Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[CH:22])[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>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>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([C:21]#[C:22][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: Brc1ncccn1
Reactant: C#CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(C#Cc2ncccn2)CC1
Reaction time: 8 h
Yield: 8 %

Procedure:
To a suspension of 2-bromopyrimidine (175 mg, 1.1 mmols), dichlorobis(triphenylphosphine)palladium(II) (35 mg, 0.05 mmols) and Cul (10 mg, 0.05 mmols) was added a solution of 4-ethynyl-piperidine-1-carboxylic acid tert-butyl ester (209 mg, 1 mmol). The mixture was stirred overnight, filtered through Celite, concentrated. The residue was partitioned between ethyl acetate and water, organic layer was isolated, dried (MgSO4), and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate in hexanes (1:1) to give un-reacted 2-bromopyrimidine (130 mg), then the title compound (23 mg). LCMS m/e (288, M+H).
Reaction SMILES: CC[N:3]([C:6]1C=C[CH:9]=[CH:10][CH:11]=1)[CH2:4][CH3:5].P(Cl)(Cl)(Cl)=O.CC(C)([O-])C.[K+].[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1COCC1>[N:3]1[CH:6]=[CH:11][C:10]([C:9]#[C:28][C:27]2[CH:30]=[CH:31][C:24]([F:23])=[CH:25][CH:26]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CCN(CC)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Fc1ccc(C#Cc2ccncc2)cc1
Reaction time: 16 h

Procedure:
4-pyridyl-hydroxymethyldiphenylphosphonate (6) (15.3 g, 46 mmol), diethylaniline (4 mL), and phosphorous oxychloride (50 mL) were warmed to 90° C. for 16 h. The reaction was quenched by pouring the reaction mixture over ice (400 g). Potassium carbonate was added until a pH of 8 was obtained for the solution followed by extraction with methylene chloride (3×200 mL). After drying ( MgSO4), the reaction was concentrated to afford crude 4-pyridyl-chloromethyldiphenylphosphonate (7) as a solid which was used in the next step without further purification: Mass Spectrum (CI) 360 (MH+). Potassium t-butoxide (3.30 g, 29.2 mmol) was added as a solid to 4-pyridyl-chloromethyldiphenylphosphonate (7) (5.00 g, 13.9 mmol), 4-fluorobenzaldehyde (8) (2.00 g, 15.3 mmol), and THF (70 mL) at 23° C. under argon. After 16 h, the reaction was quenched by adding to water (200 mL) over 3 min. After adjusting the pH of the solution to 7 with 1N HCl, the mixture was extracted with ethyl acetate (3×350 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate:methylene chloride 1:1) to afford 1-(4-pyridyl)-2-(4-fluorophenyl)ethyne (1) as a solid: Mass Spectrum (CI) 198 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.[F:26][C:27]1([F:35])[CH2:32][CH2:31][CH:30]([CH2:33][NH2:34])[CH2:29][CH2:28]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:34][CH2:33][CH:30]4[CH2:31][CH2:32][C:27]([F:35])([F:26])[CH2:28][CH2:29]4)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: NCC1CCC(F)(F)CC1
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCC(F)(F)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (4,4-difluorocyclohexyl)methanamine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ 1.09-1.25 (m, 2H) 1.60-1.82 (m, 5H) 1.95 (d, J=8.1 Hz, 2H) 2.37 (s, 3H) 3.15 (t, J=6.3 Hz, 2H) 7.59 (d, J=7.6 Hz, 1H) 7.67 (s, 1H) 8.36 (br. s., 1H) 8.70 (br. s., 1H) 8.82-8.88 (m, 1H) 13.16 (br. s., 1H). MS m/z [M+H]+ 452.5.
Reaction SMILES: C([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:35])[C:12]([CH3:34])([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[CH:15]=1)[CH3:13])=[O:5])C.[OH-].[Na+]>CO.O>[CH3:34][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[CH:15]=1)([CH3:13])[C:11]([N:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[C:4]([OH:5])=[O:3])=[O:35]
Reactant: CCOC(=O)[C@H]1CCCN1C(=O)C(C)(C)c1cccc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(C(C)(C)C(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 16 h

