in xylene (40 ml). The mixture was evaporated in vacuo and the residue was chromatographed on silica gel (10 g) eluting with a mixture of methylene chloride and acetone (5:1-2:1) to give a crystalline solid. This crude crystals were washed with ether and dried over phosphorous pentoxide to give (3R,4R)-3-benzyloxycarbonylamino-4-(2-oxoethyl)azetidin-2-one (863 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([C:13]([NH:15][O:16]C3CCCCO3)=[O:14])=[CH:7][CH:8]=2)[NH:3]1>C1COCC1.C(O)(=O)C.O>[OH:16][NH:15][C:13]([C:6]1[CH:5]=[C:4]2[C:9]([C:10](=[O:12])[NH:11][C:2](=[O:1])[NH:3]2)=[CH:8][CH:7]=1)=[O:14]
Reactant: O=C(NOC1CCCCO1)c1ccc2c(=O)[nH]c(=O)[nH]c2c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(NO)c1ccc2c(=O)[nH]c(=O)[nH]c2c1
Yield: 44.1 %

Procedure:
A solution of 2,4-dioxo-N-(tetrahydro-2H-pyran-2-yloxy)-1,2,3,4-tetrahydroquinazoline-7-carboxamide (0.12 g, 0.39 mmol) in THF (1.6 mL), acetic acid (3.2 mL) and water (0.8 mL) was heated at 60° C. for 5 h. The mixture was concentrated to dryness. The residue was purified by preparative HPLC to afford N-hydroxy-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxamide (38 mg, 44%). LC-MS: (FA) ES+ 222; 1H NMR (400 MHz, DMSO) δ 11.42 (s, 1H), 11.40 (s, 1H), 11.28 (s, 1H), 9.21 (d, J=1.6 Hz, 1H), 7.92 (d, J=8.2 Hz, 1H), 7.52 (s, 1H), 7.44 (dd, J=8.2, 1.3 Hz, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:11]([O-:18])(OCC)OCC.[Cl-].[NH4+]>C(OCC)C>[C:1]1([CH2:7][CH2:8][PH:11](=[O:18])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP([O-])OCC
Reactant: Br[Mg]CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: O=[PH](CCc1ccccc1)CCc1ccccc1
Yield: 66.7 %

Procedure:
To a solution of 25 mmol of (2-phenyl)ethylmagnesium bromide in 25 ml of diethyl ether was added dropwise with cooling (ice bath) 0.92 ml (7.14 mmol) of diethyl phosphite. The resulting solution was heated at reflux for 2 h, cooled, and treated with aqueous ammonium chloride. The product was extracted with ether, dried over MgSO4, and concentrated in vacuo. Flash chromatography using ethyl acetate gave 1.23 g (64%) of the desired compound (Rf 0.64, 10% methanol in chloroform) as a colorless oil. 1H NMR (CDCl3) δ 2.0-2.2 (m, 4H), 2.85-3.1 (m, 4H), 6.89 (dm, J=455 Hz, 1H), 7.15-7.4 (m, 10H). Mass spectrum (M+H)+ =259.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.[CH2:24]([O:31][C:32]1[CH:33]=[C:34]([CH:39]=[CH:40][CH:41]=1)[C:35](=[O:38])[CH2:36]Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:36]=1[C:35](=[O:38])[C:34]1[CH:39]=[CH:40][CH:41]=[C:32]([O:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:33]=1
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: O=C(CBr)c1cccc(OCc2ccccc2)c1
Product: COC(=O)Cc1c(C(=O)c2cccc(OCc3ccccc3)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans 4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 3-benzyloxyphenacyl bromide (A. Hernandez et al., J. Org. Chem., 1994, 59, 1058).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1F.[CH2:14]([SH:16])[CH3:15]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:10]([O-:12])=[O:11])[C:3]=1[S:16][CH2:14][CH3:15]
Reactant: CCS
Reactant: CNc1ccc(Br)c(F)c1[N+](=O)[O-]
Product: CCSc1c(Br)ccc(NC)c1[N+](=O)[O-]

