Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3B(O)O)=[N:11][N:10]=[N:9]2)C=CC=CC=1.[CH2:34]([N:38]1[CH:42]=[C:41]([CH2:43][CH2:44][CH2:45][CH3:46])[N:40]([CH2:47][C:48]2[CH:49]=[N:50][C:51](Br)=[CH:52][CH:53]=2)[C:39]1=[O:55])[CH2:35][CH2:36][CH3:37].C(=O)([O-])[O-].[Na+].[Na+].C(O)(=O)C>C(O)C.C1(C)C=CC=CC=1>[CH2:34]([N:38]1[CH:42]=[C:41]([CH2:43][CH2:44][CH2:45][CH3:46])[N:40]([CH2:47][C:48]2[CH:49]=[N:50][C:51]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[NH:8][N:9]=[N:10][N:11]=3)=[CH:52][CH:53]=2)[C:39]1=[O:55])[CH2:35][CH2:36][CH3:37]
Reactant: CCCCc1cn(CCCC)c(=O)n1Cc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1-c1nnnn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCCc1cn(CCCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reaction time: 14 h
Yield: 43 %

Procedure:
A solution of 21.7 g (50.2 mmol) of 2-(N-triphenylmethyltetrazol-5-yl)phenylboronic acid from step 6 in 80 mL of ethanol and 130 mL of toluene was added to a mixture of 5 g (4 mmol) of tetrakis(triphenylphosphine) Pd(0), 16.75 g (45.8 mmol) of 1,4-dibutyl-1,3-dihydro-3-[(6-bromo-3-pyridinyl) methyl]-2H-imidazol-2-one from step 5, 225 mL of toluene, 100 mL of 2M sodium carbonate, and 150 mL of ethanol. The reaction mixture was heated to reflux and vigorously stirred under nitrogen for 14 h. The pH was adjusted to 6 with acetic acid and the reaction concentrated in vacuo. The product was purified by silica gel chromatography (Waters Prep-500A) using 2-propanol/methylene chloride (0-50%) followed by reverse phase chromatography (Waters Deltaprep-3000) using acetonitrile/water (30-35:70-65) (0.05% TFA). The pure fractions (by analytical HPLC) were combined, the acetonitrile removed in vacuo, and the water extracted 4 times with chloroform. The extracts were combined, dried (MgSO4), and concentrated in vacuo. Recrystallization from ethyl acetate gave 8.5 g (43%) of colorless 1,4-dibutyl-1,3-dihydro-3-[[6-[2-(1H-tetrazol-5-yl)phenyl]-3-pyridinyl]methyl]-2H-imidazol-2-one as a colorless solid: mp 170°-171° C.; NMR (CDCl3) δ 0.88 (t, J=7 Hz, 3H), 0.96 (t, J=7 Hz, 3H), 1.28-1.54 (m, 6H), 1.61-1.72 (m, 2H), 2.28 (t, J=8 Hz, 2H), 3.63 (t, J=7 Hz, 2H), 4.96 (s, 2H), 5.96 (s, 1H), 7.36 (d, J=9 Hz, 1H), 7.47-7.58 (m, 3H), 7.67 (dd, J=9 and 2 Hz, 1H), 8.06-8.13 (m, 1H), 8.52 (d, J,=2 Hz, 1H); MS (FAB) m/e (rel intensity) 432 (100), 404 (18), 237 (14), 209 (92), 180 (82); HRMS. Calc'd for M+H: 432.2512. Found: 432.2554. Anal. Calc'd for C24H29N7O: C, 66.80; H, 6.77; N, 22.72. Found: C, 66.59; H, 6.85; N, 22.57. ##STR93## Step 1: Preparation of 1,4-dipropyl-1,3-dihydro-2H-imidazol-2-one.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14]O)[C:10](=[O:16])[O:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][Cl:19])[C:10](=[O:16])[O:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(-n2oc(=O)n(CO)c2=O)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-n2oc(=O)n(CCl)c2=O)cc1