Procedure:
To a stirred solution of title D compound, (R)-{2-methyl-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionyl}-pyrrolidine-2-carboxylic acid ethyl ester (0.47 g, 0.99 mmol) in methanol (25 mL) is added sodium hydroxide (0.16 g, 3.95 mmol) in water (5 mL) at RT. The reaction mixture is stirred for 16 h. The reaction mixture is concentrated at reduced pressure, poured into water, the aqueous layer is separated, washed with ethyl acetate twice, acidified with concentrated HCl and extracted three times with ethyl acetate. The combined ethyl acetate extract is dried and concentrated to give (R)-1-{2-methyl-2-[3-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionyl}-pyrrolidine-2-carboxylic acid as a white solid: MS m/z 447.3 [M−1]−.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:14](=[O:15])[CH2:13][CH:12]([NH:16][CH2:17][CH2:18]Cl)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CN(C)C=O>[CH2:3]([N:10]1[C:14](=[O:15])[CH:13]2[CH:12]([NH:16][CH2:17][CH2:18]2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C1CC(NCCCl)C(=O)N1Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C2CCNC2C(=O)N1Cc1ccccc1
Reaction time: 8 h
Yield: 55.7 %

Procedure:
17.4 g (0.58 mmol ) of sodium hydride suspension are reacted with 119 g (0.45 mol) of 1-benzyl-3-(2-chloroethylamino)-pyrrolidine-2,5-dione in 550 ml of absolute dimethylformamide in accordance with the working instructions of Example Ib. After the mixture has been left to stand overnight, it is worked up under aqueous conditions. On purification by chromatography, impurities are first eluted with ethyl acetate and the product is then eluted with ethyl acetate:methanol (3:1) (RF value 0.55). 57.7 g of product (56% of theory) are isolated.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:25]([O:27][C:28](=[O:35])[CH2:29][CH:30](Br)[CH2:31][CH2:32][CH3:33])[CH3:26]>CN(C=O)C>[CH2:25]([O:27][C:28](=[O:35])[CH2:29][CH:30]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([CH2:10][CH2:11][CH2:12][C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[N:16][CH:17]=[CH:18][CH:19]=4)[N:14]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH2:31][CH2:32][CH3:33])[CH3:26]
Reactant: CCCC(Br)CC(=O)OCC
Reactant: c1cnc2nc(CCCc3ccc4[nH]ccc4c3)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)n1ccc2cc(CCCc3ccc4cccnc4n3)ccc21
Reaction time: 0.25 h
Yield: 17 %

Procedure:
To a solution of 2-[3-(1H-indol-5-yl)-propyl]-[1,8]naphthyridine (0.18 g, 0.62 mmol) in DMF (2 mL) was added sodium hydride (30.0 mg, 1.24 mmol) at room temperature. After stirring for 15 minutes, 3-bromo-hexanoic acid ethyl ester (276 mg, 1.24 mmol) was added. The reaction mixture was stirred overnight and quenched with water. The crude product was extracted with methylene chloride, washed with brine, and purified via column chromatography with silica gel (ethyl acetate/hexane1:1), to give the title product (17% yield). 1H NMR (CDCl3) δ 9.08 (dd, J=1.7, 4.0 Hz, 1H), 8.14 (m, 1H), 8.06 (m, 1H), 7.32–7.44 (m, 4H), 7.05–7.12 (m, 2H), 6.45 (d, J=3.2 Hz, 1H), 4.81 (m, 1H), 3.99 (m, 2H), 3.08 (m, 2H), 2.83 (m, 4H), 2.22 (m, 2H), 1.90 (m, 2H), 1.20 (m, 2H), 1.07 (m, 3H), 0.87 (m, 3H). Mass Spectrum (LCMS, ESI) calculated for C27H32N3O2 430.3 (M+H); found 430.3.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:39])[C:12]2[CH:17]=[C:16]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[C:14]([C:24]3[O:25][C:26]([C:29](O)([CH3:37])[CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:28]=3)[CH:13]=2)[CH3:9])=[CH:4][CH:3]=1.[N-:40]=[N+]=[N-].[Na+].C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11](=[O:39])[C:12]2[CH:17]=[C:16]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])[CH:15]=[C:14]([C:24]3[O:25][C:26]([C:29]([NH2:40])([CH3:37])[CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[CH:27][CH:28]=3)[CH:13]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](NC(=O)c1cc(-c2ccc(C(C)(O)Cc3ccccc3)o2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1cc(-c2ccc(C(C)(N)Cc3ccccc3)o2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1

