Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[C:9]([C:11]3[CH:20]=[C:19]4[C:14]([CH2:15][CH2:16][N:17]([CH3:21])[CH2:18]4)=[CH:13][CH:12]=3)=[CH:10][C:3]=12.Br[C:32]1[C:33]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:50])[N:47]([CH3:49])[CH3:48])=[CH:41][CH:40]=2)=[N:34][N:35]([CH2:37][CH3:38])[CH:36]=1>>[CH2:37]([N:35]1[CH:36]=[C:32]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:23])=[O:24])[C:9]([C:11]4[CH:20]=[C:19]5[C:14]([CH2:15][CH2:16][N:17]([CH3:21])[CH2:18]5)=[CH:13][CH:12]=4)=[CH:10][C:3]=23)[C:33]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:46](=[O:50])[N:47]([CH3:49])[CH3:48])=[CH:41][CH:40]=2)=[N:34]1)[CH3:38]
Reactant: CCn1cc(Br)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: CN1CCc2ccc(-c3cc4c(Br)ccnc4n3S(=O)(=O)c3ccccc3)cc2C1
Product: CCn1cc(-c2ccnc3c2cc(-c2ccc4c(c2)CN(C)CC4)n3S(=O)(=O)c2ccccc2)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reaction time: 4.5 h

Procedure:
Following the procedure described for Intermediate 32 with 7-[4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-methyl-1,2,3,4-tetrahydroisoquinoline. Using this product crude and following the procedure described for Intermediate 100 using N′-[4-(4-bromo-1-ethyl-1H-pyrazol-3-yl)phenyl]-N,N-dimethylurea and stirring for 4.5 hours provided the title compound. ESMS [M+H]+: 660.6.
Reaction SMILES: Br.Br[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[O:12]=[C:13]([CH3:46])[CH2:14][S:15]([C:18]1[CH:19]=[C:20]([C@H:29]2[CH2:33][CH2:32][C@H:31]([C:34]3[CH:39]=[C:38]([O:40][CH3:41])[C:37]([O:42][CH3:43])=[C:36]([O:44][CH3:45])[CH:35]=3)[O:30]2)[CH:21]=[C:22]([OH:28])[C:23]=1[O:24][CH2:25][CH2:26][CH3:27])(=[O:17])=[O:16].C(=O)([O-])[O-]>CN(C=O)C>[O:12]=[C:13]([CH3:46])[CH2:14][S:15]([C:18]1[CH:19]=[C:20]([C@H:29]2[CH2:33][CH2:32][C@H:31]([C:34]3[CH:35]=[C:36]([O:44][CH3:45])[C:37]([O:42][CH3:43])=[C:38]([O:40][CH3:41])[CH:39]=3)[O:30]2)[CH:21]=[C:22]([O:28][CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[C:23]=1[O:24][CH2:25][CH2:26][CH3:27])(=[O:16])=[O:17]
Reactant: BrCCCc1cccnc1
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Agent: Br
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCCOc1c(OCCCc2cccnc2)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)=O
Temperature: 70 °C

Procedure:
3-(3-Bromopropyl)pyridine hydrobromide (51 mg, 0.18 mmol) was added to a solution of trans-2-[3-(2-oxopropylsulfonyl)-4-n-propoxy-5-(2-hydroxy)phenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (50.8 mg, 0.1 mmol) [Example 1, Step L] in DMF (2 mL) containing postassium carbonate (28 mg, 0.2 mmol), and the reaction mixture was heated at 70° C. for 1 h. The product was extracted with ethyl ether in the usualy way and purified by preparative TLC (hexane-ethyl acetate; 1:2, v/v) Rf 0.15; MS, m/z 628 (M+1)+. ; NMR (CDCl3) δ d 1.09 (t, J=7.5 Hz, CH2CH2CH3), 1.92 (m, CH2CH2CH3), 2.18 (m, CH2CH2CH2Pyr), 2.37 (s, CH2COCH3), 2.87 (t, CH2CH2CH2Pyr), 3.83 (s, OCH3 ), 3.88 (s, 2 OCH3), 4.08 (t, CH2CH2CH2Pyr), 4.18 (t, CH2CH2CH3), 4.48 (s, CH2CO), 5.13-5.27 (m, H-2 and H-5), 6.61 (s, 2 H, C5ArH).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C@@H:20]1[CH2:25][NH:24][CH2:23][CH2:22][N:21]1[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O.C(O)(=O)C.C1COCC1>[C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([N:24]3[CH2:23][CH2:22][N:21]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:20]([CH3:19])[CH2:25]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C[C@@H]1CN(C2CN(C(c3ccccc3)c3ccccc3)C2)CCN1C(=O)OC(C)(C)C
Yield: 89.6 %

