Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][C:3]1=[O:12].FC(F)(F)C(O)=O.[NH2:28][C@@H:29]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3](=[O:12])[C:2]2([NH:28][C@@H:29]([CH2:35][C:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38][CH:37]=1)[C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]
Reactant: CN(C)C(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: COc1ccccc1C1(Cl)C(=O)Nc2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccccc1C1(N[C@@H](Cc2c[nH]c3ccccc23)C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21

Procedure:
With 2.02 g of 3,5-dichloro-3-(2-methoxyphenyl)-1,3-dihydro-2H-indol-2-one and the compound obtained in Step 72-2 (7.54 mmol, crude form) as starting materials, respectively 0.96 g (Isomer A, colorless solid) and 1.64 g (Isomer B, pale brownish red amorphous) of two species of diastereoisomers of the title compound were obtained by a similar method to Step 4-2.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[C:28]12([NH2:38])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>C(Cl)(Cl)Cl>[C:28]12([NH:38][C:12]([C:9]3[C:8](=[O:15])[N:7]4[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]4=[N:11][CH:10]=3)=[O:14])[CH2:35][CH:34]3[CH2:33][CH:32]([CH2:31][CH:30]([CH2:36]3)[CH2:29]1)[CH2:37]2
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cccc2ncc(C(=O)NC34CC5CC(CC(C5)C3)C4)c(=O)n12
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
A mixture containing 4.08 (0.02 mole) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 3.1 ml (0.022 mol) of triethylamine in 120 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 2.52 ml (0.026 mol) of methyl chloroformate in 10 ml of chloroform is dropped to the above mixture at -15° C. during 10 minutes. After stirring for 5 minutes, 3.33 g (0.022 mol) of 1-adamantanamine dissolved in 20 ml of chloroform are dropped to the above solution at -15° C. during 15 minutes. The reaction mixture is stirred below -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 70 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 70 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 4.4 g (65.2%) of the named product as pale yellow crystals after recrystallization from ethanol, m.p.: 190°-193° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[C:11]([O:16][C:17]([F:20])([F:19])[F:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.C[O:27][B:28](OC)[O:29]C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([B:28]([OH:29])[OH:27])=[C:11]([O:16][C:17]([F:20])([F:19])[F:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)Oc1cc(OCc2ccccc2)ccc1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(OCc2ccccc2)cc1OC(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 135.8 %

Procedure:
To a mixture of 4-(benzyloxy)-1-bromo-2-(trifluoromethoxy)benzene (1.8 g, 5.19 mmol) in THF (20 mL) was added butyllithium (2.5 M in THF, 2.28 mL, 5.70 mmol) at −78° C. dropwise over 10 minutes. The reaction mixture was stirred at −78° C. for 1 h, then trimethylborate (1.73 mL, 15.6 mmol) was added. The mixture was warmed to room temperature and stirred overnight. The mixture was concentrated from diethyl ether three times and the residue was dried on high vacuum to provide the title compound as a gummy solid (2.2 g, 61% pure, 83% yield). The crude material was carried on without further purification. MS (M−1)=311.3
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][C:8]=1[O:15][CH3:16])(=O)=O.CCOC(C)=O.[CH3:25][N:26](C=O)C>[C-]#N.[Zn+2].[C-]#N>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([C:25]#[N:26])=[C:8]([O:15][CH3:16])[CH:9]=1)=[O:14]
Reactant: COc1cc(C=O)ccc1OS(=O)(=O)C(F)(F)F
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(C=O)ccc1C#N
Temperature: 110 °C
Reaction time: 8 h

Procedure:
A mixture of 4-formyl-2-methoxyphenyl trifluoromethanesulfonate (37.0 g, 130 mmol), zinc cyanide (61.0 g, 521 mmol) and tetrakis triphenylphosphine palladium (0) (22.6 g, 19.5 mmol) in DMF (300 mL) were stirred at 110° C. for 8 h. EtOAc was added to the reaction mixture and the organic layer was washed two times with water, dried, filtered and concentrated. The crude product was then purified by column chromatography (silica gel, ethylacetate/hexanes 3:7) which afforded 4-formyl-2-methoxybenzonitrile.
Reaction SMILES: Cl[C:2](=[O:25])[C@@H:3]([NH:7][C:8](=[O:24])[O:9][CH2:10][CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]([CH3:6])[CH3:5].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[NH:34][C:35]([CH:37]1[C:45]([CH3:47])([CH3:46])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH:38]1)=[O:36].N1C=CC=CC=1>C(Cl)Cl.CCOC(C)=O>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[NH:34][C:35]([CH:37]1[C:45]([CH3:47])([CH3:46])[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:38]1[C:2](=[O:25])[C@@H:3]([NH:7][C:8](=[O:24])[O:9][CH2:10][CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:4]([CH3:6])[CH3:5])=[O:36]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Cl
Reactant: CC1(C)c2ccccc2NC1C(=O)Nc1c(F)cccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1c2ccccc2C(C)(C)C1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 114.8 %

