Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:15][CH:14]([CH2:16]O)[CH:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12]1)=O)C1C=CC=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>ClCCl.FC(F)(F)C(O)=O.C(O)C>[C:22]([O:21][C:19]([N:18]1[CH2:16][CH:14]2[CH:13]1[CH2:12][NH:11][CH2:15]2)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC1CN(C(=O)OCc2ccccc2)CC1CO
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC2CNCC21
Temperature: 60 °C
Reaction time: 20 h
Yield: 101.4 %

Procedure:
3-Benzyl, 6-tert-butyl-3,6-diazabicyclo[3.2.0]heptane-3,6-dicarboxylate. To a 1 L round-bottomed flask were added 3-tert-butoxycarbonylamino-4-hydroxymethyl-pyrrolidine-1-carboxylic acid benzyl ester (44 g, 104 mmol) in dichloromethane (150 mL) and trifluoroacetic acid (51 mL). The reaction mixture was stirred for 20 h. The reaction mixture was concentrated under reduced pressure. The residual material was taken up in ethanol (250 mL) and basified with 25% NaOH(aq) to pH ˜12 (70 mL). Additional 25% NaOH(aq) (15 mL) was added and the resulting mixture was warmed to 60° C. for 1.5 h. After cooling to room temperature, the resulting mixture was then slowly added to di-tert-butyl dicarbonate (22.7 g, 104 mmol) in ethanol (30 mL) at room temperature over 40 minutes. The reaction mixture was concentrated under reduced pressure, and the resulting residual was partitioned between H2O and ethyl acetate (250 mL each). The aqueous layer was extracted one more time with ethyl acetate and the combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was further purified by flash column chromatography (2×330 g silica, 15 to 45% EA/hexanes) to provide the title compound (20.9 g, 67%). 1H-NMR (CD3OD, 400 MHz): 7.32 (m, 5H), 5.16 (s, 2H), 4.66 (m, 1H), 4.04 (m, 2H), 3.86 (d, J=12.1 Hz, 1H), 3.45 (m, 1H), 3.25 (m, 1H), 3.02-3.16 (m, 2H), 1.41 (s, 9H). MS (electrospray): exact mass calculated for C18H24N2O4, 332.17; m/z found, 233.1 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=O)(C)(C)C.CO.Cl.Cl>>[N:11]1([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:23])([F:22])[F:24])=[O:25])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: Cl
Solvent: CO
Product: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.6 %

Procedure:
A mixture of 4-(2-trifluoromethyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (2.1 g, 5.87 mmol) and MeOH.HCl (15 mL) was stirred for 30 minutes at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for a further 2 hrs. To complete the reaction HCl gas was then purged into the mixture (NaCl+H2SO4) at 0° C. for 1 hr. The methanol was then evaporated. Toluene (2×20 mL) was added and evaporated. The resultant sticky mass was recrystallized from hexane to afford 1.57 g (91% yield) of piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([Cl:16])[C:13]([Cl:15])=[CH:14][C:9]=2[NH:8][C:7]1=[O:17])[CH3:2].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([Cl:16])[C:13]([Cl:15])=[CH:14][C:9]=2[N:8]([CH2:24][C:23]2[CH:26]=[CH:27][C:20]([Cl:19])=[CH:21][CH:22]=2)[C:7]1=[O:17])[CH3:2]
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)Cn1c(=O)[nH]c2cc(Cl)c(Cl)cc21
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)cc2)c2cc(Cl)c(Cl)cc21

Procedure:
The procedure described in Example 1 was repeated (using the same molar proportions as before) except that 240 mg. (0.0008 mole) of 5,6-dichloro-2-oxo-1-benzimidazolineacetic acid ethyl ester and 134 mg. (0.00083 mole) of p-chlorobenzyl chloride were reacted to afford 3-(p-chlorobenzyl)-5,6-dichloro-2-oxo-1-benzimidazolineacetic acid ethyl ester as the desired final product.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18].[CH2:19]([NH:21][CH2:22][CH3:23])[CH3:20].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.ClCCl.C(#N)C>[CH2:19]([N:21]([CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:18])[CH3:20]
Reactant: CCNCC
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1CCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CCN(CC)CCCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 65 °C
Reaction time: 18 h

