Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@H:13]1[C@@H:16]([CH2:17][CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:15]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:14]1=[O:32].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:12][C@H:13]1[C@@H:16]([CH2:17][CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:15]([CH2:24][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[C:14]1=[O:32])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)[C@H]1CCc1ccco1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@H]1CCc1ccco1
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
A solution of benzyl chloroformate (485 μL, 3.4 mmols) in methylene chloride (2.5 mL) was added dropwise to a stirred, cooled (ice/H2O bath) solution of (±)-t-butyl 2-[cis-3-amino-4-(2-(2-furyl)ethyl)-2-oxoazetidin-1-yl]acetate (1.0 g, 3.4 mmols) and diisopropylethylamine (592 μL, 3.4 mmols) in methylene chloride (10 mL). Stirring was continued with cooling for 0.5 hr and then for 0.33 hr at ambient temperatures. The solution was sequentially washed with 0.05M (pH 4) ammonium phosphate, H2O, dilute aqueous NaHCO3, and saturated NaCl. The solution was dried (Na2SO4) and concentrated, and the residue was chromatographed on SiO2 (50 g) with hexane-ethyl acetate (2:1). The appropriate fractions were combined and concentrated to leave a viscous oil which was crystallized from diethyl ether-hexane to afford the title compound (1.05 g, 72% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:20][C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:27]=1.C[O-].[Na+].C([NH2:33])=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH2:20][C:21]4[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=4)=[C:14]([C:16]([NH2:33])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:27]=1
Reactant: NC=O
Reactant: COC(=O)c1nc2n(c1Cc1ccnn1C)C1CC(C1)c1ccc(Br)cc1-2
Agent: C[O-]
Agent: [Na+]
Product: Cn1nccc1Cc1c(C(N)=O)nc2n1C1CC(C1)c1ccc(Br)cc1-2

Procedure:
10-bromo-3-((1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-3-((1-methyl-1H-pyrazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 150 mg (110% crude yield) of the crude title compound which was carried forward without further purification.
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].[N:27]1[CH:32]=[C:31]([C:33]([C:35]2[N:36]=[CH:37][N:38]3[CH:42]=[C:41]([Sn](CCCC)(CCCC)CCCC)[S:40][C:39]=23)=[O:34])[CH:30]=[N:29][CH:28]=1>>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C: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]([C:41]3[S:40][C:39]4=[C:35]([C:33]([C:31]5[CH:30]=[N:29][CH:28]=[N:27][CH:32]=5)=[O:34])[N:36]=[CH:37][N:38]4[CH:42]=3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
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
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C(=O)c3cncnc3)c2s1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5cncnc5)c4s3)[C@H](C)[C@H]12
Yield: 73.9 %

Procedure:
4-Nitrobenzyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(pyrimidin-5-yl)carbonylimidazo[5,1-b]-thiazol-2-yl]-1-carbapen-2-em-3-carboxylate (144 mg) was prepared in substantially the same manner as in step a) of Example 1, except that 180 mg of 4-nitrobenzyl (1R,3R,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-oxo-1-carbapenam-3-carboxylate and 176 mg of 7-(pyrimidin-5-yl)carbonyl-2-(tri-n-butylstannyl)imidazo[5,1-b]thiazole were used as the starting compounds.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:34])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:33])[CH3:32])[CH:26]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:52])[C@@H:15]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si](C(C)(C)C)(C)C)[CH2:38]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:34])[CH:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N:31]([CH3:33])[CH3:32])[CH:26]=2)[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:52])[C@@H:15]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([OH:44])[CH2:38]2)=[CH:10]1
Reactant: CCC(Oc1cccc(N(C)C)c1)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1cccc(N(C)C)c1)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 17.7 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.26 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(3-dimethylaminophenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 136, above] and 33.4 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 156 mg of the title compound as yellow crystals, melting at between 124° and 126° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.I[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][N:7]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: CC(C)(C)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOCCOC
Product: CC(C)(C)COc1ccc(Cl)nc1
Reaction time: 0.5 h

