Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)=[C:4]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:24]([NH:25][CH2:26][C:27]2[C:28](=[O:35])[NH:29][C:30]([CH3:34])=[CH:31][C:32]=2[CH3:33])=[O:36])[C:5]2[CH:6]=[N:7][N:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)c(=O)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C2CCNCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred solution of tert-butyl 4-(6-bromo-4-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-1H-indazol-1-yl)piperidine-1-carboxylate (1 mmol) in DCM (5 mL) was cooled to 0° C. and TFA (2 mL) was added to it. The reaction mixture was stirred at room temperature for 1 h. On completion, the reaction was concentrated to dryness and the residue basified with aqueous sodium bicarbonate till pH 8 and aqueous layer extracted with 20% MeOH/DCM. The combined organic layers were dried over sodium sulfate and concentrated to afford 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-(piperidin-4-yl)-1H-indazole-4-carboxamide.
Reaction SMILES: [C:1]([NH:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:16])(=[O:3])[CH3:2].[C:17](OC(=O)C)(=[O:19])[CH3:18]>>[C:1]([N:4]([C:17](=[O:19])[CH3:18])[N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Nn1c(=O)[nH]c2ccccc2c1=O
Product: CC(=O)N(C(C)=O)n1c(=O)[nH]c2ccccc2c1=O

Procedure:
4 g 3-N-acetylamino(1H,3H)quinazoline-2,4-dione are refluxed for 5 hours in 200 cc acetic anhydride. Excess acetic anhydride is then distilled off under reduced pressure. The resulting residue is crystallized from benzene. M.p.=210° C.
Reaction SMILES: [C:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:14]1([SH:20])[CH:19]=[CH:18][CH:17]=CC=1>>[S:20]1[CH:14]=[C:19]([C:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[O:13])[CH:18]=[CH:17]1
Reactant: O=C(O)c1cccc2ccccc12
Reactant: Sc1ccccc1
Product: O=C(c1ccsc1)c1cccc2ccccc12
Temperature: 80 °C

Procedure:
A mixture of 1-naphthoic acid (8 g, 46.46 mmol), thiophenol (8 ml, 78.05 mmol) and polyphosphoric acid (80 g) was heated for 12 hours on water bath at 80° C. Reaction mixture was poured onto ice water and extracted with ethylacetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to give oil, which was crystallized from methanol to give the desired compound.
Reaction SMILES: [C:1]1([C:7]2([CH2:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[O:13])[CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].ClCCl>ClCCl.CO>[C:1]1([C:7]2([CH2:11][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[OH:13])[CH2:10][CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CC1(c2ccccc2)CCC1)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: OC(CC1(c2ccccc2)CCC1)c1ccccn1
Yield: 26.8 %

Procedure:
To a solution of Example 68E (1.5 g) in 27 mL of dichloromethane:methanol (9:1) was added NaBH4 (0.1 g, 2.6 mmol). The reaction was monitored by LC/MS, dichloromethane was added to the solution upon completion of the reaction. The mixture was washed with water, dried over Na2SO4, and filtered. The crude product was purified by preparative-HPLC (eluted with petroleum ether/EtOAc=5:1) to afford title compound (0.4 g, 1.6 mmol, 37.2%). LC-Ms: ESI-MS (M+H+): m/e=254.2. 1H NMR (400 MHz, CDCl3), 6 (ppm): 10.82 (br, 2H), 8.59 (d, J=5.2 Hz, 1H), 8.06 (td, J=2.0 Hz, J2=7.8 Hz, 1H), 7.60 (t, J=6.4 Hz, 1H), 7.29-7.24 (m, 3H), 7.19-7.11 (m, 3H), 4.75 (q, J=4.8 Hz, J2=8.0 Hz 1H), 2.67 (q, J1=7.3 Hz, J2=14.2 Hz 1H), 2.54-2.50 (m, 2H), 2.39-2.08 (m, 4H), 1.89-1.82 (m, 1H).
Reaction SMILES: N1C=C[CH:3]=N1.[N:6]1([CH:11](C)[CH2:12][NH:13][C:14]([C:16]2[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[NH:18][N:17]=2)=[O:15])[CH2:10][CH2:9][CH2:8][CH2:7]1>>[CH2:10]([N:6]([CH2:7][CH3:8])[CH2:11][C@H:12]([NH:13][C:14]([C:16]1[C:20]([Br:21])=[C:19]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[NH:18][N:17]=1)=[O:15])[CH3:3])[CH3:9]
Reactant: c1cn[nH]c1
Reactant: CC(CNC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br)N1CCCC1
Product: CCN(CC)C[C@@H](C)NC(=O)c1n[nH]c(NC(=O)c2ccccc2Cl)c1Br