Procedure:
To a solution of Example 50 (0.080 g, 0.15 mmol) in 1 mL CHCl3 was added a suspension of sodium azide (0.094 g, 1.45 mmol) in TFA (0.06 mL, 0.73 mmol). The solution progressively turned dark over 1 h to afford a mixture of desired product and a byproduct resulting from dehydration. Concentrated and used as is in next reaction. LCMS [M+H]+=575.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[N:4]=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][CH:7]=1.C[Si]([C:25]#[N:26])(C)C>>[F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[NH:4][CH:5]([C:6]1[CH:7]=[CH:8][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:10][CH:11]=1)[C:25]#[N:26]
Reactant: NS(=O)(=O)c1ccc(C=Nc2ccc(F)cc2F)cc1
Reactant: C[Si](C)(C)C#N
Product: N#CC(Nc1ccc(F)cc1F)c1ccc(S(N)(=O)=O)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using 2,4-difluoro-N-(4-sulfamoylbenzylidene)aniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a white powder (yield 100%).
Reaction SMILES: [C:1]([N:9]1[CH:14]=[CH:13][CH:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].CN(C)C(=O)C>[C:1]([N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([F:24])=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(c1ccccc1)N1C=CC(c2c[nH]c3cc(F)ccc23)C=C1
Agent: [Pd]
Solvent: CC(=O)N(C)C
Product: O=C(c1ccccc1)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Temperature: 80 °C

Procedure:
A mixture of 95 parts of 1-benzoyl-4-(6-fluoro-1H-indol-3-yl)-1,4-dihydropyridine and 540 parts of N,N-dimethylacetamide is hydrogenated in the Parr-apparatus with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off over Hyflo and the filtrate is poured onto water while stirring: an oil is precipitated. The supernatant aqueous phase is decanted and the residual oil is washed with water. The oily product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is washed successively with a mixture of petroleumether and 2,2'-oxybispropane, with a hydrochloric acid solution 2N and with water, and dissolved in trichloromethane. The latter is washed with a sodium hydroxide solution 1N and with water, dried, filtered and evaporated. The residue is heated in a small amount of N,N-dimethylacetamide at 80° C. and the mixture is allowed to stand over week-end. The solid product is filtered off, washed with a mixture of water and ethanol, and dried in vacuo at 80° C., yielding 25 parts of 1-benzoyl-4-(6-fluoro-1H-indol-3-yl)-piperidine; mp. 220° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[O:5][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:17][N:18]1[C:22]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[O:5][CH:6]=2)=[CH:21][CH:20]=[N:19]1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)co1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)co1
Reaction time: 1 h
Yield: 26.2 %

Procedure:
A solution of methyl 4-bromo-2-furancarboxylate (470 mg, 2.29 mmol), potassium carbonate (1584 mg, 11.46 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (525 mg, 2.52 mmol)[prepared according to Preparation 7] and bis-(tri-t-butylphosphine)Palladium (0) (58.6 mg, 0.12 mmol) in 1,4-dioxane (9.55 ml) and water (1.9 ml) was stirred at 80° C. After 1 hr, the solution was partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (30% EtOAc in hexanes) affording the title compound (124 mg, 0.60 mmol, 26% yield) as a white powder: LCMS (ES) m/e 206 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[NH:34][CH2:35][CH3:36]>>[CH2:35]([NH:34][C:28]1[CH:29]=[C:30]([F:33])[CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:21])[CH3:20])=[O:24])[CH3:36]
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CCNc1cc(F)ccc1CN
Product: CCNc1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 2-(aminomethyl)-N-ethyl-5-fluorobenzenamine. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.27 (3H, t, J=7.1 Hz, CH3), 1.63 (6H, s, 2×CH3), 3.10 (2H, q, J=7.1 Hz, CH2), 4.04 (4H, m, 2×CH2), 4.45 (2H, d, J=6.6 Hz, NCH2), 5.27 (2H, s, OCH2), 6.28 (1H, broad s, aromatic), 6.31 (1H, m, aromatic), 6.98 (1H, m, aromatic), 7.3–7.38 (3H, m, aromatics), 7.49 (2H, m, aromatics), 7.54 (1H, broad t, NH). HRMS (ESI+) calculated for C26H30FN4O4 [M+H+]: 481.2251. Found: 481.2254.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30]>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:21][CH2:22]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCNCC3)c2n1
Reactant: CC(C)CCBr
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCN(CCC(C)C)CC3)c2n1