Procedure:
This compound was synthesized according to the procedure of Example 11, Step 1, using 4-bromo-3-fluoro-N-methyl-2-nitroaniline and ethanethiol as the starting materials. LCMS calculated for C9H12BrN2O2S (M+H)+: m/z=291.0, 293.0. found: 290.9, 292.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13].O>CN(C)C=O>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12]([NH:11][CH2:10][CH2:9][Cl:8])=[O:13])=[CH:3][CH:4]=1
Reactant: O=C=NCCCl
Reactant: Nc1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCCl)Nc1ccncc1
Reaction time: 2 h

Procedure:
To the solution of 1.6 g of 4-aminopyridine in 7 ml of dimethylformamide 2 g of 2-chloroethylisocyanate are added while stirring and keeping the temperature below 40°. After 2 hours 28 ml of water are added and stirring is continued for 2 hours at room temperature. The precipitate formed is filtered off, washed with water, dried and recrystallized from aqueous ethanol, to yield the 1-(4-pyridyl)-3-(2-chloroethyl)-urea melting at 120°-122°.
Reaction SMILES: [CH3:1][C@H:2]([NH2:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[C:8]([O-])(O)=[O:9].[Na+].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[N:7]([C@@H:2]([CH3:1])[C:3]([CH3:6])([CH3:5])[CH3:4])=[C:8]=[O:9]
Reactant: C[C@H](N)C(C)(C)C
Reactant: O=C([O-])O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](N=C=O)C(C)(C)C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To a solution of (S)-1,2,2-trimethylpropylamine (626 mg, 6.2 mmol) in methylene chloride (20 mL) and satd aq NaHCO3 (20 mL) was added triphosgene (607 mg, 2.05 mmol) at 0° C. The mixture was stirred for 15 min. The organic phase was separated, dried and concentrated to give (S)-3-isocyanato-2,2-dimethyl-butane (845 mg, 90%). 1H NMR (CDCl3): 0.90 (s, 9H), 1.21 (m, 3H), 3.31 (m, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[Cl:7][C:8]1[CH:9]=[C:10]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][C:31]=3[O:33][CH2:34][CH2:35][NH:36][CH3:37])[N:26]=[CH:25][N:24]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:1][CH2:2][CH2:3][NH:4][C:5](=[O:6])[N:36]([CH2:35][CH2:34][O:33][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:32]=1[C:23]([NH:22][C:10]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[C:8]([Cl:7])[CH:9]=1)=[N:24][CH:25]=[N:26]2)[CH3:37]
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reactant: O=C=NCCCl
Product: CN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(=O)NCCCl
Yield: 80 %

Procedure:
The procedure described in Example 120 was repeated using 2-chloroethyl isocyanate and N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials) to give the title compound as a solid in 80% yield; NMR spectrum (DMSO-d6 @ 373K) 2.90 (s, 3H), 3.15-3.25 (q, 2H), 3.43-3.50 (t, 2H), 3.75-3.85 (t, 2H), 4.35-4,45 (t, 2H), 5.25, 6.35 (bs, 1H), 7.08-7.13 (d, 1H), 7.13-7.30 (m, 1H), 7.35-7.40 (m, 2H), 7.50-7.65 (m, 2H), 7.65-7.80 (m, 1H), 7.80-7.90 (t, 1H), 7.95 (d, 1H), 8.50 (s, 1H), 8.55-8.60 (d, 1H), 9.80 (s, 1H); Mass spectrum MH+ 541.3.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[O:12][CH:13]=[C:14]([CH2:16][C:17](O)=[O:18])[N:15]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[O:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1
Reactant: O=C(O)Cc1coc(-c2ccc3ccccc3c2)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCCc1coc(-c2ccc3ccccc3c2)n1
Yield: 87.7 %

