Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[F:10][C:11]1[CH:12]=[C:13]([N+:18]([O-])=O)[CH:14]=[CH:15][C:16]=1F.C([O-])([O-])=O.[K+].[K+].S([O-])([O-])(=O)=O.[Na+].[Na+]>[Zn].CCOC(C)=O.CS(C)=O>[F:10][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][C:16]=1[O:9][C:3]1[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])[NH2:18]
Reactant: Cc1cccc(C)c1O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1cccc(C)c1Oc1ccc(N)cc1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
Solid 2,6-dimethylphenol (42.4 g, 346 mmol) was added in portions to a stirred mixture of 3,4-difluoronitrobenzene (50.0 g, 314 mmol), K2CO3 (65.0 g, 138 mmol), and DMSO (500 mL). After the addition was complete, the mixture was heated to 80° C. for 8 h and then allowed to cool to rt. The mixture was poured into ice water, and the resulting precipitate was collected and dried. This material was dissolved in acetone (1 L), then 150 mL of saturated aqueous NH4Cl was added and the mixture was immersed in an ice bath with mechanical stirring. Solid Zn powder (204 g, 65.4 mmol) was added in portions at such a rate that the internal temperature of the reaction mixture did not rise above 20° C. Following completion of the addition, the mixture was allowed to warm to rt and stirring was maintained for 6 h. EtOAc (ethyl acetate) (1.5 L) and anhydrous sodium sulfate (500 g) were added, and stirring was continued for 30 min. The mixture was then filtered though a pad of Celite®, rinsing well with EtOAc, and the filtrate was concentrated. The residue was triturated with hexanes to afford a solid (64.5 g, 90%). 1H NMR (400 MHz, CDCl3): 7.10-6.99 (m, 3H), 6.55 (ddd, J=12.5, 2.1, 0.8 Hz, 1H), 6.25-6.19 (m, 2H), 3.50 (s, 2H), 2.15 (s, 6H).
Reaction SMILES: [N:1]([C@H:4]1[C@H:8](O)[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+:2]=[N-:3].CCN(S(F)(F)[F:23])CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[N:1]([C@H:4]1[C@H:8]([F:23])[CH2:7][N:6]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](N=[N+]=[N-])C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)[C@H](N=[N+]=[N-])C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.4 %

