Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][S:7][CH2:6]1)=[O:4].[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH2:14]>C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[C:9]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([I:19])=[CH:18][C:12]=2[F:11])=[CH:8][S:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CSCC1=O
Reactant: Nc1ccc(I)cc1F
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1CSC=C1Nc1ccc(I)cc1F
Temperature: 25 °C
Yield: 41.9 %

Procedure:
A solution of methyl-4-oxo-tetrahydro-thiophene-3-carboxylate (5.75 g, 35.9 mmol) and 2-fluoro-4-iodo-aniline (9.4 g, 40.9 mmol) were heated to reflux in a mixture of ethanol (25 mL) and acetic acid (0.3 mL) for 18 hours. The solution was cooled to room temperature, filtered and the solid product dried in vacuo to provide methyl-4-(2-fluoro-4-iodo-phenylamino)-2,3-dihydro-thiophene-3-carboxylate (5.70 g, 42% yield). MS (EI) for C12H11FINO2S: 380 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][N:36]=[C:35](Cl)[N:34]=2)=[CH:29][CH:28]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>CN(C)C(=O)C>[C:11]([O:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][N:36]=[C:35]([NH:1][CH2:2][CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[N:34]=2)=[CH:29][CH:28]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: NCCCN1CCCCC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ccnc(Cl)n2)cc1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ccnc(NCCCN3CCCCC3)n2)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 45.2 %

Procedure:
To a 24 mm×150 mm pyrex tube, charged with 3-aminopropylpiperidine (73 mg, 0.51 mmol), was added a solution of N-(2-t-butoxycarbonylaminophenyl)-4-(2-chloropyrimidin-4-yl)benzamide (Method 52, 85 mg, 0.20 mmol) in N,N-dimethylacetamide (4.6 ml). The reaction mixture was then heated to 50° C. and stirred for 16 hours, before being evaporated to dryness. The resultant residue was purified by flash chromatography, on silica (10 g), eluting with methanol/dichloromethane (5-15%), to give the title compound (48 mg, 45%); Mass Spectrum: M+H+ 531.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[NH:7][C:8](=[O:16])[C:9]([C:14]#[N:15])=[C:10](SC)[N:11]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH2:25][OH:26]>C(#N)C>[OH:26][CH2:25][C@@H:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:10]1[N:11]=[C:6]([CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([CH3:1])[CH:3]=2)[NH:7][C:8](=[O:16])[C:9]=1[C:14]#[N:15]
Reactant: OC[C@@H]1CCCN1
Reactant: CSc1nc(Cc2cccc(C)c2)[nH]c(=O)c1C#N
Solvent: CC#N
Product: Cc1cccc(Cc2nc(N3CCC[C@H]3CO)c(C#N)c(=O)[nH]2)c1
Temperature: 25 °C

Procedure:
0.1 g (0.37 mmol) of 2-(3-methylbenzyl)-4-(methylsulphanyl)-6-oxo-1,6-dihydro-5-pyrimidinecarbonitrile is heated with 0.11 g (1.1 mmol) of (S)-(+)-2-pyrrolidinemethanol in 3 ml of acetonitrile at 90° C. under argon for five days. After cooling to room temperature, the crude product is purified by preparative HPLC. 0.035 g (29% of theory) of the title compound is obtained as a colourless solid.
Reaction SMILES: [Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([NH2:17])=[O:16])=[C:11]([Br:18])[CH:10]=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[Na+]>C1COCC1.O>[Br:1][C:2]1[C:12]([O:13][CH2:14][C:15]([NH2:17])=[O:16])=[C:11]([Br:18])[CH:10]=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1ccc(Br)c(OCC(N)=O)c1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)COc1c(Br)ccc(C(=O)O)c1Br
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.700 g (1.80 mmol) of ethyl 2,4-dibromo-3-(aminocarbonylmethoxy)benzoate was dissolved in 15 ml of THF and 15 ml of water, and 0.147 g (3.70 mmol) of NaOH was added. The mixture was stirred for 12 hours at RT and concentrated completely. The residue was taken up in water and 6 N HCl was added. The precipitate which had formed was filtered off with suction and dried. 2,4-dibromo-3-(aminocarbonyl-methoxy)benzoic acid was obtained as a white solid.
Reaction SMILES: I[C:2]1[NH:3][C:4]([I:10])=[C:5]([CH:7]([CH3:9])[CH3:8])[N:6]=1.O.S([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH:7]([C:5]1[N:6]=[CH:2][NH:3][C:4]=1[I:10])([CH3:9])[CH3:8]
Reactant: CC(C)c1nc(I)[nH]c1I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)c1nc[nH]c1I
Temperature: 85 °C
Yield: 79.1 %

