Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:8][CH2:7]1)=[O:5].[CH3:27]I>CO.CN(C=O)C>[CH3:2][O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][N:13]([CH3:27])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:8][CH2:7]1)=[O:5]
Reactant: CI
Reactant: COC(=O)[C@H]1CC[C@H](CNS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg (4 mmol, 1.1 eq) of sodium were reacted in 2 mL of MeOH. Then 1.33 g (3.5 mmol) of trans-4-[(4-trifluoromethyl-benzenesulfonylamino)-methyl]-cyclohexane carboxylic acid methyl ester dissolved in 3 mL of dry DMF were added, followed by 0.44 mL (7 mmol, 2 eq) of CH3I. The mixture was stirred at RT for 2 h, then poured into ice-water and extracted with 3 portions of 15 mL of CH2Cl2. The combined organic phases were washed with H2O and brine, dried over anhydrous Na2SO4 and evaporated, leaving 1.34 g (97%) of trans-4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexane-carboxylic acid methyl ester as white solid, MS: 411 (M+NH4+).
Reaction SMILES: C(N(C1C=CC=CC=1C1CCC2C(=CC=C(OC)C=2)C1)CCC1C=CC(O)=CC=1)C.Cl.ClCCN1CCCCCC1.[N:42]1([CH2:49][CH2:50][O:51][C:52]2[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][N:60]([CH2:79][CH3:80])[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[CH:67]3[CH2:76][CH2:75][C:74]4[C:69](=[CH:70][CH:71]=[C:72]([O:77]C)[CH:73]=4)[CH2:68]3)=[CH:54][CH:53]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1>>[N:42]1([CH2:49][CH2:50][O:51][C:52]2[CH:53]=[CH:54][C:55]([CH2:58][CH2:59][N:60]([CH2:79][CH3:80])[C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[CH:67]3[CH2:76][CH2:75][C:74]4[CH:73]=[C:72]([OH:77])[CH:71]=[CH:70][C:69]=4[CH2:68]3)=[CH:56][CH:57]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1
Reactant: CCN(CCc1ccc(OCCN2CCCCCC2)cc1)c1ccccc1C1CCc2cc(OC)ccc2C1
Agent: CCN(CCc1ccc(O)cc1)c1ccccc1C1CCc2cc(OC)ccc2C1
Agent: Cl
Agent: ClCCN1CCCCCC1
Product: CCN(CCc1ccc(OCCN2CCCCCC2)cc1)c1ccccc1C1CCc2cc(O)ccc2C1
Yield: 87.9 %