Procedure:
To the solution of (trans)-tert-butyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (120 g, 0.44 mol, 5/6 purity, containing DCM) in DCM (1.2 L) at −78° C. was added dropwise DAST (141 g, 0.88 mol) in DCM (200 mL). After addition, the mixture was stirred at −78° C. for 1 hr, then warmed to rt and stirred overnight. The reaction mixture was poured into sat. Na2CO3 (2 L) slowly then the DCM phase was washed with water (1 L), sat. NaCl and dried over Na2SO4. Concentrated and purified via flash chromatography (petroleum ether/EtOAc 20/1˜10/1) to give the title compound (48 g, 48% yield) as light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[F:30][C:31]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=1O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:29][C:32]2[C:33]([F:40])=[C:34]([F:39])[C:35]([F:38])=[C:36]([F:37])[C:31]=2[F:30])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(F)cc3)CC2)c1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCC(Oc3c(F)c(F)c(F)c(F)c3F)c3ccc(F)cc3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2,3,4,5,6-pentafluorophenol: ESMS m/e: 564.7 (M+H)+.
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.[H-].[Na+].[CH2:18](I)[CH2:19][CH3:20]>CN(C)C=O>[CH2:18]([N:8]1[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[NH:5][C:4]2=[CH:3][S:2][CH:1]=[C:10]2[C:9]1=[O:11])[CH2:19][CH3:20]
Reactant: CCCI
Reactant: O=C1Nc2ccccc2Nc2cscc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)c2cscc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An 11.8 g. portion of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 2.8 g. of 50% sodium hydride in mineral oil in 175 ml. of dimethylformamide is stirred for 2 hours. A 12.6 g. portion of n-propyl iodide is added and the mixture is stirred overnight at room temperature. The reaction mixture is poured into ice water. After 3 hours the brown crystals are recovered by filtration, washed thoroughly with water, then ether and dried. This solid is heated to boiling in 75 ml. of methanol, filtered while hot and the filtrate is stored in a chill room. The crystals which form are recovered by filtration, washed with ether and dried giving the desired product, mp. 166°-167° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([OH:12])[CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])O.[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([O:12][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)[CH2:9][O:10][CH3:11])=[CH:6][N:7]=1
Reactant: COCC(O)c1ccc(Br)nc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC(OC1CCCCO1)c1ccc(Br)nc1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a mixture of 1-(6-bromopyridin-3-yl)-2-methoxyethanol (15.26 g), p-toluenesulfonic acid monohydrate (0.63 g) and tetrahydrofuran (65 ml) was added 3,4-dihydro-2H-pyran (7.76 g) at room temperature over 30 min, and the mixture was stirred for 2 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (19.66 g, yield 94%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). MS: 318 (MH+).
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]2[C:11]([NH2:28])=[N:12][CH:13]=[C:14]([C:16]3[N:20]([CH3:21])[N:19]=[C:18]([CH:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[N:17]=3)[N:15]=2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:29][CH2:30][C@@H:31]([CH3:35])[C:32](O)=[O:33]>>[NH2:28][C:11]1[N:12]=[CH:13][C:14]([C:16]2[N:20]([CH3:21])[N:19]=[C:18]([CH:22]3[CH2:23][CH2:24][N:25]([C:30](=[O:29])[C@H:31]([CH3:35])[CH2:32][OH:33])[CH2:26][CH2:27]3)[N:17]=2)=[N:15][C:10]=1[C:8]1[O:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6][N:7]=1
Reactant: Cn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Reactant: C[C@H](CO)C(=O)O
Product: C[C@H](CO)C(=O)N1CCC(c2nc(-c3cnc(N)c(-c4nnc(C(C)(C)C)o4)n3)n(C)n2)CC1
Yield: 47.4 %

Procedure:
Using a similar procedure as Example 4, 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine was reacted with (R)-3-hydroxy-2-methylpropanoic acid to afford the title compound (87 mg, 47.4%) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].C1COCC1.[C:22]1([CH2:28]C[Mg]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>C(OCC)C.O>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[CH2:5][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Reactant: Cl[Mg]CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CN(C)C(CCc1ccccc1)C1CCC2(CC1)OCCO2
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 3 (21.93 g, 97 mmol) in abs. THF (180 ml) was added dropwise, under argon and while cooling with ice, to a 1M solution of phenylethylmagnesium chloride in THF (242 ml, 242 mmol), and stirring was carried out for 20 h at RT. For working up the reaction mixture, saturated ammonium chloride solution (100 ml) and water (100 ml) were added, while cooling with ice, and extraction with diethyl ether (3×100 ml) was carried out. The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated.
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[F:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Fc1ccccc1CBr
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2F)CCCC1=O
Reaction time: 0.08 h
Yield: 54.5 %