Procedure:
In 240 ml of ethanol was dissolved 48.1 g (0.144 mol)of 2,5-diiodo-4-isopropyl-1H-imidazole (7), followed by addition of 240 ml of water and 20.1 g (0.159 mol)of sodium sulfite. The mixture was heated at 85° C. for 35 minutes. This reaction mixture was concentrated and extracted with methylene chloride and the extract was washed with water and dried over sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was washed with ethyl acetate-diisopropyl ether and filtered to provide 26.9 g (yield 86%)of 4-isopropyl-5-iodo-1H-imidazole (4b).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([N+:19]([O-])=O)=[CH:17][C:6]2[CH2:7][CH2:8][N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:11][C:5]=2[CH:4]=1.O.NN>CO.[Pd]>[CH3:1][O:2][C:3]1[C:18]([NH2:19])=[CH:17][C:6]2[CH2:7][CH2:8][N:9]([CH2:12][C:13]([F:14])([F:15])[F:16])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCN(CC(F)(F)F)CC2
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CO
Product: COc1cc2c(cc1N)CCN(CC(F)(F)F)CC2
Temperature: 70 °C
Yield: 89.3 %

Procedure:
Into a 1-neck round-bottom flask was added 7-methoxy-8-nitro-3-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (310 mg, 1.0 mmol), hydrazine monohydrate (10 mL, 0.2 mol), palladium (10% wt on C, 50% wet; 100 mg, 0.9 mmol), in methanol (20 mL). The reaction mixture was heated at 70° C. for 3 hours. The reaction mixture was filtered through Celite and was concentrated. The resulting precipitate was partitioned between water and dichloromethane. The organic phase was washed with another portion of water, dried (MgSO4), and concentrated, to afford 8-methoxy-3-(2,2,2-trifluoro-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (245 mg, 88%) as a waxy solid, which was used without further purification. m.p. ° C.; 1H-NMR (CDCl3) δ 6.55 (s, 1H), 6.49 (s, 1H), 3.82 (s, 3H), 3.63 (br s, 2H), 3.15 (q, J=9.5 hz, 2H), 2.88 (m, 4H), 2.77 (m, 4H); LC/MS (ESI+): 275.07 (M+H).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])[C:19]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=[O:3])[NH2:2].[Na+].[Na].Cl.[OH2:33]>>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S@:8](=[O:33])[C@@H:9]2[C@H:16]([NH:17][C:18](=[O:28])[C:19]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)=[N:20][O:21][CH3:22])[C:15](=[O:29])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[NH2:2]
Reactant: O
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(COC(N)=O)CS[C@H]12)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [Na]
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)C[S@](=O)[C@H]12)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of sodium (6R,7R)-3-carbamoyloxymethyl-7-[2-(fur-2-yl)-2-methoxyiminoacetamido]ceph-3-em-4-carboxylate (syn isomer) (2.59 g) in water (25 ml) was added sodium metaperidoate (1.93 g). The solution was stirred for 30 minutes at ambient temperature and then acidified by the dropwise addition of 2N aqueous hydrochloric acid. The resulting precipitate was collected, washed successively with water, ethanol and ether and then dried in vacuo to afford the title compound as a white powder (1.63 g.), [α]D20 + 113° (c 0.86, Me2SO); λmax (pH6 buffer) 264.5 (ε 17,200) and 279 nm (ε 15,600); νmax (Nujol) 1779 (β-lactam), 1740 and 1716(CO2H), 1688, 1654, 1589 and 1530 (CONH and OCONH2) and 1030cm-1 (S→O), τ (Me2SO-d6)0.60 (d, J 8Hz, NH), 2.11, 3.19, 3.31 (multiplets, furyl protons), 4.08 (q, J5 and 8Hz, C-7H). 4.87 and 5.45 (ABq, J13Hz, CH2OCONH2), 4.96(d, J 5Hz, C-6H), 6.08 (s, OCH3), 6.10 and 6.42(ABq, J 18Hz, C-2 CH2).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]=1[O:17][CH3:18])=[O:5])C>[OH-].[Na+]>[CH3:18][O:17][C:7]1[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[CH:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnn(-c2ccccc2)c1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C(=O)O)cnn1-c1ccccc1

