Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:20]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([CH2:15][Br:20])[CH:12]=[CH:11][C:10]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)cc1S(=O)(=O)NC(C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(CBr)cc1S(=O)(=O)NC(C)(C)C
Yield: 59.9 %

Procedure:
A solution of 54.8 g (192 mmol) of N-tert-butyl-2-methoxycarbonyl-5-methylbenzenesulfonamide in 420 ml of tetrachloromethane is heated at reflux for 6-8 h under a nitrogen protective-gas atmosphere, following addition of 36 g (202 mmol) of N-bromosuccinimide and 0.5 g of azobisisobutyronitrile (AIBN) with simultaneous irradiation with a daylight lamp. The solution is then filterd and then washed in succession with sodium disulphide solution, sodium hydrogen carbonate solution and water, dried over Na2SO4 and evaporated to dryness i.v. Crystallization of the residue from diisopropyl ether/ethyl acetate yields 41.9 g (57%) of N-tert-butyl-5-bromomethyl-2-methoxycarbonylbenzenesulfonamide of mp. 88-90° C.
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].CCO.Cl[C:9]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=[O:24])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[CH:14]2>C(Cl)Cl.CCCCCC>[CH2:2]([O:3][C:9]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=[O:24])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[CH:14]2)[CH3:1]
Reactant: O=Cc1c2ccccc2c(Cl)c2ccccc12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Solvent: ClCCl
Product: CCOc1c2ccccc2c(C=O)c2ccccc12

Procedure:
Using the procedure outlined in 11A, except that NaOEt (Aldrich)/EtOH was used instead of NaOCH3 /CH3OH, 10-chloro-9-anthraldehyde (Aldrich) gave 10-ethoxy-9-anthracenecarbaldehyde mp 88°-90°, (CH2Cl2 /hexane) (C, H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[C:8]=2[Cl:15])[N:5]=[CH:4][C:3]=1[C:16]#[N:17])(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1N
Product: CC(=O)Nc1c(C#N)cnn1-c1ccc(Cl)c(Cl)c1Cl
Yield: 3175.8 %

Procedure:
5-Amino-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (2.9 g) in acetylchloride (15 mg) was heated at reflux for 2 hours. The reaction mixture was then filtered and the solid residue was triturated with acetyl chloride (10 ml), to give 5-acetamido-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole (2.0 g), m.p. 220°-223° C., in the form of a colourless powder.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]=[C:12](Br)[CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1[C:27]2[C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[O:24][C:23]=2[C:22]([C:32]2[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH:13]=[C:12]([C:35]2[CH:36]=[CH:37][C:32]([C:22]3[C:23]4[O:24][C:25]5[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=5[C:27]=4[CH:19]=[CH:20][CH:21]=3)=[CH:33][CH:34]=2)[CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c([N+](=O)[O-])cc(Br)cn1Cc1ccccc1
Reactant: OB(O)c1ccc(-c2cccc3c2oc2ccccc23)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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=c1c([N+](=O)[O-])cc(-c2ccc(-c3cccc4c3oc3ccccc34)cc2)cn1Cc1ccccc1
Temperature: 80 °C
Yield: 99.9 %

Procedure:
A solution of 1-benzyl-5-bromo-3-nitro-1H-pyridin-2-one (1.0 g, 3.24 mmol), 4-dibenzofuran-4-yl-phenyl-boronic acid (932 mg, 3.24 mmol), K2CO3 (1.34 g, 3 equiv., 9.7 mmol) in toluene (15 mL), ethanol (10 mL) and water (5 mL) was treated with treated with Pd(PPh3)4 (125 mg). After heating to 80° C. overnight, the solution was cooled to room temperature and the resulting solids were filtered and washed with ether (2×6 mL) to give 1-benzyl-5-(4-dibenzofuran-4-yl-phenyl)-3-nitro-1H-pyridin-2-one as a yellow solid (1.53 g, 92%).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C:10](O)([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH:8]1[C:19]([O:21][CH3:22])=[O:20])=[O:6])[CH:2]=[CH2:3].P(Br)(Br)Br.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C:10]([C:12]#[C:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]1[C:19]([O:21][CH3:22])=[O:20])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CC(O)(C#C[Si](C)(C)C)CC1C(=O)OC
Agent: BrP(Br)Br
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC(=O)N1CC(C#C[Si](C)(C)C)=CC1C(=O)OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.4 %

