Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:37]=[CH:36][C:17]([CH2:18][N:19]4[CH:23]=[C:22](/[CH:24]=[CH:25]/[C:26]([O:28]CC)=[O:27])[C:21]([C:31]5[S:32][CH:33]=[CH:34][CH:35]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:37]=[CH:36][C:17]([CH2:18][N:19]4[CH:23]=[C:22](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])[C:21]([C:31]5[S:32][CH:33]=[CH:34][CH:35]=5)=[N:20]4)=[CH:16][CH:15]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1cccs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
After a mixture of ethyl(E)-3-[1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]propenoate (1.25 g), 1N aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at 50° C. for 2 hours, 1N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain (E)-3-[1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-3-(2-thienyl)-1H-pyrazol-4-yl]propenoic acid (970 mg, yield 82%). This was recrystallized from ethyl acetate-hexane. Melting point: 137˜138° C.
Reaction SMILES: [OH:1][C:2]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[C:4](=[O:10])[C:3]=1[C:11]([C:13]1[C:14]([CH2:23][OH:24])=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=1)=[O:12].[H-].[Na+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Br.Cl>CN(C)C=O.C(OCC)(=O)C>[OH:10][C:4]1[CH:5]2[CH2:9][CH:8]([CH2:7][CH2:6]2)[C:2](=[O:1])[C:3]=1[C:11]([C:13]1[C:14]([CH2:23][O:24][CH2:27][CH:29]2[CH2:30][O:31]2)=[N:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=1)=[O:12]
Reactant: O=C(C1=C(O)C2CCC(C2)C1=O)c1ccc(C(F)(F)F)nc1CO
Reactant: BrCC1CO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(C1=C(O)C2CCC(C2)C1=O)c1ccc(C(F)(F)F)nc1COCC1CO1
Reaction time: 18 h

Procedure:
1.5 g of 4-hydroxy-3-(2-hydroxymethyl-6-trifluoromethylpyridine-3-carbonyl)-bicyclo[3.2.1]oct-3-en-2-one are dissolved in 15 ml of dimethylformamide and, at room temperature, treated with 0.4 g of sodium hydride (80% suspension in oil, 0.013 mol), a little at a time. After 15 minutes at a temperature of 22° C., 3 ml (0.036 mol) of epibromohydrin are added dropwise, and the reaction mixture is stirred at this temperature for another 18 hours. Ethyl acetate is then added, and the mixture is acidified to pH 3 using 10% hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and the crude product is purified chromatographically (mobile phase: toluene/ethyl alcohol/dioxane/triethylamine/water 100:40:20:20:5 parts by volume). This gives the title compound (triethylamine salt) in the form of a yellowish resin, which is released similarly to example H4. Trituration with hexane gives 600 mg of pure 4-hydroxy-3-2-oxiranylmethoxymethyl-6-trifluoromethylpyridin-3-carbonyl)bicyclo[3.2.1]oct-3-en-2-one of melting point 54-56° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[CH3:18].Br[C:20]1[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH3:27])[CH:21]=1>>[Cl:1][C:2]1[C:3]([CH3:18])=[CH:4][C:5]([C:20]2[CH:25]=[C:24]([CH3:26])[N:23]=[C:22]([CH3:27])[CH:21]=2)=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C)c1Cl
Reactant: Cc1cc(Br)cc(C)n1
Product: Cc1cc(-c2cc(C)c(Cl)c(C)c2)cc(C)n1

Procedure:
The title compound is prepared from 2-chloro-1,3-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzene and 4-bromo-2,6-dimethyl-pyridine following a procedure analogous to that described in Step 1 of Intermediate 56. Mass spectrum (ESI+): m/z=246/248 (Cl) [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:17]([O:19][C:20](=O)[C:12]=12)=[O:18]>C(O)(=O)C>[O:18]=[C:17]1[C:13]2[C:12](=[N:11][CH:16]=[CH:15][CH:14]=2)[C:20](=[O:19])[N:1]1[CH:2]([CH2:3][CH2:4][C:5]([NH2:6])=[O:7])[C:8]([OH:10])=[O:9]
Reactant: O=C1OC(=O)c2ncccc21
Reactant: NC(=O)CC[C@H](N)C(=O)O
Solvent: CC(=O)O
Product: NC(=O)CCC(C(=O)O)N1C(=O)c2cccnc2C1=O
Yield: 25.7 %

