Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][N:6]([CH2:16][C:17]([O:19]C)=O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH3:15])[CH:8]=1)=[O:4].C[O-].[Na+].P([O-])([O-])([O-])=O>CO>[CH3:1][N:2]1[C:17](=[O:19])[CH2:16][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH3:15])[CH:8]=2)[NH:5][C:3]1=[O:4]
Reactant: CCCc1cccc(N(CC(=O)OC)NC(=O)NC)c1
Agent: C[O-]
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1cccc(N2CC(=O)N(C)C(=O)N2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
Methyl [2-[(methylamino)carbonyl]-1-(3-propylphenyl)hydrazino]acetate (0.5 g) was dissolved in methanol (20 ml) under nitrogen at room temperature. Solid sodium methoxide (0.24 g) was added to the solution which was then stirred at room temperature for 1 h. The reaction mixture was poured into pH 6.5 phosphate buffer solution (10 ml) and extracted with ethyl acetate (3×30 ml). The combined, dried organic phases were concentrated in vacuo and the residual oil was purified by FCC eluting with chloroform:ether (95:5) to give a solid (152 mg) which was triturated with ether to give the title compound (90 mg), m.p. 112°-115°.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH:8]1[C:17]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][C:9]=1[CH2:18][C:19]1[CH:20]=[C:21]([C@@H:25]2[O:33][C@H:32]([CH2:34][OH:35])[C@@H:30]([OH:31])[C@H:28]([OH:29])[C@H:26]2[OH:27])[CH:22]=[CH:23][CH:24]=1>N1C=CC=CC=1.C(OCC)(=O)C>[C:26]([O:27][C@@H:26]1[C@@H:28]([O:29][C:28](=[O:29])[CH3:30])[C@H:30]([O:31][C:32](=[O:33])[CH3:34])[C@@H:32]([CH2:34][O:35][C:5](=[O:7])[CH3:6])[O:33][C@H:25]1[C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][C:9]2[CH:10]=[C:11]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=[CH:12]3)[CH:8]=2)[CH:20]=1)(=[O:27])[CH3:25]
Reactant: OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC[C@H]1O[C@@H](c2cccc(Cc3cc4cccccc-4c3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 15 h

Procedure:
Acetic anhydride (0.3 ml) was added to a solution of (1S)-1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]-D-glucitol (0.24 g) in pyridine (5.0 ml) at room temperature and the mixture was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with 10% aqueous solution of hydrochloric acid, saturated aqueous solution of sodium hydrogencarbonate, and saturated brine in that order and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain (1S)-2,3,4,6-tetra-O-acetyl-1,5-anhydro-1-[3-(azulen-2-ylmethyl)phenyl]-D-glucitol (0.34 g).
Reaction SMILES: [C:1]([NH:4][NH2:5])(=[O:3])[CH3:2].[F:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[CH2:17][C:18]1[N:22]2[N:23]=[C:24]([C:27](=O)[CH3:28])[CH:25]=[CH:26][C:21]2=[N:20][CH:19]=1>>[F:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[CH2:17][C:18]1[N:22]2[N:23]=[C:24](/[C:27](=[N:5]/[NH:4][C:1](=[O:3])[CH3:2])/[CH3:28])[CH:25]=[CH:26][C:21]2=[N:20][CH:19]=1
Reactant: CC(=O)NN
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Product: CC(=O)N/N=C(\C)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 75 %

Procedure:
The title compound was prepared from acetic hydrazide and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 75% yield as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.86 (d, 1H), 8.83 (d, 1H), 8.07 (d, 1H), 7.95 (d, 1H), 7.79 (m, 2H), 7.70 (s, 1H), 7.47 (q, 1H), 4.58 (s, 2H), 2.28 (s, 3H). LCMS (method A): [MH]+=377, tR=4.83 min.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]([CH3:11])=[CH:10][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1.O>CN(C=O)C>[CH:20]1([O:1][C:2]2[C:7]3[O:8][C:9]([CH3:11])=[CH:10][C:6]=3[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: Cc1cc2c(C=O)ccc(O)c2o1
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(C=O)ccc(OC3CCCC3)c2o1
Temperature: 25 °C
Yield: 101.9 %

Procedure:
To a well stirred suspension of 7-Hydroxy-2-methylbenzo[b]furan-4-carbaldehyde (39.0 g, 0.221 moles) in DMF (200 mL) was added powdered potassium carbonate (76.0 g, 0.555 moles) and cyclopentyl bromide (43.0 g, 0.287 moles) and stirred at 70-75° C. for 4-5 hrs. The reaction mixture was then cooled to room temperature and water (1.5 L) was added to it. The organic material separated was extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water ((2×500 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave product (55.0 g) as light brown viscous oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17](O)=[O:18].[CH:20]([NH:23][NH:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:28][CH:27]=1)([CH3:22])[CH3:21].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][C:17]([N:23]([CH:20]([CH3:22])[CH3:21])[NH:24][C:25](=[O:37])[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:28][CH:27]=1)=[O:18]
Reactant: COCCOc1ccc(C(=O)NNC(C)C)cc1
Reactant: Cc1cccc(-c2ccccc2CCC(=O)O)c1C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCOc1ccc(C(=O)NN(C(=O)CCc2ccccc2-c2cccc(C)c2C)C(C)C)cc1
Yield: 15.3 %

Procedure:
A solution of 3-(2′,3′-dimethyl-biphenyl-2-yl)-propionic acid (110 mg, 0.44 mmoles) and 4-(2-methoxy-ethoxy)-benzoic acid-N′-isopropyl hydrazide (100 mg, 0.40 mmoles) in DMF (3 mL) was treated with triethylamine (0.16 mL, 1.19 mmoles), HOBT (64 mg, 0.48 mmoles) and EDCI (91 mg, 0.48 mmoles) at room temperature for 48 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed successively with water, 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with 10% ethyl acetate/hexanes to afford the product (30 mg, 16%). LC-MS m/e 489.40 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1.CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:40][C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1ccc(Cl)cc1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 1.59 g (11.5 mmol) of powdered potassium carbonate, 1.48 g (11.5 mmol) of 4-chlorophenol and 20 ml of dry dimethylformamide. is stirred at room temperature for 21 hours, then poured into 60 ml of water and extracted four times with methylene chloride. The organic extracts are washed twice with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. After chromatography on silica gel while eluting with ethyl acetate and subsequent recrystallization from ethyl acetate there is obtained p-chlorophenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 241°-242°.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][N:17]=1)[OH:15].O>CN(C)C=O>[CH2:22]([C:19]1[CH:20]=[CH:21][C:16]([CH:14]([OH:15])[CH2:13][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[N:17][CH:18]=1)[CH3:23]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCc1ccc(C(O)CBr)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 68.9 %

Procedure:
Into a solution of 9.635 kg (72.99 mol) of 4-hydroxy benzaldehyde dissolved in 50 lit. dimethylformamide was added 5.675 kg (236.45 mol) of sodium hydride in 5 lit. dimethylformamide and stirred for 15 min. To this was added 15 Kg (65.22 mol) of 2-bromo-1-(5-ethyl pyridin-2-yl)-ethanol dissolved in 500 lit dimethylformamide and stirring was continued for 1 hr. at 25 to 30° C. Reaction mixture was heated at 80 to 90° C. for 14 hr., allowed to cool to 25° C. and excess of water was added into it. Product was extracted with diethyl ether. Organic layer was dried (magnesium sulfate) and concentrated to obtain crude product, which was purified in methyl tert-butyl ether as described in example 17 to obtain 12.195 Kg (69%) pure 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde. m.p. 83° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C@@H:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[C:27]([C:30]1[N:37]2[C:33]([S:34][C:35]([Sn](CCCC)(CCCC)CCCC)=[CH:36]2)=[C:32]([C:51]([C:53]2[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=2)=[O:52])[N:31]=1)(=[O:29])[CH3:28]>>[C:27]([C:30]1[N:37]2[C:33]([S:34][C:35]([C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:25](=[O:26])[N:6]4[C:7]=3[C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[CH:36]2)=[C:32]([C:51]([C:53]2[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=2)=[O:52])[N:31]=1)(=[O:29])[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2c(C(C)=O)nc(C(=O)c3cccnc3)c2s1
Reactant: C[C@@H](O)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Product: CC(=O)c1nc(C(=O)c2cccnc2)c2sc(C3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)cn12
Yield: 24.5 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-2-[5-acetyl-7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (112 mg) was prepared in the same manner as in step a) of Example 1, except that 269 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 437 mg of 5-acetyl-7(pyridin-3-yl)carbonyl-2-(tri-n-butylstannyl)imidazo-[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[Br:19][Br-]Br>C1COCC1.N1C=CC=CC=1>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][C:12]=1[Br:19]
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(N)c(Br)c1
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a mechanically stirred solution of ethyl 4-aminobenzoate (165 g, 1 mol) in THF (1.2 L) and pyridine (200 mL) at ˜10° C. was added portionwise (˜10–20 g each time) of pyridine hydrobromide perbromide (tech. 90%, 365 g, 1.02 mol) over a period of 1 h. Internal temperature was kept at 10–15° C. After completion of addition, the mixture was stirred for 30 min, then filtered through celite and the filter cake was washed with THF (1 L). The filtrate was diluted with Et2O, washed with 0.5 M of aqueous NaHSO3 (2×, 400 mL), brine, dried (MgSO4) and concentrated. The residue contained too much H2O and therefore was dissolved in EtOAc (1 L), washed with brine, dried (MgSO4) and concentrated to give a semi-solid residue. The residue was swished with hexanes-Et2O (2:1) to yield 187 g (77%) of the title compound as a white powder. The mother liquor was evaporated and swished again to give 19 g (8%) of additional title compound as a light brown powder.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][OH:16])=[CH:10][CH:9]=2)[N:5]([C:17]2[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)[N:4]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C(Cl)Cl>[CH3:33][S:34]([O:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]([C:17]3[CH:18]=[N:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[N:4]=[C:3]([CH:2]([F:1])[F:25])[CH:7]=2)=[CH:9][CH:10]=1)(=[O:36])=[O:35]
Reactant: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(CCO)cc2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(-n2nc(C(F)F)cc2-c2ccc(CCOS(C)(=O)=O)cc2)cn1
Reaction time: 1 h

Procedure:
To a solution of 2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethanol (7.4 g) and Et3N (4.5 ml) in CH2Cl2 (75 ml) was added MsCl (2.5 ml) under ice-cooling. After stirring for 1 hour, the reaction mixture was quenched with water, separated. The aqueous layer was extracted with CH2Cl2 and combined organic layer was washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 10.5 g (quant) of 2-{4-[3-(difluoromethyl)-1-(6-methoxy-3-pyridinyl)-1-H-pyrazol-5-yl]phenyl}ethyl methanesulfonate as an oil.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](=[S:29])[NH:15][CH2:16][C:17]1[S:18][C:19]2[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([F:28])[C:20]=2[N:21]=1)C.[OH-].[Na+]>C(O)C>[F:13][C:11]1[CH:10]=[CH:9][C:8]([C:14](=[S:29])[NH:15][CH2:16][C:17]2[S:18][C:19]3[C:25]([F:26])=[CH:24][C:23]([F:27])=[C:22]([F:28])[C:20]=3[N:21]=2)=[C:7]([CH:12]=1)[O:6][CH2:5][C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)COc1cc(F)ccc1C(=S)NCc1nc2c(F)c(F)cc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)COc1cc(F)ccc1C(=S)NCc1nc2c(F)c(F)cc(F)c2s1
Reaction time: 2 h
Yield: 56.7 %

Procedure:
A suspension of {5-fluoro-2-[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiocarbamoyl]-phenoxy}-acetic acid ethyl ester (2.0 g, 4.3 mmol) in ethanol (22 mL) and treated with aq 2 N NaOH (13 mL, 26 mmol). After stirring for 2 h, the solution was concentrated in vacuo to remove most of the ethanol and acidified to pH 1 with aq 2 N HCl. The product was extracted with ethyl acetate and washed with saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated to give {5-fluoro-2-[(4,5,7-trifluoro-benzothiazol-2-ylmethyl)-thiocarbamoyl]-phenoxy}-acetic acid as an orange solid (1.05 g, 57%): mp 150° C.; Rf 0.50 (20% methanol in dichloromethane); 1H NMR (DMSO-d6 300 MHz) δ 13.76 (br s, 1 H), 7.83 (br t, J=8.0 Hz, 1 H), 7.79–7.70 (m, 1 H), 7.14 (dd, J1=11.1 Hz, J2=2.4 Hz, 1 H), 6.84 (dt, J1=8.4 Hz, J2=2.4 Hz, 1 H), 5.37 (d, J=5.7 Hz, 2 H), 4.58 (s, 2 H). ESI-LC/MS m/z calcd for C17H10F4N2O3S2: 430.4; Found 429.0 (M−1)−. Anal. calcd for C17H10F4N2O3S2: C, 47.44; H, 2.34; N, 6.51; S, 14.90. Found C, 46.72: H, 2.81: N. 5.85: S, 12.02. Ethanol and water may still have been in the sample for the analytical values to be off.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:51]=[CH:50][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)=[O:41])=[CH:38][CH:37]=1>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:37]=[CH:38][C:39]([C:40]([NH:42][CH:43]5[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]5)=[O:41])=[CH:50][CH:51]=4)=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Reactant: CN1CCC(NC(=O)c2ccc(N)cc2)CC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CC(C)O
Solvent: O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCCC3)CC(F)(F)C(=O)N4C)cc2)CC1
Yield: 55.9 %

Procedure:
A mixture of 0.0562 g (0.17 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.0485 g (0.255 mmole) of toluenesulfonic acid monohydrate, 0.0397 g (0.17 mmole) of 4-amino-N-(1-methyl-piperidin-4-yl)-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 140 degrees for 15 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to give 0.0501 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(1-methyl-piperidin-4-yl)-benzamide (I-262) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=1[F:34])[CH2:9][C:10](=[O:24])[N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][CH:19]=[C:13]2[CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[Br:36]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]([CH2:25][C:26]1[CH:31]=[C:30]([F:32])[C:29]([F:33])=[CH:28][C:27]=1[F:34])[CH2:9][C:10](=[O:24])[N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:20]([F:22])([F:21])[F:23])=[N:18][C:19]([Br:36])=[C:13]2[CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(cnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(Br)c2C1)Cc1cc(F)c(F)cc1F
Yield: 86.3 %

Procedure:
(R)-[3-Oxo-1-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamic acid tert-butyl ester 1l (20.0 g, 39.6 mmol) was dissolved in 300 mL of anhydrous ethanol under stirring, and 1-bromo-2,5-pyrrolidinedione (14.1 g, 79.2 mmol) was then added to the solution at room temperature. After stirring for an hour, potassium carbonate (10.9 g, 79.2 mmol) and di-tert-butyl dicarbonate (8.6 g, 39.6 mmol) were added to the mixture, and the mixture was stirred for an hour and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was filtered through a pad of coarse silica gel to remove potassium carbonate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-oxo-1-(2,4,5-trifluoro-benzyl)-3-(1-bromo-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl)-propyl]-carbamic acid tert-butyl ester 1m (20.0 g, yield 86%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:12]2=[O:29])=[CH:6][C:3]=1[C:4]#[N:5].Cl[CH2:31]I.C(=O)([O-])[O-].[Cs+].[Cs+].Cl>O1CCCC1>[OH:1][C:2]1[C:3]([C:4]#[N:5])=[CH:6][C:7]2[C:11]3([CH2:31][O:10][C:8]=2[CH:9]=1)[C:19]1[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=1)[N:13]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[C:12]3=[O:29]
Reactant: ClCI
Reactant: COc1ccc(CN2C(=O)C(c3cc(C#N)c(O)cc3O)c3ccccc32)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)C3(COc4cc(O)c(C#N)cc43)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 26.5 %

Procedure:
To a stirred solution of 2,4-dihydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (9.40 g, 24.3 mmol) and chloroiodomethane (4.40 mL, 60.4 mmol) in tetrahydrofuran (250 mL) was added cesium carbonate (23.8 g, 73.0 mmol) under nitrogen. The reaction mixture was stirred at ambient temperature for 20 h and 5% w/v hydrochloric acid was added. The mixture was extracted with ethyl acetate (3×200 mL). The combined organic extracts were washed with water and brine, and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography and eluted with ethyl acetate to afford 6-hydroxy-1′-(4-methoxybenzyl)-2′-oxo-1′,2′-dihydrospiro[1-benzofuran-3,3′-indole]-5-carbonitrile (2.57 g, 26%): mp 112-114° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 11.32 (s, 1H), 7.29-7.16 (m, 4H), 7.02-6.97 (m, 2H), 6.89-6.85 (m, 3H), 6.54 (s, 1H), 4.93-4.77 (m, 4H), 3.68 (s, 3H); MS (ES+) m/z 398.8 (M+1).
Reaction SMILES: [CH3:1][C:2]([C:11]1[O:15][N:14]=[C:13]([NH:16][C:17](=[O:25])OC2C=CC=CC=2)[CH:12]=1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)C(C)C)(C)C.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][N:41]=[C:40]2[O:49][C:50]1[CH:51]=[C:52]([CH:54]=[CH:55][CH:56]=1)[NH2:53]>C1COCC1>[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][N:41]=[C:40]2[O:49][C:50]1[CH:51]=[C:52]([NH:53][C:17]([NH:16][C:13]2[CH:12]=[C:11]([C:2]([CH3:1])([CH3:10])[CH2:3][N:4]3[CH2:5][CH2:6][O:7][CH2:8][CH2:9]3)[O:15][N:14]=2)=[O:25])[CH:54]=[CH:55][CH:56]=1
Reactant: CC(C)(CN1CCOCC1)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)CN5CCOCC5)on4)c3)c2cc1OC
Temperature: 25 °C
Yield: 17.9 %

Procedure:
A stirred solution of phenyl 5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-ylcarbamate (22 mg), N,N-diisopropylethylamine (12 mg, 0.093 mmol) and 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (prepared as described in Example 113A) (15 mg, 0.051 mmol) in THF (0.5 mL) was heated at 60° C. for 15 h. The reaction mixture was cooled to rt and partitioned between saturated aqueous sodium carbonate and dichloromethane. The organic layer was separated and concentrated under reduced pressure to give the crude product. Purification via preparative TLC afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(2-methyl-1-morpholinopropan-2-yl)isoxazol-3-yl)urea (5 mg, 1% over three steps) as a solid. 1H NMR (400 MHz, CDCl3) δ 9.35 (brs, 1H), 8.65 (brs, 2H), 7.66 (s, 1H), 7.57 (s, 1H), 7.29-7.41 (m, 3H), 7.01 (m, 1H), 6.10 (s, 1H), 4.09 (s, 6H), 3.63-3.66 (m, 4H), 2.40-2.70 (m, 6H), 1.32 (s, 6H); LC-MS (ESI) m/z 549 (M+H)+.
Reaction SMILES: C(O[C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1)C.[CH2:11]([Mg]Br)[CH3:12]>CCOCC.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:11]1[C:4]2([CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH2:5]2)[CH2:12]1
Reactant: CCOC1=CC(=O)CCC1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: CCOCC
Product: O=C1CCCC2(CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-ethoxycyclohex-2-enone (48.1 mL) in ether (1000 mL) was added titanium(IV) isopropoxide (110 mL) followed by addition of ethylmagnesium bromide (357 mL) at ambient temperature. The reaction mixture was stirred for 2 hours at ambient temperature and was then quenched with water (500 mL). The organic layer was separated (decanted) and the water layer was extracted with ether (3×300 mL). The combined extracts were partially concentrated to approximately 300 mL. p-Toluenesulfonic acid monohydrate (3.0 g) was added and the reaction mixture was stirred overnight at ambient temperature. The reaction mixture was then washed with saturated aqueous NaHCO3 solution, dried (MgSO4), filtered and concentrated. The concentrate was purified by fractional distillation (1st fraction b.p. 27° C. at 23 torr (not product), 2nd fraction (product) b.p. 75° C. at 8 torr).