Procedure:
40% Methanolic Triton B (2.82 mL, 6.2 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (1.27 g, 5.22 mM) in 10 mL of DMF at 25° C. After 5 minutes, 2-fluorobenzyl bromide (1.19 g, 6.2 mM) was added and the resultant mixture stirred at room temperature for 17 days. The mixture was diluted with ethyl acetate, washed five times with H2O, once with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient methylene chloride/ethyl acetate) to afford 1.00 g (55%) of the 9-[(2-fluorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a tan foam. 1H NMR (DMSO-d6) δ 7.7 (dd, 1H, J=1 and 8 Hz), 7.4-7.2 (m, 4H), 7.1 (t, 1H, J=8 Hz), 6.7 (t, 1H, J=8 Hz), 5.65 (s, 2H), 3.8 (s, 3H), 3.0 (t, 2H, J=6 Hz), 2.45 (t, 2H, J=6 Hz), and 2.1 (m, 2H). IR (CHCl3, cm−1) 3050, 2950, 1725, 1652, 1464, 1441, 1288 and 1120. MS (ES) m/e 350, 352.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CC(C)=O.[CH3:11][C:12]1([CH3:30])[C:16]([CH3:18])([CH3:17])[O:15][B:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[O:13]1.IC>ClCCl>[CH3:1][N:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[B:14]1[O:13][C:12]([CH3:30])([CH3:11])[C:16]([CH3:17])([CH3:18])[O:15]1)[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: CC1(C)OB(c2ccccc2NS(C)(=O)=O)OC1(C)C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: ClCCl
Product: CN(c1ccccc1B1OC(C)(C)C(C)(C)O1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A round bottom flask was charged with potassium carbonate (0.56 g, 4.0 mmol) and acetone (20 mL). To the suspension was added N-[2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (1.0 g, 3.4 mmol) followed by iodomethane (0.25 mL, 4.0 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (20 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated to a viscous oil. The material was subjected to high vacuum for 18 hours. N-Methyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide was isolated as a white solid (1.01 g, 95%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.81 (dd, J=7.5, 1.4 Hz, 1H), 7.47 (ddd, J=7.9, 7.9, 1.5 Hz, 1H), 7.38 (dd, J=7.9 Hz, 1H), 7.35-7.30 (m, 1H), 3.32 (s, 3H), 2.93 (s, 3H). MS=334 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([CH3:18])([N+:15]([O-])=O)[CH3:14].O.NN>[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([CH3:18])([CH3:14])[NH2:15]
Reactant: COc1ccc2[nH]cc(CC(C)(C)[N+](=O)[O-])c2c1
Agent: [Ni]
Agent: NN
Solvent: O
Product: COc1ccc2[nH]cc(CC(C)(C)N)c2c1

Procedure:
The nitro compound produced in Procedure 69C was reduced with Raney nickel and hydrazine hydrate according to the method of Procedure 67D. The structure of the product was confirmed by examination of the NMR spectrum, m.p. 114°-116°, yield 25.8 g. from 31.3 g. of nitro compound.
Reaction SMILES: COC(=O)C(C1C=CC(Cl)=CC=1)N.C[O:15][C:16](=[O:50])[CH:17]([C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1)[N:18]1[CH:27]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH:26]([C:35](=[O:41])[NH:36][CH2:37][CH2:38][O:39][CH3:40])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:42].[OH-].[Li+]>O1CCCC1>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([CH:17]([N:18]2[CH:27]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[CH:26]([C:35](=[O:41])[NH:36][CH2:37][CH2:38][O:39][CH3:40])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:42])[C:16]([OH:50])=[O:15])=[CH:44][CH:45]=1
Reactant: COCCNC(=O)C1c2ccccc2C(=O)N(C(C(=O)OC)c2ccc(Cl)cc2)C1c1ccc(Cl)cc1
Agent: COC(=O)C(N)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCCNC(=O)C1c2ccccc2C(=O)N(C(C(=O)O)c2ccc(Cl)cc2)C1c1ccc(Cl)cc1