Procedure:
The ester prepared as described in (a) above (390 mg, 1.58 mmol) in lN sodium hydroxide (10 ml) was refluxed for 3 hours under nitrogen and then allowed to cool and the solution was washed with ethyl acetate. The aqueous layer was then acidified to pH 2(HCl) whereupon the title compound precipitated out and was filtered and washed with water followed by drying under vacuum (268 mg, 78%), νmax (Nujol) 1680, 1595, 1560 cm-1 δ (D6 -Acetone) 4.24 (3H,s,--OCH3),7.74 (5H,m, phenyl protons), 8.06 (1H,s,C5 pyrazole proton), Found M+ ; 218.0684, C11H10N2O3Requires M,218.0689.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:24])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18](O)=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22].[CH3:25][O:26][CH2:27][CH2:28][CH2:29][NH2:30]>>[Cl:24][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:16][CH2:17][C:18]([NH:30][CH2:29][CH2:28][CH2:27][O:26][CH3:25])=[O:19])=[O:15])=[CH:11][C:10]=1[N+:21]([O-:23])=[O:22]
Reactant: COCCCN
Reactant: O=C(O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COCCCNC(=O)CNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 70 from 2-(5-((3,5-dichloropyridin-4-yl)thio)-4-nitrothiophene-2-carboxamido)acetic acid (120.0 mg, 0.29 mmol) from example 210 and 3-methoxypropylamine (31.4 mg, 0.35 mmol). The title compound was obtained as a solid (20.0 mg, 15% yield). 1H NMR (400 MHz, d6-DMSO) δ: 9.19 (1H, m), 8.99 (2H, m), 8.47 (1H, s), 7.94 (1H, m), 3.77 (2H, m), 3.29 (2H, m), 3.19 (3H, s), 3.07 (2H, m), 1.60 (2H, m). MS m/z: 477.11, 479.10 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]([CH3:36])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:25][CH:24]=2)=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[OH-].[K+]>ClCCl.CO>[CH2:1]([C:5]([CH3:36])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:35])[C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:27][CH:28]=2)=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(C)(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)OCC
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCCCC(C)(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O
Yield: 40.3 %

Procedure:
In a similar manner to that described in Example 6, ethyl 2-butyl-2-methyl-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (350 mg), which is the product of Example 19, was reacted with aqueous sodium hydroxide solution (1N, 2.00 ml) and aqueous potassium hydroxide solution (85%, 0.1g) and the reaction mixture was treated. The residue was subjected to chromatography on a silica gel column using dichlorometane/methanol=19/1 as the eluant to afford a solid which was washed with a mixture of diisopropyl ether and hexane to give the title compound (133 mg) as a white powder.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:16]3[S:30][CH2:29][CH2:28][CH2:27][C:17]=3[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:20]=2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:24]1[CH2:25][CH2:26][N:21]([C:19]2[N:20]=[C:15]([N:12]3[CH2:13][CH2:14][O:9][CH2:10][CH2:11]3)[C:16]3[S:30][CH2:29][CH2:28][CH2:27][C:17]=3[N:18]=2)[CH2:22][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CSc2c(nc(N3CCNCC3)nc2N2CCOCC2)C1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(CN2CCN(c3nc4c(c(N5CCOCC5)n3)SCCC4)CC2)cc1
Yield: 80.7 %

Procedure:
1.6 g of benzyl chloride was added dropwise to a mixture of 3 g of 4-morpholino-2-piperazino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine, 4 g of potassium carbonate and 30 ml of N,N-dimethylformamide at room temperature under stirring, followed by stirring for 5 hours. The reaction solution was extracted with ethyl acetate, and the extract was washed with water and dried. The solvent was then distilled off and the resulting crystals were recrystallized from a mixture of diethyl ether-petroleum ether to obtain 3.1 g (82% yield) of 2-(N-benzylpiperazino)-4-morpholino-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine as pale yellow prisms having a melting point of 125° C.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[C:5](C#N)=[CH:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1.O.O.N>P(=O)(O)(O)O>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[CH:13][C:14]2[N:15]([CH:17]=[CH:18][N:19]=2)[CH:16]=1
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc2nccn2c1
Agent: N
Agent: O=P(O)(O)O
Solvent: O
Product: Cc1[nH]c(=O)ccc1-c1ccc2nccn2c1
Yield: 44.4 %