Procedure:
A stirred suspension of (S)-glutamine (14.6 g, 100 mmol) and 2,3-pyridinedicarboxylic anhydride (14.9 g, 1 00 mmol) in 100 mL of acetic acid is heated and refluxed for 1 hour. The reaction solution is cooled to form a solid. The solid is removed by filtration and washed with acetic acid to yield 7.11 g (26%) of 2-(1,3-dioxo-4-azaisoindolin-2-yl)glutaramic acid. The pro duct can be further purified by slurring in 700 mL of refluxing ethanol, cooling, filtering, and drying to produce a white powder with a melting point of 222-226° C.; 1H NMR (DMSO-d6)δ 13.25 (br s, 1H, COOH), 9.04 (dd, 1H, J=1.2, 4.9 Hz, pyr), 8.37 (dd, 1H, J=1.2, 7.8 Hz, pyr), 7.85 (dd, 1H, J=4.9, 7.8 Hz, pyr), 7.20 (s, 1--H, CONH2), 6.73 (s, 1H, CONH2), 4.83 (dd, 1H, J=10.2, 4.8 Hz, CHN), 2.55-1.90 (m, 4H, CH2CH2); 13C NMR (DMSO-d6)δ 1173.22, 170.21, 165,8, 165.7, 155.4, 150.9, 131.7, 128.3, 126.9, 51.5, 31.4, 24.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.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>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[C:36]([F:42])=[CH:37][CH:38]=[CH:39][C:40]=3[F:41])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(Cl)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Fc1cccc(F)c1Sc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1cc2ccc(Cl)cc2c(-c2ccc(Sc3c(F)cccc3F)cc2)c1C
Yield: 16.1 %

Procedure:
A stirred solution of [6-chloro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.18 g, 0.48 mmol) in dimethoxyethane (4 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.055 g, 0.048 mmol), crude 1-(4-bromo-phenylsulfanyl)-2,6-difluorobenzene (0.14 g) and 2.0 M aqueous sodium carbonate (1 mL, 2 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {6-chloro-4-[4-(2,6-difluoro-phenylsulfanyl)-phenyl]-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.035 g, 13%) as a solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C([Li])CCC.[O:18]1CCC[CH2:19]1>>[Br:12][C:9]1[C:8]2[CH:7]=[N:6][CH:5]=[CH:4][C:3]=2[C:2]([CH:19]=[O:18])=[CH:11][CH:10]=1
Reactant: Brc1ccc(Br)c2cnccc12
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: O=Cc1ccc(Br)c2cnccc12
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 5,8-dibromoisoquinoline (4.0 g. 13.9 mmol) in tetrahydrofuran (120 mL) at −78° C. under nitrogen atmosphere was added dropwise a solution of n-butyllithium (2.3 M in hexane, 7.3 mL, 16.8 mmol). The reaction mixture turned dark. After stirring for 15 minutes, the reaction mixture was quenched by adding N,N-dimethylformamide (4.0 mL). After stirring at −78° C. for an additional 1 h, the reaction mixture was quenched with water, extracted with mixture of ethyl acetate/hexane (2:8), washed with water and brine, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using hexanes/ethyl acetate as eluent to afford the 8-bromo-5-isoquinolinecarboxaldehyde (0.10 g), followed by 5-bromo-8-isoquinolinecarboxaldehyde (1.0 g) as white solids.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[CH3:11][Mg+].[Br-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:11])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1
Reactant: C[Mg+]
Reactant: CSc1nc(Cl)cc(Cl)n1
Agent: [Br-]
Solvent: C1CCOC1
Product: CSc1nc(C)cc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.4 %