Procedure:
Synthesized from 4-{2-{ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amino}ethyl}phenol and 1-(2-chloroethyl)azepane hydrochloride according to an analogous synthetic method to Preparation Example 40, {2-[4-(2-azepan-1-ylethoxy)phenyl]ethyl}ethyl[2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (298 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (255 mg).
Reaction SMILES: [Na].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+].[OH-].[Na+].[CH3:15][CH2:16][O:17][C:18]([C@@H:20]([NH:29][C@H:30]([C:32]([N:34]1[C@H:38]([C:39]([O-:41])=[O:40])[CH2:37][CH2:36][CH2:35]1)=[O:33])[CH3:31])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:19].[Na+]>O>[CH3:15][CH2:16][O:17][C:18]([C@@H:20]([NH:29][C@H:30]([C:32]([N:34]1[C@H:38]([C:39]([OH:41])=[O:40])[CH2:37][CH2:36][CH2:35]1)=[O:33])[CH3:31])[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:19]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)[O-]
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
The stable formulation of enalapril salt is prepared in such manner that a compound of formula II ##STR5## is suspended in demineralized water, a stoichiometric amount of the corresponding sodium compound such as sodium carbonate, sodium hydrogen carbonate or sodium hydroxide is added thereto, to this enalapril sodium salt prepared in situ of the formula I ##STR6## formulating additives are added, the whole is homogenized and formulated.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=[O:7])=[C:4]([F:11])[CH:3]=1.O1CCCC1.[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:6][OH:7])=[C:8]([F:10])[CH:9]=1
Reactant: O=Cc1c(F)cc(Cl)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1c(F)cc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a mixture of 4-chloro-2,6-difluoro-benzaldehyde (5.7 g, 32 mmol), tetrahydrofuran (150 mL) and ethanol (20 mL) was added sodium borohydride (1.2 g, 32 mmol) at 0° C. The mixture was stirred for 30 minutes, warmed to ambient temperature, and additional sodium borohydride (0.40 g, 11 mmol) was added to drive the reaction to completion (TLC). The mixture was concentrated in vacuo, diluted with ether and treated cautiously with 1M aqueous HCl. The aqueous phase was extracted 3× with ether, and the combined organic layers were dried over MgSO4, filtered and concentrated. Trituration of the residue with pentane afforded 4.8 g (83%) of (4-chloro-2,6-difluoro-phenyl)-methanol as a colorless solid. 1H NMR (300 MHz, CDCl3) δ7.04 (d, 2H, J=7.1 Hz), 4.73 (s, 2H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([C:16]2[C:17]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][C:18]=3[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.[CH3:40][Sn](C)(C)C.CCN(CC)CC.CO.CCOC(C)=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:40][C:2]1[CH:3]=[C:4]([C:14]([C:16]2[C:17]3[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][C:18]=3[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:23][CH:22]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C(c1ccc(CN2CCCC2)c(Br)c1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2cc(O)ccc12
Reactant: C[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)cc3)sc3cc(O)ccc23)ccc1CN1CCCC1
Temperature: 135 °C
Reaction time: 23 h
Yield: 44 %

Procedure:
To a solution of 6-hydroxy-2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl 3-bromo-4-[(1-pyrrolidinyl)methyl]phenyl ketone (Example 137, Part D) (81 mg, 0.13 mmol) in DMF (2 mL) in a pressure tube were added tetrakis(triphenylphosphine)palladium(0) (18 mg) and tetramethyltin (0.3 mL) sequentially, followed by flushing with argon. The mixture was allowed to stir in the sealed pressure tube at 135° C. for 23 h in dark. The cooled reaction mixture was fractionated directly through flash chromatography with Et3N:MeOH:EtOAc (5:10:85) to afford the title compound (32 mg, 44%).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[CH:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@:10]([C:24]#[C:25][CH2:26][OH:27])([OH:23])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C(OCC)(=O)C>[CH2:1]([N:8]1[C@@H:13]2[CH:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][C@@:9]1([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C@:10](/[CH:24]=[CH:25]\[CH2:26][OH:27])([OH:23])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@]2(O)C#CCO
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@]2(O)/C=C\CO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A mixture of (1R*,2S*,5S*,6RS)-8-benzyl-2-(3-hydroxypropynyl)-1-phenyl-6-(tert-butoxycarbonyl)-8-azabicylco[3.2.1]octan-2-ol (Description 25; a 3:1 mixture of C6 epimers, 4 g, 8.9 mmol), Lindlar catalyst (800 mg) and ethyl acetate (30 ml) was stirred under hydrogen atmosphere (1 atm) at room temperature for 45 minutes. The reaction mixture was filtered through a pad of Celite™. The filtrate was concentrated to give the title compound (4.0 g, 100%) as a 3:1 mixture of C6 epimers.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1.[CH:34](=O)[CH3:35].C(O)(=O)C.[BH4-].[Na+]>O1CCCC1.O>[CH2:34]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:32](=[O:33])[C:11]2=[CH:12][N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N:27]4[CH:31]=[CH:30][CH:29]=[N:28]4)=[CH:23][CH:22]=3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:10]2=[N:9]1)[CH3:35]
Reactant: Nc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Reactant: CC=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCNc1ccccc1-n1nc2c3ccccc3n(Cc3ccc(-n4cccn4)cc3)cc-2c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(2-Aminophenyl)-5-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (Example 626, 40 mg, 0.092 mmol), acetaldehyde (4.1 mg, 0.092 mmol, 1 equiv) and acetic acid (32 μL, 0.55 mmol, 6 equiv) were combined in tetrahydrofuran (1 mL) and stirred at ambient temperature for 10 minutes. The mixture was treated with sodium borohydride (1.2 mg, 0.046 mmol, 0.5 equiv) and after 2 hours at ambient temperature, the mixture was poured into water (5 mL) and extracted with ethyl acetate (2×5 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative reverse phase HPLC (80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 9.18 (1H, s), 8.46 (1H, d, J=2.5 Hz), 8.23 (1H, dd, J=7.7, 1.2 Hz), 7.83 (2H, d, J=8.6 Hz), 7.79 (1H, d, J=8.8 Hz), 7.72 (1H, d, J=1.2 Hz), 7.65-7.61 (1H, m), 7.55 (1H, t, J=7.8 Hz), 7.47 (2H, d, J=8.6 Hz), 7.37 (1H, dd, J=7.9, 1.2 Hz), 7.25-7.20 (1H, m), 6.82 (1H, d, J=8.1 Hz), 6.75 (1H, t, J=7.5 Hz), 6.53 (1H, br m), 5.79 (2H, s) 3.14 (2H, q, J=7.2 Hz), 1.18 (3H, t, J=7.0 Hz) ppm; low resolution mass spectrometry (ES+) m/z 461.0 [(M+H)+; calculated for C28H25N6O: 461.2].
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:32][CH3:33])=[C:6]2[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[N:34]1[CH:39]=[C:38](B(O)O)[CH:37]=[N:36][CH:35]=1.ClCCl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.CO>[CH3:33][O:32][C:5]1[CH:4]=[N:3][C:2]([C:38]2[CH:39]=[N:34][CH:35]=[N:36][CH:37]=2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:31])[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:24]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[N:23]=[N:22][N:21]=4)[CH2:16][CH2:15]3)=[O:13])[C:6]=12
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: COc1cnc(-c2cncnc2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Temperature: 115 °C
Yield: 33.8 %