Procedure:
1-(3-chloropropyl)-6-nitro-3,4-dihydroquinolin-2(1H)-one (100 mg, 0.359 mmol), diethylamine (263 uL, 3.59 mmol), potassium iodide (596 mg, 3.59 mmol) and potassium carbonate (496 mg, 3.59 mmol) were weighed into an argon purged vial fitted with a magnetic stirbar. Anhydrous acetonitrile (4 mL) was added, and the yellow suspension stirred in a heating block at a temperature of 65° C. for 18 hours. As starting material remained, the reaction was stirred at this temperature for an additional 3 days. After cooling to room temperature, the reaction was diluted with water (10 mL) and dichloromethane (15 mL) and transferred to a separatory funnel. The organic layer was collected, and the aqueous layer extracted twice more with dichloromethane (2×10 mL). The combined organic layers were washed with brine (15 mL) and dried over sodium sulphate. The solution was decanted and concentrated to afford a yellow oil. The product was purified using flash chromatography (2 M NH3 in MeOH:CH2Cl2, 2.5-5:95-97.5) to afford a yellow oil. Yield: 102 mg yellow oil (93%). 1H NMR (CDCl3) δ: 8.14 (dd, J=2.7, 9 Hz, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H), 4.02 (t, J=7.5 Hz, 2H), 3.01 (t, J=7.2 Hz, 2H), 2.73-2.68 (m, 2H), 2.57-2.48 (m, 6H), 1.83-1.73 (m, 2H), 1.04 (t, J=7.2 Hz, 6H). MS (EI): 305 (M+).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1.[OH-].[Na+:19]>>[CH:3]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([S:14]([O-:17])(=[O:15])=[O:16])=[CH:6][CH:5]=1)=[CH2:2].[Na+:19]
Reactant: O=S(=O)(O)c1ccc(CCBr)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Product: C=Cc1ccc(S(=O)(=O)[O-])c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Next, 4-(2-bromoethyl)naphthalenesulfonic acid (10 g) was slowly added dropwise to a 1-mol/L aqueous solution of sodium hydroxide (100 mL), and the whole was stirred for 1 hour at room temperature. After that, the resultant was refluxed for 6 hours, and was then subjected to a dehydrobromination reaction, whereby sodium 4-ethenylnaphthalenesulfonate was obtained.
Reaction SMILES: [O:1]=[C:2]1[N:10]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]3)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[NH:3]1.[CH2:27](I)[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:27]([N:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]3)[C:2]1=[O:1])[CH3:28]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-n3c(=O)[nH]c4cccnc43)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc3c(c2)CCN3C(=O)OC(C)(C)C)c2ncccc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
A mixture of tert-butyl 5-(2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (900 mg), ethyl iodide (418 mg) and cesium carbonate (1.25 g) in DMF (10 mL) was stirred at 50° C. for 12 h, treated with water and extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give tert-butyl 5-(1-ethyl-2-oxo-1,2-dihydro-3H-imidazo[4,5-b]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (830 mg) as an amorphous solid.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([C:5]1[C:9]([O:10][C:11]2[CH:18]=[C:17](C)[C:14]([C:15]#[N:16])=[C:13](C)[CH:12]=2)=[C:8]([CH2:21][CH3:22])[N:7]([CH2:23][CH2:24][O:25]C)[N:6]=1)[CH3:4]>CO>[C:15]([C:14]1[CH:13]=[CH:12][C:11]([O:10][C:9]2[C:5]([CH2:3][CH3:4])=[N:6][N:7]([CH2:23][C:24]([OH:25])=[O:1])[C:8]=2[CH2:21][CH3:22])=[CH:18][CH:17]=1)#[N:16]
Reactant: CCc1nn(CCOC)c(CC)c1Oc1cc(C)c(C#N)c(C)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: CCc1nn(CC(=O)O)c(CC)c1Oc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95 %

