Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:11][C:12]1[N:17]=[C:16]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:2]([I:1])[CH:3]=2)[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: COc1ccc(N)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2nc(Cl)ncc2Cl)cc1I
Yield: 120.2 %

Procedure:
To a suspension of 3-iodo-4-methoxyaniline (8.0 g, 0.021 mol) and 2,4,5-trichloropyrimidine (4.13 g, 0.0225 mol) in N,N-dimethylformamide (57 mL) was added potassium carbonate (7.40 g, 0.0536 mol). The resultant mixture was stirred overnight at room temperature. The reaction mixture was filtered to remove K2CO3 and concentrated to give the residue (10 grams). The residue was triturated with EtOAc, and filtered under vacuum. The residue was purified by silica gel column chromatography to give the desired product (2.54 g, 30%). LCMS for C11H9Cl21N3O (M+H)+: m/z=396.0, 398.0.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([C:10]#[N:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[N:13]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N+:14]=[N-:15]>C1C=CC=CC=1>[CH2:20]([O:19][C:17]([CH2:16][N:13]1[C:10]([S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=2)(=[O:8])=[O:9])=[N:11][N:15]=[N:14]1)=[O:18])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CCOC(=O)CN=[N+]=[N-]
Solvent: c1ccccc1
Product: CCOC(=O)Cn1nnnc1S(=O)(=O)c1ccc(C)cc1

Procedure:
A mixture of 7.24 g. of p-toluenesulfonyl cyanide and 5.16 g. of ethyl azidoacetate (Dictionary of Organic Compounds, Vol. 1, p. 307) in 150 ml. of benzene is heated at reflux for 12 hours. The residue after evaporation is recrystallized from benzene-hexane, m.p. 98°-100° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[CH:17][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[O:9][CH:10]=[C:11]([CH2:13][O:14][C:15]4[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][N:24]5[CH:28]=[CH:27][N:26]=[CH:25]5)=[CH:17][CH:16]=4)[N:12]=3)=[CH:6][CH:7]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Oc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)cc1
Reactant: ClC(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(C(Oc2ccc(-c3nc(COc4ccc(CCCn5ccnc5)cc4)co3)cc2)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 43 %

Procedure:
To a solution of 2-(4-hydroxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole (250 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (oily, 60%, 30 mg) and stirred at room temperature for one hour, to which chlorodiphenylmethane (270 mg) was added and stirred at 80° C. for 6 hours. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with 1N-sodium hydroxide and water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with ethyl acetate-methanol (50:1, v/v), crystals of 2-(4-diphenylmethoxyphenyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole (155 mg, 43%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 106-107° C.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH:10]=[C:9]([NH2:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]1([N:7]2[CH:11]=[CH:10][C:9]([NH2:12])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=CCN(c2ccccc2)N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: Nc1ccn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-phenyl-3-amino-pyrazoline(7.4 g, 46 mmol) in dioxane (200 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (11.54 g, 50 mmol). After addition, the reaction was stirred at RT for 1 hour, then the resulting dark solution was filtered through a pad of Celite. The filtrate was acidified with 1N aqueous HCl (100 mL) and extracted with CH2Cl2 (50 mL). The organic layer was extracted with 1N aqueous HCl (50 mL). The combined aqueous layers were washed with CH2Cl2 (2×50 mL), then adjusted to pH12 with NaOH, followed by extraction with CH2Cl2 (3×100 mL). The combined CH2Cl2 extracts were washed with saturated NaCl (100 mL), dried (MgSO4), and concentrated under reduced pressure to give the title compound, 1-phenyl-3-amino-pyrazole as light orange solid (3.0 g, 41% yield). LC/MS (method A): retention time=1.43 min, (M+H)+=160.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-])=O>O1CCCC1.[Pd]>[NH:9]1[C:10]2[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.1 %