Procedure:
Compounds 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (100 mg, 0.195 mmol), pyrimidin-5-ylboronic acid (72.6 mg, 0.586 mmol), 1,1′-Bis(diphenylphosphino)ferrocene palladium (II) chloride complex with dichloromethane (16.06 mg, 0.020 mmol) and Cesium carbonate (127 mg, 0.390 mmol) were combined in Dioxane (2 mL) and Water (0.5 mL). The mixture was heated at 115° C. for 4 hours. After cooling to rt, the mixture was diluted with 10 ml of MeOH and filtered. The filtration was concentrated and purified by HPLC to give 1-(4-methoxy-7-(pyrimidin-5-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (34 mg, 0.066 mmol, 34.1% yield). LCMS: m/e 512.3 (M+H)+, ret time 1.04 min. 1H NMR (500 MHz, MeOD) δ ppm 9.35 (s, 1H) 9.19 (s, 2H) 8.61 (d, J=4.88 Hz, 1H) 8.49 (s, 1H) 8.20 (s, 1H) 8.05-8.11 (m, 1H) 7.83 (d, J=7.93 Hz, 1H) 7.53-7.58 (m, J=7.17, 5.34 Hz, 1H) 4.12 (s, 3H) 3.86-3.90 (m, 2H) 3.63-3.68 (m, 2H) 3.43-3.55 (m, 4H).
Reaction SMILES: C[O:2][C:3](=[O:45])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28]CC3C=CC=CC=3)[C:25]([C:36](=O)[CH2:37][Cl:38])=[CH:24][C:23]=2[CH2:40][CH3:41])[C:12]=1[CH2:42][CH2:43][CH3:44].Cl.C(S[C:55](=[NH:57])[NH2:56])C1C=CC=CC=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)C>[ClH:38].[CH2:40]([C:23]1[CH:24]=[C:25]([C:36]2[NH:56][CH:55]=[N:57][CH:37]=2)[C:26]([OH:28])=[CH:27][C:22]=1[O:21][CH2:20][CH2:19][CH2:18][O:17][C:13]1[C:12]([CH2:42][CH2:43][CH3:44])=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]([OH:2])=[O:45])[CH3:41]
Reactant: N=C(N)SCc1ccccc1
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(C(=O)CCl)cc2CC)cccc1Oc1ccccc1C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCc1c(OCCCOc2cc(O)c(-c3cnc[nH]3)cc2CC)cccc1Oc1ccccc1C(=O)O
Yield: 53.5 %