Procedure:
2M Sodium hydroxide (2 ml) was added to a solution of the ester of Example 34 (800 mg, 2.46 mmol), in methanol (10 ml), and the reaction mixture was then stirred at room temperature for 2 hours. The reaction mixture was evaporated and water (20 ml) was added. The aqueous solution was acidified with 2M hydrochloric acid, until pH 2 was reached. A precipitate formed and this was collected by filtration, washed with water (2×5 ml) and dried, to provide the title compound (701 mg, 95%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[CH:13][NH:12][C:11]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:6][CH:5]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:14]=[CH:13][NH:12][C:11]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1[nH]ccc1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1[nH]ccc1-c1ccc(N)cc1
Yield: 76.3 %

Procedure:
To a suspension of 0.1 g (0.942 mmol) of 10% palladium-on-charcoal in 35 cm3 of methanol is added, at a temperature in the region of 20° C., 1 g (4.061 mmol) of methyl 3-(4-nitrophenyl)-1H-pyrrole-2-carboxylate. After hydrogenating for 20 hours in an autoclave under 3 bar of hydrogen, at a temperature in the region of 35° C., the reaction mixture is filtered, the catalyst is rinsed with twice 5 cm3 of methanol and the filtrate is then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.67 g of methyl 3-(4-aminophenyl)-1H-pyrrole-2-carboxylate in the form of an orange-coloured solid; M.W.=216, IE: m/z=216 M+, m/z=184 [M-CH3OH]+, m/z=155 [M−H2COOCH3]+.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[C:27]([Si:31]([CH3:42])([CH3:41])[O:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([Si:31]([CH3:42])([CH3:41])[O:32][CH2:33][CH2:34][N:35]1[CH:39]=[CH:38][C:37]([NH:40][C:13](=[O:15])[CH:12]([N:8]2[C:9](=[O:11])[CH:10]=[C:5]([O:4][C:3]3[C:2]([F:1])=[CH:25][CH:24]=[CH:23][C:22]=3[F:26])[CH:6]=[N:7]2)[CH2:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[N:36]1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CCC(CC)CC(C(=O)O)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)n1
Product: CCC(CC)CC(C(=O)Nc1ccn(CCO[Si](C)(C)C(C)(C)C)n1)n1ncc(Oc2c(F)cccc2F)cc1=O
Yield: 49 %

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-ethyl-hexanoic acid (Intermediate 31) and 1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-ylamine (Intermediate 3) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-ethyl-hexanoic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazol-3-yl}-amide as light yellow solid (472.6 mg, 49%). 1H NMR (300 MHz, DMSO-d6) δ ppm −0.07 (s, 6H), 0.71-0.88 (m, 6H), 0.80 (s, 9H), 0.92-1.51 (m, 5H), 1.74-1.99 (m, 1H), 2.03-2.23 (m, 1H), 3.85 (t, J=5.1 Hz, 2H), 4.06 (t, J=5.1 Hz, 2H), 5.52 (dd, J=10.7, 4.4 Hz, 1H), 6.03 (d, J=2.7 Hz, 1H), 6.36 (d, J=2.1 Hz, 1H), 7.31-7.51 (m, 3H), 7.53 (d, J=2.1 Hz, 1H), 8.28 (d, J=2.7 Hz, 1H), 10.82 (s, 1H).
Reaction SMILES: N1C=CC=CC=1.[C:7]([C:11]1[C:16]2[CH2:17][CH:18]([CH2:20]O)[O:19][C:15]=2[CH:14]=[CH:13][C:12]=1[OH:22])([CH3:10])([CH3:9])[CH3:8].S(Cl)([Cl:25])=O.O>C1C=CC=CC=1>[C:7]([C:11]1[C:16]2[CH2:17][CH:18]([CH2:20][Cl:25])[O:19][C:15]=2[CH:14]=[CH:13][C:12]=1[OH:22])([CH3:10])([CH3:9])[CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)c1c(O)ccc2c1CC(CO)O2
Solvent: c1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1c(O)ccc2c1CC(CCl)O2
Temperature: 25 °C
Yield: 61.2 %