Procedure:
(S)-(9H-fluoren-9-yl)methyl 1-chloro-3-methyl-1-oxobutan-2-ylcarbamate (0.11 g, 307 μmol, Eq: 3.1) was added to a solution of N-(2,6-difluorophenyl)-3,3-dimethylindoline-2-carboxamide (30 mg, 99.2 μmol, Eq: 1.00) and pyridine (40 μL, 496 μmol, Eq: 5) in DCM (1 mL) and the resulting solution was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with 1 M aqueous HCl (10 mL), 1 M aqueous NaOH (10 mL) and brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 30% EtOAc in hexanes) to give (S)-(9H-fluoren-9-yl)methyl 1-(2-(2,6-difluorophenylcarbamoyl)-3,3-dimethylindolin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate as a viscous oil (71 mg).
Reaction SMILES: [Mg].[CH3:2][Ge:3](Cl)([CH3:5])[CH3:4].Br[C:8]1[CH:9]=[C:10]([C:14]2([CH3:19])[O:18][CH2:17][CH2:16][O:15]2)[CH:11]=[CH:12][CH:13]=1>O1CCCC1>[CH3:2][Ge:3]([CH3:5])([CH3:4])[C:8]1[CH:9]=[C:10]([C:14]2([CH3:19])[O:18][CH2:17][CH2:16][O:15]2)[CH:11]=[CH:12][CH:13]=1
Reactant: C[Ge](C)(C)Cl
Reactant: CC1(c2cccc(Br)c2)OCCO1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(c2cccc([Ge](C)(C)C)c2)OCCO1
Yield: 103.7 %

Procedure:
A mixture of 81 mg (3.33 mmol) of magnesium and 574 mg (3.75 mmol) of trimethylgermyl chloride was stirred at 40°-50° C. in an atmosphere of argon. To the mixture was added a solution of 729 mg (3.00 mmol) of 2-(3-bromophenyl)-2-methyl-1,3-dioxolane in 10 ml of tetrahydrofuran with stirring. The mixture was refluxed for 2.5 hr. and stirred at room temperature overnight. To the reaction mixture was added petroleum ether and the insoluble substance was filtered off. The filtrate was evaporated to give 874 mg of pale yellow crystals, which were purified by column chromatography on silica gel [eluent: methylene chloride-n-hexane (1:1)] to give 657 mg of white cubes, m.p. 62.5°-63.5° C. (yield 78%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][C:13]1[N:17]2[N:18]=[C:19]([C:22](=O)[CH3:23])[CH:20]=[CH:21][C:16]2=[N:15][CH:14]=1.Cl.[CH2:26]([O:28][NH2:29])[CH3:27].C(N(CC)CC)C>CO>[CH2:26]([O:28]/[N:29]=[C:22](/[C:19]1[CH:20]=[CH:21][C:16]2[N:17]([C:13]([CH2:12][C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][C:2]=3[F:1])[N:9]=[CH:8][CH:7]=[CH:6]4)=[CH:14][N:15]=2)[N:18]=1)\[CH3:23])[CH3:27]
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Reactant: CCON
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCO/N=C(\C)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a solution of 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone (50 mg, 0.16 mmol) in methanol (10 mL) was added O-ethylhydroxylamine hydrochloride (46 mg, 0.47 mmol). Triethyl amine was added dropwise to adjust the pH to 5-6. The reaction mixture was stirred at rt overnight. The solution was concentrated under reduced pressure and the residue was purified by prep-HPLC to afford 30 mg (53%) of the title compound as a white solid. 1H-NMR (400 MHz, MeOH-d4) δ ppm 8.82 (dd, 1H), 8.30 (d, 1H), 7.93 (m, 2H), 7.85 (d, 1H), 7.70 (d, 1H), 7.66 (s, 1H), 7.49 (q, 1H), 4.62 (s, 2H), 4.31 (q, 2H), 2.27 (s, 3H), 1.36 (t, 3H). LCMS (method C): [MH]+=364, tR=4.71 min.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[CH2:3][OH:4].[N:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]=[CH:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=3)[N:22]=2)=[CH:17][CH:16]=1)=[C:13]=[S:14]>>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:2]([NH:1][C:13]([NH:12][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:25]=[CH:24][N:23]([C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=4)[N:22]=3)=[CH:19][CH:20]=2)=[S:14])[CH2:3][OH:4])=[CH:6][CH:7]=1
Reactant: FC(F)(F)Oc1ccc(-n2cnc(-c3ccc(N=C=S)cc3)n2)cc1
Reactant: NC(CO)c1ccc(F)cc1
Product: OCC(NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccc(F)cc1

