Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1([CH2:8][CH3:9])[CH2:7][NH:6]1)[CH2:2][CH2:3][CH3:4].[SH:10][C:11]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C(C)=CC=CC=1C>[CH2:1]([C:5]1([CH2:8][CH3:9])[CH:7]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:11]=2[S:10][NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(C(=O)c2ccccc2)c(S)c1
Reactant: CCCCC1(CC)CN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1cccc(C)n1
Product: CCCCC1(CC)C=C(c2ccccc2)c2ccc(OC)cc2SN1
Reaction time: 1 h
Yield: 81 %

Procedure:
The product (55.2 g) from step (i), in 2,6-lutidine (100 ml), was added to a solution of the product (118.5 g) from step (c) in 2,6-lutidine (400 ml). The reaction mixture was stirred for 1 hour and p-toluenesulfonic acid (9.0 g) was added and then refluxed with a Dean Stark trap for 17 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between 5% NaHCO3 and EtOAc. The organic layer was separated, dried and concentrated to get an oil which was chromatographed on silica gel, using hexane: EtOAc (85:15) as the eluant, to afford the title product (124.3 g) as an orange oil. 1H NMR consistent with the desired structure.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([CH:8]([CH3:10])[CH3:9])[C:5](=[O:7])[N:6]=1.N[CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]1>>[CH:8]([CH:4]1[O:3][C:2]([NH:1][CH:12]2[CH2:17][C:16]([CH3:19])([CH3:18])[NH:15][C:14]([CH3:21])([CH3:20])[CH2:13]2)=[N:6][C:5]1=[O:7])([CH3:10])[CH3:9]
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CC(C)C1OC(N)=NC1=O
Product: CC(C)C1OC(NC2CC(C)(C)NC(C)(C)C2)=NC1=O

Procedure:
Synthesis was performed from 2-amino-5-isopropyl-1,3-oxazol-4(5H)-one and 4-amino-2,2,6,6-tetramethylpiperidine according to Method G+H.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([CH3:12])[CH:4]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C)C=O.ClCCl.O1CCCC1>[CH2:19]([NH:23][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:12])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN
Reactant: Cc1cc(C#N)ccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCNC(=O)c1ccc(C#N)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.7 %

Procedure:
To a solution of 4-cyano-2-methyl-benzoic acid (1.209 g, 7.5 mmol) (Example I1) and N,N-dimethylformamide (“DMF”) (2 drops) in dichloromethane (40 ml) under an atmosphere of nitrogen was added oxalyl chloride (0.95 ml, 11.25 mmol). The reaction mixture was stirred for one hour at ambient temperature and then at 60° C. for 1.5 hours. The reaction mixture was concentrated and the residue dissolved in tetrahydrofuran (50 ml). The solution was added drop-wise to a solution of n-butylamine (1.48 mg, 15 mmol) and pyridine (1.81 ml, 22.50 mmol) in tetrahydrofuran (50 ml). The reaction mixture was stirred at ambient temperature for 4 hours. Then the reaction mixture was poured into aqueous sodium hydrogen carbonate (1M) and the mixture extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (eluent: ethyl acetate/cyclohexane 1:2) to give N-butyl-4-cyano-2-methyl-benzamide (0.92 g, 57% yield). 1H-NMR (400 MHz, CDCl3): 0.97 (3H, t), 1.42 (2H, m), 1.62 (2H, m), 2.48 (3H, s), 3.45 (2H, q), 5.73 (1H, s), 7.41 (1H, d), 7.48-7.51 (2H, m) ppm.
Reaction SMILES: [C:1]([O:6]CC)(=O)[CH:2]([CH3:4])[OH:3].[CH2:9]([CH2:11][NH2:12])[OH:10]>C(O)C>[OH:10][CH2:9][CH2:11][NH:12][C:1](=[O:6])[CH:2]([CH3:4])[OH:3]
Reactant: CCOC(=O)C(C)O
Reactant: NCCO
Solvent: CCO
Product: CC(O)C(=O)NCCO
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A mixture of 70.8 gm (0.6 mole) of ethyl lactate and 36.6 gm (0.6 mole) of ethanolamine were stirred together at 60° C. for 16 hours, and the ethanol formed was subsequently distilled off under reduced pressure. 71 gm (89% of theory) of light yellow, viscous N-(2-hydroxyethyl)-lactic acid amide of refractive index (nD20) 1.4850 were obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22]O)=[CH:17][CH:16]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].Cl.[CH3:32][NH:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:33]([CH2:34][C:35]([OH:37])=[O:36])[CH3:32])=[CH:17][CH:16]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: COCc1cc(-c2nc(-c3ccc(CCO)cc3)no2)ccc1-c1ccccc1C
Agent: Cl
Product: COCc1cc(-c2nc(-c3ccc(CCN(C)CC(=O)O)cc3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following the procedure described for Example 86 Steps 2 to 4, but starting from 2-(4-(5-(2-(methoxymethyl)-2′-methylbiphenyl-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol and tert-butyl N-methylglycinate hydrochloride to give the title compound as a white solid. LC/MS (Method B): 470.0 (M−H)−; 472.0 (M+H)+. HPLC (Method F) Rt 3.22 min (Purity: 96.8%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[NH2:13][C:14]1[CH:29]=[CH:28][CH:27]=[CH:26][C:15]=1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[O:17]>CCO>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[C:16](=[O:17])[C:15]3[C:14](=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:13]=[C:6]2[C:5]2[CH:8]=[CH:9][C:2]([CH3:1])=[C:3]([N+:10]([O-:12])=[O:11])[CH:4]=2)=[CH:20][CH:21]=1
Reactant: Cc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cc1
Solvent: CCO
Product: Cc1ccc(-c2nc3ccccc3c(=O)n2-c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Yield: 63.8 %

Procedure:
4-methyl-3-nitrobenzaldehyde (0.270 g, 1.60 mmol) and anhydrous CuCl2 (0.435 g, 3.20 mmol) were added to a solution of 2-amino-N-(4-chlorophenyl)benzamide (0.400 g, 1.60 mmol) in anhydrous EtOH (10 mL). After heating at reflux temperature for 3 hours, the reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 5% to 60% EtOAc in heptane, afforded 3-(4-chlorophenyl)-2-(4-methyl-3-nitrophenyl)quinazolin-4(3H)-one (0.400 g, 63%).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][CH:8](O)[C:7]2[CH:11]=[C:12]([Cl:14])[S:13][C:6]=2[S:5]1(=[O:16])=[O:15].C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:14][C:12]1[S:13][C:6]2[S:5](=[O:16])(=[O:15])[N:4]([CH2:3][CH2:2][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:9]=[CH:8][C:7]=2[CH:11]=1
Reactant: O=S1(=O)c2sc(Cl)cc2C(O)CN1CCBr
Reactant: C1COCCN1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S1(=O)c2sc(Cl)cc2C=CN1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of the product from Step A (0.76 g, 2.20 mmol) in tetrahydrofuran (30 mL) containing triethylamine (0.56 g, 5.5 mmol) was added methanesulfonic anhydride (0.75 g, 4.3 mmol); this mixture was stirred at room temperature for 1 hr and evaporated to dryness. The residue was dissolved in DMF (30 mL), triethylamine (1 mL) was added and the mixture heated at 150° C. for 45 min. Morpholine (3 mL, 34 mmol) was added to the reaction mixture and heating continued at the same temperature for 1 hr followed by heating at 100° C. for an additional hour. The volatiles were evaporated and the residue mixed with ethyl acetate; this mixture was washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and evaporated to an oil which was purified by column chromatography (silica, 50% ethyl acetate/hexane to ethyl acetate) to give a viscous oil (0.42 g, 58%) which was used in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][C:14]3=[O:19])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[N:27]=[CH:26][C:25](/[CH:28]=[CH:29]/[CH2:30]OC(=O)C)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CC#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([CH2:30]/[CH:29]=[CH:28]/[C:25]4[CH:26]=[N:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=4)[CH2:15][C:14]3=[O:19])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COc1ccc(/C=C/COC(C)=O)cn1
Reactant: Nc1ncnc2cc(CN3CCNCC3=O)ccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(/C=C/CN2CCN(Cc3ccc4c(N)ncnc4c3)C(=O)C2)cn1
Temperature: 80 °C
Reaction time: 0.08 h

Procedure:
Nitrogen (g) is bubbled through a solution of 1-(4-amino-quinazolin-7-ylmethyl)-piperazin-2-one (100 mg, 0.39 mmol), EXAMPLE 72, in 2 mL of CH3CN. After 5 min, acetic acid 3-(6-methoxy-pyridin-3-yl)-(E)-allyl ester (75 mg, 0.36 mmol, prepared as described in EXAMPLE 19 in 2 mL of CH3CN, palladium(II) acetate (catalytic amount), triphenylphosphine (catalytic amount), 2 mL of H2O and 0.5 mL of triethylamine are added to the solution. The mixture is heated at 80° C. for 1 hours. At this time, the mixture is cooled, filtered and concentrated in vacuo. The crude material is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 60% CH3CN/H2O (0.1% TFA) and the appropriate product fractions are combined and lyopholized to give the title compound (44 mg, 0.07 mmol) as a white solid. 1H NMR (DMSO-d6, 300 MHz) δ9.86 (s, 1H), 9.79 (s, 1H), 8.83 (s, 1H), 8.40 (d, 1H), 8.25 (s, 1H), 7.95 (d, 1H), 7.75 (s, 1H), 7.63 (d, 1H), 6.86 (d, 1H), 6.82 (d, 1H), 6.32 (dt, 1H), 4.78 (s, 2H), 3.98 (s, 2H), 3.93 (m, 2H), 3.85 (s, 3H), 3.53 (m, 4H). ESI MS, [M+H]+=405.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.C(N(CC)CC)C.[OH:15][CH2:16][C:17]1[CH2:18][S:19][C@@H:20]2[C@H:27]([NH:28][C:29](=[O:39])/[C:30](/[C:34]3[O:35][CH:36]=[CH:37][CH:38]=3)=[N:31]\[O:32][CH3:33])[C:26](=[O:40])[N:21]2[C:22]=1[C:23]([OH:25])=[O:24].[OH-].[Na+:42]>C(OC)(=O)C.O>[CH3:33][O:32]/[N:31]=[C:30](\[C:29]([NH:28][C@@H:27]1[C:26](=[O:40])[N:21]2[C:22]([C:23]([O-:25])=[O:24])=[C:17]([CH2:16][O:15][C:6]([NH2:5])=[O:7])[CH2:18][S:19][C@H:20]12)=[O:39])/[C:34]1[O:35][CH:36]=[CH:37][CH:38]=1.[Na+:42]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12)c1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.5 h

Procedure:
Chlorosulphonyl isocyanate (226 ml) was added to a solution of triethylamine (10 ml) in methyl acetate (3.8 1). The resulting clear solution was cooled to -15° and a suspension of (6R,7R)-3-hydroxymethyl-7-[(Z)-2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylic acid (763g) in methyl acetate (2.3 1), pre-cooled to -15°, was added over 10 minutes. The residual solid was rinsed in with methyl acetate (700 ml). The mixture was stirred at -5° for 30 minutes, a clear solution being obtained after 10 minutes. Water (1.2 1) at 18° was added rapidly to the reaction mixture, the temperature rising quickly to 10° and then slowly to 17°. The mixture was stirred for 60 minutes at 15° to give a thick, white suspension. Methyl acetate (3.6 l) was added followed by a steady addition of a solution of sodium hydroxide (288 g) in water (5.2 l). This gave a clear two-phase mixture at 26° with a pH of 2.35. The layers were separated and the upper, organic layer was washed with a solution of sodium chloride (600 g) in water (2 l). The two aqueous layers were washed sequentially with methyl acetate (2 l). The organic layers were bulked, stirred with Norit SX Plus charcoal (76 g) for 30 minutes and filtered through a bed of Hyflo Supercel, the bed being washed with methyl acetate (1.5 1). The filtrate and wash were combined and stirred at 20° whilst a solution of sodium 2-ethylhexanoate (338 g) in a mixture of methyl acetate (2 l) and water (40 ml) was added over 20 minutes to give a white suspension with a pH of 5.5. The suspension was stirred for 10 minutes and filtered, and the cake was washed with methyl acetate (5×1 l), sucked dry, and dried at 30° in vacuo for 24 hours to give cefuroxime sodium (851.9 g); [α]D20 +60°, (c0.5; 0.1 M pH 4.5 buffer); λmax (H2O) 273 nm (E1 cm1% 387); impurities by HPLC 2.0%.
Reaction SMILES: [CH3:1][CH:2]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:11]=2[CH:12]=[CH:13][C:14]([CH3:20])=[N:15]3)[CH2:6][CH2:5]1.[CH3:28][C:29]1[S:30][C:31]([C:35](O)=[O:36])=[C:32]([CH3:34])[N:33]=1>>[CH3:28][C:29]1[S:30][C:31]([C:35]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:21]([CH:2]([CH3:1])[CH2:3][N:4]3[CH2:5][CH2:6][N:7]([C:10]4[CH:19]=[CH:18][CH:17]=[C:16]5[C:11]=4[CH:12]=[CH:13][C:14]([CH3:20])=[N:15]5)[CH2:8][CH2:9]3)[CH:22]=2)=[O:36])=[C:32]([CH3:34])[N:33]=1
Reactant: Cc1ccc2c(N3CCN(CC(C)c4cccc(N)c4)CC3)cccc2n1
Reactant: Cc1nc(C)c(C(=O)O)s1
Product: Cc1ccc2c(N3CCN(CC(C)c4cccc(NC(=O)c5sc(C)nc5C)c4)CC3)cccc2n1
Yield: 87 %

Procedure:
The title compound was prepared in 87% yield according to the general procedure for the preparation of amides (Method C) starting from 3-{1-methyl-2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D21) and 2,4-dimethyl-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][C:28](=O)[C:29]3[CH:34]=[CH:33][C:32]([CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[CH:31][CH:30]=3)=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15].P(Cl)(Cl)(Cl)(Cl)Cl.C([BH3-])#N.[Na+]>C1C=CC=CC=1>[Br:8][C:9]1[CH:10]=[C:11]([N:16]2[C:20](=[O:21])[O:19][N:18]=[C:17]2[C:22]2[C:23]([NH:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([CH2:35][N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:33][CH:34]=3)=[N:24][O:25][N:26]=2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(Nc1nonc1-c1noc(=O)n1-c1ccc(F)c(Br)c1)c1ccc(CN2CCOCC2)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccccc1
Product: O=c1onc(-c2nonc2NCc2ccc(CN3CCOCC3)cc2)n1-c1ccc(F)c(Br)c1

Procedure:
A solution of N-{4-[4-(3-bromo-4-fluorophenyl)-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl]-1,2,5-oxadiazol-3-yl}-4-(morpholin-4-ylmethyl)benzamide trifluoroacetate (60 mg, 91 μmol) in benzene (1.8 mL) was treated with phosphorus pentachloride (76 mg, 0.36 mmol) and stirred at reflux for 2.5 h. The reaction mixture was concentrated to a residue which was diluted with ethanol (1.4 mL), treated with sodium cyanoborohydride (17 mg, 0.27 mmol), and stirred for 2 h. The reaction mixture was quenched with acetic acid (50 μL) and purified by preparative LCMS to give the intermediate, 4-(3-bromo-4-fluorophenyl)-3-(4-{[4-(morpholin-4-ylmethyl)benzyl]amino}-1,2,5-oxadiazol-3-yl)-1,2,4-oxadiazol-5(4H)-one. This material was diluted with ethanol (1 mL), treated with 2.0 M sodium hydroxide in water (0.2 mL, 4 mmol), and stirred for 45 min. The reaction mixture was purified by preparative LCMS to give the desired product (15 mg, 27%). LCMS for C21H23BrFN6O3 (M+H)+: m/z=505.0, 507.0.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.Cl>CCOC(C)=O.O1CCOCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Reactant: COc1ccc2ncnc(Cl)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2c1

Procedure:
To 1-(5-tert-butylisoxazol-3-yl)-3-(3-hydroxyphenyl)urea from Example 1A (275 mg, 1 mmol) was added 4-chloro-6-methoxyquinazoline (194 mg, 1 mmol) according to the procedure described in Example 1B Step 1. The resulting compound was dissolved in EtOAc and 4N HCl in dioxane was added. The mixture was sonicated, stirred and concentrated in vacuo to give 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-methoxyquinazolin-4-yloxy)phenyl)urea as the mono-hydrochloride (299 mg, 0.64 mmol, 64%). 1H NMR (300 MHz, DMSO-d6) δ 9.65 (s, 1H), 9.20 (s, 1H), 8.65 (s, 1H), 7.95 (d, 1H), 7.75-7.60 (m, 3H), 7.42 (t, 1H), 7.29 (d, 1H), 6.98 (d, 1H), 6.48 (s, 1H), 3.98 (s, 3H), 1.29 (s, 9H); LC-MS (ESI) m/z 434 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:7][O:6][C:5]([CH2:15][S:16][CH2:17][C:18]([N:20]2[C@@H:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][O:22][C:21]2=[O:31])=[O:19])([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[O:4][CH2:3]1.[F:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[CH:41][C:42]2[CH:56]=[CH:55][C:45]([O:46][CH2:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[CH:44][CH:43]=2)=[CH:36][CH:35]=1.C(N(C(C)C)C(C)C)C.C(O)(C)C>C(Cl)Cl.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4].Cl[Ti](Cl)(Cl)Cl.O>[CH3:1][C:2]1([CH3:32])[CH2:3][O:4][C:5]([CH2:15][S:16][C@@H:17]([C:18](=[O:19])[N:20]2[C@@H:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][O:22][C:21]2=[O:31])[C@H:41]([C:42]2[CH:56]=[CH:55][C:45]([O:46][CH2:47][C:48]([O:50][C:51]([CH3:52])([CH3:53])[CH3:54])=[O:49])=[CH:44][CH:43]=2)[NH:40][C:37]2[CH:36]=[CH:35][C:34]([F:33])=[CH:39][CH:38]=2)([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[O:6][CH2:7]1
Reactant: Cc1ccc(C2(CSCC(=O)N3C(=O)OC[C@@H]3c3ccccc3)OCC(C)(C)CO2)cc1
Reactant: CC(C)(C)OC(=O)COc1ccc(C=Nc2ccc(F)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C2(CS[C@@H](C(=O)N3C(=O)OC[C@@H]3c3ccccc3)[C@@H](Nc3ccc(F)cc3)c3ccc(OCC(=O)OC(C)(C)C)cc3)OCC(C)(C)CO2)cc1
Temperature: -30 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
Tetraisopropyl orthotitanate (0.37 ml, 1.23 mmol) was added to a solution of TiCl4 (1M in CH2Cl2, 3.3 ml, 3.3 mmol) in CH2Cl2 (50 ml) at 0° C. under inert atmosphere. The mixture was stirred for ten minutes. (4S)-3-[({[5,5-Dimethyl-2-(4-methylphenyl)-1,3-dioxan-2-yl]methyl}thio)acetyl]-4-phenyl-1,3-oxazolidin-2-one (2.0 g, 4.4 mmol) in dry CH2Cl2 (50 ml) was added dropwise over 20 minutes and the mixture was stirred for ten minutes. tert-Butyl (4-{[(4-fluorophenyl)imino]methyl}phenoxy)acetate (2.9 g, 8.8 mmol) in dry CH2Cl2 (50 ml) was added dropwise over 30 minutes. The mixture was cooled to −30° C. and stirred for 20 minutes. Ethyl diisopropyl amine (1.5 ml, 8.8 mmol) in 10 ml dry CH2Cl2 was added dropwise over ten minutes. The mixture was stirred at −30° C. for four hours. The mixture was cooled to −78° C. and isopropanol (60 ml) was added. The temperature was allowed to reach room temperature over two hours. H2O (100 ml) was added and the mixture was stirred for 20 minutes and extracted twice with diethyl ether. The combined organic layers were washed with water, dried (MgSO4) and concentrated under reduced pressure. Purification by flash-chromatography (hexane:EtOAc 5:1 then 4:1) afforded 2.55 g (74%) of the title compound as a white solid. 1H-NMR (CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.3 (s, 3H), 1.5 (s, 9H), 2.4 (s, 3H), 2.6-2.9 (m, 2H), 3.3-3.5 (m, 4H), 4.1-4.3 (m, 1H), 4.5 (s, 2H), 4.6-4.8 (m, 2H), 5.0-5.3 (s, broad, 1H), 5.2 (m, 1H), 5.7 (d, 1H), 6.4 (m, 2H), 6.6-6.8 (m, 4H), 6.9 (m, 2H), 7.1-7.4 (m, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][N:28]=[C:27]4[NH:33][C:34]([C@@H:36]3[CH2:40][CH2:39][CH2:38][N:37]3C(OC(C)(C)C)=O)=[O:35])=[CH:20][CH:19]=2)=[CH:16][N:17]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]1[NH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][N:28]=[C:27]4[NH:33][C:34]([C@@H:36]3[CH2:40][CH2:39][CH2:38][NH:37]3)=[O:35])=[CH:20][CH:19]=2)=[CH:16][N:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1n[nH]c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc12
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1n[nH]c2ccc(-c3ccc(-c4cnc([C@@H]5CCCN5)[nH]4)cc3)cc12)[C@@H]1CCCN1
Yield: 73 %

Procedure:
(S)-tert-Butyl 2-(5-(4-(2-((S)-1-(tert-butoxycarbonyl)-pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)-1H-indazol-3-ylcarbamoyl)pyrrolidine-1-carboxylate was deprotected with TFA by the method given in Step 2 of Example 11. Obtained a light yellow solid (183 mg, ca. 73%). 1H NMR (500 MHz, CD3OD) δ 8.16 (s, 1H), 7.88 (app d, J=8.2 Hz, 2H), 7.84 (s, 1H), 7.76-7.79 (m, 3H), 7.59 (d, J=8.9 Hz, 1H), 5.10 (unresolved dd, J=7.9, 8.9 Hz, 1H), 4.63 (unresolved dd, J=7.3, 8.2 Hz, 1H), 3.51-3.62 (m, 3H), 3.43-3.48 (m, 1H), 2.62-2.69 (m, 2H), 2.48-2.55 (m, 1H), 2.15-2.40 (m, 1H). LCMS: Anal. Calcd. for C25H27N7O: 441; found: 442 (M+H)+.
Reaction SMILES: [H-].[Na+].C([O:6][CH2:7][CH:8]([F:10])[F:9])(=O)C.[C:11]([O:14][CH2:15][CH3:16])(=[O:13])[CH3:12].S(=O)(=O)(O)O>O1CCCC1>[F:9][CH:8]([F:10])[C:7](=[O:6])[CH2:12][C:11]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(C)=O
Reactant: CC(=O)OCC(F)F
Agent: O=S(=O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under a nitrogen atmosphere, 46.7 g (1.168 mol) of sodium hydride (60% dispersion in paraffin) were added to 600 ml of tetrahydrofuran. A mixture of 125 g (1.008 mol) of difluoroethyl acetate and 88.7 g (1.010 mol) of ethyl acetate was added dropwise at 35° C., while the temperature was kept below 40° C. The mixture was then further stirred at room temperature overnight. The reaction mixture was carefully poured into 1.7 l of ice water and the pH adjusted to pH 3 by addition of sulphuric acid. The mixture was extracted twice, each time with 500 ml of methyl tert-butyl ether, and the combined organic phases were washed twice with saturated sodium chloride solution, dried over sodium sulphate, concentrated at 40° C. and 150 mbar and distilled at 60 mbar (Vigreux column). The product was obtained at 85-87° C. as a colourless liquid (104 g, 62% of theory with a purity of >99% (GC)).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([CH:13]=O)[CH2:9][CH2:8]1)=[O:5].[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:34]=[C:33]([NH2:35])[NH:32][N:31]=2)=[CH:26][CH:25]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@@H:10]([CH2:13][NH:35][C:33]2[NH:32][N:31]=[C:30]([C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[CH:34]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: Nc1cc(-c2ccc(F)cc2)n[nH]1
Reactant: O=C[C@H]1CC[C@@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@@H](CNc2cc(-c3ccc(F)cc3)n[nH]2)CC1)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Cis-2-Chloro-N-(4-formyl-cyclohexyl)-5-trifluoromethyl-benzamide (100 mg, 0.300 mmol) in DCM (3 mL) is added 3-(4-fluorophenyl)-1H-pyrazol-5-amine (58.4 mg, 0.330 mmol) to give a pale orange solution. This is stirred for 10 mins at room temperature before sodium triacetoxyborohydride (102 mg, 0.479 mmol) is added. The reaction mixture is stirred at room temperature for 1 hour. The reaction mixture is quenched by the addition of saturated sodium bicarbonate. The DCM layer is separated and further washed with water. The aqueous extracts are combined and re-extracted with DCM. The combined organic extracts are then dried over MgSO4, filtered and concentrated under vacuum. Purification by chromatography on a pre-packed 12 g silica gel column using 0-100% EtOAc in isohexane (gradient elution) gave the desired product as a colourless solid. [MH+495.29].