Procedure:
5.2 g (40.0 mmol) 6-chloropyridin-3-ol, 11.9 g (60.0 mmol) 1-iodo-2,2-dimethylpropane, 19.6 g (60.0 mmol) cesium carbonate and 120 ml diethylene glycol dimethyl ether are divided into five portions of equal size and are reacted in portions at 160° C. for 4 h in a single mode microwave (CEM Explorer). Thereafter, the five reaction mixtures obtained are combined, the solid is filtered off and rinsed with diethylene glycol dimethyl ether and the filtrate and wash solutions are combined. The majority of the solvent is removed and 300 ml water are added to the concentrated solution (approx. 50 ml). The mixture is stirred for 30 min and the solid obtained is filtered off, washed once with water and dried under a high vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][CH2:18][C:19](Cl)=[O:20])[CH2:12]1>>[CH2:11]1[CH2:16][CH2:15][CH2:14][CH:13]([CH2:17][CH2:18][C:19]([NH:1][C:2]2[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=2)=[O:20])[CH2:12]1
Reactant: O=C(Cl)CCC1CCCCC1
Reactant: Nc1ccc(C(=O)O)cc1
Product: O=C(CCC1CCCCC1)Nc1ccc(C(=O)O)cc1

Procedure:
4-(3-Cyclohexanepropionylamino)-benzoic acid was prepared as described in Example 3 from 10.0 g (0.073 mol) of p-aminobenzoic acid and 14.0 g (0.08 mol) of 3-cyclohexanepropionyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH2:20][C:21]([O:23]C(C)(C)C)=[O:22])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=O)=[O:9]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])=[O:9]
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1-c1ccc(S(C)(=O)=O)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)c1ccc(-c2cc(Cl)ccc2OCC(=O)O)cc1Cl

