Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C1C=C(Br)C2SC(NC(NCC)=O)=NC=2C=1)=[N+]=[N-].C=O.CN.[N:24]([C:27]1[CH:28]=[C:29]([Br:46])[C:30]2[S:34][C:33]([N:35]3[CH2:40][N:39]([CH3:41])[CH2:38][N:37]([CH2:42][CH3:43])[C:36]3=[O:44])=[N:32][C:31]=2[CH:45]=1)=[N+:25]=[N-:26].[CH2:47]([O:49][CH:50]([O:53][CH2:54][CH3:55])[C:51]#[CH:52])[CH3:48].CCN(C(C)C)C(C)C>CO.CN(C=O)C.[Cu]I.O>[Br:46][C:29]1[C:30]2[S:34][C:33]([N:35]3[CH2:40][N:39]([CH3:41])[CH2:38][N:37]([CH2:42][CH3:43])[C:36]3=[O:44])=[N:32][C:31]=2[CH:45]=[C:27]([N:24]2[CH:52]=[C:51]([CH:50]([O:53][CH2:54][CH3:55])[O:49][CH2:47][CH3:48])[N:26]=[N:25]2)[CH:28]=1
Reactant: C#CC(OCC)OCC
Reactant: CCN1CN(C)CN(c2nc3cc(N=[N+]=[N-])cc(Br)c3s2)C1=O
Agent: [Cu]I
Agent: C=O
Agent: CCNC(=O)Nc1nc2cc(N=[N+]=[N-])cc(Br)c2s1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(OCC)c1cn(-c2cc(Br)c3sc(N4CN(C)CN(CC)C4=O)nc3c2)nn1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Compound i (1.68 g, 4.89 mmol) was suspended in MeOH (65 mL) and formaldehyde (37 wt % in H2O, 7.94 g, 97.9 mmol) then methylamine (2 M in MeOH, 24.5 mL, 49 mmol) added. The suspension was heated to 80° C. for 5 h. H2O was added and the mixture extracted with EtOAc and then DCM. The organic layers were dried (Na2SO4), filtrated and concentrated in vacuo to give a residue that contained 1-(5-azido-7-bromo-1,3-benzothiazol-2-yl)-3-ethyl-5-methyl-1,3,5-triazinan-2-one (1.31 g). A part of this mixture (827 mg; 2.09 mmol) was suspended in DMF (36 mL), cooled down at 0° C. and then treated with 3,3-diethoxyprop-1-yne (535 mg, 4.17 mmol), DIPEA (320 mg, 2.5 mmol) and CuI (70 mg; 0.37 mmol). The ice bath was removed and the reaction let to stir overnight at RT. The mixture was freeze-dried and the residue purified by chromatography on silica (0-5% MeOH gradient in DCM) to give a residue that was triturated with EtOAc affording ii (354 mg, 13%) 1H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1H), 8.26 (d, J=1.8 Hz, 1H), 8.10 (d, J=1.8 Hz, 1H), 5.75 (s, 1H), 5.13 (s, 2H), 4.40 (s, 2H), 3.63 (qq, J=9.6, 7.1 Hz, 4H), 3.38 (q, J=7.1 Hz, 2H), 2.55 (s, 3H), 1.18 (t, J=7.1 Hz, 6H), 1.13 (t, J=7.1 Hz, 3H).