Procedure:
Pyridine (180 mg, 2.2 mmol) was added to a solution of 4-tert-butyl-5-hydroxy-2-hydroxymethyl-2,3-dihydrobenzofuran (430 mg, 1.9 mmol) in benzene (15 ml) and, subsequently, thionyl chloride (310 mg, 2.6 mmol) was added dropwise under ice cooling. After being allowed to warm to room temperature, the mixture was heated under reflux for 24 h. After cooling, water was added and the solution was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, then dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (chloroform) to afford 4-tert-butyl-2-chloromethyl-5-hydroxy-2,3-dihydrobenzofuran [280 mg (yield, 61%)] as a colorless oil. Mass 242(M+2), 240(M+), 227, 225, 57
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH4+].[Cl-].[CH2:14](Br)[CH:15]=[CH2:16]>C1COCC1.[Zn]>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:5])[CH2:16][CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: O=C(CCCl)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Product: C=CCC(O)(CCCl)c1ccccc1
Reaction time: 1 h
Yield: 97.3 %

Procedure:
A solution of 3-chloro-1-phenylpropan-1-one (100 g, 0.595 mol) in THF (280 ml) was added dropwise to a well-stirred mixture of zinc powder (need not be activated) (40 g, 1.231 mol, satd aq NH4Cl solution (1500 ml) and THF (400 ml). Allyl bromide (143 g, 1.19 mol) was dissolved in THF (200 ml) was slowly added to the reaction mixture. The reaction was mildly exothermic, and the mixture began to reflux spontaneously. After refluxing had ceased, the mixture was stirred for 1 h. The mixture was extracted with EtOAc, dried over anhydrous Na2SO4, and concentrated to give 1-chloro-3-phenylhex-5-en-3-ol (122 g, 97%). 1H NMR: (400 MHz, CDCl3): δ=2.24(s, 1H), 2.34 (m, 2H), 2.53 (m, 1H), 2.75 (m, 1H), 3.20 (m, 1H), 3.58 (m, 1H), 5.18 (t, 1H), 5.51 (m, 1H), 7.26 (m, 1H), 7.26-7.39 (m, 3H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([OH:23])(=[O:22])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[CH3:21].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)#[N:25]>ClCCl.CN(C)C1C=CN=CC=1>[C:16]([O:23][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[CH:28]=[CH:27][C:26]([C:24]#[N:25])=[CH:31][CH:30]=2)=[CH:37][CH:36]=1)(=[O:22])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[CH3:21]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: C/C=C/C=C/C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C/C=C/C=C/C(=O)Oc1ccc(-c2ccc(C#N)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of N,N'-dicyclohexylcarbodiimide (0.87 g, 0.0042 mol) in dichloromethane (10 CM3) was added to a solution of (E,E)-hexa-2,4-dienoic acid (0.47 g, 0.0042 mol), 4-cyano-4'-hydroxybiphenyl (0.67 g, 0.0035 mol), 4-(dimethylamino)pyridine (0.05 g) in dichoromethane (25 cm3), cooled in an ice bath (0° C.) under an atmosphere of nitrogen. The reaction mixture was stirred overnight, filtered to remove precipitated material and the filtrate was evaporated down under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane as eluent, followed by recrystallisation from a 1:1 ethanol/ethyl acetate mixture to yield 0.76 g (76%). K 160° C., N-I 227° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8]O)=[C:6]([CH3:10])[C:5]([I:11])=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O>C1C=CC=CC=1>[Cl:14][CH2:8][C:7]1[C:6]([CH3:10])=[C:5]([I:11])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1c(I)ccc(F)c1CO
Solvent: c1ccccc1
Product: Cc1c(I)ccc(F)c1CCl