Procedure:
A solution of the more polar product from Example 2 step d) (35 mg) in TFA (2 ml) was stirred for 24 h. The solvent was removed in vacuo, the mixture was azeotroped with toluene and purified by chromatography (silica, CH2Cl2-MeOH—AcOH as eluent) to give the title compound (22 mg) as a white solid.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(N(CC)CC)C.[C:35]1([CH2:41][CH2:42][S:43][CH:44]([C:48](O)=[O:49])[C:45](O)=[O:46])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[O:15][C:45](=[O:46])[C:44]([S:43][CH2:42][CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:48]([OH:49])[CH:14]=2)[CH:8]=1
Reactant: CC(=O)c1cccc(-c2ccccc2)c1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1oc(-c2cccc(-c3ccccc3)c2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 3'-phenylacetophenone (2.00 g, 10.21 mmol), trimethylsilyltriflate (2.36 mL, 12.24 mmol), triethylamine (2.84 mL, 20.40 mmol), methylene chloride (26 mL), and diethyl ester of [(2-phenylethyl)thio]propanedioic acid (1.00 g, 3.37 mmol). m.p. 93°-94° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.79 (t, 2 H), 3.01 (t, 2 H), 6.92 (s, 1 H), 7.21 (m, 5 H), 7.42 (t, 1 H), 7.52 (t, 2 H), 7.64 (t, 1 H), 7.75 (d, 2 H), 7.82 (t, 2 H), 8.02 (s, 1 H).
Reaction SMILES: [CH:1]1([N:4]2[CH2:9][CH2:8][N:7]([C:10]3[N:15]=[N:14][C:13]([C:16]4[CH:17]=[C:18]([NH2:22])[CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[CH2:3][CH2:2]1.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>>[CH:1]1([N:4]2[CH2:5][CH2:6][N:7]([C:10]3[N:15]=[N:14][C:13]([C:16]4[CH:17]=[C:18]([NH:22][C:26]([CH:23]5[CH2:25][CH2:24]5)=[O:27])[CH:19]=[CH:20][CH:21]=4)=[CH:12][CH:11]=3)[CH2:8][CH2:9]2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)c1
Product: O=C(Nc1cccc(-c2ccc(N3CCN(C4CC4)CC3)nn2)c1)C1CC1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 170, starting from 3-[6-(4-cyclopropyl-piperazin-1-yl)-pyridazin-3-yl]-phenylamine and cyclopropanecarbonyl chloride. 1H NMR (300 MHz, CD3OD) δ 8.08 (d, 1H), 7.82 (d, 1H), 7.66-7.62 (m, 2H), 7.44-7.39 (m, 1H), 7.33 (d, 1H), 3.69-3.65 (m, 4H), 2.80-2.77 (m, 4H), 1.79-1.71 (m, 2H), 0.97-0.94 (m, 2H), 0.89-0.85 (m, 2H), 0.55-0.49 (m, 4H).
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][N:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)[CH3:33])=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][N:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=3)=[CH:36][CH:35]=2)[CH3:33])=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CN(C)c2ccc(-c3ccc(Cl)cc3)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(Cc1ccc(Cl)cc1-c1ccc(C(=O)NCCC(=O)O)nc1)c1ccc(-c2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
A 3M aqueous solution of NaOH (0.29 mL, 0.88 mmol) was added to a THF (2 mL) and MeOH (1 mL) solution of ethyl 3-(5-(5-chloro-2-(((4′-chloro-[1,1′-biphenyl]-4-yl)(methyl)amino)methyl)phenyl)picolinamido)propanoate (165 mg, 0.29 mmol) and the resulting homogeneous mixture was stirred at room temperature. After 16 h the mixture was concentrated in vacuo, suspended in water, and acidified with 2 M HCl. The resulting precipitate was filtered off and dried in vacuo to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]([N:6]([CH3:8])[CH3:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.[C:59]([C:61]1[CH:66]=[CH:65][C:64]([CH2:67][C:68]([NH:70][NH:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])=[O:69])=[CH:63][CH:62]=1)#[CH:60]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][N:6]([CH3:8])[C:5]1[CH:9]=[CH:10][C:2]([C:60]#[C:59][C:61]2[CH:62]=[CH:63][C:64]([CH2:67][C:68]([NH:70][NH:71][C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])=[O:69])=[CH:65][CH:66]=2)=[CH:3][CH:4]=1
Reactant: C#Cc1ccc(CC(=O)NNC(=O)OC(C)(C)C)cc1
Reactant: CN(C)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CN(C)c1ccc(C#Cc2ccc(CC(=O)NNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 38.3 %

Procedure:
To a mixture of 4-bromo-N,N-dimethylaniline (175 mg, 0.88 mmol), cesium carbonate (476 mg, 1.46 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (22 mg, 0.04 mmol) and bis(acetonitrile)dichloropalladium (II) (10 mg, 0.04 mmol) was added anhydrous acetonitrile (2 ml), and the mixture was stirred at room temperature for 15 mins. A solution of tert-butyl 2-[(4-ethynylphenyl)acetyl]hydrazinecarboxylate (200 mg, 0.73 mmol) in anhydrous acetonitrile (4 ml) was added, and the mixture was stirred at 80° C. for 5 hrs. After cooling, the reaction mixture was filtered, and the insoluble material was washed with ethyl acetate. The filtrate and washing solution were combined and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (chloroform:methanol=97:3) to give tert-butyl 2-[(4-{[4-(dimethylamino)phenyl]ethynyl}phenyl)acetyl]hydrazinecarboxylate (110 mg, yield 38%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:9]([CH2:22][NH:23][CH3:24])=[C:10]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>>[C:1]([O:5][C:6]([C:8]1[C:9]([CH2:22][NH:23][CH3:24])=[C:10]([C@H:14]2[CH2:15][CH2:16][C@H:17]([N:20]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH3:21])[CH2:18][CH2:19]2)[CH:11]=[CH:12][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1c(C(=O)OC(C)(C)C)cccc1[C@H]1CC[C@H](NC)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CNCc1c(C(=O)OC(C)(C)C)cccc1[C@H]1CC[C@H](N(C)C(=O)c2ccc(Cl)cc2)CC1