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[NH:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.C([O-])(=O)C.[K+].[OH-].[Na+]>C(Cl)Cl>[N:17]1([CH2:16][C:12]2[NH:11][C:15]([CH:4]=[O:5])=[CH:14][CH:13]=2)[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: c1c[nH]c(CN2CCOCC2)c1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=Cc1ccc(CN2CCOCC2)[nH]1
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
To a solution of DMF (18.04 mmoles) in DCM (10 ml) there is added POCl3, dropwise, at 0° C. After stirring for 5 minutes, a solution of the compound obtained in Step A (9.02 mmoles) is added dropwise. After stirring for 3 hours at 0° C., the reaction mixture is heated at 40° C. for 30 minutes. At ambient temperature, an aqueous solution of potassium acetate (32 mmoles) is added and then the reaction mixture is stirred at 40° C. for 30 minutes. At ambient temperature, the solution is brought to alkaline pH using 2M NaOH solution and is then extracted with DCM. The organic phase is washed with water and with saturated NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness. The residue obtained is purified on silica gel (SiO2; gradient DCM/AcOEt) to yield the title product.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4](/[C:9](=[N:16]/[C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][C:18]=2[CH:26]([CH3:28])[CH3:27])/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]=1[OH:29].[Li]CCCC.Br[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[O:42][CH3:43].O>C1COCC1.[Cl-].[Cl-].[Zn+2].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:23]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH:26]([CH3:27])[CH3:28])[C:17]=1/[N:16]=[C:9](\[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[O:42][CH3:43])[C:3]=1[OH:29])([CH3:24])[CH3:25]
Reactant: Cc1cc(Br)c(O)c(/C(=N/c2c(C(C)C)cccc2C(C)C)c2ccccc2)c1
Reactant: COc1ccccc1Br
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1-c1cc(C)cc(/C(=N/c2c(C(C)C)cccc2C(C)C)c2ccccc2)c1O
Temperature: -100 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To a solution of 2.25 g (5.0 mmol) of 34 in 20 mL of THF, 4.0 mL (10.0 mmol) of 2.5 M nBuLi in hexanes was added at −80° C. This mixture was stirred for 1 hr, then cooled to −100° C. and 10.8 mL (10.8 mmol) of 1.0 M ZnCl2 in THF was added. The resulting mixture was slowly warmed to ambient temperature, stirred for 30 min, and then 2.82 g (15.0 mmol) of 2-bromoanisole and 0.14 g (0.25 mmol) of Pd(PtBu3)2 was added. This mixture was refluxed for 8 hr, then 5 mL of water was added. The resulting mixture was passed through a short layer of silica gel 60. The silica gel layer was additionally washed with 30 mL of dichloromethane. The combined organic elute was evaporated to dryness. The product was isolated by flash chromatography on silica gel 60 (40-63 um, eluent: from hexanes to hexanes-diethyl ether, 20:1, vol.) to give 0.55 g (26%) of a yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2Br)[CH:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[O:17].[F-].[Cs+].C([Sn](CCCC)(CCCC)/[CH:32]=[CH:33]/[CH2:34][OH:35])CCC>O1CCOCC1.C(#N)C.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]>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[CH:32]=[CH:33]/[CH2:34][OH:35])[CH:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[O:17]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2Br)cc1Cl
Reactant: CCCC[Sn](/C=C/CO)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cs+]
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccccc2/C=C/CO)cc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Under an atmosphere of argon, a solution of {2-chloro-4-[(2-bromophenyl)amino]phenyl}(2-methylphenyl)methanone (300 mg) (disclosed in WO 01/42189) in dioxane (1.5 mL) and a solution of P-t-Bu3 (18 mg) in dioxane (1.0 mL) were added in turn to a Schlenk tube charged with Pd2(dba)3 (21 mg) and CsF (152 mg). (2E)-3-(tributylstannyl)prop-2-en-1-ol (273 mg) was then added by syringe, and the Schlenk tube was sealed, placed in an 35–50° C. oil bath, and stirred for 48 h. The reaction mixture was then cooled to room temperature, diluted with acetonitrile, and filtered through a pad of celite. The celite was washed with acetonitrile, and the combined organic phase was then washed thoroughly with petroleum ether and concentrated in vacuo. The product was purified by flash chromatography eluting with a mixture of petroleum ether/EtOAc 4:1 to afford the title compound as a yellow syrup.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[N:8]=[CH:9][N:10]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][C:12]=3[C:20]([F:23])([F:22])[F:21])[C:6]=2[CH:5]=[CH:4][NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:55][C:56]1[CH:67]=[CH:66][C:59]2[NH:60][C:61]([C@@H:63]([NH2:65])[CH3:64])=[N:62][C:58]=2[CH:57]=1.ClCl>CS(C)=O.ClCCl.CO>[Cl:55][C:56]1[CH:67]=[CH:66][C:59]2[NH:60][C:61]([C@@H:63]([NH:65][C:15](=[O:16])[C:14]3[CH:18]=[CH:19][C:11]([N:10]4[C:6]5[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=5[N:8]=[CH:9]4)=[C:12]([C:20]([F:21])([F:22])[F:23])[CH:13]=3)[CH3:64])=[N:62][C:58]=2[CH:57]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(-n2cnc3c(=O)[nH]ccc32)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: C[C@H](NC(=O)c1ccc(-n2cnc3c(=O)[nH]ccc32)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 51 %

Procedure:
Prepared analogously to Example 1g from 4-(4-oxo-4,5-dihydroimidazo[4,5-c]pyridin-1-yl)-3-trifluoromethylbenzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in dimethylsulfoxide. Yield: 51%; Rf value: 0.16 (silica gel: dichloromethane/methanol=10:1); C23H16ClF3N6O2 (500.866); mass spectrum: (M+H)+=501/503 (chlorine isotope).