Procedure:
A mixture of 2-(3-{3-[5-benzyloxy-4-(2-chloroacetyl)-2-ethylphenoxy]propoxy}-2-propylphenoxy)benzoic acid methyl ester (800 mg, 1.27 mmol), 2-benzyl-2-thiopseudourea hydrochloride (313 mg, 1.52 mmol), sodium iodide (77 mg, 0.51 mmol), and potassium carbonate (700 mg, 5.06 mmol) in N,N-dimethylformamide (20 mL) was treated at 80° C. for 6 h. The mixture was cooled, diluted with diethyl ether, and washed once with water. The organic layer was dried (sodium sulfate), filtered, and concentrated in vacuo. Chromatography (silica gel, 30% ethyl acetate/70% hexane) of the residue provided 376 mg (40%) of the title compound as a yellow amorphous solid. 1H NMR (CDCl3) δ 7.89 (d, J=8 Hz, 1H), 7.36 (m, 9H), 7.20 (m, 5H), 7.21 (d, J=9 Hz, 1H), 7.06 (d, J=8 Hz, 1H), 6.79 (d, J=8 Hz, 1H), 6.67 (d, J=8 Hz, 1H), 6.55 (s, 1H), 6.43 (d, J=8 Hz, 1H), 5.07 (s, 2H), 4.21 (t, J=6 Hz, 2H), 4.18 (t, J=6 Hz, 2H) , 4.10 (s, 2H), 3.83 (s, 3H), 2.63 (m, 4H), 2.31 (quintet, J=6 Hz, 2H), 1.55 (hextet, J=7 Hz, 2H), 1.18 (t, J=8 Hz, 3H), 0.90 (t, J=7 Hz, 3H); TOF MS ES exact mass calculated for C45H47N2O6S (p+1): m/z=743.3155. Found: 743.3142; IR (CHCL3, cm−1) 2963, 1720, 1602, 1453. Anal. Calcd for C45H46N2O6S: C, 72.75; H. 6.24; N, 3.77. Found: C, 72.69; H, 6.17; N, 3.56.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([O:9][CH3:10])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:17]([OH:20])[CH:18]=[CH2:19]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([O:20][CH2:17][CH:18]=[CH2:19])[C:5]([O:9][CH3:10])=[CH:4][N:3]=1
Reactant: C=CCO
Reactant: COc1cnc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: C=CCOc1nc(Cl)ncc1OC
Temperature: 70 °C
Yield: 99.7 %