Procedure:
from trans-4-(3-tert.butoxycarbonyl-methylaminomethylphenyl)-N-methylcyclohexylamine and 4-chlorobenzoylchloride. Melting point: 134°-135° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:21]=[CH:20][C:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19][C:13]=3[CH:12]=2)=[C:6]([O:22][CH3:23])[CH:5]=1.[C:25]1(=O)[CH2:28][CH2:27][CH2:26]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C.CO>[CH:25]1([N:17]2[CH2:16][CH2:15][C:14]3[CH:20]=[CH:21][C:11]([O:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:2][CH3:1])=[O:24])=[CH:5][C:6]=4[O:22][CH3:23])=[CH:12][C:13]=3[CH2:19][CH2:18]2)[CH2:28][CH2:27][CH2:26]1
Reactant: CNC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)c(OC)c1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CNC(=O)c1ccc(Oc2ccc3c(c2)CCN(C2CCC2)CC3)c(OC)c1
Reaction time: 0.25 h
Yield: 21.9 %

Procedure:
N-Methyl-3-(methyloxy)-4-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yloxy)benzamide (E264, Step 6) (78 mg, 0.24 mmol) was dissolved in dry dichloromethane (5 ml), treated with cyclobutanone (0.04 ml, 0.48 mmol) and acetic acid (1 drop) and the resulting mixture stirred for 15 minutes. Sodium triacetoxyborohydride (102 mg, 0.48 mmol) was added and the mixture stirred for 30 minutes. The mixture was diluted with methanol and applied to a SCX column eluting with methanol and then a mixture of 0.880 ammonia/methanol (1:9). The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography eluting with a mixture of ammonia:methanol:dichloromethane (0.5:4.5:95.880) to afford the title compound (20 mg); MS (ES+) m/e 381 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21]Cl)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=2)[NH:27][CH:26]=1)#[N:24].[OH-].[Na+].[Cl-]>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][N:27]4[C:28]5[C:33](=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=5)[C:25]([C:23]#[N:24])=[CH:26]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCCCl)ccc3o2)n1
Reactant: Cc1ccc2c(C#N)c[nH]c2c1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc2c(C#N)cn(CCCc3ccc4oc(-c5nc(C(C)(C)C)cs5)cc4c3)c2c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 42.5 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(3-chloropropyl)-benzofuran-2-yl]thiazole (0.19 g), 3-cyano-6-methylindole (73 mg), sodium hydroxide (90 mg) and small amount of cetyl trymethylammonium chloride in tetrahydrofuran (1 ml) was stirred at 60° C. for 1 day. After the mixture was cooled to room temperature, the insolble mass was filtered off and the filtrate was concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fraction containing the objective compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-{5-[3-(3-cyano-6-methylindole-1-yl)propyl]-benzofuran-2-yl}thiazole (90 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19]C4CCNCC4)=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)[N:7]=[C:6]([C:30]#[N:31])[C:5]=2[N:4]=[CH:3]1.[CH3:32][N:33](C)[CH2:34]C(O)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN1C(=O)CCC1.CCOC(C)=O>[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:32][NH:33][CH3:34])=[C:13]([C:26]([F:29])([F:28])[F:27])[CH:12]=3)[N:7]=[C:6]([C:30]#[N:31])[C:5]=2[N:4]=[CH:3]1
Reactant: Cn1cnc2c(C#N)nc(-c3ccc(OCCC4CCNCC4)c(C(F)(F)F)c3)cc21
Reactant: CN(C)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CNCCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Methyl-6-(4-(2-(piperidin-4-yl)ethoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (0.188 g), 2-(dimethylamino)acetic acid (0.090 g) and DIPEA (0.362 ml) were dissolved in NMP (2.5 ml) and HATU (0.250 g) was then added. The reaction was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (30 mL) and washed with saturated sodium bicarbonate solution. Organics were dried over sodium sulphate to yield crude. Purification by flash chromatography (10 g SiO2 column, DCM to 5% MeOH in DCM gradient) afforded methyl-6-(4-(3-(methylamino)propoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile. (59 mg)
Reaction SMILES: C[O:2][C:3](=[O:38])[C@H:4]([OH:37])[CH2:5][NH:6][C:7](=[O:36])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[OH-].[Na+]>CO>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([O:19][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][C@@H:4]([OH:37])[C:3]([OH:38])=[O:2])=[O:36])=[CH:13][CH:12]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:21][CH:22]=2)=[CH:31][CH:30]=1)([CH3:34])([CH3:35])[CH3:33]
Reactant: COC(=O)[C@H](O)CNC(=O)c1ccc(C(CC(C)C)Oc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(Oc1ccc(-c2ccc(C(C)(C)C)cc2)cc1)c1ccc(C(=O)NC[C@@H](O)C(=O)O)cc1
Reaction time: 5 h
Yield: 104.2 %