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of the product of Step C (4.01 g, 15.4 mmol) in anhydrous benzene (40 mL) was added dropwise thionyl chloride (3.7 g, 30.8 mmol). The mixture was stirred 80° C. overnight. The mixture was cooled to rt, washed with saturated aqueous sodium bicarbonate solution, water and brine, and dried over magnesium sulfate, and concentrated to dryness to give the title compound as a colorless oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:9][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])[CH:6]=[CH:7][CH:8]=1.[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([NH:9][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([O:13][C@@H:22]2[CH:23]3[CH2:26][CH2:27][N:20]([CH2:25][CH2:24]3)[CH2:21]2)=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1cccc(F)c1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1cccc(F)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
2-(3-Fluorophenylamino)-2-phenylacetic acid hydrochloride (I40) (1.34 g, 4.74 mmol), (R)-quinuclidin-3-ol (3.01 g, 23.7 mmol), DCC (1.95 g, 9.47 mmol), and HOBt (1.45 g, 9.47 mmol) were dissolved in THF (60 ml). The reaction was stirred at room temperature overnight. The solvent was evaporated, and the crude product was taken up with EtOAc and washed with NaHCO3 and then with brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=9/1) to give (R)-quinuclidin-3-yl 2-(3-fluorophenylamino)-2-phenylacetate (1.17 g, 68.9% yield).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]([C:12]1[CH:13]=[C:14](/[CH:29]=[CH:30]/[CH3:31])[C:15]([O:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22](OC)=[O:23])=[N:16][CH:17]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[H-].[Al+3].[Li+].[H-].[H-].[H-].CO.O>O1CCCC1>[F:33][C:2]([F:1])([F:32])[C:3]([C:12]1[CH:13]=[C:14](/[CH:29]=[CH:30]/[CH3:31])[C:15]([O:18][C:19]2[CH:20]=[C:21]([CH2:22][OH:23])[CH:26]=[CH:27][CH:28]=2)=[N:16][CH:17]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: C/C=C/c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cnc1Oc1cccc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C/C=C/c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cnc1Oc1cccc(CO)c1
Yield: 95 %

Procedure:
To a solution of methyl (E)-3-(5-(1,1,1,3,3,3-hexafluoro-2-(methoxymethoxy)propan-2-yl)-3-(prop-1-enyl)pyridin-2-yloxy)benzoate (81 mg, 0.168 mmol) in tetrahydrofuran (2 mL), lithium aluminum hydride (9.6 mg, 0.252 mmol) was added under ice-cold conditions, and the resultant mixture was stirred at room temperature for 3 hours. The reaction solution was added with methanol and water, filtered using celite, and extracted with ethyl acetate. The organic layer was washed with brine, dried using anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (ethyl acetate), and the title compound (72 mg, yield 94.9%) was obtained as a yellow oil.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[N:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=4[C:14]3=[N:13][C:12]=2[C:26]([NH2:28])=[O:27])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.BrC1C=CC2OCCN3C(CN4C=CN=C4C)=C(C(N)=O)N=C3C=2C=1.N1C2C(=CC=CC=2)C=N1.[CH3:63][C:64]([OH:68])([C:66]#[CH:67])[CH3:65]>>[N:1]1([CH2:10][C:11]2[N:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:67]#[C:66][C:64]([OH:68])([CH3:65])[CH3:63])=[CH:21][C:20]=4[C:14]3=[N:13][C:12]=2[C:26]([NH2:28])=[O:27])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: NC(=O)c1nc2n(c1Cn1ncc3ccccc31)CCOc1ccc(Br)cc1-2
Reactant: C#CC(C)(C)O
Agent: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: c1ccc2[nH]ncc2c1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(Cn3ncc4ccccc43)n1CCO2
Yield: 19 %