Procedure:
To a solution of 1-allyloxycarbonyl-4-hydroxy-2-methoxycarbonyl-4-trimethylsilylethynylpyrrolidine (7.0 g) in toluene (70 ml) was slowly added phosphorus tribromide (2.25 ml) at room temperature and the mixture was stirred at room temperature for one day. The reaction mixture was then poured into iced water-ethyl acetate. The aqueous layer was then separated and extracted with ethyl acetate twice. The organic layers were combined, washed with saturated aqueous sodium hydrogen carbonate solution twice and further with water and aqueous sodium chloride solution successively, and dried over anhydrous magnesium sulfate. Finally the solvent was distilled off under reduced pressure to give 1-allyloxycarbonyl-2-methoxycarbonyl-4-trimethylsilylethynyl-3-pyrroline (3.0 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[NH:7][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.[C:26](OC)(=O)[C:27](C)=O.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[C:26]([CH3:27])=[N:7][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1
Reactant: COC(=O)C(C)=O
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Cl)c3oc(=O)[nH]c23)c1=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2oc1=O
Yield: 43 %

Procedure:
3-[7-Chloro-5-fluoro-2(3H)benzoxazolinon-4-yl]-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione (0.50 g) was dissolved in anhydrous toluene (15 ml) and methyl pyruvate (0.15 g) was added. The solution was refluxed with azeotropic removal of water for 2 hours and the solvent was then removed under reduced pressure. The residue was chromatographed on silica gel using hexane-ethyl acetate (3:1) as the eluent to afford the title compound (0.23 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:8]([C:17]([NH:19][C:20]1[CH:25]=[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]([C:31]#[N:32])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[CH3:33][N:34]1[C:38](B(O)O)=[CH:37][CH:36]=[N:35]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(Cl)Cl.O.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]>[C:31]([C:23]1[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:25][C:20]([NH:19][C:17]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:38]4[N:34]([CH3:33])[N:35]=[CH:36][CH:37]=4)=[C:11]([CH:12]([O:15][CH3:16])[O:13][CH3:14])[N:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:18])=[N:21][CH:22]=1)#[N:32]
Reactant: Cn1nccc1B(O)O
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(Br)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: COCCNc1cc(NC(=O)N2CCCc3cc(-c4ccnn4C)c(C(OC)OC)nc32)ncc1C#N
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
A suspension of 6-bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 315, 50.9 mg, 0.101 mmol), 1-methylpyrazole-5-boronic acid pinacolester (23.9 mg, 0.111 mmol), PdCl2(dppf) (8 mg, 10.93 μmol) and saturated aqueous Na2CO3 (160 μl) in DME (480 μl) was sealed in a vial and purged with argon. Then reaction mixture was stirred at 120° C. for 15 min in a microwave. Additional 1-methylpyrazole-5-boronic acid pinacolester (10 mg, 0.047 mmol) and PdCl2(dppf) (8 mg, 10.93 μmol) were added and the reaction mixture was stirred in microwave for 15 min at 120° C. The suspension was diluted with DCM and water, phases were separated and the aqueous layer was extracted with DCM. The organic layers were combined, dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (1-5%) in DCM. Product containing fractions were combined, evaporated and dried to yield the title compound as a yellow film. (UPLC-MS 3) tR 0.98 min; ESI-MS 507.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>>[OH:27][CH2:26][C:25]([NH:24][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)([CH3:29])[CH3:28]
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: CC(C)(N)CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 53 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (200 mg, 0.65 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of methylamine, to the title compound (130 mg, 53%) which was obtained as an off white solid. MS: m/e=380.5 [M−H]−.
Reaction SMILES: N#N.[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[N:14]2)[O:8][CH2:7][CH2:6][O:5]1.[NH4+].[Cl-]>CCO.O.[Fe]>[CH3:3][C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]2)[O:8][CH2:7][CH2:6][O:5]1
Reactant: CC1(CCCCn2ccc([N+](=O)[O-])n2)OCCO1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CC1(CCCCn2ccc(N)n2)OCCO1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-3-nitro-1H-pyrazole (300 mg, 1.18 mmol), iron powder (199 mg, 3.53 mmol) and NH4Cl (317 mg, 5.88 mmol) in a mixture of EtOH (4.0 mL) and water (2.0 mL) was stirred at 75° C. for 30 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (20 mL) was added followed by water (20 mL). The aq. layer was extracted with CH2Cl2 (3×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a colorless oil. LC-MS-conditions 02: tR=0.59 min; [M+H]+=226.47.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:26][C:27]2[CH:28]=[N:29][C:30](Cl)=[CH:31][CH:32]=2)=[N:6][N:7]([C:9]2([CH2:23][C:24]#[N:25])[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[O:16])[CH2:11][CH2:10]2)[CH:8]=1)(=[O:3])[NH2:2].[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>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].O>[C:1]([C:4]1[C:5]([NH:26][C:27]2[CH:28]=[N:29][C:30]([C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=3)=[CH:31][CH:32]=2)=[N:6][N:7]([C:9]2([CH2:23][C:24]#[N:25])[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[O:16])[CH2:11][CH2:10]2)[CH:8]=1)(=[O:3])[NH2:2]
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(Cl)nc3)n2)CCN(C(=O)OCC(F)(F)F)CC1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2ccc(Nc3nn(C4(CC#N)CCN(C(=O)OCC(F)(F)F)CC4)cc3C(N)=O)cn2)cn1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
2,2,2-Trifluoroethyl 4-(4-carbamoyl-3-(6-chloropyridin-3-ylamino)-1H-pyrazol-1-yl)-4-(cyanomethyl)piperidine-1-carboxylate (45 mg, 0.093 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (23 mg, 0.11 mmol), Pd(dppf)Cl2 (8 mg, 0.009 mmol), potassium phosphate (59 mg, 0.28 mmol), 1,4-dioxane (0.25 mL), and water (0.03 mL) were combined in a 4 mL vial. The vial was then sealed and flushed with argon. The mixture was heated to 90° C. and was allowed to stir for 90 minutes. The mixture was cooled to ambient temperature, diluted with EtOAc and washed sequentially with water and brine. The organic layer was dried with anhydrous MgSO4, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM) to afford the title compound, Example #11-1.
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:11]1[C:16]([Br:17])=[CH:15][N:14]=[CH:13][C:12]=1Br)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu](C#N)[C:20]#[N:21].O>CN(C=O)C>[CH2:1]([O:8][CH:9]([C:11]1[C:12]([C:20]#[N:21])=[CH:13][N:14]=[CH:15][C:16]=1[Br:17])[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(OCc1ccccc1)c1c(Br)cncc1Br
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Solvent: O
Product: CC(OCc1ccccc1)c1c(Br)cncc1C#N
Temperature: 150 °C
Reaction time: 3 h
Yield: 64.5 %