Procedure:
Prepared similarly to Example 80 from 2-(butyloxy)-8-(methyloxy)-9-[2-(4-piperidinyl)ethyl]-9H-purin-6-amine and 1-bromo-3-methylbutane.
Reaction SMILES: [F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[CH2:4][C@H:5]([CH2:12][CH3:13])[CH2:6]OS(C)(=O)=O.[I-:19].[Na+]>CC(C)=O>[F:1][C:2]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:3]=1[CH2:4][C@@H:5]([CH2:6][I:19])[CH2:12][CH3:13]
Reactant: CC[C@H](COS(C)(=O)=O)Cc1ccc(F)cc1F
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC[C@H](CI)Cc1ccc(F)cc1F
Yield: 91.2 %

Procedure:
A flask was charge with 9.54 g (34.3 mmol) of (2S)-methanesulfonic acid 2-(2,4-difluoro-benzyl)-butyl ester, 10.3 g (68.6 mmol) of sodium iodide, and 60 mL of acetone. The solution was heated at reflux for 30 hours. The acetone was removed under reduced pressure. The residue was partitioned between water and hexanes. The organic layer was collected and washed with sodium bisulfite solution and brine. The hexane was removed under reduced pressure, and the crude oil was purified by column chromatography (hexanes eluent). This procedure gave 9.7 g (91% yield) of the titled compound as a clear oil.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH2:16][CH3:17])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]2[C:28]([O:30][C:31](=O)[C:19]=12)=[O:29]>C(O)(=O)C>[CH2:16]([O:15][C:9]1[CH:8]=[C:7]([CH:2]([N:1]2[C:31](=[O:30])[C:19]3[CH:18]=[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]4=[CH:21][C:20]=3[C:28]2=[O:29])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14])[CH3:17]
Reactant: O=C1OC(=O)c2cc3ccccc3cc21
Reactant: CCOc1cc(C(N)CC(=O)O)ccc1OC
Solvent: CC(=O)O
Product: CCOc1cc(C(CC(=O)O)N2C(=O)c3cc4ccccc4cc3C2=O)ccc1OC
Yield: 93.5 %

Procedure:
3-(3-Ethoxy-4-methoxyphenyl)-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)-propanoic acid was prepared according to Example 2A from 3-amino-3-(3-ethoxy-4-methoxyphenyl)propanoic acid (3.00 g, 12.5 mmol), 2,3-napthalene dicarboxylic anhydride (2.59 g, 12.5 mmol) in acetic acid (20 mL) to afford 3-(3-ethoxy-4-methoxyphenyl)-3-(1,3-dioxo-2,3-dihydro-1H-benzo[f]isoindol-2-yl)propanoic acid as an off-white solid (4.9 g, 93% yield): mp, 193.0-194.0° C.; 1H NMR (DMSO-d6) δ1.32 (t, J=6.9 Hz, 3H, CH3), 3.34 (dd, J=7.1, 16 Hz, 1H, CHH), 3.57 (dd, J=8.9, 16 Hz, 1H, CHH), 3.74 (s, 3H, CH3), 4.02 (q, J=6.9 Hz, 2H, CH2), 5.71 (dd, J=7, 8 Hz, 1H, NCH), 6.91-6.98 (m, 2H, Ar), 7.09 (br s, 1H, Ar), 7.74-7.78 (m, 2H, Ar), 8.23-8.27 (m, 2H, Ar), 8.50 (br s, 2H, Ar), 12.5 (br s, 1H, OH); 13C NMR (DMSO-d6) δ14.62, 36.03, 50.28, 55.43, 63.71, 111.79, 112.28, 119.45, 124.55, 126.87, 129.27, 130.24, 131.24, 135.03, 147.74, 148.57, 167.29, 171.75; Anal Calcd for C24H21NO6: C, 68.73; H, 5.05; N, 3.34. Found: C, 68.59; H, 5.25; N, 3.17.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:18][C:19](OCC)=[O:20])[C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[NH3:27]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([CH2:18][C:19]([NH2:27])=[O:20])[C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cc1cc2ccc(OCc3cccc(Cl)c3)cc2[nH]c1=O
Reactant: N
Solvent: CO
Product: NC(=O)Cc1cc2ccc(OCc3cccc(Cl)c3)cc2[nH]c1=O
Temperature: 25 °C
Yield: 74 %