Procedure:
To a 5000 mL autolcave equipped with a H2 inlet, a thermometer, and a mechanical stirrer is added a solution of 5-nitro-1H-indazole (500 g, 3.06 mol) in tetrahydrofuran (THF, 3500 mL), followed by palladium on carbon (10%, 50 g, 141 mmol). The resulting mixture is stirred overnight at 25° C. under H2 atmosphere (5 kg pressure). After it is purged with N2, the mixture is filtered, and the filtrate is concentrated under vacuum to give the title compound (420 g, 100%) as a brown solid. MS (m/z): 134.1 (M+H).
Reaction SMILES: [I:1][C:2]1[C:3]([O:20][CH3:21])=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>O1CCCC1>[NH2:15][C:9]1[C:8]([O:7][C:6]2[CH:16]=[C:2]([I:1])[C:3]([O:20][CH3:21])=[CH:4][C:5]=2[CH:17]([CH3:19])[CH3:18])=[CH:13][N:12]=[C:11]([NH:14][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[N:10]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1I
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(C(C)C)c(Oc2cnc(NC(=O)C(C)C)nc2N)cc1I
Reaction time: 0.5 h
Yield: 53.9 %

Procedure:
To 5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (1 g, 2.50 mmol), dissolved in anhydrous tetrahydrofuran, was added triethylamine (0.38 mL, 2.75 mmol) and isobutyryl chloride (0.29 mL, 2.75 mmol). After stirring 30 minutes, the reaction was concentrated under reduced pressure. The residue was dissolved in dichloromethane (100 mL), and the dichloromethane layer was washed with water, dried using anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by silica gel column chromatography eluting with 96/4/0.1 dichloromethane/methanol/ammonium hydroxide yielded 634 mg (54%) of N-[4-amino-5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidin-2-yl]-isobutyramide as pale yellow solid, MS (M+H)=471.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][C@@H:18]([CH3:22])[C:17]1=[O:23]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][OH:12])[C:17](=[O:23])[C@@H:18]2[CH3:22])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@@H]1NCCN(CCCO)C1=O
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Product: C[C@H]1C(=O)N(CCCO)CCN1C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 92.1 %

Procedure:
3,4-Dichlorophenyl isocyanate (334 mg, 1.74 mmol) was added at 0° C. to a solution of (S)-1-(3-hydroxy-propyl)-3-methyl-piperazin-2-one (intermediate 20D; 300 mg, 1.74 mmol) in tetrahydrofuran (3 ml), then after 2.5 h the reaction mixture was evaporated. Chromatography (SiO2; dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (577 mg, 92%). White foam, MS (ISP)=360.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)[S:10][C:3]=12.[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([NH2:26])=[CH:21][CH:20]=2.ClC(Cl)C>C(O)(C)(C)C>[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([NH:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[S:12][CH:13]=[CH:14][N:15]=4)[S:10][C:3]=13)=[CH:21][CH:20]=2
Reactant: Clc1ccnc2cc(-c3nccs3)sc12
Reactant: Cc1cc2cc(N)ccc2[nH]1
Solvent: CC(C)(C)O
Solvent: CC(Cl)Cl
Product: Cc1cc2cc(Nc3ccnc4cc(-c5nccs5)sc34)ccc2[nH]1
Yield: 65.3 %

Procedure:
7-Chloro-2-thiazol-2-yl-thieno[3,2-b]pyridine (400 mg, 1.58 mmol) and 2-methyl-5-aminoindole (231 mg, 1.58 mmol) were dissolved in 6 mL of t-butyl alcohol and 6 mL of dichloroethane and the solution was heated to 85° C. After allowing the reaction to go dry overnight the reaction mixture was cooled and absorbed onto silica gel. Chromatography of the residue with 5% methanol:methylene chloride afforded 374 mg (68%) (2-methyl-1H-indol-5-yl)-(2-thiazol-2-yl-thieno[3,2-b]pyridin-7-yl)-amine. 1H NMR (400 MHz, DMSO) δ8.78 (s, 1H), 8.18 (d, 1H), 7.84 (m, 2H), 7.27 (m, 2H), 6.90 (d, 1H), 7.39 (d, 1H), 6.59 (d, 1H), 6.10 (s, 1H), 2.36 (s, 3H). LC-MS: 363 (MH+); HPLC RT: 5.01 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:43])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:42][C:39]1[N:38]=[CH:37][C:36]([C:32]2[CH:31]=[C:30]([C:28]3[CH2:27][C:26](=[O:43])[NH:19][C:9]4[CH:10]=[C:11]([N:14]5[CH:18]=[CH:17][CH:16]=[CH:15]5)[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)=[CH:41][CH:40]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-n2cccc2)cc1N
Reactant: Cc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Product: Cc1ccc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-amino-4-pyrrol-1-yl-phenyl)-carbamic acid tert-butyl ester (Example J11) (273 mg, 1 mmol) and 3-[3-(6-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (311 mg, 1 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a yellow solid (195 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([NH:30][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][N:16]=1)[N:13]=[CH:12][C:11]([C:21]#[N:22])=[C:10]2[NH:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Product: N#Cc1cnc2cnc(NCc3ccccc3)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 54 %