Procedure:
The pyrazole acid, prepared as described in Procedure 8, was coupled with (R)—N,N-diethyl-1,2-propanediamine (prepared as shown in Procedure 2) using the method of Procedure 3.
Reaction SMILES: [C:1]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]=2[CH:8]=[C:7]([C:16](=[O:18])[CH3:17])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Br-:19].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[Br-].[Br-].[Br-].C([NH3+])CCC.C([NH3+])CCC.C([NH3+])CCC>C(O)(=O)C>[Br:19][CH2:17][C:16]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:14]2[O:13][CH2:12][CH2:11][N:10]([CH3:15])[C:9]=2[CH:8]=1)=[O:18]
Reactant: CC(=O)c1cc2c(c(C(C)(C)C)c1)OCCN2C
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCCC[NH3+]
Solvent: CC(=O)O
Product: CN1CCOc2c1cc(C(=O)CBr)cc2C(C)(C)C
Reaction time: 0.75 h
Yield: 28.3 %

Procedure:
A solution of the 1-[8-(tert-butyl)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]-1-ethanone (2.61 g, 10.6 mmol) and tetra-n-butylammonium tribromide (6.62 g, 13.7 mmol) in acetic acid was stirred at room temperature for 3.5 hours under a nitrogen atmosphere, and then n-butylammonium tribromide (1.02 g, 2.12 mmol) was added and stirring was continued for 45 minutes. After distilling off the solvent under reduced pressure, ethyl acetate was added to the residue and the mixture was washed with saturated aqueous sodium hydrogencarbonate (twice) and brine in that order. It was then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (Wakogel-C200,80 g) and fractionated with hexane-toluene (1:3) to yield the title compound (977 mg, 28.4% yield) as bright golden yellow crystals.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[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]=3F)[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>O>[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:3][CH2:2][CH2:1][OH:4])[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
Reactant: OCCO
Reactant: Fc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: OCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 120 °C
Yield: 95 %

Procedure:
Ethylene glycol (150 ml) was treated with sodium hydride (60% in oil, 3.15 g) and the exotherm controlled to about 10° C. with an ice-bath. N-[3-Chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-fluoroquinazolin-4-amine (obtained as described in Example 1, preparation of starting materials, 12 g) was added in small portions and the mixture heated at 120° C. for 1 hour. The slurry was cooled, poured into water/saturated ammonium chloride (1.5 litres) and the solid collected and dried to give 2-[(4-{[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]amino}quinazolin-5-yl)oxy]ethanol (12.6 g, 95%); NMR spectrum (DMSO-d6) 3.89-3.98 (m, 2H), 4.33 (t, 2H), 5.27 (s, 2H), 5.37 (t, 1H), 7.13 (d, 1H), 7.23 (d, 1H), 7.31-7.38 (m, 2H), 7.57 (d, 1H), 7.68-7.75 (m, 2H), 7.83-7.90 (m, 1H), 8.26 (d, 1H), 8.54 (s, 1H), 8.58 (d, 1H), 10.41 (s, 11H); Mass spectrum MH+ 422.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:24][PH:25]([O-])([O-:29])[O:26][CH2:27][CH3:28].CCN(CC)CC>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C@H:8]([NH:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[C:5]1[CH:6]=[CH:7][C:2]([P:25]([CH3:24])(=[O:29])[O:26][CH2:27][CH3:28])=[CH:3][CH:4]=1
Reactant: CC(C)(C)[S@@](=O)N[C@H](c1ccc(Br)cc1)c1ccc(F)cc1F
Reactant: CCO[PH](C)([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)c1ccc([C@@H](N[S@](=O)C(C)(C)C)c2ccc(F)cc2F)cc1
Reaction time: 8 h
Yield: 81 %