Procedure:
To a solution of 4-(1-benzyloxy-ethyl)-3,5-dibromo-pyridine (400 mg, 1.1 mmol) in DMF (5 mL) is added copper cyanide (116 mg, 1.3 mmol). The mixture is heated and stirred at 150° C. for 3 h, then stirred at room temperature for 16 h. H2O is added and the mixture is extracted with EtOAc. The organic layers are combined and concentrated to give the crude product. Purification by flash column chromatography provides 225 mg of 4-(1-benzyloxy-ethyl)-5-bromo-nicotinonitrile.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH:25]=O)[CH:8]=2)[N:3]=1.[CH:31]1([NH2:34])[CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O1CCCC1.O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:22]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][NH:34][CH:31]3[CH2:33][CH2:32]3)[CH:8]=2)[N:3]=1
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3C=O)ccc2n1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3CNC3CC3)ccc2n1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
200 mg of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]benzaldehyde are dissolved in 3 ml of 1,2-dichloroethane and 3 ml of tetrahydrofuran. 81 μl of cyclopropylamine and 35 μl of glacial acetic acid are added, and the mixture is stirred at 60° C. for 6 h. After cooling to 25° C., 226 mg of sodium triacetoxyborohydride are added and stirred at 25° C. for a further 12 h. The mixture is poured into water, extracted three times with dichloromethane, and the combined organic phases are dried over sodium sulfate. After filtration, the filtrate is evaporated to dryness and purified by chromatography (reversed phase HPLC).
Reaction SMILES: [CH:1]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[C:22]#[C:23][CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CN(C)C=O.[Cu](I)I>[CH:1]([N:14]1[C:15]2[C:16](=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH:22]=[C:23]1[CH2:24][CH2:25][N:26]1[C:27](=[O:36])[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]1=[O:35])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1c2ccccc2C(=O)N1CCC#Cc1cc(Cl)ccc1NC(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCc1cc2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 95 %

