Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[NH2:21].CC1C=CC=CC=1C.CC1C=CC(S(O)(=O)=O)=CC=1>O>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1
Reactant: Nc1c(Cl)cccc1Cl
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)N1CCC(=Nc2c(Cl)cccc2Cl)CC1

Procedure:
A mixture of 171 parts of ethyl 4-oxo-1-piperidinecarboxylate, 162 parts of 2,6-dichlorobenzenamine, 800 parts of dimethylbenzene and 1 part of 4-methylbenzenesulfonic acid is stirred and refluxed with water-separator. The reaction mixture is evaporated, yielding 250 parts of ethyl 4-[(2,6-dichlorophenyl)imino]-1-piperidinecarboxylate as a residue.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([O:30][N:31]1[C:37](=[O:38])[N:36]2[CH2:39][C@H:32]1[CH2:33][CH2:34][C@H:35]2[C:40]([NH:42][NH:43][CH:44]=O)=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH2:23]([O:30][N:31]1[C:37](=[O:38])[N:36]2[CH2:39][C@H:32]1[CH2:33][CH2:34][C@H:35]2[C:40]1[S:10][CH:44]=[N:43][N:42]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Solvent: C1CCOC1
Product: O=C1N2C[C@@H](CC[C@H]2c2nncs2)N1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.9 %

Procedure:
Lawesson's reagent (2.40 g, 6.0 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-N′-formyl-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbohydrazide (1.6 g, 6.0 mmol) in THF (30 mL) at rt. The mixture was stirred at rt for 8 hrs., then the solvent was concentrated and the residue was purified by silica gel column chromatography (1:6 to 1:1 EtOAc/hexanes) to give (2S,5R)-6-(benzyloxy)-2-(1,3,4-thiadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (568 mg, 30%) as a yellow solid. ESI-MS (EI+, m/z): 317.1 [M+H]+. 1H-NMR (400 MHz, CDCl3): δ 9.12 (s, 1H), 7.38-7.29 (m, 5H), 5.02 (d, J=8.8 Hz, 1H), 4.89-4.83 (m, 2H), 3.28 (m, 1H), 2.86-2.83 (m, 1H), 2.70-2.54 (m, J=2H), 2.29-2.24 (m, 1H), 2.17-2.13 (m, 1H), 2.07-1.79 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1([OH:8])[CH2:7][CH2:6]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:1][CH2:2][CH2:3][CH2:4][C:5]1([OH:8])[CH2:7][CH2:6]1)(=[O:19])=[O:18]
Reactant: OCCCC1(O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCC1(O)CC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1-(3-hydroxypropyl)cyclopropanol (140 mg, 1.2 mmol) and triethylamine (0.3 mL, 2.1 mmol) in 8 mL of dichloromethane was stirred at 0° C. for 10 min. Methane-sulfonyl chloride (180 mg, 1.6 mmol) was then added to the mixture via a syringe. After stirring at 0° C. for 1 hr, the mixture was quenched with 2 mL of ice-water and extracted with dichloromethane (10 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo to give 3-(1-hydroxycyclo-propyl)propyl methanesulfonate as yellow oil (used for the next step immediately).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:9])[CH2:7][CH2:8][C:2]1=2.[H-].[Na+].C([O:14][C:15]([C:17]1[CH:21]=[CH:20][O:19][CH:18]=1)=O)C.Cl>C1COCC1.C(OCC)(=O)C.O>[O:19]1[CH:20]=[CH:21][C:17]([C:15]([CH:7]2[CH2:8][C:2]3[S:1][CH:5]=[CH:4][C:3]=3[C:6]2=[O:9])=[O:14])=[CH:18]1
Reactant: O=C1CCc2sccc21
Reactant: CCOC(=O)c1ccoc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1ccoc1)C1Cc2sccc2C1=O
Temperature: 100 °C
Yield: 27 %