Procedure:
According to Scheme 12, a solution of 4,6-dichloro-2-methylthiopyrimidine (1.95 g, 10 mmol) in 30 mL of dry THF was cooled to 0° C. and treated with a solution of MeMgBr (14 mL of 1.4 M solution, 19.6 mmol). After overnight stirring at RT, the reaction mixture was quenched with sat. NH4Cl. The organic layer washed with brine, dried and evaporated. The residue was purified by chromatography (silica gel, hexane:ethyl acetate, 9:1) to provide 1.3 g of 4-chloro-6-methyl-2-methylthiopyrimidine (95).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:33]=[CH:34][C:35]2[C:36]([CH:40]=1)=[N:37][O:38][N:39]=2>>[N:39]1[O:38][N:37]=[C:36]2[CH:40]=[C:32]([CH2:31][O:1][C:2]3[CH:3]=[C:4]([C:8]4[C:17]5[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=5)[N:11]=[CH:10][C:9]=4[C:22]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[O:23])[CH:5]=[CH:6][CH:7]=3)[CH:33]=[CH:34][C:35]=12
Reactant: BrCc1ccc2nonc2c1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Product: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(OCc2ccc3nonc3c2)c1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 5-Bromomethyl-benzo[1,2,5]oxadiazole following the procedure of Example 478: MS (ESI) m/z 526; MS (ESI) m/z 524; HRMS: calcd for C30H18F3N3O3+H+, 526.13730; found (ESI, [M+H]+), 526.1356.
Reaction SMILES: C[Si](C)(C)[O:3][NH2:4].[C:7]([NH:10][CH2:11][C@@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[CH2:13]1)(=[O:9])[CH3:8]>C(O)C>[C:7]([NH:10][CH2:11][C@@H:12]1[O:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24](=[NH:25])[NH:4][OH:3])=[C:20]([F:26])[CH:19]=2)[CH2:13]1)(=[O:9])[CH3:8]
Reactant: C[Si](C)(C)ON
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C#N)c(F)c2)C(=O)O1
Solvent: CCO
Product: CC(=O)NC[C@H]1CN(c2ccc(C(=N)NO)c(F)c2)C(=O)O1
Reaction time: 48 h

Procedure:
O-Trimethylsilylhydroxylamine (0.37 ml, 3.0 mmol) and 5-(S)-acetamidomethyl-3-[4′-cyano-3′-fluorophenyl]oxazolidine-2-one (0.277 g, 1.0 mmol) in ethanol (3.0 ml) were stirred at 80° C. in a sealed reaction vial for 2.5 h. The mixture was left at r.t. for 48 h, and the crystallized product filtered, rinsed with ethanol (ca. 0.75 ml), washed with ether, and dried under vacuum. Yellow crystals. Yield 0.260 g (84%). HPLC: Rt 2.6 min. MS (m/z): [M+H]+=311.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH:25]([C:28]1[CH:29]=[CH:30][C:31]([O:46][CH3:47])=[C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2CO)[CH:33]=1)([CH3:27])[CH3:26]>C(Cl)Cl>[Br:5][CH2:1][C:35]1[CH:36]=[C:37]([C:40]([F:41])([F:42])[F:43])[CH:38]=[CH:39][C:34]=1[C:32]1[CH:33]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:29]=[CH:30][C:31]=1[O:46][CH3:47]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
CBr4 (112 mg, 0.211 mmol) and Ph3P (55 mg, 0.211 mmol) were added successively to a stirred solution of [5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methanol (57.1 mg, 0.176 mmol) in dry CH2Cl2 (1 mL) at 0° C. under N2. The solution was stirred at room temperature for 1 h and the reaction mixture was concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-20% EtOAc in hexanes gradient) to give 2-(bromomethyl)-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl as a colorless oil. Rf=0.95 (20% EtOAc/hexanes). LCMS calc.=387.05; found=387.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.83 (br s, 1H), 7.60 (dd, J=8.0, 1.3 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.29 (dd, J=8.5, 2.3 Hz, 1H), 7.14 (d, J=2.3 Hz, 1H), 6.95 (d, J=8.5, 1H), 4.45 (d, J=10.6 Hz, 1H), 4.33 (d, J=10.6 Hz, 1H), 3.76 (s, 3H), 2.94 (septet, J=6.9 Hz, 1H), 1.29 (d, J=6.9 Hz, 6H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:13][CH2:12]2)=O)=[CH:5][CH:4]=1.[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[N:16]([C:15]([CH3:14])=[N:19][CH:18]=3)[CH2:12][CH2:13][CH:11]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)C2CC2)cc1
Reactant: Cc1ncc[nH]1
Product: Cc1ncc2n1CCC=C2c1ccc(O)cc1
Temperature: 225 °C