Reaction SMILES: [Li+].CCC[CH2-].[CH3:6][C:7]([OH:10])([CH3:9])[CH3:8].C[O:12][C:13](=O)[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1.[Cl-].[NH4+]>O1CCCC1>[C:7]([O:10][C:13](=[O:12])[CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Br:23])[CH:18]=1)([CH3:9])([CH3:8])[CH3:6]
Reactant: CC(C)(C)O
Reactant: COC(=O)CCCc1cccc(Br)c1
Agent: [CH2-]CCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCc1cccc(Br)c1
Reaction time: 0.17 h
Yield: 74 %

Procedure:
N-Butyllithium (4.43 mL, 11.07 mmol) was added to a solution 2-methyl-2-propanol (1.0 mL, 10.53 mmol) in tetrahydrofuran (21 mL) at −10° C. under an argon atmosphere, and the mixture was stirred for 10 minutes. A solution of 4-(3-bromophenyl)butyric acid methyl ester (1.35 g, 5.27 mmol) in tetrahydrofuran (5.3 mL) was added dropwise at −10° C., and the mixture allowed to reach room temperature and stirred for 16 hours. Saturated ammonium chloride was added and the product extracted with ethyl acetate. The extract was dried over sodium sulfate and concentrated to dryness. Purification by flash chromatography, eluting with hexane/ethyl acetate (98:2), gave 4-(3-bromophenyl)butyric acid tert-butyl ester as a yellow oil (74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1.CS(O)(=O)=O.[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C>>[CH2:1]([O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: COC1=CC(=O)NC1
Reactant: CCCCCCCCO
Agent: CS(=O)(=O)O
Product: CCCCCCCCOC1=CC(=O)NC1
Temperature: 100 °C

Procedure:
A mixture of 4-methoxy-3-pyrrolin-2-one (3 g), 1-octanol (7.4 ml) and methanesulfonic acid (0.2 g) were heated at 100° C. for 2 hours under reduced pressure (40 mbars). The product was chromatographed on silica gel, eluting with 2% methanol in methylene chloride, to give 4-octyloxy-3-pyrrolin-2-one.
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][N:30]([CH2:38][C@H:39]([OH:49])[C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-])=O)=[CH:42][CH:41]=4)[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:23][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].C(OCC)(=O)C>O.C(O)C.[Fe]>[NH2:46][C:43]1[CH:42]=[CH:41][C:40]([C@@H:39]([OH:49])[CH2:38][N:30]([CH2:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:10]3[CH:11]=[CH:12][C:13]([C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[O:15])=[C:8]([O:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:9]=3)=[CH:22][CH:23]=2)[C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc(-c2ccc(C(=O)NS(C)(=O)=O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N(CCCc1ccc(-c2ccc(C(=O)NS(C)(=O)=O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccc(N)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
A mixture of tert-butyl [3-[3′-(cyclohexyloxy)-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]propyl][(2R)-2-hydroxy-2-(4-nitrophenyl)ethyl]carbamate (200 mg), iron powder (48.2 mg) and ammonium chloride (7.7 mg) in water (1.0 ml) and ethanol (3.0 ml) was stirred 80° C. for 1 hour. After cooling to room temperature, ethyl acetate (15 ml) was added to the reaction mixture and iron powder was removed by filtration through a Celite cake. The filtrate was washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave a crude product which was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give tert-butyl [(2R)-2-(4-aminophenyl)-2-hydroxyethyl][3-[3′-[cyclohexyloxy]-4′-[[(methylsulfonyl)-amino]carbonyl]-4-biphenylyl]propyl]carbamate (129 mg) as a white solid (foam).