Procedure:
The title compound was prepared with 2-amino-2-(4-fluorophenyl)ethanol and 3-(4-isothiocyanato-phenyl)-1-(4-trifluoromethoxy-phenyl)-1H-1,2,4-triazole and isolated as an off-white solid (1.42 g, 81%): 1H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.72-7.57 (m, 2H), 7.27 (s, 1H), 7.23-7.14 (m, 2H), 6.87-6.72 (m, 4H), 6.64-6.56 (m, 2H), 6.38-6.22 (m, 3H), 5.05 (s, 1H), 3.47-3.28 (m, 2H), 3.20 (s, 3H); ESIMS m/z 530 ([M+H]+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[C:6]([CH3:17])[CH:5]=1)([O-])=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:30].Cl>[Zn].[Cl-].[NH4+].O.C(O)C>[ClH:30].[ClH:30].[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16])=[C:6]([CH3:17])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1NCCCCCO
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Cc1cc(N)ccc1NCCCCCO

Procedure:
The 5-(4-nitro-2-methylphenylamino)pentan-1-ol (19) obtained above was reduced with a boiling zinc/ammonium chloride/water/ethanol mixture. The corresponding amine was isolated in dihydrochloride form.
Reaction SMILES: [Br:1][C:2]1[C:10](Br)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1.FC1(F)OC2C=C(C)C(C3N=C[C:25]([NH:28][C:29](=O)[C:30]4[CH:35]=[CH:34]C=CC=4F)=[N:26]C=3)=CC=2O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(=O)OCC>C(#N)C.O1CCOCC1.O>[Br:1][C:2]1[C:10]([C:30]2[CH:35]=[CH:34][C:25]([NH2:26])=[N:28][CH:29]=2)=[CH:9][C:5]2[O:6][CH2:7][CH2:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1-c1cnc(NC(=O)c3ccccc3F)cn1)OC(F)(F)O2
Reactant: Brc1cc2c(cc1Br)OCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: Nc1ccc(-c2cc3c(cc2Br)CCO3)cn1
Temperature: 85 °C
Yield: 13.9 %

Procedure:
A mixture of 5,6-dibromo-2,3-dihydrobenzo[b]furan (138) (489 mg, 1.75 mmol), 2-aminopyridine-5-boronic acid pinacol ester (11) (465 mg, 1.2 eq), bis(ditertbutyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II) (124 mg, 10% mol) and K3PO4 (371 mg, 1.75 mmol) in 2 ml ACN, 2 ml dioxane, 0.5 ml H2O was bubbled with argon before heated at 85° C. for 2 h. After cooling down to r.t., the reaction mixture was taken up in EA, washed with aq. NaHCO3 and brine. Org. phase was dried over Na2SO4, concentrated and then subjected to silica gel flash column chromatography (0-100% B, A: hexane; B: EA) to give 5-(5-bromo-2,3-dihydrobenzo[3,4-b]furan-6-yl)-2-pyridylamine (139) (48.5 mg, yield: 9.5%) as yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:33]([C:34](=[O:45])[NH:35][C:36]3[CH:44]=[C:43]4[C:39]([CH:40]=[N:41][NH:42]4)=[CH:38][CH:37]=3)=[CH:32][C:17]3[N:18]=[C:19]([NH:21][C:22]4[N:23]([CH:27]5[CH2:31][CH2:30][CH2:29][CH2:28]5)[CH:24]=[CH:25][N:26]=4)[NH:20][C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:42]1[C:43]2[C:39](=[CH:38][CH:37]=[C:36]([NH:35][C:34]([C:33]3[C:14]([N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[CH:15][C:16]4[NH:20][C:19]([NH:21][C:22]5[N:23]([CH:27]6[CH2:28][CH2:29][CH2:30][CH2:31]6)[CH:24]=[CH:25][N:26]=5)=[N:18][C:17]=4[CH:32]=3)=[O:45])[CH:44]=2)[CH:40]=[N:41]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3[nH]c(Nc4nccn4C4CCCC4)nc3cc2C(=O)Nc2ccc3cn[nH]c3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccc2cn[nH]c2c1)c1cc2nc(Nc3nccn3C3CCCC3)[nH]c2cc1N1CCNCC1