Procedure:
25 g (0.14 mol) of cyclopropyl 4-methoxyphenyl ketone is combined with 50 g (0.61 mol) of 2-methylimidazole and heated to 225° C. under nitrogen for 16 hr. The reaction is extracted with sodium hydroxide solution and the extract neutralized with ammonium chloride. Recrystallization from methylene chloride/methanol (1:1) provides the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[S:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:18])=[O:17].C([O-])(=O)C.[Na+].[Br:30]Br>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Br:30])[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:5]2[S:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)(=[O:17])=[O:18]
Reactant: CCOC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1CCOCC1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2cc(Br)c(Br)cc2c1S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl 5-bromo-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxylate (108 mg, 0.26 mmol, 1.0 equiv) and sodium acetate (64 mg, 0.78 mmol, 3.0 equiv) were dissolved in 2 mL of acetic acid. A 1 mL solution of Br2 (41 mg, 0.26 mmol, 1.0 equiv) in acetic acid was added dropwise to the mixture and was stirred for 3 hours at ambient temperature, after which the vessel was heated at 50° C. for 18 hours. An additional 1 mL solution of Br2 (41 mg, 0.26 mmol, 1.0 equiv) in acetic acid was added dropwise to the mixture and stirred at 50° C. for 90 minutes. An additional 1 mL solution of Br2 (82 mg, 0.52 mmol, 2.0 equiv) was added and the vessel was heated for 30 more minutes. The reaction mixture was partitioned between ethyl acetate and aqueous saturated NaHCO3, which was extracted three times with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (ethyl acetate/hexanes) provided the titled compound. Proton NMR for the product was consistent with the titled compound. ESI+MS: 496.9 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[CH:48]=[N:47][CH:46]=[C:45]2[NH:49][CH:50]=[CH:51][C:44]=12>O1CCOCC1.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.[Cu]I>[CH3:40][C:36]([N:33]1[CH2:32][CH2:31][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:12][C:11]([C:43]4[CH:48]=[N:47][CH:46]=[C:45]5[NH:49][CH:50]=[CH:51][C:44]=45)=[N:10][C:9]=3[CH:26]=2)[CH2:35][CH2:34]1)([CH3:41])[C:37]([NH2:39])=[O:38]
Reactant: Brc1cncc2[nH]ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4cncc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1
Temperature: 140 °C
Yield: 27.5 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributlystannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (1.17 g, 1.69 mmol), 4-bromo-1H-pyrrolo[2,3-c]pyridine (432 mg, 2.19 mmol), tetrakis(triphenylphosphine)palladium (194 mg, 10 mol %) and CuI (385 mg, 2.02 mmol) in dioxane (20 mL) was purged with argon gas then heated at 140° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH/DCM then eluted with 2 M NH3 in MeOH/DCM. The resulting residue was purified by column chromatography (Si—PPC, MeOH:DCM, gradient 0:100 to 20:80). The resulting solid was dissolved in MeOH, loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH to afford 105 as a pale yellow solid (242 mg, 39%). LCMS (Method F): RT 4.51 min, [M+H]+ 521.2. 1H NMR (DMSO, 400 MHz): δ 11.75 (s, 1 H); 9.13 (s, 1 H); 8.81 (s, 1 H); 7.71 (t, J=2.7 Hz, 1 H); 7.45 (s, 1 H); 7.40-7.37 (m, 1 H); 7.07 (d, J=3.5 Hz, 1 H); 6.95 (d, J=3.5 Hz, 1 H); 4.01 (t, J=4.6 Hz, 4 H); 3.87 (s, 2 H); 3.83 (t, J=4.6 Hz, 4 H); 2.58 (s, 4 H); 2.49 (s, 4 H); 1.10 (s, 6 H)
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([O:14]CC(C)=C)[CH:10]=[CH:9][C:8]=2[CH3:19])([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[OH:14][C:11]1[C:10]([CH2:3][C:1]([CH3:4])=[CH2:2])=[CH:9][C:8]([CH3:19])=[C:7]2[C:12]=1[CH:13]=[C:4]([CH:1]([CH3:2])[CH3:3])[C:5](=[O:20])[NH:6]2
Reactant: C=C(C)COc1ccc(C)c2[nH]c(=O)c(C(C)C)cc12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=C(C)Cc1cc(C)c2[nH]c(=O)c(C(C)C)cc2c1O
Yield: 185.3 %

Procedure:
Using 3-isopropyl-8-methyl-5-(2-methylallyl)oxycarbostyril (1.0 g, 3.7 mmol), the procedure of Reference Example 65 was followed (reaction, post-treatment, recrystallization from ethyl acetate-hexane). 930 mg of the title compound was obtained as colorless needles (92.6%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([NH:17][CH3:18])[CH2:13][CH2:12]2)=[C:7]([CH2:19][NH:20][CH3:21])[CH:6]=1.[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][CH:23]1[C:32](Cl)=[O:33]>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([N:17]([CH3:18])[C:32]([CH:23]3[CH2:24][CH2:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:22]3)=[O:33])[CH2:13][CH2:12]2)=[C:7]([CH2:19][NH:20][CH3:21])[CH:6]=1
Reactant: O=C(Cl)C1CCc2ccccc2C1
Reactant: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](NC)CC1
Product: CNCc1cc(CCCO)ccc1[C@H]1CC[C@H](N(C)C(=O)C2CCc3ccccc3C2)CC1