Procedure:
Ethyl 2-(7-((3-chlorobenzyl)oxy)-2-oxo-1,2-dihydroquinolin-3-yl)acetate (Example 51, product from Step E, 200 mg, 0.54 mmol) was dissolved in a 7 N solution of ammonia in methanol (10 mL) and stirred at room temperature for 2 weeks. The resulting precipitate was collected by filtration, washed with methanol (3 mL) and was dried under vacuum to give the title compound as a white solid (136 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.70 (s, 1H), 7.54 (s, 2H), 7.43 (s, 3H), 7.35 (br s, 1H), 6.86 (s, 2H), 6.85 (br s, 1H), 5.16 (s, 2H), 3.27 (s, 2H). [M+H]=343.1.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>C1COCC1>[C:6]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])#[CH:5]
Reactant: C[Si](C)(C)C#Cc1cccc(C(N)=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cccc(C(N)=O)c1
Yield: 95 %

Procedure:
3-((Trimethylsilyl)ethynyl)benzamide (I143) (0.565 g, 2.60 mmol) was dissolved in THF (33 mL), and 1 M TBAF in THF (3.25 mL, 3.25 mmol) was added. After two hours the reaction was poured into water (200 mL) and the resulting solution was extracted with diethyl ether (3×200 mL). The combined ether phases were washed with brine (200 mL), dried over sodium sulfate then evaporated to give the title compound (I144) (0.357 g, 95% yield) as a tan solid; 1H NMR (400 MHz, CDCl3) δ 7.92 (t, J=1.5 Hz, 1H), 7.83-7.79 (m, 1H), 7.64 (dt, J=7.7, 1.4 Hz, 1H), 7.42 (td, J=7.8, 0.5 Hz, 1H), 6.07 (br s, 1H), 5.77 (br s, 1H), 3.13 (s, 1H). LCMS Method C: rt 4.74 min, m/z 146.2 [M+H]+.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C:16](OS(C)(=O)=O)([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:24]>C(Cl)Cl.CO>[CH:1]([N:14]1[CH2:17][C:16]([NH2:24])([CH3:18])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N
Reactant: CC1(OS(C)(=O)=O)CN(C(c2ccccc2)c2ccccc2)C1
Solvent: ClCCl
Solvent: CO
Product: CC1(N)CN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 3 h
Yield: 58 %

Procedure:
To a solution of methanesulfonic acid 1-benzhydryl-3-methyl-azetidin-3-yl ester (12 g, 36.3 mmol) in DCM (100 mL) was added a saturated solution of ammonia in MeOH (200 mL) and the mixture was stirred for 3 h. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 0-100% EtOAc in petroleum ether) to give 1-benzhydryl-3-methyl-azetidin-3-ylamine (5.31 g, 58%), which was used directly in step F. Alternatively, 1-benzhydryl-3-methyl-azetidin-3-ylamine can be prepared via steps D and E. TLC (eluting with 20% EtOAc/heptane) Rf=0.2.
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
2-Phenoxybenzoic acid (324 mg) was added gently to a suspension of lithium aluminum hydride (172 mg) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature overnight. Water (1 mL) was added gently to the reaction mixture, and the resulting mixture was stirred for 30 minutes. The reaction mixture was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give the title compound (256 mg).
Reaction SMILES: [CH3:1][C:2]([NH2:13])([CH3:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1.[O:14]([CH2:21][CH2:22][CH2:23]Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[ClH:25].CO>C(#N)C>[ClH:25].[O:14]([CH2:21][CH2:22][CH2:23][NH:13][C:2]([CH3:1])([CH3:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][CH:5]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(CC(C)(C)N)cc1
Reactant: BrCCCOc1ccccc1
Agent: Cl
Solvent: CO
Solvent: CC#N
Product: COc1ccc(CC(C)(C)NCCCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 62 h

Procedure:
To a stirred suspension of 50% KF-Celite (0.35 g, 3 mmol) in anhydrous acetonitrile (10 mL) was added 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (0.27 g, 1.5 mmol) and 3-phenoxypropyl bromide (0.484 g, 2.25 mmol). The reaction mixture was refluxed under nitrogen for 6 hours, followed by stirring at room temperature for 62 hours. The mixture was filtered and the filtrate, was evaporated. The hydrochloride was prepared by dissolving the residue in HCl/methanol. The resulting solution was concentrated and dried on a lyophilizer. The residue was redissolved in dry methanol and diluted with diethyl ether, which caused precipitation of 210 mg of the title compound as a white solid: GC/EI-MS, m/z (rel. int.) 298 (M-15, 2), 193 (15), 192 (100), 120 (13), 107. (5), 98 (9), 77 (8), 72 (7), 71 (8), 70 (6), 41 (4).