Procedure:
2-(4-Methylphenyl)-4-hydroxymethyl-1,2,4-oxadiazolidin-3,5-dione (0.03 mole) dissolved in chloroform (40 ml) and thionyl chloride (0.06 mole) dissolved in chloroform (10 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the reaction mixture is stripped of solvent under reduced pressure, leaving a residue. This residue is dissolved in toluene, and the toluene solution is stripped of solvent and unreacted starting materials to yield the desired product 2-(4-methylphenyl)-4-chloromethyl-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:18])[C:15]([OH:17])=[O:16])=[CH:5][CH:4]=1>C(O)C>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:18])[C:15]([OH:17])=[O:16])=[CH:7][CH:8]=1
Reactant: O=C(O)C(=O)CCCCCc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Product: O=C(O)C(O)CCCCCc1ccc(Cl)cc1
Reaction time: 3 h
Yield: 65 %

Procedure:
A solution of 1.84 g (48.6 mmol) of sodium hydroboride in 175 ml of ethanol is added rapidly, with stirring, to a solution of 11.25 g (44 mmol) of 7-(4-chlorophenyl)-2-oxoheptanoic acid in 175 ml of ethanol at 50° C. Then the mixture is let stand for 3 hours at room temperature, the reaction mixture is concentrated, and the residue is dissolved with water. After acidification the aqueous phase is extracted with acetic ester. The organic extracts are dried and concentrated. The residual oil is dissolved in aqueous sodium hydrogen carbonate solution, the solution is clarified with charcoal, and the oil that separates after acidification is dissolved with ether. By concentrating the dried ether solution, 7.4 g is obtained (65% of theory) of 7-(4-chlorophenyl)-2-hydroxyheptanoic acid, M.P. 78°-81° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[C:13]=2[Cl:20])[C:7]=1[NH:8][CH2:9][CH2:10]O)#[N:2].S(Cl)([Cl:23])=O>>[Cl:23][CH2:10][CH2:9][NH:8][C:7]1[N:6]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[C:13]=2[Cl:20])[N:5]=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1NCCO
Reactant: O=S(Cl)Cl
Product: N#Cc1cnn(-c2ccc(Cl)c(Cl)c2Cl)c1NCCCl

Procedure:
A solution of 4-cyano-5-(2-hydroxyethyl)amino-1-(2,3,4-trichlorophenyl)pyrazole (3.0 g; prepared as described in Example 27) in thionyl chloride (25 ml) was heated under reflux for 5 hours. The solution was evaporated under reduced pressure and the residue was dissolved in dichloromethane (100 ml). The dichloromethane solution was washed with water (2×200 ml), dried over anhydrous magnesium sulphate and evaporated to give an orange gum, whicn was chromatographed using dichloromethane as eluent. Evaporation of the eluate containing the major component gave 5-(2-chloroethyl)amino-4-cyano-1-(2,3,4-trichlorophenyl)pyrazole, m.p. 125°-128° C., in the form of a cream-coloured solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][B-](F)(F)F)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:31]1[CH:40]=[CH:39][C:38]2[CH2:37][CH2:36][CH:35]([NH:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:34]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[CH:49]=3)[C:33]=2[CH:32]=1)(=O)=O>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:45]([O:44][C:42](=[O:43])[NH:41][CH:35]1[CH2:36][CH2:37][C:38]2[C:33](=[CH:32][C:31]([CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])=[CH:40][CH:39]=2)[CH:34]1[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[C:50]([Cl:54])[CH:49]=1)[CH3:46]
Reactant: O=C(NCC[B-](F)(F)F)OCc1ccccc1
Reactant: CCOC(=O)NC1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2C1Cc1cccc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)NC1CCc2ccc(CCNC(=O)OCc3ccccc3)cc2C1Cc1cccc(Cl)c1
Yield: 75.6 %