Procedure:
A solution of ethyl ester of [2-(2-naphthyl)-oxazol-4-yl]acetic acid (434 mg, 1.54 mmol) in tetrahydrofuran (20 ml) was added dropwise to a suspension of lithium aluminium hydride (66 mg, 1.74 mmol) in tetrahydrofuran (15 ml) with stirring under ice cooling and the mixture was stirred at the same temperature for 2.5 hrs. To the reaction mixture were added water (0.1 ml), 15% aqueous solution of sodium hydroxide (0.1 ml), water (0.3 ml) and sodium sulfate (3 g )in turn. Insoluble materials were filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2−1) to give 2-[2-(2-naphthyl)-oxazol-4-yl]ethanol (323 mg, 88%) as pale yellow crystals.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][CH2:7][S:8][C:9]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:10]=2[NH2:11])[CH:3]=[N:2]1.[O:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[CH:19]=[C:18]1[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[Cl:16][C:13]1[CH:14]=[CH:15][C:9]([S:8][CH2:7][CH2:6][C:4]2[CH:5]=[N:1][NH:2][CH:3]=2)=[C:10]([NH:11][S:26]([C:18]2[O:17][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH:19]=2)(=[O:27])=[O:28])[CH:12]=1
Reactant: Nc1cc(Cl)ccc1SCCc1cn[nH]c1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)ccc1SCCc1cn[nH]c1)c1cc2ccccc2o1
Yield: 45.9 %

Procedure:
Following General Procedure B, the title compound (123 mg) was prepared from 2-((2-(1H-pyrazol-4-yl)ethyl)thio)-5-chloroaniline (157 mg, 0.618 mmol) and benzofuran-2-sulfonyl chloride (133 mg, 0.618 mmol) in pyridine (3 ml).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:28]([CH3:29])=[CH:27][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[C:23](Cl)[N:22]=[C:21]([Cl:26])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CC(N(C)C)=O>C(O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:28]([CH3:29])=[CH:27][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[C:23]([N:41]4[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]4)[N:22]=[C:21]([Cl:26])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)nc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Solvent: CC(=O)N(C)C
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cc(Cl)nc(N4CCN(C)CC4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2,6-dichloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (10 mg), N-methylpiperazine (10 mg), and DMA (250 μL) were combined in a microwave tube and heated to 100° C. for 30 min. Reaction was cooled to 23° C. and diluted with absolute ethanol and was purified by reverse phase HPLC, eluting by 5-100% acetonitrile in H2O with 0.1% TFA to give the title compound. LCMS-ESI+: calc'd for C32H36Cl2N4O3S: 627.2, 629.2 (M+H+); Found: 627.2, 629.2 (M+H+).
Reaction SMILES: CN(/C=[C:5]1\[C:6](=O)[CH2:7][CH2:8][C:9]2[C:17]3[C:16]([O:18][CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:11][C:10]\1=2)C.C(O[C:36]([NH:38][NH:39][CH2:40][CH2:41][OH:42])=O)(C)(C)C>>[N+:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][O:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[C:17]=2[C:9]2[CH2:8][CH2:7][C:6]4[N:39]([CH2:40][CH2:41][OH:42])[N:38]=[CH:36][C:5]=4[C:10]=2[S:11]3)=[CH:22][CH:23]=1)([O-:29])=[O:28]
Reactant: CC(C)(C)OC(=O)NNCCO
Reactant: CN(C)/C=C1\C(=O)CCc2c1sc1ncnc(OCCc3ccc([N+](=O)[O-])cc3)c21
Product: O=[N+]([O-])c1ccc(CCOc2ncnc3sc4c(c23)CCc2c-4cnn2CCO)cc1