Procedure:
Similar to as described in General Procedure G, 3-((1H-indazol-1-yl)methyl)-10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing 2-methylimidazole with indazole) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (11 mg, 19%).
Reaction SMILES: [F-].[Cs+].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:10](#N)[CH3:11]>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH:7]1[C:8]2[C:10]3[C:11](=[CH:11][CH:10]=[CH:8][CH:7]=3)[C:9]3[C:9](=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1
Reactant: CC#N
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: c1ccc2c(c1)c1ccccc1c1ccccc21

Procedure:
1-trifluoromethanesulfonato-2-trimethylsilylbenzene (3 equivalents) is reacted with 1 equivalent of the appropriate iodoaromatic (see scheme 5a), in the presence of 5 mol % of Pd(OAc)2, 5 mol % of dppf and 4 equivalents of CsF in toluene/acetonitrile, to obtain the desired ligands of the formulae IId), IIe) and IIf).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.C[O-].[Na+].[C:13](OCC)(=[O:15])C.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([O:15][CH3:13])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: CCOC(C)=O
Reactant: Clc1cc(Cl)nc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(Cl)nc(Cl)c1
Reaction time: 12 h

Procedure:
To a solution of 2,4,6-trichloropyridine (4.5 g) in methanol was added sodium methoxide (25% in methanol, 6.8 mL) at room temperature. The mixture was stirred for 12 h then poured into ethyl acetate/water and separated. The organic layer was washed with water, brine and dried over magnesium sulfate. Upon evaporating, the residue was purified by crystallization (100% hexanes) to give title compound as solid (3.1 g).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=3[C:16]#[N:17])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.Cl.[OH-].[Na+].O>CO>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][C:14]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:15]=3[C:16]#[N:17])=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: CC(=O)n1ncc2cc(Oc3ccc(F)cc3C#N)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: N#Cc1cc(F)ccc1Oc1ccc2[nH]ncc2c1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
2-(1-Acetyl-1H-indazol-5-yloxy)-5-fluorobenzonitrile (369.4 mL, 221.7 mmol) in 370 mL MeOH was treated with 1.0 N HCl (243.8 mL, 243.8 mmol) at ambient temperature. The brown suspension was warmed to 70° C. for 28 hours and then cooled to 0° C. Sodium hydroxide (254.9 mL, 254.9 mmol) was added, followed by water (400 mL). The reaction was stirred at 0° C. for 15 minutes and then filtered. The solids were washed with water (1.5 and dried under high vacuum at 40° C. for 72 hours to provide 51.2 g of the desired product as a tan solid (91% yield for steps 2 and 3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([O:14][C:15](=[O:17])[CH3:16])[N:8]([C:11](=[O:13])[CH3:12])[C:9]=1[CH3:10])=[O:4].[Br:18]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([O:14][C:15](=[O:17])[CH3:16])[N:8]([C:11](=[O:13])[CH3:12])[C:9]=1[CH2:10][Br:18])=[O:4]
Reactant: COC(=O)c1nc(OC(C)=O)n(C(C)=O)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc(OC(C)=O)n(C(C)=O)c1CBr
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of 4b (9.0 g, 38 mmol) in 300 mL of CCl4 was added N-bromosuccinimide (7.1 g, 40 mmol) and benzoyl peroxide (80 mg). The solution was refluxed for 4 h and then cooled down to rt. Succinimide was then removed through filtration and the filtrate was concentrated to provide 2-acetoxy-1-acetyl-5-bromomethyl-1H-imidazole-4-carboxylic acid methyl ester 4c (12 g, 95%). MS (ESI+) (M+1)=318.9, 320.9.