Procedure:
Using 4-chlorophenyl-2-amino-acetic acid methyl ester as a primary amine, (4-Chloro-phenyl)-[3-(4-chloro-phenyl)-4-(2-methoxy-ethylcarbamoyl)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-acetic acid methyl ester was prepared according to the general procedure of example 1 and 3. The final acid (4-Chloro-phenyl)-[3-(4-chloro-phenyl)-4-(2-methoxy-ethylcarbamoyl)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-acetic acid was prepared by treatment with lithium hydroxide in tetrahydrofuran. Molecular Weight=527.4087, calculated from Molecular Formula=C27H24Cl2N2O5. ([M+H]+) observed 526.9.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30](O)=[O:31])[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[C:63]([O:67][C:68](=[O:79])[CH2:69][C:70]1[CH:75]=[CH:74][C:73]([NH2:76])=[C:72]([O:77][CH3:78])[CH:71]=1)([CH3:66])([CH3:65])[CH3:64]>>[C:63]([O:67][C:68](=[O:79])[CH2:69][C:70]1[CH:75]=[CH:74][C:73]([NH:76][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:72]([O:77][CH3:78])[CH:71]=1)([CH3:65])([CH3:66])[CH3:64]
Reactant: COc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.4 g, 0.69 mmol), was reacted with diisopropylethylamine (0.45 g, 3.5 mmol), diphenylphosphinic chloride (0.49 g, 2.1 mmol), then reacted with (4-amino-3-methoxy-phenyl)-acetic acid tert-butyl ester prepared in Example 158 (0.25 g, 1 mmol) to give chiral (4-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-phenyl)-acetic acid tert-butyl ester as a off white solid (Yield 0.18 g, 38%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[CH:31]=[CH2:32].C(N(CC)CC)C>C(#N)C>[C:35]([O:34][C:30](=[O:33])/[CH:31]=[CH:32]/[C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Temperature: 100 °C

Procedure:
To a solution of 5-(2-benzyloxy-4-iodo-phenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (544 mg, 1 mmol), t-butyl acrylate (154 mg, 1.2 mmol) and triethylamine (1.01 g, 10 mmol) in 5 mL of acetonitrile is added Pd (OAc)2 (10 mg). The mixture is heated at 100° C. for 18 h. After allowing to cool to RT the solvent is removed under reduced pressure and the residual oil purified by flash chromatography using methylene chloride to elute the title compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[C:16]#[N:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=2[C:16]#[N:17])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccccc2C#N)CC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2C#N)CC1
Reaction time: 15 h

Procedure:
To a solution of 2-[(1-tert-butoxycarbonyl-(1,2,3,6-tetrahydropyridin-4-yl)]benzonitrile (5.3 g, 0.019 mol) and acetic acid (0.28 ml, 4.9 mmol) in ethanol (200 ml), degassed with argon was added palladium on carbon. The reaction was hydrogenated on a Parr apparatus at 50 psi for 15 hours. The mixture was recharged twice with acetic acid (0.14 ml, 0.28 ml) and palladium on carbon (900 mg, 1.8 g), hydrogenated as above and filtered through celite. Solvent evaporation gave 2-(1-tert-butoxycarbonylpiperidin-4-yl)benzonitrile.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[NH2-].[Na+]>C1C=CC=CC=1>[CH3:16][CH2:15][O:14][C:12]([CH:11]1[O:3][C:1]1([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2])=[O:13]
Reactant: CCOC(=O)CCl
Reactant: CC(=O)c1ccccc1
Agent: [NH2-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)C1OC1(C)c1ccccc1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
To a mixture of 120 g of acetophenone, 123 g of ethyl chloroacetate, and 200 ml of benzene was added 47.2 g of powder sodium amide over a period of 2 hours at 15° C. At the end of a 2-hour stirring at room temperature, the resulting red colored mixture was poured into 700 g of ice water. The organic phase was extracted with benzene, dried, and stripped of the solvent. The residue was fractionally distilled, yielding 130 g of ethyl 3-methyl-3-phenylglycidate having a boiling point of 107°-113° C./3 mmHg.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:6])[C:2]#[CH:3].[H-].[Na+].Cl>C1COCC1.C(#N)C.[Cl-].[Na+].O>[CH3:3][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=2)[C:5](=[O:6])[NH:4][CH:1]=1
Reactant: C#CCNC(=O)Nc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: Cc1c[nH]c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.8 %