Procedure:
This compound was prepared in a similar fashion as described in Example 80 starting from (8E)-8-[(dimethylamino)methylene]-4-[2-(4-nitrophenyl)ethoxy]-5,8-dihydro[1]benzothieno[2,3-d]pyrimidin-7(6H)-one (7.05 g, 16.61 mmol) and 2-tert-butyloxycarbonyl-2-hydroxyethylhydrazine (4.39 g, 24.91 mmol). The desired product was obtained as a yellow solid (3.82 g, 53%). 1H-NMR (DMSO-d6) δ 8.50 (s, 1H), 8.18 (m, 2H), 7.64 (m, 3H), 4.88 (m, 1H), 4.77 (t, 2H, J=6.1 Hz), 4.10 (t, 2H, J=5.5 Hz), 3.68 (m, 2H), 3.28 (m, 2H), 3.05 (m, 2H), 2.96 (m, 2H); LCMS RT=2.92 min; [M+H]+=438.1
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:11]=[N:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([OH:29])[CH3:28])=[CH:18][CH:17]=2)=[N:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.ClCCl.[C:40](Cl)(=[O:43])[CH2:41][CH3:42]>C(Cl)(Cl)Cl>[CH2:1]([O:9][C:10]1[CH:15]=[N:14][C:13]([C:16]2[CH:17]=[CH:18][C:19](/[CH:22]=[CH:23]/[CH2:24][CH2:25][CH2:26][CH:27]([O:29][C:40](=[O:43])[CH2:41][CH3:42])[CH3:28])=[CH:20][CH:21]=2)=[N:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCC(=O)Cl
Reactant: CCCCCCCCOc1cnc(-c2ccc(CCCCCC(C)O)cc2)nc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCOc1cnc(-c2ccc(/C=C/CCCC(C)OC(=O)CC)cc2)nc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
A reactor was charged with 1.6 g (4 mmol) of the (-)-5-octyloxy-2-{4-(6-hydroxy-heptyl)-phenyl}-pyrimidine obtained in Example 9, 2 g of triethylamine and 30 g of dichloromethane, to which was dropwise added 0.6 g (6 mmol) of propionyl chloride at a temperature not exceeding 10° C. The mixture was reacted first at 0°-10° C. for one hour and thereafter at 20°-30° C. for 2 hours. After the reaction, the reaction mixture was poured into ice water, and the mixture thus obtained was separated into two phases. The organic layer was washed successively with 5% hydrochloric acid, water, 5% aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by silica gel column chromatography gave 1.6 g (yield 85%) of (+)-5-octyloxy-2-{4-(6-propionyloxy-1-trans-heptenyl)-phenyl}-pyrimidine, [α]D20 =+0.96 (c=1.1, CHCl3).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15]C[O:17][C:11]=2[CH:10]=1)=[O:7].B(Br)(Br)Br.CO>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:17])[CH:10]=1)=[O:7]
Reactant: COc1cc(C(=O)Nc2ccc3c(c2)OCO3)ccc1NS(C)(=O)=O
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(=O)Nc2ccc(O)c(O)c2)cc1O
Reaction time: 20 h
Yield: 35 %

Procedure:
To a stirred suspension of 3-Methoxy-4-methanesulfonylamino-N-(3,4-methylenedioxyphenyl)benzamide (200 mg) in dry CH2Cl2 (20 ml) under nitrogen, was added boron tribromide (0.3 ml) then stirring continued for a further 20 hours. Methanol (50 ml) was added carefully, then the solvent evaporated in vacuo to a volume of 1 ml, this was repeated 2 more times. Purification by column chromatography over silica gel eluting with chloroform containing methanol (10-20%) gave 3-Hydroxy-4-methanesulfonylamino-N-(3,4-dihydroxyphenyl)benzamide (DC51-DB) (65 mg, 34%) as pale brown crystals.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1F.C1(NN=CC2C(Br)=CC(C)=CC=2Br)C=CC=CC=1>>[Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cc(Br)c2cnn(-c3ccccc3F)c2c1
Agent: Cc1cc(Br)c(C=NNc2ccccc2)c(Br)c1
Product: Cc1cc(Br)c2cnn(-c3ccccc3)c2c1

Procedure:
Similarly prepared to Intermediate 26 from 2,6-dibromo-4-methylbenzaldehyde phenylhydrazone (Intermediate 32).
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].O1CCCC1>[NH:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCNC1
Yield: 9.9 %

Procedure:
A mixture of 101.5 g (0.37 mole) of 1,1-dimethylethyl [1-(phenylmethyl)-3-pyrrolidinyl]carbamate, 5.0 g of 20% Palladium on carbon and 1 liter of tetrahydrofuran was shaken in an atmosphere of hydrogen at about 50 psi and room temperature for 24 hours. The catalyst was removed by filtering through Celite, and the filtrate was concentrated in vacuo to give 6.8 g of 1,1-dimethylethyl (3-pyrrolidinyl)carbamate which solidified upon standing and was of sufficient purity to be used as is for the ensuing steps.