Procedure:
To (R)—N—((R)-(4-bromophenyl)(2,4-difluorophenyl)methyl)-2-methylpropane-2-sulfinamide, 20-c, (1 g, 2.5 mmol), ethyl methylphosphite (0.54 g, 5 mmol) and Et3N (0.63 g, 6.25 mmol) in THF (10 ml) was added PdCl2(dppf) (183 mg). The mixture was allowed to stir overnight at reflux. The mixture was filtered and the filtrate was concentrated under vacuum. The residue was taken into ethyl acetate and washed with brine. The organic layer was concentrated under vacuum and the residue was purified over silica gel to give compound, 20-d, (dichloromethane:methanol=50/1) to provide the product (866 mg, 81%).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14].[Cl:17][C:18]1[CH:33]=[CH:32][C:21]2[N:22]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:23](=[O:25])[NH:24][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[Cl:17][C:18]1[CH:33]=[CH:32][C:21]2[N:22]([CH:26]3[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][NH:4][C:5](=[O:16])[C:6]4[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=4[N+:13]([O-:15])=[O:14])[CH2:30][CH2:31]3)[C:23](=[O:25])[NH:24][C:20]=2[CH:19]=1
Reactant: O=C(NCCBr)c1ccc(F)cc1[N+](=O)[O-]
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: O=C(NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1)c1ccc(F)cc1[N+](=O)[O-]

Procedure:
A mixture of 7.3 parts of N-(2-bromoethyl)-4-fluoro-2-nitrobenzamide, 6.2 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 5.2 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The aqueous phase is extracted with 4-methyl-2-pentanone. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2-propanone. The product is filtered off and dried, yielding 1 part of N-{2-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]-ethyl}-4-fluoro-2-nitrobenzamide.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][C:7]1[CH:8]=[C:9]([N:13]2[C:17](=[O:18])[CH2:16][C:15]([CH3:21])([CH2:19][CH3:20])[C:14]2=[O:22])[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>CC(C)=O>[C:1]([NH:6][C:7]1[CH:8]=[C:9]([N:13]2[C:17](=[O:18])[CH2:16][C:15]([CH3:21])([CH2:19][CH3:20])[C:14]2=[O:22])[CH:10]=[CH:11][CH:12]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: CCC1(C)CC(=O)N(c2cccc(N)c2)C1=O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCC(=O)Nc1cccc(N2C(=O)CC(C)(CC)C2=O)c1

Procedure:
Two and eight-tenths g. of propionylchloride was added dropwise to a well-stirred solution of 7 g. of N-m-aminophenyl-2-methyl-2-ethylsuccinimide and 3.5 g. of triethylamine in 50 ml. of acetone in a water bath. When the reaction was complete (after approximately 30 minutes), the mixture was poured into approximately 500 ml. of water and the product extracted with approximately 50 ml. of methylene chloride, dried and the solvent stripped under vacuum. The yield was 7.7 g. of a thick oil having a nD30 of 1.5510. The product was identified as the title compound by analysis of infrared spectra.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C([Li])(C)(C)C.I[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=1>C1COCC1.CCOCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=2)=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCc1ccc(Br)cc1
Reactant: CCOC(=O)CCc1ccc(I)cc1
Agent: [Pd]
Agent: [Li]C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1ccc(-c2ccc(CCC(=O)OCC)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirred solution of 3.20 g (15.0 mmol) of 1-bromo-4-butylbenzene (Aldrich Chemical Company #33,576-2) at -78° C. under argon was added, dropwise over 30 min, 18.0 mL (30.6 mmol, 1.7M in pentane) of t-butyllithium solution. The resulting light yellow solution was warmed to 0° C. and stirred for 1 h. To this solution was added 3.4 g (25 mmol) of thrice-fused zinc chloride in 20 mL of THF. The resulting slurry was stirred for 30 min and then a solution of 2.0 g (6.5 mmol) of 4-iodobenzenepropanoic acid, ethyl ester (Example 43, Part B) and 0.4 g (0.35 mmol) of tetrakis(triphenylphosphine)-palladium(0) in 5 mL of THF was added. The reaction was stirred for 16 h, diluted with ether and washed once with 10% citric acid. The organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (5×20 cm column) eluted with 1:1 hexanes/dichloromethane gave title compound as a colorless oil, 1.79 g , 91% yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[F:9].C([N-]C(C)C)(C)C.[Li+].B(OC)(OC)[O:19]C.C(OO)(=O)C>O1CCCC1.O>[Br:1][C:2]1[C:3]([F:9])=[C:4]([OH:19])[C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: COB(OC)OC
Reactant: Fc1cc(Cl)ccc1Br
Agent: CC(=O)OO
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Oc1c(Cl)ccc(Br)c1F
Temperature: -20 °C
Yield: 63 %