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.[NH2:32][C:33]1[N:38]=[C:37]([NH:39][CH2:40][CH2:41][CH2:42][N:43]2[CH:47]=[C:46]([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=3[Cl:55])[CH:45]=[C:44]2[C:56](O)=[O:57])[CH:36]=[CH:35][C:34]=1[N+:59]([O-:61])=[O:60]>CN(C=O)C>[NH2:32][C:33]1[N:38]=[C:37]([NH:39][CH2:40][CH2:41][CH2:42][N:43]2[CH:47]=[C:46]([C:48]3[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][C:49]=3[Cl:55])[CH:45]=[C:44]2[C:56]([NH:24][CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:57])[CH:36]=[CH:35][C:34]=1[N+:59]([O-:61])=[O:60]
Reactant: Nc1nc(NCCCn2cc(-c3ccc(Cl)cc3Cl)cc2C(=O)O)ccc1[N+](=O)[O-]
Reactant: NCCN1CCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NCCCn2cc(-c3ccc(Cl)cc3Cl)cc2C(=O)NCCN2CCCC2)ccc1[N+](=O)[O-]
Reaction time: 12 h
Yield: 13 %

Procedure:
Hünig's Base (2.5 eq), HOBT (1.2 eq), EDC (1.2 eq) and 1-(2-aminoethyl)pyrrolidine (1.5 eq) were added sequentially to a solution of 1-{3-[(6-amino-5-nitro(2-pyridyl))amino]propyl}-4-(2,4-dichlorophenyl)pyrrole-2-carboxylic acid (11) (1 eq) in DMF (2M) at room temperature with stirring. After 12 hours, the DMF was removed under high vacuum via a centrifugal evaporator. The residue is dissolved in EtOAc and washed with sat. aq. NaHCO3, dried (Na2SO4), filtered, and concentrated. The crude product was purified using a plug of silica eluting with 4% MeOH in CH2Cl2 to give (1-{3-[(6-amino-5-nitro(2-pyridyl))amino]propyl}-4-(2,4-dichlorophenyl)pyrrol-2-yl)-N-(2-pyrrolidinylethyl)carboxamide (12) as a yellow solid (13% yield, 96% pure).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[C:9]([NH2:14])[CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][CH:5]=1)[CH3:2].[Cl:15][C:16]1[C:21]([C:22](O)=[O:23])=[C:20]([F:25])[C:19]([CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:18][CH:17]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:15][C:16]1[C:21]([C:22]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:8]=2[N:7]=[CH:6][CH:5]=[C:4]3[O:3][CH2:1][CH3:2])=[O:23])=[C:20]([F:25])[C:19]([CH2:26][NH:27][C:28](=[O:33])[C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:18][CH:17]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: CCOc1ccnc2c(N)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1ccnc2c(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)cccc12
Yield: 23.6 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-ethoxyquinolin-8-amine (Intermediate-56, 80 mg, 0.425 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 159 mg, 0.553 mmol), oxalyl chloride (162 mg, 1.27 mmol), DMF (1 drop) and DIPEA (219 mg, 1.7 mmol) in CH2Cl2 (2 mL) to afford 46 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1H), 8.71-8.68 (m, 2H), 8.13 (t, 1H), 7.93-7.90 (dd, J=1.2, 8.4 Hz, 1H), 7.61-7.57 (t, J=8.0 Hz, 1H), 7.42-7.40 (d, J=8.4 Hz, 1H), 7.36-7.23 (t, J=8.0 Hz, 1H), 7.12-7.11 (d, J=5.2 Hz, 1H), 4.35-4.29 (m, 4H), 1.50-1.47 (t, J=7.2 Hz, 3H), 1.14 (s, 9H); MS (m/z): 458.24 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[C:26][C:27]4[CH:32]=[C:31]([CH2:33][C:34]5[C:35]([NH2:41])=[N:36][C:37]([NH2:40])=[N:38][CH:39]=5)[CH:30]=[C:29]([O:42][CH3:43])[C:28]=4[O:44][CH3:45])[CH:23]=3)[C:18](=[O:46])[C:17]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:16]2)[CH2:11][CH2:10]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OCC)C>C(Cl)Cl>[NH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([N:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[C:26][C:27]4[CH:32]=[C:31]([CH2:33][C:34]5[C:35]([NH2:41])=[N:36][C:37]([NH2:40])=[N:38][CH:39]=5)[CH:30]=[C:29]([O:42][CH3:43])[C:28]=4[O:44][CH3:45])[CH:23]=3)[C:18](=[O:46])[C:17]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:16]2)[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1cn([C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2cc(C#Cc3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)ccc2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CCOC(=O)c1cn([C@H]2CC[C@H](N)CC2)c2cc(C#Cc3cc(Cc4cnc(N)nc4N)cc(OC)c3OC)ccc2c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
