Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23](=O)[CH2:24][N:25]5[C:29]([CH3:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[N:26]5)[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:37]>N1C=CC=CC=1>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23](=[S:37])[CH2:24][N:25]5[C:29]([CH3:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[N:26]5)[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: Cc1cc(C(F)(F)F)nn1CC(=S)N1CCC(c2nc(C3=NOC(c4ccccc4)C3)cs2)CC1

Procedure:
A solution of 4-[4-[4,5-dihydro-5-phenyl-3-isoxazolyl]-2-thiazolyl]-1-[[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl]piperidine (i.e. the product of Example 1, Step B) (235 mg, 0.47 mmol) and phosphorus pentasulfide (104.5 mg, 0.235 mmol) in pyridine (5 ml) was heated under reflux for 2 h. The reaction mixture was then concentrated under reduced pressure, and the residue was distributed between dichloromethane (10 mL) and water (10 mL). The organic layer was washed with 1 N hydrochloric acid, water, saturated aqueous sodium bicarbonate solution and brine, dried (MgSO4), and concentrated under reduced pressure to give 240 mg of the title product, a compound of the present invention, as a white foam.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:20]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)=[CH:21][CH:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].N>C(O)C.O1CCCC1>[CH:22]1([CH:21]=[C:20]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([OH:36])([CH3:34])[CH3:35])=[CH:29][CH:28]=2)[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([F:19])[CH:18]=[C:13]3[CH:12]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cc(F)cnc3[nH]2)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
To a solution of 2-{4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-propan-2-ol (220 mg, 0.43 mmol) in ethanol (20 mL) and tetrahydrofuran (10 mL) was added an aqueous sodium hydroxide solution (10%, 3.0 mL) and an aqueous saturated ammonia solution (1.5 mL). The mixture was refluxed for 12 h, cooled to room temperature, extracted with ethyl acetate, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{4-[2-cyclopentyl-1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-propan-2-ol (150 mg, 94%) which was used in the next step without purification: LC/MS m/e calcd for C23H25FN2O [M+H]+ 365.47, observed 365.3.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6](Cl)[C:7]=1[NH:8][C:9]([C:11]1[C:19]2[C:18]3[CH:20]=[C:21]([NH:24][C:25](=[O:27])[CH3:26])[CH:22]=[CH:23][C:17]=3[O:16][C:15]=2[C:14]([O:28][CH3:29])=[CH:13][CH:12]=1)=[O:10].[OH-].[NH4+]>C1COCC1.[Pd]>[N:4]1[CH:3]=[CH:2][C:7]([NH:8][C:9]([C:11]2[C:19]3[C:18]4[CH:20]=[C:21]([NH:24][C:25](=[O:27])[CH3:26])[CH:22]=[CH:23][C:17]=4[O:16][C:15]=3[C:14]([O:28][CH3:29])=[CH:13][CH:12]=2)=[O:10])=[CH:6][CH:5]=1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1oc1ccc(NC(C)=O)cc12
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccncc2)c2c1oc1ccc(NC(C)=O)cc12
Yield: 41.4 %

Procedure:
A solution of N-(3,5-dichloropyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide (60 mg) (Example 4) and 25–28% aqueous ammonium hydroxide (3 ml) in THF (35 ml) was hydrogenated at 50 psi using 10% Pd/C (60 mg) for 24 h at room temperature. The reaction was filtered through celite and the filtrate was concentrated. The residue was dissolved in DCM, washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography using 2–10% methanol in DCM as eluent to obtain 21 mg (42%) of N-(pyrid-4-yl)-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid. mp: 267–268° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:28])=[C:4]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([CH3:8])=[CH:6][CH:7]=1.[C:29]1(=[O:43])[N:33]([CH2:34][C:35](Cl)=[O:36])[C:32](=[O:38])[C:31]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:30]12.O>N1C=CC=CC=1.CN(C)C=O>[Si:11]([O:10][CH2:9][C:4]1[C:5]([CH3:8])=[CH:6][CH:7]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][N:33]2[C:32](=[O:38])[C:31]3=[CH:39][CH:40]=[CH:41][CH:42]=[C:30]3[C:29]2=[O:43])[C:3]=1[CH3:28])([C:24]([CH3:25])([CH3:27])[CH3:26])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(N)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)CN2C(=O)c3ccccc3C2=O)c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a suspension of 3-amino-1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethylbenzene (42.4 g) in pyridine (17.2 g) and dimethylformamide (212 ml) was dropwise added phthalimidoacetyl chloride (25.6 g) over the period of 15 minutes under ice-cooling, and the mixture was stirred for 1 hour at the same temperature. To the reaction mixture was added water, and the resulting precipitates were collected by filtration and washed with acetonitrile to give 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-(phthalimidoacetylamino)benzene (59.1 g) as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:14]2[NH:15][C:16](=[O:31])[C:17]3[C:18](=[C:20]([CH2:29][CH3:30])[N:21]([CH:23]4[CH2:26][N:25]([CH2:27][CH3:28])[CH2:24]4)[N:22]=3)[N:19]=2)[C:7]([O:10][CH2:11][CH2:12][CH3:13])=[N:8][CH:9]=1)(=[O:3])[CH3:2].[C:32](=O)([O-])[O-].[Cs+].[Cs+]>C(O)CCC>[C:1]([C:4]1[CH:5]=[C:6]([C:14]2[NH:15][C:16](=[O:31])[C:17]3[C:18](=[C:20]([CH2:29][CH3:30])[N:21]([CH:23]4[CH2:26][N:25]([CH2:27][CH3:28])[CH2:24]4)[N:22]=3)[N:19]=2)[C:7]([O:10][CH2:11][CH2:12][CH2:13][CH3:32])=[N:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CN(CC)C3)nc2c(=O)[nH]1
Agent: [Cs+]
Solvent: CCCCO
Product: CCCCOc1ncc(C(C)=O)cc1-c1nc2c(CC)n(C3CN(CC)C3)nc2c(=O)[nH]1
Temperature: 90 °C
Yield: 64.3 %

Procedure:
The title compound from example 119 (120 mg, 0.28 mmol) and cesium carbonate (274 mg, 0.84 mmol) were dissolved in n-butanol (4 ml), and heated at 90° C. under nitrogen with molecular sieves for 96 h. The mixture was then partitioned between water (10 ml) and dichloromethane (10 ml). The organic layer was separated, and the aqueous layer extracted further with dichloromethane (3×15 ml). The combined organic layers were dried (MgSO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (95:5:0.5-90:10:1 ethyl acetate:methanol:0.88 NH3 as eluents), to yield the title compound as a colourless glass (77 mg, 0.18 mmol).
Reaction SMILES: [C:1]([C:3]1[C:4](Cl)=[N:5][C:6]([Cl:10])=[C:7]([F:9])[CH:8]=1)#[N:2].[CH3:12][N:13]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14]1>>[Cl:10][C:6]1[C:7]([F:9])=[CH:8][C:3]([C:1]#[N:2])=[C:4]([O:18][CH:15]2[CH2:16][CH2:17][N:13]([CH3:12])[CH2:14]2)[N:5]=1
Reactant: CN1CCC(O)C1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Product: CN1CCC(Oc2nc(Cl)c(F)cc2C#N)C1

Procedure:
3-cyano-2,6-dichloro-5-fluoropyridine was reacted with 1-methyl-pyrrolidin-3ol according to the method of Example 85A to provide the title compound. MS (ESI+) m/z 256 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:4][CH2:3]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:25][O:24][C:17]1[CH:16]=[C:15]([N:11]2[CH2:12][CH2:13][CH:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH2:9][CH2:10]2)[CH:20]=[CH:19][C:18]=1[N+:21]([O-:23])=[O:22]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CN1CCN(C2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 89.8 %

Procedure:
To a solution of 1-methyl-4-(piperidin-4-yl)piperazine (4.2 g, 22.91 mmol) in anhydrous DMF (40 mL) was added 4-fluoro-2-methoxy-1-nitrobenzene (3.92 g, 22.91 mmol) and potassium carbonate (3.80 g, 27.5 mmol). This suspension was heated at 70° C. overnight. After cooling, the reaction mixture was concentrated, and the residue partitioned between ethyl acetate and brine. The aqueous phase was extracted with ethyl acetate. The combined organic phases were concentrated. The residue was separated by flash chromatography (0-15% 2% ammonium hydroxide MeOH solution in dichloromethane) to give 6.88 g of the title compound. Yield: 90%. MS (DCI) m/z 335 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 1.58-1.68 (m, 2H), 1.93-1.99 (m, J=11.53 Hz, 2H), 2.29 (s, 3H), 2.44-2.51 (m, 4H), 2.62 (s, 4H), 2.92-3.02 (m, 2H), 3.90-3.98 (m, 7H), 6.31 (d, J=2.37 Hz, 1H), 6.42 (dd, J=9.32, 2.54 Hz, 1H), 7.99 (d, J=9.49 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(O)(c2cncnc2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(O)(c3cncnc3)CC2)C1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-pyrimidin-5-yl-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:19])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3O)=[CH:8][O:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].O.Cl>C(O)C>[CH:4]1[CH:3]=[C:2]([OH:1])[CH:11]=[C:10]2[C:5]=1[CH:6]1[O:19][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH:7]1[CH2:8][O:9]2
Reactant: O=c1c(-c2ccccc2O)coc2cc(O)ccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Oc1ccc2c(c1)OCC1c3ccccc3OC21
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.4 %

Procedure:
To a stirred solution of 7-hydroxy-3-(2-hydroxy-phenyl)-chromen-4-one (3 gm, 11.8 mmol) in absolute ethanol (30 ml) at 0° C. was added NaBH4 (2.7 gm, 70.8 mmol). The reaction mixture was then stirred for 24 hours at room temperature. The reaction was stopped by adding ice-cooled water and the solution was neutralized with 10% HCl to get the white precipitate. The white precipitate was washed with water and the purified by silica gel column chromatography using hexane-chloroform as the eluent to give 6a,11a-dihydro-6H-benzo[4,5]furo[3,2-c]chromen-3-ol (1.6 gm, 57%) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH2:20][C:21]3[S:22][CH:23]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:25]=3)[CH2:17][CH2:18][CH3:19])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].O1CCCC1.O.[OH-].[Li+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([CH2:20][C:21]3[S:22][CH:23]=[C:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:25]=3)[CH2:17][CH2:18][CH3:19])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:32][CH2:33][C:34]([OH:36])=[O:35]
Reactant: CCCC(Cc1nc(-c2ccccc2)cs1)c1ccc(CNc2ccc(CCC(=O)OCC)c(F)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCCC(Cc1nc(-c2ccccc2)cs1)c1ccc(CNc2ccc(CCC(=O)O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.1 %

Procedure:
To a solution of ethyl 3-{2-fluoro-4-[(4-{1-[(4-phenyl-1,3-thiazol-2-yl)methyl]butyl}benzyl)amino]phenyl}propanoate (0.420 g, 0.790 mmol) in a mixture of ethanol (6 mL), tetrahydrofuran (12 mL) and water (6 mL) was added lithium hydroxide monohydrate (0.198 g, 4.74 mmol), and the mixture was stirred at room temperature for 2.5 hr. The reaction mixture was neutralized with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (15%-60% ethyl acetate/hexane) to give the title compound (330 mg, yield 83%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.Br[CH2:81][CH2:82][OH:83].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH2:81][CH2:82][OH:83])[CH2:28][CH2:27]5)=[N:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1
Reactant: OCCBr
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CCO)CC5)nc4)cnc32)cc1
Yield: 43.9 %

Procedure:
Using similar reaction conditions as described in step-i of example-126, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (150 mg, 0.297 mmol) was alkylated using 2-bromoethanol (62 mg, 0.494 mmol) and potassium carbonate (69 mg, 0.494 mmol) in DMF (1 ml) to afford 85 mg (52.7% yield) of the titled compound after purification by column (Silica gel 60/120) chromatography using 5% methanol in dichloromethane as eluent. MS: m/z=652.2 (M+1).
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:24](=[O:25])[N:12]2[C:13]([C:18]([O:20]CC=C)=[O:19])=[C:14]([CH2:16]O)[CH2:15][C@H:11]12)[CH3:9])=O)C=C.[S:26]1[CH:30]=[CH:29][N:28]2[CH:31]=[N:32][CH:33]=[C:27]12>>[OH:7][C@@H:8]([C@H:10]1[C:24](=[O:25])[N:12]2[C:13]([C:18]([O-:20])=[O:19])=[C:14]([CH2:16][N:32]3[CH:33]=[C:27]4[S:26][CH:30]=[CH:29][N+:28]4=[CH:31]3)[CH2:15][C@H:11]12)[CH3:9]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)C[C@H]12
Reactant: c1cn2cncc2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(Cn3cc4scc[n+]4c3)C[C@H]12
Yield: 12.5 %

Procedure:
The same procedure as in Example 1 was repeated except that 43 mg of allyl (5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-carbapen-2-em-3-carboxylate and 31 mg of imidazo[5,1-b]thiazole were used, thereby obtaining 5.1 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[NH2:26]>CCO>[CH3:9][C:5]1[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)=[N:7][C:2]([NH:26][C:25]2[CH:27]=[C:28]([O:32][CH3:33])[C:29]([O:30][CH3:31])=[C:23]([O:22][CH3:21])[CH:24]=2)=[N:3][CH:4]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Cc1cnc(Cl)nc1Cl
Solvent: CCO
Product: CCOC(=O)C1CCCN(c2nc(Nc3cc(OC)c(OC)c(OC)c3)ncc2C)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (Sigma-Aldrich, 1 g, 6.13 mmol) and TEA (0.855 mL, 6.13 mmol) in EtOH (6.39 mL) was added ethyl piperidine-3-carboxylate (0.993 mL, 6.13 mmol) in EtOH (1.278 mL). The reaction was then allowed to stir at room temperature. After 4 hours, 3,4,5-trimethoxyaniline (1.124 g, 6.13 mmol) was added and the reaction was heated in the microwave to 150° C. for 30 minutes. The reaction was then cooled to room temperature and concentrated to dryness. The residue was adsorbed onto a plug of silica gel and purified by chromatography through a 100 g silica gel column, eluting with 10% to 100% EtOAc in hexanes to provide 8.1. ESI-MS M+H 430.8.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[Cl:17][C:18]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]1)=[O:6])=[O:21]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CC1

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (25 mg, 0.115 mmol) and 2-chloro-4-fluorobenzoyl chloride (32 μL, 0.229 mmol) and mixing for 24 h, 44.9 mg (>100%) of the title compound were recovered.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[C:11](=O)([O-])[O-].[Cs+].[Cs+].BrCBr>CN(C=O)C>[O:10]1[C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[O:1][CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: BrCBr
Product: O=Cc1ccc2c(c1)OCO2
Temperature: 110 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a stirred solution of 3,4-dihydroxybenzaldehyde (10 g, 72.40 mmol, 1.00 equiv) in DMF (150 mL) was added cesium carbonate (35.4 g, 108.31 mmol, 1.50 equiv) and dibromomethane (18.7 g, 107.57 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at 110° C. The solution was cooled to room temperature and the solid was removed by filtration. The filtrate was diluted with H2O (300 mL). The resulting solution was extracted with EtOAc (2×300 mL). The organic layers were combined, dried over sodium sulfate, and concentrated under reduced pressure. The crude residue was purified by silica gel column chromatography, eluted with with EtOAc/petroleum ether (1:9) to afford 8 g (74%) of the title compound as a yellow solid. 1H-NMR (300 MHz, CDCl3): δ ppm 9.81 (s, 1H), 7.41 (d, J=8.1 Hz, 1H), 7.34 (s, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.08 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C:4]2[CH:8]=[C:9]([OH:12])[CH:10]=[CH:11][C:3]1=2.O1C2C=C(O)C=CC=2CC1.[F:23][C:24]([F:43])([F:42])[C:25]1[O:29][C:28]([CH2:30][N:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33](=[O:40])[C:32]2=[O:41])=[CH:27][CH:26]=1.ClC1C=CC=C2C=1N(C(C1C=CC=CC=1)C1C=CC=CC=1)C(=O)C2=O>>[OH:40][C:33]1([C:10]2[C:9]([OH:12])=[CH:8][C:4]3[O:5][CH2:6][CH2:7][N:2]([CH3:1])[C:3]=3[CH:11]=2)[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:31]([CH2:30][C:28]2[O:29][C:25]([C:24]([F:42])([F:23])[F:43])=[CH:26][CH:27]=2)[C:32]1=[O:41]
Reactant: CN1CCOc2cc(O)ccc21
Reactant: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2c(Cl)cccc21
Agent: Oc1ccc2c(c1)OCC2
Product: CN1CCOc2cc(O)c(C3(O)C(=O)N(Cc4ccc(C(F)(F)F)o4)c4ccccc43)cc21

Procedure:
Following the procedure as described in PREPARATION 21B, and making non-critical variations using 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ol to replace 2,3-dihydrobenzofuran-6-ol, and 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione to replace 7-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione, 3-hydroxy-3-(7-hydroxy-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl)-1-{[5-(trifluoromethyl)furan-2-yl]methyl}-1,3-dihydro-2H-indol-2-one was obtained (56%) as a colourless powder: mp 184-186° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ8.63 (s, 1H), 7.24-7.18 (m, 2H), 7.13 (s, 1H), 7.00-6.90 (m, 3H), 6.59 (d, J=3.3 Hz, 1H), 6.50 (s, 1H), 6.03 (s, 1H), 4.99 (s, 2H), 4.20 (t, J=4.1 Hz, 2H), 3.14-3.09 (m, 2H), 2.80 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ176.8, 153.8, 145.8, 144.1, 142.8, 139.3 (q, J=42 Hz), 132.7, 128.9, 128.5, 123.7, 122.2, 119.6, 119.1 (q, J=266 Hz), 114.1, 112.3, 109.1, 108.3, 103.1, 74.7, 64.9, 49.2, 39.4, 36.4; MS (ES+) m/z 461.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:18]1[CH2:23][C@H:22]([C:24](O)=O)[NH:21][CH2:20][CH2:19]1.[CH3:27][N:28]1[C:32](=[O:33])C=[CH:30][C:29]1=[O:34]>CC#N>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[N:21]4[CH:22]([CH2:23][CH2:18][CH2:19][CH2:20]4)[CH:24]4[C:32](=[O:33])[N:28]([CH3:27])[C:29](=[O:34])[CH:30]34)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN1C(=O)C=CC1=O
Reactant: O=C/C=C/c1ccc(-c2cccc(F)c2)cn1
Reactant: O=C(O)[C@H]1CCCCN1
Solvent: CC#N
Product: CN1C(=O)C2C(C1=O)C1CCCCN1C2/C=C/c1ccc(-c2cccc(F)c2)cn1

Procedure:
A mixture of 235 mg of (E)-3-[5-(3-fluorophenyl)pyridin-2-yl]propenal, 133 mg of D-pipecolinic acid, 115 mg of N-methylmaleimide and 30 ml of MeCN is heated at the boil for 2 h. The volatile components are removed under reduced pressure and the residue is purified by column chromatography (silica gel, MeOH:DCM=97:3). In this manner, 2 pure fractions are isolated.
Reaction SMILES: Br[C:2]1[N:6]([CH:7]([CH3:9])[CH3:8])[C:5]2[CH:10]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[F:28])[N:11]([C:14]3[N:15]([CH3:20])[N:16]=[C:17]([CH3:19])[CH:18]=3)[C:12](=[O:13])[C:4]=2[CH:3]=1.[CH3:29][O:30][C:31]1[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=[C:33]([N:46]([CH3:48])[CH3:47])[N:32]=1.BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=C(Cl)C=CC=3C)C(=O)C=2C=1.COC1C(B2OC(C)(C)C(C)(C)O2)=CN=C(N)N=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:10]2[C:5]3[N:6]([CH:7]([CH3:9])[CH3:8])[C:2]([C:36]4[C:31]([O:30][CH3:29])=[N:32][C:33]([N:46]([CH3:47])[CH3:48])=[N:34][CH:35]=4)=[CH:3][C:4]=3[C:12](=[O:13])[N:11]2[C:14]2[N:15]([CH3:20])[N:16]=[C:17]([CH3:19])[CH:18]=2)=[C:22]([F:28])[CH:23]=1
Reactant: COc1nc(N(C)C)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(N2C(=O)c3cc(Br)n(C(C)C)c3C2c2ccc(Cl)cc2F)n(C)n1
Agent: COc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Agent: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Product: COc1nc(N(C)C)ncc1-c1cc2c(n1C(C)C)C(c1ccc(Cl)cc1F)N(c1cc(C)nn1C)C2=O

Procedure:
The title compound was prepared in analogy to the procedure described for Example 25 but 2-bromo-6-(4-chloro-2-fluoro-phenyl)-5-(2,5-dimethyl-2H-pyrazol-3-yl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate BI) and 4-methoxy-N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (Intermediate W) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 4-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine respectively. ESI-MS: tR=1.19 min, [M+H]+ 538/540 (LC-MS 1).