Procedure:
A solution of 1-bromo-4-chloro-2-fluorobenzene (20.4 g, 0.100 mol) in tetrahydrofuran (THF; 50 mL) was slowly added to lithium diisopropyl amide (LDA; 0.125 mol) in THF (600 mL) at −50° C. After addition the solution was warmed to −20° C. and then cooled to −50° C. and a solution of trimethyl borate (13.5 g, 0.130 mol) in tetrahydrofuran (20 mL) was added slowly and the temperature was warmed to −20° C. The mixture was then cooled to −70° C. and solution of peracetic acid (32% in acetic acid, 0.150 mol) was slowly added and the mixture was warmed to ambient temperature. Water (250 mL) was added and solution extracted with ethyl acetate (2×200 mL). The combined organic phases were dried and concentrated. The black oil was purified by column chromatography (20% ethyl acetate in hexanes) to give 3-bromo-6-chloro-2-fluorophenol (14.1 g, 0.063 mol): 1H NMR (CDCl3): δ 7.05 (m, 2H), 5.5 (bs, 1H).
Reaction SMILES: N(OCCC(C)C)=O.[F:9][C:10]1[CH:11]=[C:12]([F:20])[C:13]2[S:17][C:16](N)=[N:15][C:14]=2[CH:19]=1.[ClH:21]>C(#N)C.[Cu](Cl)Cl>[Cl:21][C:16]1[S:17][C:13]2[C:12]([F:20])=[CH:11][C:10]([F:9])=[CH:19][C:14]=2[N:15]=1
Reactant: Cl
Reactant: Nc1nc2cc(F)cc(F)c2s1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: Fc1cc(F)c2sc(Cl)nc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a solution containing copper chloride (II) (0.89 g, 6.64 mmol) and tri(ethylene glycol) dimethyl ether (6 mL) in acetonitrile (60 mL) was added isoamyl nitrite (0.97 g, 8.30 mmol) and the reaction mixture was stirred at rt for 30 minutes. To this suspension was added dropwise a solution of 5,7-difluoro-1,3-benzothiazol-2-amine (1.03 g, 5.53 mmol) in tri(ethylene glycol) dimethyl ether (20 mL) and acetonitrile (30 mL). The reaction mixture was stirred at rt for 10 minutes and heated at 50° C. for 2.5 h. The reaction mixture was cooled to rt, and then poured cautiously into cold aqueous 6 M HCl (400 mL). The solution was extracted with EtOAc. The organic layer was washed with HCl (1.0 M), water and brine, filtered, and concentrated. The residue was purified by flash chromatography (Biotage Flash 40M) using 5% ethyl acetate in hexane to afford 2-chloro-5,7-difluoro-1,3-benzothiazole (0.55 g, 48%). 1H NMR (400 MHz, CD2Cl2) 7.02 (m, 1H), 7.52 (m, 1H).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:3]1([CH3:8])[CH:4]=[CH:5][C:6]([O:7][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:1][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccc(C)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a mixture of p-cresol (500 mg, 4.63 mmol) and ethyl 2-bromoacetate (928 mg, 5.56 mmol) in CH3CN (10 mL) was added K2CO3 (3 g, 21.7 mmol). The reaction mixture was stirred at 80° C. for 4 h. The solid was removed by filtration and the filtrate was concentrated to give the title compound which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[S:10])[NH2:9].[OH:11]C1C=CC=C(O)C=1C#N.P(S)(OCC)(OCC)=S>O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:11])[C:3]=1[C:8](=[S:10])[NH2:9]
Reactant: N#Cc1c(O)cccc1O
Reactant: NC(=S)c1ccccc1O
Agent: CCOP(=S)(S)OCC
Solvent: O
Product: NC(=S)c1c(O)cccc1O
Yield: 43 %