16ad) A suspension of 0.415 g of ethyl 1-(trans-4-tert-butoxycarbonylamino-cyclohexyl)-7-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-4-oxo-1,4-dihydro-quinoline-3-carboxylate (Example 12t)) in 4 ml of methylene chloride and 0.4 ml of anisole is treated at 0° C. under argon with 1.9 ml of trifluoroacetic acid. The reaction mixture is warmed to room temperature and is stirred at room temperature for 4 hrs. After cooling with ice the reaction mixture is treated with 10 ml of diethyl ether. The separated crystals are filtered off under suction, washed with diethyl ether and dried. The crude product is dissolved in 50 ml of water, the resulting suspension is filtered and the filtrate is lyophilized. 0.39 g (92%) of ethyl 1-(trans-4-amino-cyclohexyl)-7-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-4-oxo-1,4-dihydro-quinoline-3-carboxylate is obtained as a beige amorphous solid. Mass spectrum (FAB): peaks inter alia at 597 (M++H, 100%), 500 (90%), 454 (92%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[Cl:16][C:17]1[C:18]([CH3:32])=[C:19]([C:30]#[N:31])[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:21][C:22]=1[CH3:23].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C>[Cl:16][C:17]1[C:18]([CH3:32])=[C:19]([C:30]#[N:31])[C:20]([N:24]2[CH2:25][CH2:26][N:27]([C:5](=[O:6])/[CH:4]=[CH:3]/[C:2]([F:9])([F:8])[F:1])[CH2:28][CH2:29]2)=[N:21][C:22]=1[CH3:23]
Reactant: Cc1nc(N2CCNCC2)c(C#N)c(C)c1Cl
Reactant: O=C(O)/C=C/C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)c(C#N)c(C)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 4.7 %

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (25 mg, 0.18 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (16 μl, 0.18 mol) and one drop of DMF were added and the resulting solution was stirred at room temperature for 10 minutes. This solution was added to a solution of 5-chloro-4,6-dimethyl-2-piperazin-1-yl-pyridine-3-carbonitrile (38 mg, 0.15 mmol) and DIPEA (79 μl, 0.45 mmol) in anhydrous DCM (2 ml) and the resulting mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and acetonitrile) to yield 2.7 mg of a solid (0.007 mmol, 5%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH2:26]([O:25][C:23]([CH2:22][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[N:15]3[CH:16]=[N:17][CH:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1)=[O:24])[CH3:27]
Reactant: Oc1ccc(C=Cc2cccc3cncn23)cc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(C=Cc2cccc3cncn23)cc1

Procedure:
A solution of 5-[2-(p-hydroxyphenyl)ethen-1-yl]imidazo[1,5-a]pyridine (2.36 g) in 10 ml of dimethylformamide is added to a slurry of 0.5 g of sodium hydride in 30 ml of dry dimethylformamide at 0° under nitrogen. After warming to room temperature ethyl bromoacetate (1.67 g) is added and the reaction is heated to 60° for 5 hours. Water (200 ml) is added and the solution is extracted with ethyl acetate. The combined organic phases are washed with water, dried over sodium sulfate and evaporated to yield 5-[2-(p-[ethoxycarbonylmethoxy]phenyl)ethen-1-yl]imidazo[1,5-a]pyridine.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]([CH:11]=[C:12]([CH3:20])[CH2:13][P:14]([O:18][CH3:19])([O:16][CH3:17])=[O:15])[CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[OH:23].[Na+].O=O>O.O1CCOCC1.[Pt].[Pt]=O>[C:1]([O:5][C:6]([NH:7][C@H:8]([CH:11]=[C:12]([CH3:20])[CH2:13][P:14]([O:16][CH3:17])([O:18][CH3:19])=[O:15])[C:9]([OH:23])=[O:10])=[O:21])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C([O-])O
Reactant: COP(=O)(CC(C)=C[C@H](CO)NC(=O)OC(C)(C)C)OC
Agent: O=[Pt]
Agent: [Pt]
Agent: O=O
Solvent: O
Solvent: C1COCCO1
Product: COP(=O)(CC(C)=C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)OC
Yield: 22.7 %

Procedure:
To a solution of 0.66 g of 8 and 0.2 g of sodium hydrogen carbonate in 20 ml of water and 2 ml of dioxane there is added a suspension of platinum prepared by hydrogenation of 313 mg of platinum oxide in 50 ml of water. In a cylindrical apparatus, oxygen is passed through the mixture from bottom to top at 55° by means of a glass frit, with vigorous stirring. The mixture is filtered and washed with water, and the filtrate is extracted five times with 100-150 ml of ethyl acetate each time. Concentration of the extracts by evaporation yields 220 mg of educt 5. 1 gof Amberlyst® 15 (strongly acidic) is added to the aqueous phase, whichis then filtered and concentrated by evaporation in vacuo at 40°. Purification as in f,a) yields 156 mg of 9. 1H-NMR (300 MHz, CDCl3): 1.43 (s, (CH3)3C); 1.96 (d, J=3 Hz, CH3 --C(4)); 2.55 and 2.71 (2 d×d, J=22 and 15, 2H--C(5)); 3.75 and 3.76(2 d, J=11, 2 OCH3); 4.97 (m, H--C(2)); 5.25-5.45 (m, NH and H--C(3)).