Procedure:
The product from Example 182 was treated with 4M HCl in dioxane employing the procedure described for Example 156 to afford 2-(1-cyclopentyl-1H-imidazol-2-ylamino)-6-piperazin-1-yl-1H-benzoimidazole-5-carboxylic acid (1H-indazol-6-yl)amide as a hydrochloride salt. MS: m/z 511 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].FC1C=CC=CC=1CC(=O)C(OCC)=O.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[F:28])[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CCOC(=O)C(=O)Cc1ccccc1F
Agent: [Br-]
Product: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 79 %

Procedure:
The title compound was prepared as described for (C4) by using ethyl 3-(2-fluorophenyl)-2-oxopropanoate B4 (100 mg, 0.476 mmol), sodium hydride (13 mg, 0.523 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-galactose bromide (196 mg, 0.476 mmol). The compound was isolated in the form of white solid in 79% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si:27]([C:31]#[CH:32])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.N#N>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.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11]([F:14])([F:13])[CH2:10][CH:9]1[C:15]1[NH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:32]#[C:31][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:22][CH:21]=2)=[CH:18][N:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(Br)cc2)[nH]1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(F)(F)CC1c1ncc(-c2ccc(C#C[Si](C)(C)C)cc2)[nH]1
Temperature: 80 °C
Yield: 78.8 %

Procedure:
A solution of 2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carboxylic acid tert-butyl ester (700 mg, 1.56 mmol), TMS-acetylene (1.11 mL, 7.79 mmol) and triethylamine (1.1 mL, 7.8 mmol) in DMF (8 mL) was degassed with N2 gas for 20 minutes. To the degassed solution was added Pd(PPh3)4 (180 mg, 0.16 mmol) and CuI (14.8 mg, 0.078 mmol). The pressure flask was sealed then heated at 80° C. overnight. After cooling to room temperature, the reaction was concentrated then diluted with EtOAc and washed with water. The aqueous phase was back-extracted two times then the organic phases were combined and dried over Na2SO4. After concentration, the crude material was purified by silica gel chromatography (10-50% EtOAc-hexanes gradient) to afford 4,4-difluoro-2-[5-(4-trimethylsilanylethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (547 g, 1.23 mmol, 79% yield). LCMS-ESI+: calc'd for C23H30F2N3O2Si: 446.2 (M+H+). Found: 445.8 (M+H+).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:8]=[CH:9][C:10]([NH2:13])=[CH:11][CH:12]=1.C([O:16][C:17](=O)[CH2:18][CH:19]1[CH2:24][CH2:23][C:22]([N:31]([CH3:33])[CH3:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)C.[Cl-].[NH4+]>C1COCC1>[CH3:32][N:31]([CH3:33])[C:22]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21][CH2:20][CH:19]([CH2:18][C:17]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=2)=[O:16])[CH2:24][CH2:23]1
Reactant: CCOC(=O)CC1CCC(c2ccccc2)(N(C)C)CC1
Reactant: Cc1ccc(N)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)CC2CCC(c3ccccc3)(N(C)C)CC2)cc1
Reaction time: 1 h

Procedure:
n-Butyllithium (1.6 M solution in hexane; 11.9 ml; 19 mmol) was added dropwise at 0° C. to a solution of p-tolylamine (1.02 g; 9.5 mmol) in 10 ml THF. The mixture was allowed to come to RT and was subsequently stirred for 1 h. A solution of (4-dimethylamino-4-phenyl-cyclohexyl)-acetic acid ethyl ester (2.5 g; 8.6 mmol) in 15 ml THF was added dropwise at −78° C. The mixture was subsequently stirred for 1 h and then allowed to come to RT. It was hydrolysed with ammonium chloride solution and extracted with MC. After concentration, the crude product was taken up in ether. A solid then remained (less polar diastereoisomer; 1.518 g; 50%); the supernatant was chromatographed on silica gel (eluent:ether, then ether/methanol 4:1). 142 mg (4.7%) of the less polar and 1.20 g (40%) of the more polar diastereoisomer were obtained.
Reaction SMILES: [CH2:1]([C@H:8]1[C@H:11]([CH2:12][CH2:13][OH:14])[NH:10][C:9]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([C@H]1[C@H]([CH2:23][CH2:24][OH:25])NC1=O)(C)C>>[CH2:1]([C@H:8]1[C@H:11]([CH2:12][CH2:13][O:14][C:24](=[O:25])[CH3:23])[NH:10][C:9]1=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1N[C@@H](CCO)[C@@H]1Cc1ccccc1
Reactant: CC(C)[C@@H]1C(=O)N[C@H]1CCO
Product: CC(=O)OCC[C@@H]1NC(=O)[C@H]1Cc1ccccc1