Procedure:
The procedure used for the preparation of 3a was repeated with 2,6-dihydroxybenzonitrile (8.75 g, 64.8 mmol), (EtO)2P(S)SH (32.6 mL, 194 mmol) and water (26 mL) at 60° C. for 36 hr to give 3b (4.76 g, 43%) as a light yellow solid after chromatographic purification on silica gel (gradient EtOAc/CH2Cl2 : 0-5%) and crystallization from EtOAc/hexane. mp 180° C. (dec); IR (KBr) 3411, 3295, 3177, 2380, 1612, 1577, 1464, 1267, 1010 cm-1 ; 1H NMR (DMSO-d6) δ 6.31 (2H, d, J=8.1 Hz, Ar), 7.00 (1H, t, J=8.1 Hz, Ar), 9.60 (1H, br s, NH), 9.96 (1H, br s, NH), 10.93 (2H, s, OH); FABMS m/z 169 (M+), 170 (M+ +1); Anal. Calcd for C7H7NO2S: C, 49.69; H, 4.17; N, 8.28. Found: C, 49.89; H, 4.23; N, 8.36.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10](=[O:13])[CH2:11][CH3:12].[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([O:24][CH3:25])[CH:16]=1>CCCCCCC.CCOC(C)=O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[NH:8][CH2:9][C:10](=[O:13])[CH2:11][CH3:12])=[C:17]([O:24][CH3:25])[CH:16]=1
Reactant: CCC(=O)CNc1cnccc1I
Reactant: COc1cc(F)ccc1B(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCC(=O)CNc1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to Example 72, from 1-(4-iodo-pyridin-3-ylamino)-butan-2-one and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Yellow oil (43%). MS (ESI): m/z=289.134 [M+H]+.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:40])[N:22]([C@@H:24]([CH2:32][NH:33][C:34]([NH:36][CH:37]1[CH2:39][CH2:38]1)=[S:35])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:25]([C@@H:24]([N:22]([CH3:23])[C:21](=[O:40])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)[CH2:32][NH:33][C:34]([NH:36][CH:37]1[CH2:38][CH2:39]1)=[S:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C)[C@@H](CNC(=S)NC1CC1)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@@H](CNC(=S)NC1CC1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 41.9 %

Procedure:
N-((1R)-1-(N-((1R)-1-((3-Cyclopropylthioureido)methyl)-2-phenylethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butylester (579 mg, 1.01 mmol) was dissolved in dichloromethane (2 ml). The solution was cooled to 0° C. Trifluoroacetic acid (2 ml) was added. The solution was stirred for 5 min. The solvents were removed in vacuo without warming. The residue was dissolved in dichloromethane (100 ml) and the solvent was removed in vacuo. This latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (45 g) using dichloromethane/methanol/25% aqueous ammonia 100:10:1 as eluent to give 201 mg of (2R)-N-((1R)-1-benzyl-2-(3-cyclopropylthioureido)ethyl)-N-methyl-2-methylamino-3-(2-naphthyl)propionamide.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:7]=1.I[CH2:31][CH3:32].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:31]([O:1][C:2]1[C:3](=[O:29])[C:4]([C:18]2[N:22]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:21]=[CH:20][CH:19]=2)=[N:5][N:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=2)[CH:7]=1)[CH3:32]
Reactant: CCI
Reactant: O=c1c(O)cn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cn(-c2cccc(C(F)(F)F)c2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.3 %

Procedure:
A suspension of 5-hydroxy-3-(1-phenyl-1H-pyrazol-5-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (100 mg, 0.25 mmol), iodoethane (0.040 mL, 0.50 mmol), and K2CO3 (104 mg, 0.75 mmol) in DMF (1 mL) was stirred for 24 h at room temperature. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with hexane/AcOEt (1/1) to give the title compound (94.1 mg, 88% yield) as an off-white
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12]([OH:14])=O)[CH:10]=[CH:11][C:5]=2[S:4][CH2:3]1.[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][CH:33]([NH:36][CH3:37])[CH2:32][CH2:31]3)=[N:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:15][O:16][C:17]1[CH:26]=[C:25]2[C:20]([N:21]=[CH:22][C:23]([S:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH:33]([N:36]([CH3:37])[C:12]([C:9]4[CH:10]=[CH:11][C:5]5[S:4][CH2:3][C:2](=[O:1])[NH:7][C:6]=5[CH:8]=4)=[O:14])[CH2:34][CH2:35]3)=[N:24]2)=[CH:19][CH:18]=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: CNC1CCN(CCSc2cnc3ccc(OC)cc3n2)CC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(SCCN3CCC(N(C)C(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 38.2 %

Procedure:
3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid (26 mg, 0.11 mmol, 1.0 eq) is added at room temperature to a stirred solution of {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amine (40 mg, 0.11 mmol, 1.0 eq) in N,N-dimethylformamide (3 mL), followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (45 mg, 0.11 mmol, 1.0 eq), and triethylamine (16 μL, 0.11 mmol, 1.0 eq). After 4 hours stirring at room temperature, solvent is evaporated and the residue is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid {1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-methyl-amide as a yellow solid (22 mg, 35% yield).