Procedure:
from trans-4-[4-(3-hydroxypropyl)methylaminomethyl-phenyl]-N-methylcyclohexylamine and 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid chloride. Melting point: 93°-95° C.
Reaction SMILES: CCN(CC)CC.[C:8]1([N:14]=[C:15]=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[N:25]=[C:26]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[NH:30][C:29]4[N:37]=[CH:38][CH:39]=[CH:40][C:28]=4[N:27]3[C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([C:48]3([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:51][CH2:50][CH2:49]3)=[CH:44][CH:43]=2)=[CH:20][CH:19]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH:14]([C:15]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]2[N:25]=[C:26]3[C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[NH:30][C:29]4[N:37]=[CH:38][CH:39]=[CH:40][C:28]=4[N:27]3[C:41]=2[C:42]2[CH:47]=[CH:46][C:45]([C:48]3([NH:52][C:53](=[O:59])[O:54][C:55]([CH3:57])([CH3:56])[CH3:58])[CH2:49][CH2:50][CH2:51]3)=[CH:44][CH:43]=2)=[CH:22][CH:23]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: O=C=Nc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(NC(=O)Nc5ccccc5)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
Et3N (36.6 μL, 0.263 mmol) and phenyl isocyanate (10.4 μL, 0.0964 mmol) were added to a solution of tert-butyl (1-{4-[2-(4-aminophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (50.0 mg, 0.0876 mmol) in DCM (1 mL) at 0° C., and stirred at room temperature. After reaction was completed, the mixture was diluted with sat. NaHCO3 and extracted with CHCl3 (3×). The combined organic layers were dried over anhydrous Na2SO4, and concentrated. The residue was purified by PTLC (CHCl3/MeOH=9:1). The fractions were concentrated and solidified with CHCl3. The precipitated solids were collected by filtration and washed with CHCl3 to afford desired product (33.5 mg, 55.4%) as cream colored solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.16-8.11 (m, 1H), 8.03-7.99 (m, 1H), 7.54-7.48 (m, 2H), 7.38-7.21 (m, 9H), 7.16-7.05 (m, 4H), 6.95 (d, J=8.2 Hz, 1H), 6.89-6.73 (m, 3H), 6.59 (dd, J=8.0, 4.8 Hz, 1H), 6.29 (s, 1H), 5.19 (s, 1H), 2.61-2.23 (m, 4H), 2.20-2.06 (m, 1H), 1.95-1.80 (m, 1H), 1.49-1.16 (m, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[O:25]([CH2:32][C:33](Cl)=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCCC1>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][N:9]2[C:10]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:13][C:14]=3[C:15](=[O:16])[N:17]=[C:33]2[CH2:32][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Reactant: O=C(Cl)COc1ccccc1
Solvent: C1CCOC1
Product: Cc1c(Cl)cccc1Cn1c(COc2ccccc2)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.273 mmol) in Tetrahydrofuran (THF) (1363 μl) at 0° C. was added phenoxyacetyl chloride (75 μl, 0.545 mmol). The mixture was stirred at room temperature overnight, then quenched with methanol and concentrated. The residue was purified by reversed-phase HPLC to provide 4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-5-[(phenyloxy)methyl][1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (19 mg, 14%); LC/MS: MS (ES+) m/e 483 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H), 3.52 (t, J=4.7 Hz, 4H), 3.67 (t, J=4.7 Hz, 4H), 5.07 (s, 2H), 5.55 (s, 2H), 6.55 (m, 1H), 6.69 (d, J=7.8 Hz, 2H), 6.94 (m, 1H), 7.12 (m, 1H), 7.22 (m, 2H), 7.36 (d, J=7.8 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1OC)([O-:3])=[O:2].[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>O>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:16][CH2:17][CH:18]([OH:20])[CH3:19])([O-:3])=[O:2]
Reactant: CC(O)CN
Reactant: COc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(NCC(C)O)c([N+](=O)[O-])c1
Temperature: 60 °C

Procedure:
0.05 mol (10.6 g) of 2,6-dinitro-4-methylanisole is introduced gradually, whilst stirring, into 30 ml of 1-aminopropan-2-ol. The reaction medium is heated at 60° C. for 30 minutes and then poured into 120 g of iced water. The expected product precipitates. It is filtered off, washed with water and then recrystallised from an aqueous-alcoholic mixture. After drying in vacuo, it melts at 80° C.