Procedure:
A solution of 1-prop-2-yn-1-yl-3-[3-(trifluoromethyl)phenyl]urea (intermediate 1) (11.2 g, 46 mmol) in THF (60 mL) and acetonitrile (120 mL) was added, under a nitrogen atmosphere, to a stirred suspension of sodium hydride (60% dispersion in mineral oil) (4.62 g, 115 mmol) in THF (60 mL) at such a rate that gas evolution was not over-vigorous and the internal temperature remained below 30° C. The mixture was stirred at RT for 2.5 h, a thick precipitate having formed within 1 h. The reaction mixture was cautiously quenched with water (15 mL) and the resulting solution was treated with 1 M hydrochloric acid (150 mL, 150 mmol). The mixture was stirred for 4 hours then allowed to stand for 15 hours. Saturated brine (150 mL) was added and the phases were partitioned. The aqueous phase was extracted with EtOAc (100 mL). The combined organic phase was washed with saturated brine (100 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was triturated with EtOAc (33 mL). The resultant solid was taken into DCM and filtered. The filtrate was concentrated in vacuo to afford the title compound (10.0 g) as a fawn solid.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:25][C:18]3([NH:22]C(=O)N[C:19]3=[O:24])[CH2:17][O:16]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-:26].[Na+].Cl>O>[NH2:22][C:18]1([C:19]([OH:24])=[O:26])[CH2:25][CH:15]([C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=2)[O:16][CH2:17]1
Reactant: CCCCCCCCc1ccc(C2CC3(CO2)NC(=O)NC3=O)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCCCCCc1ccc(C2CC(N)(C(=O)O)CO2)cc1
Temperature: 100 °C
Yield: 60.4 %

Procedure:
8-(4-Octylphenyl)-7-oxa-1,3-diazaspiro[4.4]nonane-2,4-dione (0.5 g, 1.452 mmol) and sodium hydroxide (10.89 ml, 21.77 mmol) were combined in water (8.54 ml) and equipped with a reflux condensor. The mixture was heated at about 100° C. for about 72 h. The reaction was cooled and acidified with concentrated HCl until pH=4-5. The product was collected by vacuum filtration and dried under vacuum. The residue was purified by flash column chromatography (1″×6″ of silica) eluting with 1:1 EtOAc/(6:3:1 CHCl3/MeOH/NH4OH). The product fractions were combined. The solvents were removed under reduced pressure and the residue triturated with ether. The resulting solid was collected by vacuum filtration and washed with ether to provide 3-amino-5-(4-octylphenyl)tetrahydrofuran-3-carboxylic acid (0.280 g, 0.877 mmol, 60.4% yield) as a white solid:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:24][C:25](OC(C)=O)=[O:26]>C(Cl)Cl>[C:25]([N:21]1[CH2:20][CH2:19][N:18]([CH:15]2[CH2:14][CH2:13][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:17][CH2:16]2)[CH2:23][CH2:22]1)(=[O:26])[CH3:24]
Reactant: COc1cc(N2CCC(N3CCNCC3)CC2)ccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: COc1cc(N2CCC(N3CCN(C(C)=O)CC3)CC2)ccc1[N+](=O)[O-]
Yield: 92 %

Procedure:
To a solution of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (Example 57, step C) (0.500 g, 1.56 mmol) in DCM (20 mL) was added Ac2O (0.22 mL, 2.34 mmol). TEA (0.33 mL, 2.34 mmol) was then added dropwise and the resultant mixture was stirred at rt overnight. TLC indicated that the reaction had gone to completion. The reaction mixture was evaporated onto silica gel and purified by flash chromatography to afford the title compound of step A (0.52 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=9.6 Hz, 1H), 6.57 (dd, J=9.5, 2.5 Hz, 1H), 6.48 (d, J=2.6 Hz, 1H), 4.07-4.00 (m, 2H), 3.88 (s, 3H), 3.41-3.34 (m, 4H), 2.99-2.89 (m, 2H), 2.43-2.36 (m, 2H), 1.95 (s, 3H), 1.85-1.78 (m, 2H), 1.48-1.38 (m, 2H).