Procedure:
To a mixed solution of a commercially available product of 1-(diphenylmethyl)azetidin-3-one (300 mg, 1.26 mmol), THF (6.0 mL) and acetic acid (500 μL) was added a commercially available product of tert-butyl(2R)-2-methylpiperazine-1-carboxylate (304 mg, 1.51 mmol) at room temperature. The resultant mixture was stirred at room temperature for 25 minutes. Sodium triacetoxyborohydride (536 mg, 2.52 mmol) was added to the reaction mixture at room temperature, and the resultant mixture was stirred at room temperature for 18 hours and 35 minutes. Sodium hydrogen carbonate and water were added to the reaction mixture, and the resultant solution was extracted with ethyl acetate. An organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate and then filtrated. The resultant residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=5:1) to give the title compound (476 mg, yield: 90%).
Reaction SMILES: [Cl-].[OH:2][CH:3]1[CH2:8][C:7]([CH3:10])([CH3:9])[C:6]([CH:11]=[CH:12][C:13]([CH3:35])=[CH:14][CH2:15][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[C:5]([CH3:36])[CH2:4]1.[CH3:37][C:38](=[CH:41][CH:42]=[CH:43][CH:44]=[C:45]([CH3:48])[CH:46]=O)[CH:39]=O.[OH-:49].[Na+]>C(O)C>[CH3:36][C:5]1[CH2:4][C@@H:3]([OH:49])[CH2:8][C:7]([CH3:9])([CH3:10])[C:6]=1/[CH:11]=[CH:12]/[C:13](/[CH3:35])=[CH:14]/[CH:15]=[CH:46]/[C:45](/[CH3:48])=[CH:44]/[CH:43]=[CH:42]/[CH:41]=[C:38](\[CH3:39])/[CH:37]=[CH:15]/[CH:14]=[C:13](\[CH3:35])/[CH:12]=[CH:11]/[C:6]1[C:7]([CH3:9])([CH3:10])[CH2:8][C@H:3]([OH:2])[CH2:4][C:5]=1[CH3:36]
Reactant: CC(C=CC1=C(C)CC(O)CC1(C)C)=CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C=O)=CC=CC=C(C)C=O
Reactant: [OH-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C2=C(C)C[C@@H](O)CC2(C)C)C(C)(C)C[C@H](O)C1
Temperature: -10 °C

Procedure:
32.88 g (95.8%; 2.03 eq.) of [5-(4-hydroxy-2,6,6-trimethyl-1-cyclohexenyl)-3-methyl-2,4-pentadienyl]triphenylphosphonium chloride and 4.92 g (1 eq.) of 2,7-dimethyl-2,4,6-octatrien-1,8-dial (C10 -dial) in 490 ml of ethanol were placed in a 500 ml four-necked sulphonation flask equipped with an internal thermometer, stirrer and reflux condenser and cooled to -10° C. while stirring. A solution of 3.60 g of sodium hydroxide in 50 ml of ethanol was added dropwise to the resulting yellowish suspension at -10° C. while stirring and subsequently the reaction mixture was stirred at -10° C. for one hour. After heating to about 80° C. internal temperature within 30 minutes the product suspension was heated at reflux temperature during the following 17 hours. Subsequently, it was cooled to 0° C. and stirred for a further 1 hour, and the thus-obtained zeaxanthin was isolated by suction filtration. Then the filter cake was washed well with ethanol and subsequently freed from neutral salt with water.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1)=[O:16].C1(P(=[CH:44][CH:45]=[O:46])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:47]1C=CC=CC=1>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:47]=[CH:44][CH:45]=[O:46])=[CH:19][CH:18]=1)=[O:16]
Reactant: c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(C=O)cc1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(C=CC=O)cc1
Reaction time: 24 h
Yield: 63 %

Procedure:
A mixture of 4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]benzaldehyde (6.0 g), (triphenylphosphoranylidene)acetaldehyde [(C6H5)3P=CHCHO](6.29 g) and benzene (100 ml) was stirred under refluxing conditions for 24 hours. The reaction mixture was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography. From the fraction eluted with ethyl acetate-hexane (1:2), 4-[3-(5-methyl-2-phenyl-4-oxazolyl)propionyl]cinnamaldehyde (4.08 g, 63%) was obtained, which was then recrystallized from dichloromethane-isopropyl ether to yield colorless prisms having a melting point of 119°-120° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH: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>>[NH2:1][C:2]1[N:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Nc1cccc(C2CCC(=O)CC2)n1
Product: Nc1cccc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)n1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(6-amino-pyridin-2-yl)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26]Cl)=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[I-:30].[Na+]>C(#N)C>[C:1]([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][I:30])=[O:24])=[O:17])[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(C)(C)C(=O)OCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCCCC(C)(C)C(=O)OCI
Temperature: 60 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
To a solution of chloromethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate (3.85 g, 9 mmol) in acetonitrile (50 mL), was added sodium iodide (5.40 g, 36 mmol). The solution was stirred for 4 h at 60° C. The resulting suspension was filtered and the filtrate was evaporated. The residue was dissolved in CH2Cl2 and washed with aqueous sodium thiosulfate (0.1 M). The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The crude product was column chromatographed (silica gel, 1% MeOH in CH2Cl2), to give 4.26 g of iodomethyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[NH:11][C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:13]=2.C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:36][CH:37]1[CH2:41][CH2:40][O:39][CH2:38]1)(=O)=O>CN(C=O)C>[CH3:8][O:9][C:10]1[N:11]([CH2:36][CH:37]2[CH2:41][CH2:40][O:39][CH2:38]2)[C:12]2[C:17]([N:18]=1)=[C:16]([NH2:19])[N:15]=[C:14]([O:20][CH2:21][CH2:22][O:23][CH3:24])[N:13]=2
Reactant: CS(=O)(=O)OCC1CCOC1
Reactant: COCCOc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2nc(OC)n(CC3CCOC3)c2n1
Temperature: 60 °C
Yield: 44.9 %

Procedure:
8-(Methoxy)-2-{[2-(methoxy)ethyl]oxy}-9H-purin-6-amine trifluoroacetate salt (0.30 g) was dissolved in dry DMF (5 mL). To this was added anhydrous potassium carbonate (0.47 g) and then heated to 60° C. for 1.5 hours. The reaction mixture was cooled to room temperature and tetrahydro-3-furanylmethyl methanesulfonate (0.168 g) was added. The reaction mixture was then heated to 90° C. for 3.5 hours. The reaction mixture was then quenched into water (100 mL) and extracted into ethyl acetate (50 mL, 3 times). The organic was separated and dried by passing through a hydrophobic frit and then evaporated under reduced pressure to give a glassy solid. This was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (10-45%). This gave the title compound as a white solid (0.1233 g).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.C([N:18]1[CH:22]=[CH:21]N=C1)(N1C=CN=C1)=O.O[NH:24]C(=O)C>C(OCC)(=O)C.C1COCC1.C1(C)C=CC=CC=1>[CH3:21][C:22]1[N:18]=[C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:10][CH:9]=2)[O:8][N:24]=1
Reactant: O=C(O)c1ccc(O)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)NO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1noc(-c2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10.3 %

Procedure:
To a mixed solution of 4-hydroxybenzoic acid (1.0 g) in a mixed solution (15 mL) of toluene and THF (toluene:THF=2:1, v/v) was added carbonyldiimidazole (1.29 g), and the mixture was stirred at room temperature for 1 hour. Subsequently, N-hydroxyacetamide (644 mg) was added thereto, and the mixture was further heated at 150° C. for 2 hours under reflux. The reaction solution was allowed to stand for cooling down to room temperature, diluted with ethyl acetate, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:1, v/v) to give the title compound (132 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH:27]5[CH2:30][CH2:31][N:32](C(OC(C)(C)C)=O)[CH:26]5[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)Cl.CO.Cl>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][CH:27]5[CH2:30][CH2:31][NH:32][CH:26]5[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CCN(C(=O)OC(C)(C)C)C2C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CCC2CCNC2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 124.8 %

Procedure:
To a solution of tert-butyl 6-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy) propyl)octahydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1.16 g) in the mixture solvent of CH2Cl2 and MeOH was added a solution of HCl in EtOAc (30 mL). The reaction mixture was stirred at room temperature for 4 h, and filtered to give the title compound as a solid (1.20 g, 100%), HPLC: 99.69%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.45 (m, 2H), 1.78 (m, 3H), 1.80 (m, 2H), 2.10 (m, 1H), 2.42 (m, 5H), 2.82 (m, 3H), 4.03 (s, 3H), 4.10 (m, 2H), 6.76 (s, 1H), 7.16 (d, J=8.2 Hz, 1H), 7.24 (s, 1H), 7.28 (d, J=8.2 Hz, 1H), 7.41 (s, 1H), 8.54 (s, 1H) ppm.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][C:6]([N:16]2[CH2:21][CH2:20][N:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH2:18][CH2:17]2)=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].CCN(C(C)C)C(C)C.[F:35][C:36]([F:51])([F:50])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:40](Cl)=[O:41]>C(Cl)Cl>[CH3:25][S:22]([N:19]1[CH2:18][CH2:17][N:16]([C:6]2[N:5]=[CH:4][C:3]([N:2]([CH3:1])[C:40](=[O:41])[C:39]3[CH:38]=[C:37]([C:36]([F:51])([F:50])[F:35])[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=3)=[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])[CH:7]=2)[CH2:21][CH2:20]1)(=[O:24])=[O:23]
Reactant: CNc1cnc(N2CCN(S(C)(=O)=O)CC2)cc1-c1ccccc1C
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1-c1cc(N2CCN(S(C)(=O)=O)CC2)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 79.9 %

Procedure:
A solution of N-methyl-6-(4-(methylsulfonyl)piperazin-1-yl)-4-o-tolylpyridin-3-amine (37 mg, 0.10 mmol) and DIPEA (50 μL, 0.29 mmol) in CH2Cl2 was treated with 3,5-bis-trifluoromethylbenzoyl chloride (43 mg, 0.15 mmol, CAS RN 1271-19-8). After stirring for 1 h, the reaction mixture was loaded directly onto a silica gel column. Elution with 50% EtOAc in n-hexane afforded the title compound as a yellow solid (48 mg, 80%). MS (ESI): m/z=601.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:18])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][CH:10]=2)[CH:8]=1)#[N:2].[O:19]=[S:20]1(=[O:34])[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.O>[O:34]=[S:20]1(=[O:19])[CH2:21][CH2:22][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:7]4[CH:8]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=4[CH3:18])=[CH:14][CH:13]=3)=[O:17])=[CH:29][CH:28]=2)[CH2:24][CH2:25]1
Reactant: Cc1ccc(C#N)cc1-c1ccc(C(=O)O)cc1
Reactant: Nc1ccc(CN2CCS(=O)(=O)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(C#N)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reaction time: 18 h