Procedure:
Following the procedure described above in Example 34, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile was reacted with benzylamine. The crude product was purified by flash column chromatography (1% methanol in methylene chloride) to give a yellow solid (0.051 g, 54%). 1H NMR (400 MHz, DMSO-D6) δ ppm 4.5 (d, J=6.3 Hz, 2 H) 7.0 (s, 1 H) 7.2 (t, J=7.2 Hz, 1 H) 7.3 (m, 5 H) 7.5 (m, 2 H) 7.6 (dd, J=6.6, 2.5 Hz, 1 H) 8.3 (s, 1 H) 8.9 (s, 1 H) 9.6 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1.[CH3:11][O:12][C:13](Cl)=[O:14].N1C=CC=CC=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:11][O:12][C:13]([NH:1][C:2]1[S:3][C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]=1)=[O:14]
Reactant: COC(=O)Cl
Reactant: Nc1nc2cnccc2s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)Nc1nc2cnccc2s1
Reaction time: 8 h
Yield: 78 %

Procedure:
To a mixture of 2-aminothiazolo[4,5-c]pyridine (50 mg, 0.33 mmole) and 0.4 ml of methylchloroformate in 1 ml of dry DMF was added 0.4 ml of pyridine. The mixture was allowed to stand overnight at room temperature and aqueous NaHCO3 and ethyl acetate were then added. The organic layer was separated, washed with saturated aqueous NaCl solution, dried over Na2SO4 and evaporated in vacuo to give 54 mg (78%) of the title compound, which was recrystallized from CHCl3 --CH3OH to give pure crystalline solid. Mp 146°~152° C. (dec.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(=[N:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)C1C=CC=CC=1.S([O-])(O)(=O)=O.[K+]>ClCCl>[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH2:21][CH2:20]1
Reactant: C(=NCC1CCNCC1)c1ccccc1
Reactant: O=C(O)c1ccccn1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Product: NCC1CCN(C(=O)c2ccccn2)CC1
Temperature: 25 °C
Yield: 58.5 %

Procedure:
N,N'-Carbonyl diimidazole (6.58 g) was added to a suspension of pyridine-2-carboxylic acid (5.0 g) in dichloromethane (75 ml) stirring under nitrogen at ambient temperature. Stirring continued until gas evolution had ceased (~2 hours) then N-benzylidene-1-(4-piperidyl)methylamine (8.2 g) was added and the reaction mixture stirred for 18 hours. The solvent was evaporated to give a viscous yellow oil, which was then stirred with aqueous potassium hydrogen sulphate solution (1 M; 200 ml) for 18 hours. The mixture was washed with dichloromethane (2×250 ml) and adjusted to pH 14 with aqueous sodium hydroxide solution (5 M) then extracted with methane (3×250 ml). The combined extracts were dried over magnesium and the the solvent removed in vacuo to give 4-(aminomethyl)-1-(2-pyridylcarbonyl)piperidine (5.2 g) as a viscous yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:36])[CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:36])[CH:10]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cn1c2c(c3ccc(-n4ccc(O)cc4=O)cc31)CN(C(=O)OC(C)(C)C)CC2
Temperature: 90 °C