Procedure:
To a solution of 2-{4-[2-(Benzhydryl-amino)-5-chloro-phenyl]-but-3-ynyl}-isoindole-1,3-dione made in Example 2 (13.1 g, 26.7 mmol) in dimethylformamide (65 ml) at ambient temperature was added copper iodide (1.02 g, 5.3 mmol). The reaction mixture suspension was heated at 120 C for 16 h. Then it was heated at 140 C for 4 h. The reaction mixture was filtered at 60° C. Water (200 ml) was added to the filtrate. The product was collected after filtration and washing with water (20 ml×4). Drying the product in vacuo at 60° C. provided an off-white solid product, 2-[2-(1-Benzhydryl-5-chloro-1H-indol-2-yl)-ethyl]-isoindole-1,3-dione (12.5 g, yield 95%). HPLC (area %): 97.3%
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[C:34]([N:1]1[CH2:6][CH2:5][O:4][CH:3]([CH2:7][NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:2]1)(=[O:37])[CH2:35][CH3:36]
Reactant: O=C(NCC1CNCCO1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CCC(=O)Cl
Product: CCC(=O)N1CCOC(CNC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (morpholin-2-ylmethyl)-amide (example A147) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:3]=1.[CH2:15]([C:17]1([C:23]#[N:24])[CH2:21][CH2:20][NH:19][C:18]1=[O:22])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCCC1.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]>[CH2:15]([C:17]1([C:23]#[N:24])[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=3)[N:3]=2)[C:18]1=[O:22])[CH3:16]
Reactant: Cn1cc(Nc2nccc(Cl)n2)cn1
Reactant: CCC1(C#N)CCNC1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCC1(C#N)CCN(c2ccnc(Nc3cnn(C)c3)n2)C1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
To a mixture of 4-chloro-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine (110 mg) obtained in Step C, 3-ethyl-2-oxopyrrolidine-3-carbonitrile (82 mg) obtained in Step H, cesium carbonate (350 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (19 mg) in tetrahydrofuran (3 mL) was added tris(dibenzylideneacetone)dipalladium(0) (10 mg), and the mixture was stirred overnight at 90° C. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), and recrystallized (hexane/ethyl acetate) to give the title compound (87 mg)
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][NH:7][CH2:6]1.F[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]2[N:26]=[C:25]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]([CH3:36])[CH:28]=3)[C:24]([CH3:37])=[CH:23][N:22]=2)=[C:13]([O:38][CH3:39])[CH:12]=1.CCN(C(C)C)C(C)C>FC(F)(F)CO>[CH3:3][N:4]([CH3:9])[CH:5]1[CH2:8][N:7]([C:11]2[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][C:14]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:29]([CH3:36])[CH:28]=4)[C:24]([CH3:37])=[CH:23][N:22]=3)=[C:13]([O:38][CH3:39])[CH:12]=2)[CH2:6]1
Reactant: CN(C)C1CNC1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 71.6 %

Procedure:
N,N-dimethylazetidin-3-amine (Intermediate 26, 113 mg, 0.65 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)-pyrimidin-2-amine (Intermediate 79, 250 mg, 0.61 mmol) and DIPEA (0.374 mL, 2.15 mmol) in 2,2,2-trifluoroethanol (5 mL). The mixture was heated in a microwave at 140° C. for 1 h. The cooled mixture was purified by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo onto silica. Further purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (213 mg, 71%) as an orange foam; 1H NMR: 2.13 (6H, s), 2.37 (3H, s), 3.09-3.16 (1H, m), 3.72 (2H, dd), 3.89 (3H, s), 3.93 (3H, s), 4-4.08 (2H, m), 6.27 (1H, s), 7.04 (1H, t), 7.20-7.26 (1H, m), 7.49 (1H, d), 7.90 (1H, s), 8.03 (1H, s), 8.23 (1H, s), 8.35 (1H, d), 8.46 (1H, s); m/z: ES+ MH+ 488.63.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([Cl:19])=[CH:14][C:13]=1[S:20](Cl)(=[O:22])=[O:21]>>[C:1]([C:4]1[S:8][C:7]([NH:9][S:20]([C:13]2[CH:14]=[C:15]([Cl:19])[C:16]([Cl:18])=[CH:17][C:12]=2[Cl:11])(=[O:22])=[O:21])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)c1sc(N)nc1C
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Product: CC(=O)c1sc(NS(=O)(=O)c2cc(Cl)c(Cl)cc2Cl)nc1C

Procedure:
The title compound was prepared from 5-acetyl-2-amino-4-methylthiazole (42 mg) and 2,4,5-trichlorobenzenesulfonyl chloride (76 mg) as described in the synthetic METHOD B to give a white solid (23.7 mg) with purity >90%: MS (pos) m/z 399.2, 401.2; HRMS m/z 397.9103 (calc. of monoisotopic mass for C12H9Cl3N2O3S2 gives 397.9120).
Reaction SMILES: ClC1C=C(Cl)C(Cl)=CC=1O[C:11](=[O:27])[C@H:12]([CH3:26])[NH:13][C:14](=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1.Cl.[CH3:29][O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH2:33]>>[CH3:29][O:30][C:31](=[O:41])[C@H:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[NH:33][C:11](=[O:27])[C@H:12]([CH3:26])[NH:13][C:14](=[O:25])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Agent: Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure Z and using N-(3-nitrophenylacetyl)-L-alanine 2,4,5-trichlorophenyl ester (from Example D8 above) and L-phenylalanine methyl ester hydrochloride (Sigma), the title compound was prepared as a solid (mp=154-158° C.). The reaction was monitored by tlc (Rf=0.3 in 1:1 EtOAc/hexanes) and the product was purified by silica gel chromatography using 50-100% EtOAc/hexanes as the eluent. NMR data was as follows: