Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([N:6]1[C:11](=[O:12])[N:10]([CH2:13][CH:14]2[O:16][CH2:15]2)[C:8](=[O:9])[N:7]1[CH2:17][CH:18]1[O:20][CH2:19]1)[CH:3]1[O:5][CH2:4]1>[Cl-].[Na+]>[CH2:2]([N:6]1[C:11](=[O:12])[N:10]([CH2:13][CH:14]([OH:16])[CH2:15][Cl:1])[C:8](=[O:9])[N:7]1[CH2:17][CH:18]1[O:20][CH2:19]1)[CH:3]1[O:5][CH2:4]1
Reactant: Cl
Reactant: O=c1n(CC2CO2)c(=O)n(CC2CO2)n1CC1CO1
Agent: [Cl-]
Agent: [Na+]
Product: O=c1n(CC(O)CCl)c(=O)n(CC2CO2)n1CC1CO1

Procedure:
A total of 36.5 g of 10% hydrochloric acid was added dropwise at 40° C. to a solution of 26.9 g (0.1 mole) of 1,2,4-triglycidyl urazole (TGU) in 700 ml of 10% aqueous sodium chloride solution so slowly that the pH-value could be kept constant at pH 5. The addition was over after about 70 minutes. Thereafter the reaction mixture was extracted 4 times with 250 ml of methylene chloride and the methylene chloride distilled off.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][C:8]=2[O:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:3]=1.[CH3:21][C:22]1[CH:23]=[N:24][NH:25][CH:26]=1.CN[C@@H]1CCCC[C@H]1NC.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.[Cu]I>[CH3:21][C:22]1[CH:23]=[N:24][N:25]([C:2]2[S:10][C:9]3[C:4](=[N:5][CH:6]=[CH:7][C:8]=3[O:11][C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)[CH:3]=2)[CH:26]=1
Reactant: Cc1cn[nH]c1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(Br)sc23)cc1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cnn(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4)c3s2)c1
Yield: 29.3 %

Procedure:
A mixture of 197 (300 mg, 0.86 mmol, scheme 42), 4-methyl-1H-pyrazole (69 mg, 0.86 mmol), CuI (16.4 mg, 0.086 mmol), trans-N1,N2-dimethylcyclohexane-1,2-diamine (24.4 mg, 0.172 mmol) [J. C. Antilla, A. Klapars, et. al. JACS, 2002, 124, 11684-1688] and K2CO3 (238 mg, 1.72 mmol) in toluene (1.7 mL) was stirred at room temperature in an atmosphere of nitrogen overnight, diluted with EtOAc (100 mL), filtered through a Celite® pad, and concentrated under reduced pressure. The residue was purified by flash chromatography with gradient elution with EtOAc/hexane (1:1) to EtOAc/hexane (2:1) to afford title compound 256 (88.8 mg, 37% yield) as a white solid. MS (m/z): 352.06 (M+1).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:30][CH2:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)=[O:33].CO>CN(C)C=O.O.C(O)C>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]([NH:10][CH2:11][C:12]([NH:30][CH2:31][C:32]([NH:34][C:35]1[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=1)=[O:33])=[O:14])=[O:9]
Reactant: NCC(=O)Nc1ccncc1
Reactant: O=C(O)CNC(=O)CN1CCCC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: CCO
Solvent: O
Product: O=C(CNC(=O)CN1CCCC1=O)NCC(=O)Nc1ccncc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
9.01 g of N-[(2-oxo-1-pyrrolidinyl)acetyl]glycine was dissolved in 160 ml of dimethylformamide and the solution was cooled to -13° C., to which 10.32 g of dicyclohexylcarbodiimide dissolved in 15 ml of dimethylformamide was added at -13° to -10° C. After stirring at -10° C. for 30 minutes, 4.53 g of 4-(glycylamino)pyridine was added at -10° to -8° C., which was stirred at -10° to -5° C. for 2 hours and 200 ml of methanol was added while maintaining the temperature at -5° to 0° C. The reaction liquid was allowed to stand so as to rise its temperature to room temperature over 2 hours and then methanol was distilled off under reduced pressure and the precipitated crystal was filtered off. This crystal was extracted with 20 ml of methanol and 100 ml of water, the insoluble matter was filtered off and the filtrate was concentrated to about 15 ml, to which 150 ml of ethanol was added and again the solution was concentrated to about 30 ml, allowed to stand and filterd to obtain 8.1 g of the crude crystal. This was dissolved in 20 ml of water and 200 ml of ethanol with warming and the resultant solution was concentrated to about 40 ml and allowed to stand and the crystal was filterd to obtain the titled compound.
Reaction SMILES: [ClH:1].[CH2:2]1[C:9]2([C:10]([OH:12])=O)[N:5]([CH2:6][CH2:7][CH2:8]2)[CH2:4][CH2:3]1.S(Cl)([Cl:15])=O>>[ClH:15].[CH2:2]1[C:9]2([C:10]([Cl:1])=[O:12])[N:5]([CH2:6][CH2:7][CH2:8]2)[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C12CCCN1CCC2
Agent: Cl
Product: O=C(Cl)C12CCCN1CCC2
Reaction time: 17 h
Yield: 95.6 %

Procedure:
A mixture of pyrrolizidine-7a-carboxylic acid hydrochloride (24.6 g, 0.128 mol, prepared as described in Reference Example 2) and thionylchloride (280 ml, 3.89 mol) was stirred for 17 hours at 20° to 25° C. and the excess of thionylchloride was evaporated in vacuo to give 25.7g (95.9%) of the desired compound, as yellowish solids.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:18](=[O:19])[N:17]2[C@H:20]([C:24]([O:26]C(C)(C)C)=[O:25])[CH2:21][CH2:22][CH2:23][N:16]2[C:15](=[O:31])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:18](=[O:19])[N:17]2[C@H:20]([C:24]([OH:26])=[O:25])[CH2:21][CH2:22][CH2:23][N:16]2[C:15](=[O:31])[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)OCc3ccccc3)C(=O)N12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@H]1CCC(=O)N2CCC[C@@H](C(=O)O)N2C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a 10 mL round-bottomed flask, (1S,9S)-tert-butyl 9-(benzyloxycarbonylamino)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (1.3 g, 3.01 mmol) was combined with CH2Cl2 (5 ml) to give a colorless solution. TFA (3.53 g, 2.38 ml, 31.0 mmol) was added and stirred at room temperature for 5 hr. The crude reaction mixture was concentrated in vacuo and redissolved in EtOAc (10 ml). It was evaporated to afford (1S,9S)-9-(benzyloxycarbonylamino)-6,10-dioxooctahydro-1H-pyridazino[1,2-a][1,2]diazepine-1-carboxylic acid as a foaming solid (1.0 g, 88.4%).
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]3[CH2:18][C@H:17]([O:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:16][NH:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:34](Cl)(=[O:36])[CH3:35]>C1COCC1.C([O-])(O)=O.[Na+]>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C@@H:14]3[CH2:18][C@H:17]([O:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH2:16][N:15]3[C:34](=[O:36])[CH3:35])=[O:13])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CC(=O)Cl
Reactant: O=C([C@@H]1C[C@H](Oc2ccc(F)cc2)CN1)N1CCCN(C2CCC2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1C[C@@H](Oc2ccc(F)cc2)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Reaction time: 48 h
Yield: 20.1 %

Procedure:
To a solution of (2S,4S)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(4-fluoro-phenoxy)-pyrrolidine (102 mg, 0.85 mmol) and Et3N (0.197 mL) in THF (2.82 mL) was added acetyl chloride (60 μL, 0.85 mmol). After 48 h, the mixture was diluted with saturated (satd.) aq. NaHCO3 and extracted with CH2Cl2 (3×). The combined organic layers were dried and evaporated. The residue was purified by FCC, followed by reverse phase HPLC (5-99% CH3CN/20 mM NH4OH) to give the desired product (69 mg, 61%). MS (ESI): mass calcd. for C22H30FN3O3, 403.23; m/z found, 404.3 [M+H]+. 1H NMR (CDCl3): 7.02-6.92 (m, 2H), 6.87-6.77 (m, 2H), 4.92-4.79 (m, 2H), 4.12-3.96 (m, 1H), 3.84-3.47 (m, 5H), 2.92-2.77 (m, 1H), 2.66-2.51 (m, 2H), 2.50-2.41 (m, 2H), 2.39-2.30 (m, 1H), 2.22-2.12 (m, 1H), 2.10 (d, J=2.1 Hz, 3H), 2.07-1.98 (m, 2H), 1.92-1.72 (m, 4H), 1.71-1.54 (m, 2H).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22]CC)[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18])[CH3:2].C(O)CO.C1(C)C(S(O)(=O)=O)=CC=CC=1>C(OCC)(=O)C>[CH2:1]([N:3]([CH2:20][CH:21]1[O:22][CH2:27][CH2:26][O:25]1)[C:4]1[C:5]([N+:17]([O-:19])=[O:18])=[CH:6][C:7]([C:13]([F:14])([F:16])[F:15])=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CCOC(CN(CC)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])OCC
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: OCCO
Solvent: CCOC(C)=O
Product: CCN(CC1OCCO1)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 110 °C

Procedure:
N-Ethyl-N-(2,2-diethoxyethyl)-2,6-dinitro-4-trifluoromethylaniline (6.10 grams; 0.0154 mole), ethylene glycol (0.96 grams; 0.0154 mole) and toluenesulfonic acid (200 mg) were charged into a glass reaction vessel equipped with stirrer and thermometer. The reaction mixture was heated at 110° C. for a period of 2 hours. After this time the mixture was cooled to room temperature, dissolved in ethyl acetate and washed with water and saturated aqueous sodium bicarbonate. The washed product was then dried and stripped of solvent to yield the desired product N-ethyl-N-1,3-dioxolan-2-ylmethyl-2,6-dinitro-4-trifluoromethylaniline as an oil.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])([CH3:8])([CH3:7])[CH3:6]>S(=O)(=O)(O)O>[C:5]([C:9]1[CH:10]=[C:11]([N+:1]([O-:4])=[O:2])[C:12]([O:18][CH3:19])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15])([CH3:8])([CH3:6])[CH3:7]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C(C)(C)C)cc1C(=O)O
Agent: O=S(=O)(O)O
Product: COc1c(C(=O)O)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2.3 ml 65% nitric acid and 2.6 ml 96% sulphuric acid is added dropwise to an ice-cooled solution of 5.00 g 5-tert-butyl-2-methoxy-benzoic acid in 15 ml 96% sulphuric acid. The solution is stirred for 1.5 h in the cooling bath and then for 1 h at ambient temperature. Then the solution is added to ice water, and the precipitate formed is filtered off and taken up in dichloromethane. The dichloromethane phase is dried (Na2SO4), and the solvent is eliminated completely.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.C([O-])([O-])=O.[K+].[K+].[CH2:18]([NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:19]([CH3:21])[CH3:20]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CC(C)CNCC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)CN(CC(C)C)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Yield: 29.8 %

Procedure:
To a solution of 3,4-difluoronitrobenzene (1.59 g, 10 mmol) in DMSO (15 mL) were added K2CO3 (3.04 g, 22 mmol) and diisobutylamine (1.42 g, 11 mmol). The mixture was heated at 90° C. overnight, then cooled to rt, diluted with water (50 mL) and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as pale yellow oil (0.80 g, 30%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][N:33]=[C:34]=[O:35]>CCCCCC>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:34]([NH:33][CH3:32])=[O:35])[NH:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCNCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CN=C=O
Solvent: CCCCCC
Product: CCCCCCCN(CCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)C(=O)NC
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.1 %

Procedure:
To a solution of N-[5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentyl]-1-heptanamine (0.30 g, 0.0007 mol) in hexane (15 mL) was added methylisocyanate (0.06 mL, 0.057 g, 0.001 mol) and the reaction mixture was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated under vacuum and the residue was chromatographed with 1:1 hexane-ethyl acetate. The resulting oil was triturated with hexane to give the title compound (0.23 g, 0.00047 mol) as a white solid, mp 93°-96°. 1H NMR (CDCl3) δ7.6-7.2(m,11H), 4.35-2.7(m,9H), 1.9-1.2(m,16H), 0.9(t,3H,J=8Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[N:40]1([C:46](=[O:48])[CH3:47])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:26])([F:28])[F:27])=[N:20][C:21]([C:22]([N:43]3[CH2:44][CH2:45][N:40]([C:46](=[O:48])[CH3:47])[CH2:41][CH2:42]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CC(=O)N1CCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C(=O)c2nc(C(F)(F)F)n3c2CN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)CC3)CC1
Yield: 44.9 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), 1-piperazin-1-yl-ethanone hydrochloride (90 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(4-acetyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 17a (80 mg, yield 45%) as a white solid.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6]1[CH:11]=[C:10](/[CH:12]=[C:13](\[CH2:19][CH3:20])/[C:14]([O:16]CC)=[O:15])[CH:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:38])[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:29])[CH:22]=1)[CH3:4]>C(O)C>[CH2:3]([O:5][C:6]1[CH:11]=[C:10](/[CH:12]=[C:13](\[CH2:19][CH3:20])/[C:14]([OH:16])=[O:15])[CH:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:38])[C:28]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:29])[CH:22]=1)[CH3:4]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)OCC)cc2OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\CC)C(=O)O)cc2OCC)c1
Temperature: 50 °C
Yield: 73.2 %

Procedure:
249 mg (6.2 mmol) of sodium hydroxide are added to a solution of 616 mg (0.65 mmol) of ethyl 2-[1-[2-ethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]meth-(E)-ylidene]butyrate in 15 mL of ethanol. The reaction mixture is heated at 50° C. for 3 hours. The reaction medium is evaporated to dryness, taken up in water and extracted with ethyl acetate. The aqueous phase is acidified with aqueous 2 N hydrochloric acid solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and the oil obtained is purified by chromatography on a column of silica eluted with a 50/50 heptane/ethyl acetate mixture. 222 mg (77%) of 2-[1-[2-ethoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]meth-(E)-ylidene]butyric acid are obtained in the form of a yellowish oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][CH:19]=[N:20]4)[N:11]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C1COCC1>CC(O)=O>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH2:17][CH2:18][CH2:19][NH:20]4)[N:11]=2)=[CH:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(-c2nc(-c3cccc4ncccc34)no2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCc1ccc(-c2nc(-c3cccc4c3CCCN4)no2)cc1
Yield: 48.6 %

Procedure:
To a solution of the product of Step C (0.069 g; 0.219 mmol) in AcOH (1 ml) and anhydrous THF (1.5 ml) NaBH3CN (3×0.07 g; 3.34 mmol) was added portion wise over a period of 2 h, while the temperature of the reaction mixture was kept <15° C. The solvents were removed in vacuo and the residue was diluted to 15 ml with EtOAc, washed with 5% NaOH, H2O, brine, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness under reduced pressure. The residue was dissolved in a mixture of CF3CO2H and EtOH (2 ml+2 ml), refluxed for 1 h and re evaporated. The residue was treated with NH4OH saturated CH2Cl2 (5 ml) and evaporated under reduced pressure. The residue was purified by FCC (SiO2, CH2Cl2) to give the title compound (0.034 g; 48%), as colourless solid. 1H-NMR (CDCl3) 0.95 (tr, 3H, J=7.4 Hz); 1.61-1.75 (m, 2H); 1.91-2.0 (m, 2H); 2.66 (tr, 2H, J=7.8 Hz); 3.09 (tr, 2H, J=6.5 Hz); 3.29-3.33 (m, 2H); 3.8 (broad s, 1H); 6.6 (dd, 1H, J=1, 8 Hz); 7.07 (tr, 1H, J=7.9 Hz); 7.3-7.35 (m, 3H); 8.1 (d, 2H, J=8.3 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:25]4[N:24]([CH3:23])[CH:28]=[CH:27][CH:26]=4)[CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cn1cccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
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: COCCOC
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3cccn3C)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1-methyl-2-pyrroleboronic acid pinacol ester (96.8 mg, 0.56 mmol) and K2CO3 (116 mg, 0.84 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.014 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(1-methyl-1H-pyrrol-2-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) d (ppm): 7.61 (dd, 1H), 7.57 (d, 1H), 7.4 (s, 1H), 7.37 (m, 2H), 7.17 (d, 1H), 7.07 (d, 1H), 6.8 (d, 1H), 6.21 (d, 1H), 6.1 (dd, 1H), 4.76 (m, 1H), 4.4 (m, 1H), 3.8 (m, 1H), 3.7 (m, 3H), 3.57 (m, 1H), 3.2 (m, 4H), 3.03 (m, 1H), 2.42 (s, 3H).
Reaction SMILES: [CH2:1]([O:5][CH:6]([C:8]1[C:16]2[C:15]([NH:17][CH:18]3[CH2:20][CH2:19]3)=[N:14][C:13]([NH:21][C:22]3[CH:30]=[C:29]4[C:25]([CH:26]=[N:27][NH:28]4)=[CH:24][CH:23]=3)=[N:12][C:11]=2[N:10](S(C2C=CC(C)=CC=2)(=O)=O)[CH:9]=1)[CH3:7])[CH2:2][CH2:3][CH3:4].[OH-].[K+]>O1CCOCC1>[CH2:1]([O:5][CH:6]([C:8]1[C:16]2[C:15]([NH:17][CH:18]3[CH2:19][CH2:20]3)=[N:14][C:13]([NH:21][C:22]3[CH:30]=[C:29]4[C:25]([CH:26]=[N:27][NH:28]4)=[CH:24][CH:23]=3)=[N:12][C:11]=2[NH:10][CH:9]=1)[CH3:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(C)c1cn(S(=O)(=O)c2ccc(C)cc2)c2nc(Nc3ccc4cn[nH]c4c3)nc(NC3CC3)c12
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCOC(C)c1c[nH]c2nc(Nc3ccc4cn[nH]c4c3)nc(NC3CC3)c12
Temperature: 65 °C
Reaction time: 18 h
Yield: 20.6 %

Procedure:
To a solution of 5-(1-butoxyethyl)-N4-cyclopropyl-N2-(1H-indazol-6-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (20 mg, 0.036 mmol) in dioxane (2 mL), aq. 1N KOH (1.0 mL, 1.0 mmol) was added. The mixture was stirred at 65° C. for 18 h. After being concentrated in vacuo, the residue was acidified with HOAc (1 mL); it was then purified by HPLC to give the titled compound (3 mg). MS 406.2 (M+H); UV 203.8, 223.8, 243.8, 315.0 nm.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[C:6][C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1)([CH3:4])[CH3:3].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.Br[CH:30]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC#N.Cl[Si](C)(C)C>[CH:30]([N:11]1[CH:12]=[C:7]([C:6]#[C:5][Si:2]([CH3:3])([CH3:4])[CH3:1])[C:8](=[O:14])[NH:9][C:10]1=[O:13])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: C[Si](C)(C)C#Cc1c[nH]c(=O)[nH]c1=O
Agent: C[Si](C)(C)Cl
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1cn(C(c2ccccc2)c2ccccc2)c(=O)[nH]c1=O
Temperature: 25 °C

Procedure:
2.09 g (10 mmol) 5-TMSU (5-trimethylsilanylethynyluracil) dried over P4O10 are suspended in about 50 mL absolute MeCN, then 6 mL (25 mmol) BSA and a few drops of chlorotrimethylsilane are added via a septum, and the suspension is stirred at room temperature under argon until it is completely clear. Then 2.72 g (11 mmol) 1-bromodiphenylmethane are added to the resulting solution. The batch is now stirred for 24 h on an oil bath under exclusion from moisture at 84° C. The dark brown solution is concentrated and left to stand in the ice bath. The brown raw product that precipitates is separated, washed with a little cold MeCN, and recrystallized from about 50 mL MeCN.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:17])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH2:15][OH:16].[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:23]Br>CCCCCC.CN(C)C=O>[F:18][C:19]([F:32])([F:33])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=1)[CH2:23][O:16][CH2:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:17]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1-c1ccncc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1ccccc1-c1ccncc1COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Sodium hydride (89.1 mg, 2.04 mmol, 1.1 eq) was washed twice with n-hexane under argon and suspended in 1 ml dimethyl formamide. (4-o-Tolyl-pyridin-3-yl)-methanol (370 mg, 1.86 mmol), dissolved in 4 ml dimethyl formamide, was added dropwise and the mixture was stirred lh at room temperature. 3,5-Bis(trifluoromethyl)benzyl bromide (627 mg, 2.04 mmol, 1 eq), dissolved in 2 ml dimethyl formamide, was added and the mixture was stirred 2.5 h at room temperature.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CN(C)C=O.[OH:19][C@H:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25]>O>[Si:6]([O:19][C@H:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: O=C1NCC[C@@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.2 %

Procedure:
In an ice bath, 570 mg of imidazole and 947 mg of t-butyldimethylsilyl chloride were added to a dimethylformamide (5 ml) solution of 503 mg of (3S)-3-hydroxypyrrolidin-2-one, and stirred at room temperature for 1 hour. Water was added to the reaction liquid, extracted with ethyl acetate, the organic layer was washed with water and saturated saline water, and dried. The solvent was evaporated away under reduced pressure to obtain 452 mg of the entitled compound as a pale yellow oil.