Procedure:
To a solution of tert-butyl 7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (0.98 g, 2.0 mmol) in CH3OH (30 mL) was added 5% Pd/C (0.3 g) and ammonium formate (0.32 g, 5.1 mmol) under an atmosphere of argon. The reaction was stirred at 90° C. until complete. The reaction mixture was cooled and filtered through a layer of Celite. The solvent was removed under reduced pressure to give tert-butyl 7-(4-hydroxy-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate, which was used directly in the next step. To a solution of tert-butyl 7-(4-hydroxy-2-oxopyridin-1(2H)-yl)-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (800 mg, 2.02 mmol) in THF (10 mL) was added LiN(SiMe3)2 (1.0 M in THF, 2.6 mL, 2.6 mmol) followed by PhN(Tf)2 (0.94 g, 2.6 mmol) under an atmosphere of argon. The reaction was stirred at room temperature until complete. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography (silica gel, hexanes/EtOAc, 1:1) to give the title compound (0.42 g, 40% yield) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.57-7.53 (m, 2H), 7.30 (d, J=1.5 Hz, 1H), 7.02-6.99 (m, 1H), 6.60 (d, J=2.7 Hz, 1H), 6.27 (dd, J=7.8, 2.7 Hz, 1H), 4.65 (s, 2H), 3.85 (m, 2H), 3.65 (s, 3H), 2.84 (m, 2H), 1.51 (s, 9H); ESI MS m/z 528 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:11]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:7][NH:8][CH2:9][CH2:10][N:11]1[S:12]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)(=[O:13])=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1S(=O)(=O)c1ccc(F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CNCCN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a solution of 0.75 g (1.803 mmol) of the product of Example 51 in 5 mL of dichloromethane was added was added 2.0 mL of trifluoroacetic acid and the resulting mixture was stirred for 2 h at room temperature. The reaction mixture was then concentrated in vacuo and the residue was diluted with ether. The organics were washed with saturated sodium bicarbonate solution, dried over Na2SO4, filtered and concentrated in vacuo to provide 0.515 g (90%) of the amine as a colorless oil pure enough for use in the next step. Electrospray Mass Spec: 316.9 (M+H)+
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])[CH2:24][CH2:23]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]([OH:20])=[O:19])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:37](OCC)C.C[Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.CCCCCC>[C:1]([O:5][C:6]([NH:8][C@@:9]1([CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])=[O:29])[CH2:26][CH2:27]2)[C:16](=[O:17])[N:15]2[C@@H:11]([S:12][CH2:13][C@H:14]2[C:18]([O:20][CH3:37])=[O:19])[CH2:10]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@]1(CC2CCN(C(=O)OCC[Si](C)(C)C)CC2)C[C@@H]2SC[C@@H](C(=O)O)N2C1=O
Reactant: CCOCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1CS[C@H]2C[C@@](CC3CCN(C(=O)OCC[Si](C)(C)C)CC3)(NC(=O)OC(C)(C)C)C(=O)N21
Reaction time: 1 h

Procedure:
497 mg of (3R,6R,7aS)-6-tert-butoxycarbonylamino-5-oxo-6-[1-(2-trimethylsilanylethoxycarbonyl)piperidin-4-ylmethyl]hexahydropyrrolo[2,1-b]thiazole-3-carboxylic acid were dissolved in 8 ml of methanol and 8 ml of diethyl ether and cooled to 0° C. 914 μl of a 1 N solution of trimethylsilyldiazomethane in hexane were added dropwise. The mixture was stirred for 1 h and then 1 ml of acetic acid was added dropwise. After 1 h, the solvents were removed in vacuo, and the residue was purified by chromatography on silica gel.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][N:22]4[C:27]([NH:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:28])[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C(C1C=CC(NC(=O)NCCC(OCC)=O)=CC=1)CCCCCCC>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][N:22]4[C:27]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:28])[N:14]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)CNC(=O)N1CCc2c(-c3noc(-c4ccc(OCC)c(OCC)c4)n3)cccc21
Agent: CCCCCCCCc1ccc(NC(=O)NCCC(=O)OCC)cc1
Product: CCOc1ccc(-c2nc(-c3cccc4c3CCN4C(=O)NCC(=O)O)no2)cc1OCC
Yield: 75 %