Procedure:
Trans-3-benzyl-4-(2-hydroxyethyl)-2-azetidinone is acetylated as described for the acetylation of trans-3-isopropyl-4-(2-hydroxyethyl)-2-azetidinone to give trans-3-benzyl-4-(2-acetoxyethyl)-2-azetidinone.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:18][C:19]1[CH:40]=[CH:39][C:22]([C:23]([N:25]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29][N:28]3[N:36]=[CH:37][CH:38]=[C:27]3[CH2:26]2)=[O:24])=[CH:21][CH:20]=1>C(Cl)Cl>[N:36]1[N:28]2[C:27]([CH2:26][N:25]([C:23]([C:22]3[CH:21]=[CH:20][C:19]([NH:18][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[CH3:1])=[CH:40][CH:39]=3)=[O:24])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[CH2:29]2)=[CH:38][CH:37]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccnn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 3 mmol of 2-methylbenzoyl chloride in 10 ml of methylene chloride is added 5 mmol of triethylamine and 3 mmol of 5,10-dihydro-5-(4-aminobenzoyl)-4H-pyrazolo-[5,1-c][1,4]benzodiazepine. The mixture is stirred at room temperature for 5 hours and is then washed with water, NaHCO3, and brine. The organic layer is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid, m.p. 142°-146° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][N:15]=1.[C:21](=[O:23])=[O:22]>C1COCC1.O>[Cl:13][C:14]1[C:19]([Cl:20])=[C:18]([CH:17]=[CH:16][N:15]=1)[C:21]([OH:23])=[O:22]
Reactant: Clc1cccnc1Cl
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=C(O)c1ccnc(Cl)c1Cl
Temperature: -78 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of diisopropylamine (7.0 mL, 50 mmol) in anhydrous THF (100 mL) at −25° C. was added a 1.6M solution of nBuLi in hexanes (31 mL, 50 mmol) dropwise under an inert atmosphere. The reaction mixture was then cooled to −78° C. and 2,3-dichloropyridine was added. The reaction mixture was stirred at −78° C. for 3 hours, then poured onto solid carbon dioxide and aged for 18 hours at room temperature. The mixture was diluted with water (100 mL) and washed with diethyl ether (3×40 mL) then cooled to 0° C., acidified with concentrated HCl (ca. 5 mL) and extracted with diethyl ether (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to give the title compound as a white solid (7.7 g, 80%). 1H NMR (d6-DMSO, 400MHz) 8.49 (d, J=5.0 Hz, 1H), 7.72 (d, J=5.0 Hz, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:20]([NH:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[N:28][CH:27]=[CH:26]3)=[O:21])[CH2:10][N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][CH:4]=1.C(Cl)CCl.[CH3:37][C:38]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:39]=1[C:40](O)=[O:41]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:37][C:38]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][C:39]=1[C:40]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([CH2:10][N:11]([C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH3:19])[C:20]([NH:22][C:23]2[CH:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[CH:29]=[N:28][CH:27]=[CH:26]3)=[O:21])=[CH:7][CH:8]=1)=[O:41]
Reactant: CN(CC(C(=O)Nc1ccc2cnccc2c1)c1ccc(CO)cc1)C(=O)OC(C)(C)C
Reactant: Cc1ccc(C(=O)O)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)OCc2ccc(C(CN(C)C(=O)OC(C)(C)C)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 2-(4-(hydroxymethyl)phenyl)-3-(isoquinolin-6-ylamino)-3-oxopropyl(methyl)carbamate (E205-1) in pyridine was added was added EDC, DMAP, and 2,4-dimethylbenzoic acid, and the solution was stirred overnight at room temperature. The mixture was poured into NaHCO3(sat) and extracted with EtOAc. The organics were dried (MgSO4), filtered, and evaporated. Column chromatography (SiO2, 0-5% MeOH/CH2Cl2gradient) gave pure 4-(3-(tert-butoxycarbonyl(methyl)amino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E205-2).