Procedure:
A mixture of potassium (2-(benzyloxycarbonylamino)ethyl)trifluoroborate (1,130 g, 3.96 mmol), cesium carbonate (2.58 g, 7.93 mmol), 8-(3-chlorobenzyl)-7-(ethoxycarbonylamino)-5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (1.3 g, 2.64 mmol), Pd(OAc)2 (0.030 g, 0.132 mmol) and 2-dicyclohexyphosphino-2′,6′-di-1-propoxy-1,1′-biphenyl (0.130 g, 0.264 mmol) under N2 in toluene/water 3:1 (15 ml) was heated to refluxed for 13 h. The reaction was filtered, the solvent evaporated and the residue purified by chromatography to afford 1.04 g of product as colorless oil.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[C:6]1([C@H:12]([NH:14][CH:15]2[CH2:19][O:18][CH2:17][CH:16]2[OH:20])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[OH-].[K+]>ClCCl.O>[C:6]1([C@H:12]([N:14]2[CH:15]3[CH:16]([CH2:17][O:18][CH2:19]3)[O:20][CH2:2][C:3]2=[O:4])[CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: C[C@@H](NC1COCC1O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C[C@H](c1ccccc1)N1C(=O)COC2COCC21
Reaction time: 2 h
Yield: 64.1 %

Procedure:
Chloroacetyl chloride (0.88 ml, 11 mmol) was added to a solution of (3RS,4SR)-4-((1R)-1-phenyl-ethylamino)-tetrahydro-furan-3-ol (1.9 g, 9.2 mmol) and triethylamine (1.8 ml, 13 mmol) in dichloromethane (30 ml) at 0° C. and the solution was stirred for 2 hours at that temperature. The resulting mixture was poured into water and extracted with chloroform. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The crude material was dissolved into 2-propanol (30 ml) at room temperature and 85% potassium hydroxide (1.3 g, 20 mmol) was added to the resulting solution with vigorous stirring at room temperature. After 15 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography (eluent; hexane/ethyl acetate=100/0 to 3/1) to yield (3aRS,7aSR)-7-((1R)-1-Phenyl-ethyl)-tetrahydro-2,4-dioxa-7-aza-inden-6-one (1.46 g, 5.9 mmol, 64%) as colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8][N:7]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[CH2:28][CH2:27]1)=[O:25].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:14]([O:13][C:11]([C:9]1[CH:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]([CH2:23][C:24]([N:26]2[CH2:27][CH2:28][N:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:30][CH2:31]2)=[O:25])[N:8]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cc(C(=O)OCC)[nH]n1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)N2CCN(c3ccc(F)cc3)CC2)n1

Procedure:
Protocol T was followed using 1H-Pyrazole-3,5-dicarboxylic acid diethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.38 (s, 1H), 6.94-7.0 (m, 2H), 6.82-7.90 (dd, 2H), 5.54 (s, 2H), 4.36-4.42 (q, 2H), 4.26-4.32 (q, 2H), 3.60-3.80 (m, 4H), 3.02-3.20 (m, 4H), 1.22-1.42 (m, 6H). 13C NMR (400 MHz, CDCl3): 164.2, 162.2, 158.2, 157.4, 156.2, 148.5, 144.4, 134.2, 118.4, 116.2, 115.8, 114.2, 62, 61.8, 54.2, 50.6, 50.2, 45.2, 42.2, 14.6, 14.2.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([OH:12])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[C:23](=O)([O-])[O-].[Cs+].[Cs+]>CO>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C@H:7]([CH2:9][C:10]([O:12][CH3:23])=[O:11])[OH:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)[C@@H](O)CC(=O)O
Agent: [Cs+]
Solvent: CO
Product: COC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
250 mg of Z-Sta-OH(cf. stage 1.12) are dissolved in 4 ml of 90% strength methanol. 1 ml of a 20% aqueous cesium carbonate solution is added to the solution, and the solvent is then removed in a rotary evaporator. The residue is twice dissolved in 2.5 ml of DMF and each time the DMF is removed again in a rotary evaporator. The residue is dried in a high vacuum, then dissolved in 2.5 ml of DMF and 55 μl of methyl iodide are added to the solution. The whole is stirred for 18 hours at 25° C., the solvent is then removed and the residue is taken up in ethyl acetate. After extraction twice with sodium chloride solution, the organic phase is dried over sodium sulphate and concentrated by evaporation. The residue is flash-chromatographed over 55 g of silica gel (eluant: chloroform/methanol [95:5]). The product-containing fractions are combined and concentrated by evaporation, yielding Z-Sta-OMe in the form of a yellowish oil; Rf (chloroform/methanol [95:5])=0.49.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[F:20]>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:15][C:14]=1[F:20]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1ccc(Br)c(F)c1
Product: N#Cc1cc(C=O)ccc1Oc1ccc(Br)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-bromo-3-fluorophenol.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Br[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[CH3:19].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][O:15][C:13](=[O:14])[C:12]1[CH:17]=[CH:18][C:9]([N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[C:10]([CH3:19])[CH:11]=1
Reactant: OC1CCNCC1
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(N2CCC(O)CC2)c(C)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 44.2 %

Procedure:
A mixture of 4-hydroxypiperidine (2.65 g, 25.4 mmol), methyl 4-bromo-3-methylbenzoate (5.00 g, 21.8 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.37 g, 2.17 mmol), palladium acetate (0.247 g, 1.10 mmol), cesium carbonate (21.5 g, 65.3 mmol) in 1,4-dioxane (100 mL) is heated in a 350 mL pressure vessel for 18 h at 80° C. under nitrogen and then at 120° C. for 4 h. The mixture is filtered and concentrated under reduced pressure. The residue is purified on silica (120 g) using a gradient of 0 to 90% ethyl acetate in heptane to provide the title compound (2.4 g, 44%). LC-ES/MS m/z 250.2 (M+1)
Reaction SMILES: Cl.[C:2]1([CH3:19])[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[C:12]([CH2:13][NH2:14])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]2)[CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:24]=[CH:25][C:26]=1[N:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1>C(#N)C>[F:20][C:21]1[CH:22]=[C:23]([NH:32][C:33]([NH:14][CH2:13][C:12]2[N:8]([C:4]3[CH:3]=[C:2]([CH3:19])[CH:7]=[CH:6][CH:5]=3)[N:9]=[C:10]([C:15]([F:17])([F:16])[F:18])[CH:11]=2)=[O:34])[CH:24]=[CH:25][C:26]=1[N:27]1[CH2:30][CH:29]([OH:31])[CH2:28]1
Reactant: O=C(Nc1ccc(N2CC(O)C2)c(F)c1)Oc1ccccc1
Reactant: Cc1cccc(-n2nc(C(F)(F)F)cc2CN)c1
Agent: Cl
Solvent: CC#N
Product: Cc1cccc(-n2nc(C(F)(F)F)cc2CNC(=O)Nc2ccc(N3CC(O)C3)c(F)c2)c1
Yield: 59.6 %

Procedure:
To a stirred solution of (1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (75 mg, 0.257 mmol, 1.0 eq) in acetonitrile (6 mL) was added TEA (0.14 mL, 1.0 mmol, 4.0 eq) followed by phenyl 3-fluoro-4-(3-hydroxyazetidin-1-yl)phenylcarbamate (78 mg, 0.262 mmol, 1.02 eq) and stirred at reflux for 16 h. The solvent of the reaction mixture was evaporated and the residue was purified by column chromatography (EtOAc/cyclohexane (4:1) as eluent) to get 1-(3-fluoro-4-(3-hydroxyazetidin-1-yl)phenyl)-3-((1-m-tolyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)urea (71 mg, 71%).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][N:15]=1.[C:22]([Si:26](Cl)([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23].[Cl-].[NH4+]>C1COCC1.O>[Si:26]([C:18]1[C:17]([F:21])=[CH:16][N:15]=[C:14]([F:13])[C:19]=1[F:20])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27]
Reactant: Fc1cnc(F)c(F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)[Si](C)(C)c1c(F)cnc(F)c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.3 %

Procedure:
A solution of diisopropylamine (98.85 g, 136.9 mL, 976.9 mmol) in THF (1.350 L) was cooled to −65° C. n-BuLi (2.5 M in hexanes) (375.8 mL of 2.5 M, 939.4 mmol) was added dropwise via cannula over 1 h at such a rate as to maintain reaction temperature below −60° C. Once the addition was complete the cooling bath was removed and the reaction mixture was allowed to warm up to 0° C. The reaction mixture was stirred for 15 min at 0° C., then re-cooled to −78° C. 2,3,5-trifluoropyridine (100 g, 751.5 mmol) was added dropwise via cannula over 20 min at such a rate to maintain the reaction temperature below −69° C. The reaction mixture was stirred for 45 min at −78° C. during which time the solution turned orange brown. A solution of tert-butyl-chloro-dimethyl-silane (147.2 g, 976.9 mmol) in THF (150 mL) was then added via cannula over 30 min. The reaction mixture was stirred at −78° C. for 90 minutes during which time the solution darkened. Lc/Ms after this time indicated that the reaction was complete. A saturated ammonium chloride solution (300 ml) was then added and mixture was allowed to warm up to RT. The reaction mixture was diluted with water (100 ml) and extracted with EtOAc (1.5 L then 2×500 ml). The combined organics were washed with saturated NaHCO (500 ml) and brine (400 ml). The crude mixture was partially concentrated in vacuo, dried over magnesium sulfate, filtered and concentrated in vacuo to an oil. The crude was purified by flash chromatography (CombiFlash Companion XL, 1.5 kg column, 0-20% ethyl acetate in petroleum ether). This afforded the title compound as a colourless oil (136.2 g, 73%); 1H NMR (CDCl3) 0.34 (6H, s), 0.89 (9H, s), 7.73 (1H, s); MS ES(+) 248.25 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:22])[C:5](C(O)=O)=[N:6][N:7]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[CH:8]=1.C1C=CC(P([N:37]=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(CC)CC.[OH-].[Na+]>C1(C)C=CC=CC=1.CN(C=O)C>[NH2:37][C:5]1[C:4](=[O:22])[C:3]([O:2][CH3:1])=[CH:8][N:7]([C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:18]=2[N:17]=[CH:16][CH:15]=[CH:14]3)[N:6]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1cn(-c2cccc3cccnc23)nc(C(=O)O)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cn(-c2cccc3cccnc23)nc(N)c1=O
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 20.5 %

Procedure:
A mixture of 5-methoxy-4-oxo-1-quinolin-8-yl-1,4-dihydropyridazine-3-carboxylic acid (2.59 g, 8.71 mmol), DPPA (2.81 mL, 13.1 mmol) and Et3N (1.82 mL, 13.1 mmol) in toluene (26 mL) was heated to reflux for 1 h. To the suspension were added DMF (52 mL), DPPA (2.81 mL, 13.1 mmol) and Et3N (1.82 mL, 13.1 mmol) at room temperature. The mixture was heated to 100° C. for 1.5 h. To the mixture was added 8 M NaOH aqueous solution (10.9 mL) at 0° C. The mixture was stirred at room temperature for 1.5 h, extracted with EtOAc, dried over Na2SO4, filtered, concentrated in vacuo, purified by column chromatography on basic silica gel (hexane/EtOAc=50/50 to 0/100 and EtOAc/MeOH=100/0 to 80/20) and on silica gel (EtOAc/MeOH=100/0 to 50/50) and triturated with EtOAc/hexane to yield the title compound (479 mg, 20% yield) as a pale yellow solid: 1H NMR (DMSO-d6, 300 MHz): δ ppm 3.75 (3H, s), 6.11 (2H, s), 7.67 (1H, dd, J=8.5, 4.4 Hz), 7.72-7.80 (1H, m), 7.99 (1H, dd, J=7.6, 1.5 Hz), 8.12 (1H, dd, J=8.3, 1.1 Hz), 8.48-8.61 (2H, m), 8.99 (1H, dd, J=4.4, 1.7 Hz).
Reaction SMILES: N12CCCN=C1CCCCC2.[C:12]([O:16][C:17]([N:19]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH:21]=[C:20]1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]#[C:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][C:43]=2[NH:44][C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:31][C:30]1=[O:52])=[O:18])([CH3:15])([CH3:14])[CH3:13]>CC#N>[C:12]([O:16][C:17]([N:19]1[C:27]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2[CH:21]=[C:20]1[CH2:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[N:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[C:43]3[CH:42]=[CH:41][N:40]=[CH:39][C:38]=3[CH:37]=2)[CH2:31][C:30]1=[O:52])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C#CCN1CCN(Cc2cc3cnccc3n2C(=O)OC(C)(C)C)C(=O)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)n1c(CN2CCN(Cc3cc4cnccc4n3C(=O)OC(C)(C)C)C(=O)C2)cc2cnccc21
Temperature: 50 °C
Reaction time: 4 h
Yield: 108.3 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (42 mg, 0.27 mmol) is added to a suspension containing 2-{4-[3-(4-tert-butoxycarbonylamino-pyridin-3-yl)-prop-2-ynyl]-2-oxo-piperazin-1-ylmethyl}-pyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester (77 mg, 0.14 mmol) in anhydrous CH3CN (10 mL) and the mixture is warmed to 50° C. After 4 h, the reaction mixture is concentrated to dryness and the residue is partitioned between CH2Cl2 (50 mL) and water (50 mL) and the layers are separated. The aqueous layer is extracted twice with CH2Cl2 (25 mL) and the combined organic phase is washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to provide 85 mg of the title compound as a crude solid which is used directly without further purification. 1H NMR (300 MHz, CDCl3) δ1.68 (s, 9H), 1.70 (s, 9H), 2.91 (m, 2H), 3.41 (s, 2H), 3.49 (m, 2H), 4.26 (s, 2H), 4.95 (d, J=1.1 Hz, 2H), 6.39 (d, J=0.7 Hz, 1H), (d, J=0.7 Hz, 1H), 7.86 (m, 1H), 8.41 (m, 1H), 8.76 (br s, 1H), 8.82 (br s, 1H) ppm; MS (EI): m/z 561 (M+H).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[NH:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[CH:15][CH:14]=3)[N:10]=[C:9]([NH:30][CH:31]3[CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:33]1[CH2:32][CH:31]([NH:30][C:9]2[N:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[N:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[O:29])=[CH:17][CH:18]=3)[N:10]=2)[CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CC(Nc2nc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)nc(N3CCOCC3)n2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(-c2nc(NC3CNC3)nc(N3CCOCC3)n2)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of tert-butyl 3-[(4-morpholin-4-yl-6-{4-[(4-fluoro-phenylcarbamoyl)amino]phenyl}-1,3,5-triazin-2-yl)amino]azetidine-1-carboxylate 30 mg (0.053 mmoles) in DCM, (20 ml) TFA (1.5 ml) was added at room temperature and stirred for 24 hours. At the end, reaction mixture was concentrated and purified by Gilson HPLC, using ACN/water and TFA. Yield: 20 (83%); (M+H) 465.5.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(-c4ccccc4F)ccc3NC(=O)OC(C)(C)C)c2)on1
Yield: 80.4 %

Procedure:
Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G37) (151 mg, 0.5 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butyl ester (Example H14) (190 mg, 0.63 mmol) according to the general procedure K. Obtained as a white solid (213 mg).