Procedure:
When the product of Step D was substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 11, Step B the identical process afforded the title compound in 75% yield. 1H-NMR (DMSO-d6) 8.03 (d, 1H, J=9 Hz); 7.73 (dd, 1H, J=2, 8 Hz); 7.61-7.59 (m, 2H); 7.29 (t, 1H, J=7.9 Hz); 7.17 (d, 1H, J=8.6 Hz); 7.09 (broad m, 1H); 4.17-4.0 (m, 4H); 3.98 (t, 2H, J=5.8 Hz); 3.74 (d, 2H, J=5.2 Hz); 3.47 (t, 2H, J=9 Hz); 1.38-1.32 (m, 6H).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1.Br[CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1>C1COCC1>[O:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH2:13][CH2:12]1
Reactant: OC1CCOCC1
Reactant: N#Cc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(COC2CCOCC2)cc1
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
Add sodium bis(trimethylsilyl)amide (2.8 mL, 5.61 mmol, 2M solution in THF) to a solution of tetrahydro-pyran-4-ol (572 mg, 5.61 mmol) in anhydrous THF (20 mL) and stir for 30 min. Add a solution of 4-bromomethyl-benzonitrile (1 g, 5.1 mmol) in anhydrous THF (5 mL) and stir the resulting mixture overnight at room temperature. Concentrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with cyclohexane/EtOAc (98:2 to 1:1 gradient) to obtain the desired intermediate as a white solid (845 mg, 76%). GC-MS m/z: 217 (M+).
Reaction SMILES: C(OC(C[CH:12]([O:17][C:18](=[O:58])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C@H:28]2[C@H:32]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=3[F:40])[C@:31]([C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=3[F:50])([C:41]#[N:42])[C@H:30]([CH2:51][C:52]([CH3:55])([CH3:54])[CH3:53])[NH:29]2)=[O:27])=[C:21]([O:56][CH3:57])[CH:20]=1)[O:13][C:14](=[O:16])[NH2:15])=O)C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[Cl:39][C:35]1[C:34]([F:40])=[C:33]([C@@H:32]2[C@:31]([C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][C:44]=3[F:50])([C:41]#[N:42])[C@H:30]([CH2:51][C:52]([CH3:55])([CH3:53])[CH3:54])[NH:29][C@H:28]2[C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([C:18]([O:17][CH2:12][O:13][C:14]([NH:15][CH2:19][C:18]([OH:58])=[O:17])=[O:16])=[O:58])=[CH:20][C:21]=2[O:56][CH3:57])=[O:27])[CH:38]=[CH:37][CH:36]=1
Reactant: COc1cc(C(=O)OC(CC(=O)OCc2ccccc2)OC(N)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)OCOC(=O)NCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 24, a solution of 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid benzyloxycarbonylmethyl-carbamoyloxymethyl ester (Example 29) in ethyl acetate was treated with 10% palladium on carbon under 1 atm of hydrogen to give 2-(((4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)methoxy)-carbonylamino)acetic acid as a white solid. MS (ES+) m/z calcd. for C35H36Cl2F2N4O8 [(M+H)+]: 747, found: 747.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:14][C:15]([O:17]CC1C=CC=CC=1)=O)[CH2:4][N:5]1[CH2:13][CH2:12][CH2:11][C@H:6]1C(OC)=O.[H][H]>CO.[Pd]>[OH:1][CH2:2][C@@H:3]1[CH2:4][N:5]2[CH2:13][CH2:12][CH2:11][C@H:6]2[C:15](=[O:17])[NH:14]1
Reactant: COC(=O)[C@@H]1CCCN1C[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1N[C@H](CO)CN2CCC[C@@H]12
Yield: 84.9 %

Procedure:
A solution of methyl 1-[(2S)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate (3.50 g, 10.4 mmol) in methanol was added to 5% palladium on carbon (50 wt. % in water) in methanol and treated with hydrogen at 40 psi for 1 h. The mixture was filtered and the filtrate was brought to reflux briefly and then cooled and concentrated in vacuo to afford (3S,8aS)-3-(hydroxymethyl)hexahydropyrrolo[1,2-a]pyrazin-1(2H)-one as a colorless solid (1.50 g, 8.83 mmol, 85% yield). 1H NMR (400 MHz, CDCl3): 7.28-7.22 (m, 1H), 3.83-3.75 (m, 1H), 3.69 (dd, 1H), 3.56 (dd, 1H), 3.31 (t, 1H), 3.08 (dd, 1H), 2.92 (dt, 1H), 2.76-2.70 (m, 1H), 2.66 (dd, 1H), 2.28-2.16 (m, 1H), 2.02-1.73 (m, 3H); MS (EI) for C8H14N2O2: 171 (MH+).