Procedure:
A mixture of 2,4-dichloro-5-methoxypyrimidine (85 g, 475 mmol), and K2CO3 (78.8 g, 570 mmol) in allyl alcohol (320 mL, 4.75 mol) was heated to 70° C. for 5 h before being cooled to r.t. and diluted with DCM, filtered through Celtic (DCM wash) and concentrated to give 95.0 g (99.7%) of 2-chloro-5-methoxy-4-(prop-2-en-1-yloxy)pyrimidine. 1H-NMR (CDC3, 300 MHz) δ 7.85 (s, 1H), 6.09-5.99 (m, 1H), 5.43-5.38 (in, 1H), 5.31-5.27 (m, 1H), 4.91 (m, 2H), 3.87 (s, 3H). MS (ESI) m/z (M+H)+ 201.0.
Reaction SMILES: [BH4-].[Na+].O1CCCC1.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:13]([C:15](O)=[O:16])[CH:14]=1.II>CO>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[C:13]([CH:14]=1)[CH2:15][OH:16]
Reactant: Nc1ccc(N2CCOCC2)c(C(=O)O)c1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(N2CCOCC2)c(CO)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A 50 mL two necked round bottom flask was fitted with a magnetic stirrer bar and a dropping funnel. A suspension of NaBH4 in tetrahydrofuran (100 mg, 2.4 mmol/10 mL) was added, followed by 5-amino-2-morpholinobenzenecarboxylic acid (222 mg, 1.0 mmol) in one portion. A reflux condenser was fitted and the reaction mixture was cooled to 0° C. under nitrogen atmosphere. A solution of iodine in tetrahydrofuran (250 mg, 1.0 mmol/15 mL) was added dropwise to the reaction mixture. After iodine addition was completed and gas evolution had ceased, the reaction mixture was heated at reflux for 6 hours and left stirring at room temperature overnight. Methanol was added slowly until the mixture became clear. The resulting solution stirred at room temperature for 30 minutes then solvent was removed under reduced pressure. The residue was dissolved in 20% KOH (30 mL), stirred for 4 hours and extracted with dichloromethane (3×30 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated to give 5-amino-2-morpholinobenzyl alcohol as an off-white solid (150 mg, 72% yield). 1H NMR (300 MHz, CDCl3) δ 7.05 (d, J=8.7 Hz, 1H), 6.59 (dd, J=8.4, 2.7 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 5.51 (br s, 1H), 4.71 (s, 2H), 3.84 (t, J=5.1 Hz, 4H), 3.60 (br s, 2H), 2.91 (t, J=5.1 Hz, 4H). LC-ESI-MS (method B): rt 2.31 min.; m/z 209.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C=O)C>[N:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:10]=[C:9]3[C:5]([CH2:6][CH2:7][N:8]3[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Br)cc21
Reactant: OB(O)c1ccncc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(-c3ccncc3)cc21
Temperature: 70 °C
Reaction time: 6 h
Yield: 40.1 %

Procedure:
To a 20 ml vial was added tert-butyl 6-bromoindoline-1-carboxylate 50.A (500 mg, 1.7 mmole), 4-pyridylboronic acid (309 mg, 2.5 mmol), tetrakis(triphenylphosphine) palladium(388, 0.34 mmol), DMF and 3 ml of saturated sodium carbonate. The reaction was stirred at 70° C. for 6 hours at which time the reaction mixture was partitioned between 300 ml EtAc and 200 ml of water. The organic solvent was removed by rotary evaporation and the crude product purified by reverse phase preparative HPLC to give tert-butyl 6-(pyridin-4-yl)indoline-1-carboxylate 50.B as a yellow solid (202 mg, 41% yield).
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].Br[C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[O:23][CH3:24]>>[NH2:1][C:2]1[C:3]([C:4]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Reactant: COc1ccc(F)cc1Br
Product: COc1ccc(F)cc1C(=O)c1ccc(Cl)nc1N

Procedure:
The title compound was prepared from 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (Example 3) and 2-bromo-4-fluoroanisole (Aldrich) using the procedure described in Example 7. HRMS, observed: 280.0417, Calcd for M+: 280.0415.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:34])[CH:12]([NH:13][C:14](=[O:33])[CH:15]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:32])=[O:31])=[CH:26][CH:25]=3)[NH:16]C(OC(C)(C)C)=O)[C@H:4]2[S:3]1>C(O)=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:34])[CH:12]([NH:13][C:14](=[O:33])[CH:15]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([CH3:32])=[O:31])=[CH:26][CH:25]=3)[NH2:16])[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(NC(=O)OC(C)(C)C)c3ccc(S(C)=O)cc3)[C@H]2S1
Solvent: O=CO
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccc(S(C)=O)cc3)[C@H]2S1
Yield: 64.4 %