Procedure:
To a mixture of 3-{4-[1-(4′-tert-butyl-biphenyl-4-yloxy)-3-methyl-butyl]-benzoylamino}-2(R)-hydroxy-propionic acid methyl ester (60 mg, 0.12 mmol) in methanol (2 mL) is added sodium hydroxide (5 N aqueous, 0.5 mL) and stirred for 5 h. The reaction mixture is concentrated and acidified by 5 N HCl (0.5 mL), extracted with ethyl acetate. Combined organic layers are washed with water and brine, dried over sodium sulfate. Concentration gives the title compound (63 mg). MS (ES): 504.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[C:16]([CH2:18][C:19]([OH:21])=[O:20])#[N:17]>>[C:19](/[C:18](=[CH:8]/[CH:7]=[CH:6]/[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=1)/[C:16]#[N:17])([OH:21])=[O:20]
Reactant: COc1cc(C=CC=O)cc(OC)c1O
Reactant: N#CCC(=O)O
Product: COc1cc(/C=C/C=C(\C#N)C(=O)O)cc(OC)c1O

Procedure:
The compound was prepared as described in Example 3 by adding 3,5-dimethoxy-4-hydroxycinnamaldehyde (0.15 g, 0.72 mmol) to cyanoacetic acid (0.061 g, 0.72 mmol). After refluxing for 1 h and recrystallization from ethanol a yellow solid was obtained (0.15 g, 75%). The product gave the following analytical data:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:31]/[O:32][C:33]2([C:36]([O:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:35][CH2:34]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH2:29][OH:30])[CH:26]=[N:25]2)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:61][S:62](Cl)(=[O:64])=[O:63]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:31]/[O:32][C:33]2([C:36]([O:38][CH:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[O:37])[CH2:34][CH2:35]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][N:24]2[N:28]=[C:27]([CH2:29][O:30][S:62]([CH3:61])(=[O:64])=[O:63])[CH:26]=[N:25]2)=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CO)n2)cs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(COS(C)(=O)=O)n2)cs1
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2R,3S)-2-((4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (178 mg, 0.25 mmol) and DIPEA (65 μL, 0.37 mmol) in DCM (2.5 mL) at 0° C. was added MsCl (25 μL, 0.32 mmol). After 1 h at 0° C., the reaction mixture was diluted with DCM (10 mL), washed with 0.2 N HCl and saturated NaHCO3 (aq). The organic layer was dried over Na2SO4, concentrated in vacuo to afford the title compound (190 mg, 96%). The crude residue was used as such in the following step. LCMS: Rt=1.05 min, m/z=795.4 (M+1) Method 2m_acidic.