Procedure:
5,6-Dihydro-cyclopenta[b]thiophen-4-one in 40 mL of THF was treated with NaH (60 percent, 0.8 g, 36.25 mmol). After the addition of Furan-3-carboxylic acid ethyl ester, the reaction mixture was heated at 100° C. for 8 hr. The solution was cooled to room temperature and poured into water. The resulting mixture was acidified with concentrated HCl and was added with ethyl acetate (70 mL). The organic layer was collected, brined, dried over MgSO4(s), and concentrated under reduced pressure. The resultant precipitate was collected and recrystallized from ethanol to provide the corresponding 5-(Furan-3-carbonyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (0.9 g, 38 mmol) as brown solid in 27% yield.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:21]([CH3:22])[CH2:20][C@@:19]2([CH3:23])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[C:17](=[O:24])[CH2:16][C@@:15]2([CH3:25])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:26]Br>CO>[Br:26][CH2:13][C:12](=[O:14])[C@@H:11]1[C@:15]2([CH3:25])[C@H:8]([C@H:7]3[C@H:18]([C:17](=[O:24])[CH2:16]2)[C@:19]2([CH3:23])[C@H:4]([CH2:3][C@H:2]([OH:1])[C@H:21]([CH3:22])[CH2:20]2)[CH2:5][CH2:6]3)[CH2:9][CH2:10]1
Reactant: BrBr
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](C)C[C@]4(C)[C@H]3C(=O)C[C@]12C
Solvent: CO
Product: C[C@@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(=O)CBr)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
A solution of 3α-hydroxy-2β-methyl-5α-pregnane-11,20-dione (1.04 g.) in dry methanol (150 ml) was stirred at 0°-5° during the dropwise addition of a solution of bromine (0.16 ml) in dry methanol (20 ml) over a period of 2.5 hours. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was separated, washed with water, dried (MgSO4) and evaporated to a white foam. Purification by preparative t.l.c. (ethyl acetate:benzene 1:2.5) gave the title compound (510 mg.), m.p. 140° dec.; [α]D + 133° (c 0.95).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.[K+].[Br-]>>[CH3:11][O:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:15][CH:14]=1
Reactant: COc1ccc(N)cc1
Reactant: CSc1ccc(C#N)cc1
Agent: [Br-]
Agent: [K+]
Product: COc1ccc(NC(=N)c2ccc(SC)cc2)cc1
Yield: 76.84 %

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (12.11 g, 81 mmol) and 4-methoxyaniline (10 g, 81 mmol) by following the procedure described in preparation 10 (17 g, yield 76.84%, mp 166-168° C., purity 97.25% by HPLC). 1H-NMR (CDCl3):δ 2.51 (s, 3H), 3.80 (s, 3H), 4.80 (bs, 2H, D2O exchangeable), 6.91 (s, 4H), 7.26-7.29 (m, 2H), 7.78-7.8 (d, 2H). IR (KBr) cm−1: 3461, 3320, 2949, 2922, 2829, 1615. MS m/z:273.1 (M+).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][C:18]([OH:20])=[O:19])[CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21]N1C(=O)CCC1=O.Cl>O1CCCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][C:18]([OH:20])=[O:19])[CH:15]=2)[C:10]([Cl:21])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc2c(Cl)cn(Cc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.6 %

Procedure:
To a solution of the compound [4] obtained in Example 4 (82 mg) in tetrahydrofuran (1 mL) was added N-chlorosuccinimide (26 mg) at room temperature, and then the reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 4N-hydrochloric acid for acidification, and then extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (19 mg) as a red solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:18][C:19]([F:28])([F:27])[C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]#[N:16])[CH:12]=[C:11]([O:26][C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:18])([F:27])[F:28])[CH:21]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: N#Cc1cc(Cl)nc(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(OCc2ccccc2)nc(Oc2cccc(C(F)(F)F)c2)c1

Procedure:
2-Benzyloxy-6-chloro-4-cyanopyridine (0.8 g, 0.0033 mol) and meta-trifluoromethyl phenol (0.58 g, 0.0033×1.1 mol) were dissolved in 20 ml of N-methyl-pyrrolidinone, and anhydrous potassium carbonate (0.5 g, 0.0033×1.1 mol) was added thereto and the resultant solution was stirred for about 2.5 hours at about 100° C.
Reaction SMILES: C(O[NH:9][CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([OH:14])=[O:13])C1C=CC=CC=1.[C:20]([O:23][C:24](=O)[CH3:25])(=[O:22])C>C(O)=O.ClCCl>[CH2:24]([O:23][C:20]([NH:9][CH2:10][C@@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:12]([OH:14])=[O:13])=[O:22])[C:25]1[CH:17]=[CH:16][CH:15]=[CH:11][CH:10]=1
Reactant: CCCCC[C@H](CNOCc1ccccc1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O=CO
Product: CCCCC[C@H](CNC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 189.3 %

Procedure:
To a cold solution of (R)-3-benzyloxyamino-2-pentylpropionic acid (1.03 g, 3.89 mmol) in HCO2H (19 mL) and dichloromethane (19 mL) at 0° C. was added acetic anhydride (3.9 mL, 41.2 mmol). The mixture was stirred at 0° C. for 3 hours. The volatiles were removed by evaporation under vacuum. Dichloromethane (50 mL) was added. The organic solution was washed with brine (50 mL×2), and dried over MgSO4. Filtration and evaporation under vacuum provided the title compound (1.08 g, 95%). 1H NMR (400 MHz, CHCl3) δ 8.07 (br s, 1H), 7.29 (m, 5H), 4.91-4.71 (m, 2H), 3.76 (m, 2H), 2.67 (m, 1H), 1.54 (m, 1H), 1.41(m, 1H), 1.20 (m, 6H), 0.80 (t, J=7.0 Hz, 3H). MH+294.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([CH:13]([CH2:21][CH2:22][C:23](=[O:25])[NH2:24])[C:14]([O:16]C(C)(C)C)=[O:15])[C:7]2=[O:12])#[N:2].FC(F)(F)C(O)=O>>[C:1]([C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][N:6]([CH:13]([CH2:21][CH2:22][C:23](=[O:25])[NH2:24])[C:14]([OH:16])=[O:15])[C:7]2=[O:12])#[N:2]
Reactant: CC(C)(C)OC(=O)C(CCC(N)=O)N1Cc2c(C#N)cccc2C1=O
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc2c1CN(C(CCC(N)=O)C(=O)O)C2=O
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A mixture of tert-butyl 2-(4-cyano-1-oxoisoindolin-2-yl)-4-carbamoylbutanoate (1.0 g, 2.91 mmol) and trifluoroacetic acid (5 mL) was stirred for 2 hours. The mixture was concentrated and the residue was crystallized from ether (15 mL) to give 2-(4-cyano-1-oxoisoindolin-2-yl)-4-carbamoylbutanoic acid (0.74 g, 89%) as a white solid: 1H NMR (DMSO-d6) δ 13.12 (b, 1H), 8.12 (d, J=7.6 Hz, 1H), 8.03 (d, J=7.6 Hz, 1H), 7.73 (t, J=7.6 Hz, 1H), 7.23 (s, 1H), 6.76 (s, 1H), 4.80-4.62 (m, 3H), 2.32-2.09 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])=[N:3]1.Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccn(C)n2)n1
Reactant: N#Cc1cc(Br)ccn1
Product: Cc1cc(-c2ccnc(C#N)c2)cc(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2-cyanopyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=319.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:3]=1[CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]3[NH:37][CH2:36][C:35]4([CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)[C:32]3=[N:33][CH:34]=2)[CH2:25][CH2:24]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([N:37]1[C:31]3[C:32](=[N:33][CH:34]=[C:29]([N:26]4[CH2:27][CH2:28][O:23][CH2:24][CH2:25]4)[CH:30]=3)[C:35]3([CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH2:36]1)=[C:3]([CH3:22])[C:4]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH3:21])[CH:15]=1)=[N:5]2
Reactant: c1nc2c(cc1N1CCOCC1)NCC21CCOCC1
Reactant: COc1cc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)ccn1
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: COc1cc(-c2nc3cc(F)cc(F)c3c(N3CC4(CCOCC4)c4ncc(N5CCOCC5)cc43)c2C)ccn1

Procedure:
Prepared according to procedure Y by stirring 4-chloro-5,7-difluoro-2-(2-methoxypyridin-4-yl)-3-methylquinoline (50 mg, 0.16 mmol), 6′-morpholino-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridine] (42.9 mg, 0.16 mmol), sodium tert-butoxide (33.0 mg, 0.34 mmol), XPhos precatalyst (23.0 mg, 0.031 mmol), and toluene (1.7 mL) at 85° C. for 6 h. Purification by reverse-phase HPLC (0-70% acetonitrile in water) gave 1′-(5,7-difluoro-2-(2-methoxy-4-pyridinyl)-3-methyl-4-quinolinyl)-6′-(4-morpholinyl)-1′,2,2′,3,5,6-hexahydrospiro-[pyran-4,3′-pyrrolo[3,2-b]pyridine] as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.32-8.36 (1H, m), 7.66-7.71 (1H, m), 7.60 (1H, d, J=2.3 Hz), 7.09 (1H, dd, J=5.2, 1.5 Hz), 6.99-7.07 (1H, m), 6.95-6.97 (1H, m), 5.73-5.76 (1H, m), 4.14-4.20 (2H, m), 4.03 (3H, s), 3.96-4.01 (1H, m), 3.89-3.94 (1H, m), 3.74-3.81 (4H, m), 3.52-3.62 (2H, m), 2.98-3.07 (4H, m), 2.31-2.46 (2H, m), 2.27-2.30 (3H, m), 1.78-1.86 (1H, m), 1.67-1.75 (1H, m). Mass Spectrum (ESI) m/e=560.0 (M+1).
Reaction SMILES: [Na:1].N1C(N)=C2C(N(C3(OC[C@H](OCP(O)(O)=O)[C@H]3O)O)C=N2)=NC=1.[N:25]1([C:33]2([O:51][CH2:50][C@H:37]([O:38][CH2:39][P:40]([O:46]C(C)C)([O:42]C(C)C)=[O:41])[C@H:35]2[OH:36])[OH:34])[CH:32]=[CH:31][C:29]([NH2:30])=[N:28][C:26]1=[O:27]>>[Na:1].[N:25]1([C:33]2([O:51][CH2:50][C@H:37]([O:38][CH2:39][P:40]([OH:42])([OH:46])=[O:41])[C@H:35]2[OH:36])[OH:34])[CH:32]=[CH:31][C:29]([NH2:30])=[N:28][C:26]1=[O:27]
Reactant: CC(C)OP(=O)(CO[C@H]1COC(O)(n2ccc(N)nc2=O)[C@@H]1O)OC(C)C
Agent: Nc1ncnc2c1ncn2C1(O)OC[C@H](OCP(=O)(O)O)[C@H]1O
Agent: [Na]
Product: Nc1ccn(C2(O)OC[C@H](OCP(=O)(O)O)[C@H]2O)c(=O)n1
Yield: 43 %

Procedure:
This compound was prepared as described for 3a, using 18 (150 mg, 0.38 mmol) as a starting material. Compound 3d (58 mg, 0.16 mmol) was obtained as a colorless solid, in 43% yield, which was characterized as follows:
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]#[N:16])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5].[C:17](=O)([O:25]C1C=CC([N+]([O-])=O)=CC=1)[O:18][CH:19]([O:21][C:22](=[O:24])[CH3:23])[CH3:20].C(N(CC)CC)C>ClCCl>[C:22]([O:21][CH:19]([O:18][C:17]([NH:2][C@H:3]([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]#[N:16])=[O:9])[C@H:4]([CH2:6][CH3:7])[CH3:5])=[O:25])[CH3:20])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C#N
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@H](NC(=O)OC(C)OC(C)=O)C(=O)N1CCC[C@H]1C#N
Yield: 69.6 %

Procedure:
A solution of (2S)-1-(isoleucyl)pyrrolidine-2-carbonitrile hydrochloride (500 mg, 2.04 mmol; prepared according to Jenkins et al., WO95/15309), α-acetoxyethyl p-nitrophenyl carbonate (610 mg, 2.27 mmol; prepared according to Alexander et al., J. Med. Chem. 31, 318, 1988) and triethylamine (250 mg, 2.50 mmol) in dichloromethane (40 ml) was stirred at room temperature for 18 hours. After this time the solvent was removed in vacuo and the residue was taken up in ethyl acetate (70 ml). This solution was washed with 0.3M KHSO4, sat. NaHCO3, water and brine, dried (Na2SO4) and evaporated. The residue was purified by flash chromatography (eluant EtOAc:Pet. Ether 60-80° C.; 3:7) yielding a colourless oil identified as the title compound (480 mg, 1.42 mmol, 70%).
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[N:12][C:13]([NH:16][C@H:17]([C:22]2[CH:23]=[N:24][C:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[N:26][CH:27]=2)[CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:15]=1)=[O:9])C.C(OCC)(=O)C.[OH-].[Na+].Cl>O1CCCC1.CO>[CH3:20][CH:19]([CH3:21])[CH2:18][C@H:17]([NH:16][C:13]1[N:12]=[CH:11][C:10]([C:8]([NH:7][CH2:6][CH2:5][C:4]([OH:38])=[O:3])=[O:9])=[CH:15][CH:14]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=2)=[N:26][CH:27]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N[C@@H](CC(C)C)c2cnc(-c3ccc(C(F)(F)F)cc3)nc2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C[C@H](Nc1ccc(C(=O)NCCC(=O)O)cn1)c1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
3-[(6-{(S)-3-Methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamino}-pyridine-3-carbonyl)-amino]-propionic acid ethyl ester (29.2 g wet with ethyl acetate, theoretically 54.0 mmol) was dissolved in tetrahydrofuran (135 mL) and methanol (45 mL), and 1.0 M sodium hydroxide (135 mL) was added. This was stirred at room temperature for 20 min before most of the organics were rotovapped off. A small amount of tetrahydrofuran was added and the mostly aqueous contents were stirred in an ice bath. 1 N HCl (130 mL) was added until pH 5. Ethyl acetate was added and stirred for ˜20 min to ensure constant pH. The material was added to a sep funnel and the layers separated. The aqueous was back extracted with additional ethyl acetate and the combined organics were washed with brine and dried over MgSO4. This was concentrated and the solid was placed in a vacuum oven for two days to give 3-[(6-{(S)-3-methyl-1-[2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butylamino}-pyridine-3-carbonyl)-amino]-propionic acid as a white foam. 1H NMR (400 MHz, DMSO-d6, δ): 12.16 (s, 1H) 8.97 (s, 2H) 8.54 (d, J=8.2 Hz, 2H) 8.41 (d, J=2.0 Hz, 1H) 8.19 (t, J=5.4 Hz, 1H) 7.87 (d, J=8.4 Hz, 2H) 7.78 (dd, J=8.8, 2.3 Hz, 1H) 7.68 (d, J=8.0 Hz, 1H) 6.58 (d, J=8.6 Hz, 1H) 5.09-5.26 (m, 1H) 3.38 (q, J=6.7 Hz, 2H) 2.44 (t, J=7.0 Hz, 2H) 1.80-1.94 (m, 1H) 1.57-1.77 (m, 2H) 0.96 (d, J=6.1 Hz, 3H) 0.92 (d, J=6.3 Hz, 3H); MS (M+1): 502.3.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[CH2:10][CH2:9][C:8]([C:21]([OH:23])=[O:22])=[CH:7][C:6]=2[CH:24]=1.B([O-])([O-])O[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH3:39])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(O)C>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:11]2[C:5]3[CH:4]=[CH:3][C:2]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][CH3:39])=[CH:29][CH:28]=4)=[CH:24][C:6]=3[CH:7]=[C:8]([C:21]([OH:23])=[O:22])[CH2:9][CH2:10]2)=[CH:14][CH:15]=1
Reactant: CCCOCCOc1ccc(OB([O-])[O-])cc1
Reactant: COc1ccc(CN2CCC(C(=O)O)=Cc3cc(Br)ccc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccc(OC)cc2)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 31.1 %

Procedure:
In toluene (20 ml), ethanol (2 ml) and water (2 ml) were suspended 7-bromo-1-(4-methoxybenzyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (300 mg), 4-propoxyethoxyphenyl borate (346 mg) and potassium carbonate (534 mg), and the suspension was stirred under argon atmosphere for 30 minutes. Then, to the suspension was added tetrakistriphenylphosphinepalladium (63 mg), and the mixture was heated at 100° C. for 4 hours under argon atmosphere. After allowing to cool, water was added to the mixture, which was made acidic (pH=4) with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) and the resulting solid was recrystallized from hexane-ethyl acetate to give 1-(4-methoxybenzyl)-7-(4-propoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylic acid (117 mg) as yellow crystals.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([N+:12]([O-])=O)[CH:11]=[C:5]2[CH2:4]1)[CH3:2]>[Pd].C(O)C>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]2[N:9]=[C:10]([NH2:12])[CH:11]=[C:5]2[CH2:4]1)[CH3:2]
Reactant: CCN1CCn2nc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CCN1CCn2nc(N)cc2C1
Reaction time: 1 h
Yield: 71 %

Procedure:
A 500-mL Parr hydrogenation bottle was charged with 285a (1.8 g, 9 mmol), 10% palladium on carbon (50% wet, 500 mg dry weight) and ethanol (100 mL). The bottle was evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 1 h on a Parr hydrogenation apparatus. The catalyst was removed by filtration through a pad of Celite 521 washing with 1:1 methylene chloride:methanol (500 mL). The resulting solution was concentrated under reduced pressure to afford a 71% yield (1.7 g) of crude 285b.
Reaction SMILES: [OH-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][O:13][C@H:12]([CH2:16][C:17]2[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=2[OH:24])[CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C(N1CCO[C@H](CC2C=CC=C(C=CC3C=NC=CC=3)C=2)C1)(OC(C)(C)C)=O.Cl[CH:54]([F:56])[F:55]>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1>[C:3]([N:10]1[CH2:15][CH2:14][O:13][C@H:12]([CH2:16][C:17]2[CH:22]=[C:21]([Br:23])[CH:20]=[CH:19][C:18]=2[O:24][CH:54]([F:56])[F:55])[CH2:11]1)([O:5][C:6]([CH3:8])([CH3:9])[CH3:7])=[O:4]
Reactant: FC(F)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cc(Br)ccc2O)C1
Agent: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=Cc3cccnc3)c2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cc(Br)ccc2OC(F)F)C1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
To a solution of sodium hydroxide (186 mg, 4.64 mmol) in water (1.0 mL) was added tetra n-butylammonium bromide (50 mg, 0.155 mmol) followed by N-Boc-(R)-2-(5-bromo-2-hydroxybenzyl)morpholine (576 mg, 1.55 mmol), example 1, intermediate (a) in dioxane (8.0 mL). The reaction mixture was cooled to 10° C. and chlorodifluoromethane gas passed into the reaction mixture whilst the vessel was stoppered. After 15 mins, the solution was warmed to 23° C. whilst continuing to pass the gas into the solution. After 30 mins, the gas flow was ceased and the reaction stirred for 17 hrs before concentration and partition of the residue between ethyl acetate and water. The crude product was purified by silica gel chromatography, eluting with 10% ethyl acetate/iso-hexane, affording N-Boc-(R)-2-(5-bromo-2-difluoromethoxy-benzyl)-morpholine as an oil (357 mg, 55%).
Reaction SMILES: C[O:2][C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:5][CH2:6][CH:7](Cl)CC.[H-].[Na+].CN(C=[O:26])C>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:4]2([C:3]([OH:2])=[O:19])[CH2:5][CH2:6][CH2:7][O:26]2)=[CH:12][CH:13]=1
Reactant: CN(C)C=O
Reactant: CCC(Cl)CCC(C(=O)OC)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C2(C(=O)O)CCCO2)cc1
Reaction time: 1 h

Procedure:
To a solution of 5-chloro-2-(4-methoxyphenyl)-heptanoic acid methyl ester (0.26 g, 0.96 mmol) in 5 ml of DMF at 0° C. was added sodium hydride (0.6 g, 1.4 mmol). The reaction was stirred for 1 h at this temperature then quenched with 10 ml of water. The product was extracted into ethyl acetate (3×15 ml), washed with brine (20 ml), dried with magnesium sulfate and concentrated in vacuo to give a yellow oil. Silica gel chromatography eluting with hexane/ethyl acetate (4:1) gave 0.063 g of the title compound as a colorless oil.