Procedure:
A solution of 2-methyl-7-[N-(tert.-butoxycarbonyl)-2-(4-methylsulfinylphenyl)glycyl]amino-3-cephem-4-carboxylic acid (2.9 g) in formic acid (7.5 ml) was stirred for 1 hour at room temperature under anhydrous condition. After the reaction was completed, the solvent was removed under reduced pressure from the reaction mixture, and the residue was dissolved in a small amount of water, after which acetonitrile was added to the solution, and the precipitated crystals were collected by filtration. The crystals were dissolved in water and the solution was lyophilized to give powdery 2-methyl-7-[2-(4-methylsulfinylphenyl)glycyl]amino-3-cephem-4-carboxylic acid (1.5 g), mp 178° to 180° C. (dec.). ##STR48##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]2[N:6]([CH2:8][CH2:9][N:10]=2)[CH:7]=1>CC(C)=O.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]([Cl:11])[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1
Reactant: ClC1=CC(Br)=CN2CCN=C12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: Clc1cc(Br)cn2ccnc12
Temperature: 25 °C
Yield: 61.6 %

Procedure:
2.08 g of 6-bromo-8-chloro-2,3-dihydroimidazo[1,2-a]pyridine was dissolved in 36 mL acetone, and together with 9.1 g of manganese dioxide, the mixture was heated for 9 hours under reflux. The reaction solution was cooled to room temperature, filtered through Celite and washed with ethyl acetate. The solvent was removed, and the resulting crude product was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 1.27 g of the title compound (pale yellow crystals).
Reaction SMILES: [CH3:1][C:2](=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].[Cl-].[Ce+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:1][C:2](=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)[CH2:3][OH:4]
Reactant: CCOC(=O)C(C)=Cc1ccc(C)cc1
Agent: [Al+3]
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CC(=Cc1ccc(C)cc1)CO
Reaction time: 0.5 h
Yield: 42.5 %

Procedure:
To a suspension of ethyl 2-methyl-3-(4-methylphenyl)-2-propenoate (26.31 g, 128.8 mmol) and cerium chloride (10.32 g, 41.89 mmol) in tetrahydrofuran (120 ml) was added in four portions at −40° C. over a period of 30 minutes lithium aluminum hydride (4.89 g, 129 mmol) and the resulting mixture was stirred at the same temperature for 30 minutes. Water was added into the reaction solution and the product was extracted twice with ethyl acetate. The combined extracts were washed with water, dried on magnesium sulfate, and then concentrated under reduced pressure to obtain 8.87 g (42% yield) of the oily title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[C:15]([O:19][C:20]([NH:22][C:23]1([C:27](O)=[O:28])[CH2:26][CH2:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:15]([O:19][C:20]([NH:22][C:23]1([C:27]([NH:1][C:2]2[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=2)=[O:28])[CH2:26][CH2:25][CH2:24]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(NC(=O)C2(NC(=O)OC(C)(C)C)CCC2)cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 46.4 %

Procedure:
To a solution of ethyl 4-aminocinnamate (1.00 g, 5.23 mmol) and 1-tert-butoxycarbonylaminocyclobutanecarboxylic acid (1.24 g, 5.75 mmol) in N,N-dimethylformamide (10 ml) were added 1-hydroxybenzotriazole monohydrate (1.44 g, 9.41 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (1.80 g, 9.41 mmol) under ice-cooling, and the mixture was stirred at room temperature for 21 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure and hexane:diethyl ether (2:3) solution was added to the obtained residue. The precipitated solid was collected by filtration and washed with hexane:diethyl ether (2:3) solution. The obtained solid was dried in vacuo to give ethyl (E)-3-{4-[(1-tert-butoxycarbonylaminocyclobutanecarbonyl)amino]phenyl}acrylate (943 mg, yield 46%).