Reaction SMILES: C1(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:40]1([S:46]([C:49]2[CH:50]=[C:51](Br)[CH:52]=[CH:53][CH:54]=2)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[C:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][NH:66][CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]>O1CCOCC1>[C:40]1([S:46]([C:49]2[CH:50]=[C:51]([N:66]3[CH2:65][CH2:64][N:63]([C:61]([O:60][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:62])[CH2:68][CH2:67]3)[CH:52]=[CH:53][CH:54]=2)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S(=O)(c1ccccc1)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2cccc3ccccc23)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(S(=O)(=O)c3ccccc3)c2)CC1
Temperature: 100 °C
Yield: 71.2 %

Procedure:
A solution of 2 2,2′-bis(diphenylphosphino-1,1′-binaphthyl (BINAP) (62 mg, 0.1 mmol) and cesium carbonate (329 mg, 1.01 mmol) in dry dioxane (2 ml) were sonicated for 45 min, under argon. To this solution was added 3-phenylsulfonylbromobenzene (D2) (200 mg, 0.67 mmol) and 1-(tert-butyloxycarbonyl)piperazine (314 mg, 1.68 mmol) and the reaction heated at 100° C. for 18 h. The reaction mixture was evaporated in vacuo and the residue partitioned between water (50 ml) and dichbromethane (50 ml). The organic layer was washed with sat. sodium hydrogen carbonate (50 ml), 10% citric acid (50 ml), brine (50 ml) and then dried (MgSO4). Solvents evaporated in vacuo and the residue purified by column chromatography (silica gel; 0-60% ethyl acetate/petroleum ether) to give the product as a colourless oil (192 mg, 71%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:11])=[C:4]([NH2:10])[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].[CH:12]1([N:15]=[C:16]=S)[CH2:14][CH2:13]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C[N+]1(CCN=C=NC2CCCCC2)CCOCC1>N1C=CC=CC=1>[CH:12]1([NH:15][C:16]2[NH:10][C:4]3[CH:5]=[C:6]([Cl:9])[C:7]([Cl:8])=[C:2]([Cl:1])[C:3]=3[N:11]=2)[CH2:14][CH2:13]1
Reactant: S=C=NC1CC1
Reactant: Nc1cc(Cl)c(Cl)c(Cl)c1N
Agent: C[N+]1(CCN=C=NC2CCCCC2)CCOCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: c1ccncc1
Product: Clc1cc2[nH]c(NC3CC3)nc2c(Cl)c1Cl
Yield: 83.3 %

Procedure:
3,4,5-Trichloro-1,2-phenylenediamine (3.02 g, 14.28 mmol), cyclopropyl isothiocyanate (1.53 g, 15.42 mmol), 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (8.24 g, 19.45 mmol) and pyridine (55 mL) were used according to general procedure I. The product was recrystallized from 1,4-dioxane to afford 3.29 g (83%) of a white solid. MS (CI): m/z 274. Anal. Calcd for C10H8Cl3N3-(0.6 C4H8O2): C, 45.21; H, 3.92; N, 12.76. Found C, 45.37; H, 3.91; N, 12.76.