Procedure:
A mixture of 5′-cyano-2′-methyl-biphenyl-4-carboxylic acid (100 mg), 4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenylamine (101 mg), EDAC (81 mg), HOBT (57 mg) and N-methylmorpholine (0.09 ml) in dry DMF (2 ml) was stirred at 20 C for 18 h. Water (8 ml) was then added and the resulting solid collected by filtration and dried (160 mg).
Reaction SMILES: C([Li])CCC.[Br-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])[CH2:12][PH3+].[Si:21]([O:28][C:29]1[C:36]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])=[C:35]([O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[CH:34]=[CH:33][C:30]=1[CH:31]=O)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>C1COCC1>[Si:21]([O:28][C:29]1[C:30](/[CH:31]=[CH:12]\[C:11]2[CH:10]=[C:9]([O:8][CH3:7])[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:33][CH:34]=[C:35]([O:45][Si:46]([C:49]([CH3:50])([CH3:52])[CH3:51])([CH3:48])[CH3:47])[C:36]=1[O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)c(O[Si](C)(C)C(C)(C)C)c1O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(C[PH3+])cc(OC)c1OC
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(/C=C\c2ccc(O[Si](C)(C)C(C)(C)C)c(O[Si](C)(C)C(C)(C)C)c2O[Si](C)(C)C(C)(C)C)cc(OC)c1OC
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (0.89 mL, 2.23 mmol, 2.5 M in hexanes) was added dropwise over 10 min to a solution of 3,4,5-trimethoxybenzylphosphonium bromide (0.96 g, 1.83 mmol) in THF (10 mL) at −10° C. The reaction mixture was stirred at this temperature for 15 min then cooled to −70° C. and a solution of 31 (0.93 g, 1.88 mmol) in THF (4 mL) was added and the reaction mixture was allowed to warm to room temperature with stirring overnight. The reaction mixture was cooled to 0° C. and water was added. The reaction mixture was extracted with TBME (3×) and the organic phase was washed successively with water and brine, dried (Na2SO4) and concentrated in vacuo to give crude product (1.5 g). Purification by column chromatography (SiO2; 5:95 TBME:cyclohexane+1% Et3N) gave 32 compound (0.6 g, 50%) as a 86:14 mixture of Z:E isomers:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O-:25])=[S:24])=[C:15]([CH:18]4[CH2:22][CH2:21][O:20][CH2:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:32]([O:38][CH2:39]I)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:28]/[O:29][CH3:30])/[C:8]([NH:10][CH:11]2[C:26](=[O:27])[N:13]3[C:14]([C:23]([O:25][CH2:39][O:38][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[S:24])=[C:15]([CH:18]4[CH2:22][CH2:21][O:20][CH2:19]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C([O-])=S)=C(C3CCOC3)CS[C@H]12)c1csc(N)n1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OCOC(=O)C(C)(C)C)=C(C3CCOC3)CS[C@H]12)c1csc(N)n1
Temperature: -20 °C
Yield: 68.4 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(tetrahydrofuran-3-yl)thio-3-cephem-4-carboxylate (80 mg) (as obtained in Example 1) was dissolved in dimethylformamide (1.6 ml) and the solution was cooled to -20° C. The solution, after addition of iodomethyl pivalate (77 mg) thereto, was stirred at a temperature of -20° to -10° C. for 30 minutes (for the esterification reaciton), after which cold water (5 ml) was added to the reaction solution. The resulting mixture was extracted with ethyl acetate, and the organic layer separated was washed with an aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure to leave a yellow oil. The oily residue was purified by a column chromatography on a silica gel column (15 g) with elution using ethyl acetate as eluent to collect fractions containing the titled compound. Concentration of the fractions so collected under reduced pressure gave the titled compound (65 mg; 68%) as white powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[F:21][C:22]1[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=1[CH2:30][C:31](O)=[O:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[CH3:20][N:12]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([NH2:19])=[C:18]2[C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:31](=[O:32])[CH2:30][C:23]2[CH:24]=[C:25]([F:29])[CH:26]=[C:27]([F:28])[C:22]=2[F:21])[CH2:2][CH2:3]3)=[N:11]1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cc(F)cc(F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)cc(F)c2F)c2c(N)ncnc21
Yield: 49.8 %

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.330 mmol), (2,3,5-trifluorophenyl)acetic acid (69.1 mg, 0.363 mmol), HATU (151 mg, 0.396 mmol), DIEA (0.173 mL, 0.991 mmol) was stirred overnight at room temperature. At this time, LCMS analysis indicated complete conversion, so the reaction mixture was poured into water (10 mL), whereupon a beige precipitate formed. The precipitate was filtered, suspended in DCM-methanol and dry-loaded onto silica, then purified by flash chromatography (0-10% methanol in DCM) to afford 1-methyl-3-{1-[(2,3,5-trifluorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (72 mg) as a white solid. LC-MS (ES) m/z=439 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 3.26-3.32 (m, 2H), 3.94 (s, 3H), 4.06 (s, 2H), 4.28-4.37 (m, 2H), 7.09-7.20 (m, 1H), 7.41-7.52 (m, 2H), 7.53-7.57 (m, 1H), 8.11-8.18 (m, 1H), 8.25 (s, 1H).
Reaction SMILES: Br[CH:2]([CH2:6]Br)[C:3](Cl)=[O:4].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.C(Cl)Cl>[CH2:16]([N:23]1[CH2:6][CH:2]1[C:3]([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)C(Br)CBr
Reactant: OCc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1CN1Cc1ccccc1
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of 2,3-dibromopropionyl chloride (5.00 g, 19.97 mmol) in THF (25 ml) at 0° C. was added dropwise benzyl alcohol (2.10 ml, 19.97 mmol). After stirring for 1 h, the reaction was concentrated in vacuo and the resulting oil dissolved in CH2Cl2 (25 ml) and treated with a solution of benzyl amine (2.20 ml, 19.97 mmol) and TEA (5.80 ml, 41.94 mmol) in CH2Cl2 (10 ml) at 0° C. After stirring for 3 h, the reaction was filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with hexane/ethyl acetate (4:1) to afford N-benzyl-aziridine-2-carboxylic acid, benzyl ester as a colorless oil (2.35 g).