Procedure:
In 10 ml of 85% phosphoric acid was refluxed 1 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-3-pyridinecarbonitrile for 18 hours. After cooling, water was added and then conc. ammonia water was further added to the reaction mixture to render the mixture alkaline. The mixture was extracted with chloroform. After washing with water and drying over magnesium sulfate, chloroform was removed by distillation under reduced pressure. The residue was recrystallized from ethanol-ether to obtain 0.4 g of 1,2-dihydro-6-methyl-5-(imidazo[1,2-a]pyridin-6-yl)-2-oxo-pyridine.
Reaction SMILES: [C:1]([C:4]([S:7]([CH2:10][CH:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12]([OH:14])=O)(=[O:9])=[O:8])([CH3:6])[CH3:5])(=[O:3])[NH2:2].[NH2:22][C@@H:23]([CH2:42][C:43]1[N:44]=[CH:45][NH:46][CH:47]=1)[C:24]([NH:26][C@@H:27]([CH2:35][CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[C@@H:28]([OH:34])[C@H:29]([CH:31]1[CH2:33][CH2:32]1)[OH:30])=[O:25].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:1]([C:4]([S:7]([CH2:10][C@H:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12]([NH:22][C@@H:23]([CH2:42][C:43]1[N:44]=[CH:45][NH:46][CH:47]=1)[C:24]([NH:26][C@@H:27]([CH2:35][CH:36]1[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]1)[C@@H:28]([OH:34])[C@H:29]([CH:31]1[CH2:32][CH2:33]1)[OH:30])=[O:25])=[O:14])(=[O:8])=[O:9])([CH3:5])[CH3:6])(=[O:3])[NH2:2]
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CC(C)(C(N)=O)S(=O)(=O)CC(Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C(N)=O)S(=O)(=O)C[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 239 mg (0.76 mmol) of rac-α-[[(1-carbamoyl-1-methylethyl)sulfonyl]methyl]hydrocinnamic acid, 250 mg (0.69 mmol) of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide, 77 mg (0.76mmol) of triethylamine, 118 mg (0.76 mmol) of HOBT and 289 mg (0.76 mmol) of HBTU in 10 ml of dimethylformamide was stirred at room temperature overnight. Subsequently, the reaction solution was evaporated to dryness in a high vacuum, the residue was taken up in 75 ml of ethyl acetate and washed twice with 20 ml of saturated sodium hydrogen carbonate solution each time. The ethyl acetate solutions were dried over sodium sulphate and subsequently evaporated under reduced pressure. For purification and separation of the two epimeric products, the residue (450 mg) was chromatographed on 30 g of silica gel using a 97:3:0.1 o mixture of methylene chloride, methanol and ammonia as the eluent. After lyophilization from dioxan and water there were obtained the less polar epimer (S)-α-[(R)-α-[[(1-carbamoyl-1-methylethyl)sulfonyl]methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-imidazole-4-propionamide as a colourless amorphous powder, MS: 660 (M+H)+, and the more polar epimer (S)-α-[(S)-α-[[(1-carbamoyl-1-methylethyl)sulfonyl]methyl]hydrocinnamamido]-N-[(1S ,2R,3S)-1-(cyclohexylmethyl )-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide, likewise as a colourless amorphous powder, MS: 660 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]([O:25]C(OC)=O)=[CH:16][C:15]=2[NH:30][C:31]([CH:33]2[O:38][C:37]3[CH:39]=[CH:40][C:41]([C:43]#[N:44])=[CH:42][C:36]=3[N:35](C(OCC)=O)[CH2:34]2)=[O:32])[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+].Cl>CO.O>[C:43]([C:41]1[CH:40]=[CH:39][C:37]2[O:38][CH:33]([C:31]([NH:30][C:15]3[CH:16]=[C:17]([OH:25])[C:18]([CH:20]4[CH2:21][CH2:22][CH2:23][CH2:24]4)=[CH:19][C:14]=3[C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[O:32])[CH2:34][NH:35][C:36]=2[CH:42]=1)#[N:44]
Reactant: CCOC(=O)N1CC(C(=O)Nc2cc(OC(=O)OC)c(C3CCCC3)cc2C2=CCN(C(=O)OC(C)(C)C)CC2)Oc2ccc(C#N)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#Cc1ccc2c(c1)NCC(C(=O)Nc1cc(O)c(C3CCCC3)cc1C1=CCNCC1)O2
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 19.7 %

Procedure:
Ethyl 2-(2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-4-cyclopentyl-5-(methoxycarbonyloxy)phenylcarbamoyl)-6-cyano-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate (50 mg, 0.08 mmol) and NaOH (162 mg, 4.05 mmol) were dissolved in 5:1 methanol/water (3.6 mL) and heated at 60° C. for 2 h. The mixture was added to 1 N HCl (25 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Removal of the Boc protecting group was achieved by dissolving the compound in dichloromethane (3.0 mL) and TFA (3.0 mL) and stirring for 10 min before being concentrated in vacuo. HPLC purification (10-99% CH3CN/0.05% TFA) provided 6-cyano-N-(4-cyclopentyl-5-hydroxy-2-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamide (7 mg, 19% yield). LC/MS m/z 562.2 [M+H]+. 1H NMR (400.0 MHz, MeOD) δ 9.56 (s, 1H), 9.15 (s, 1H), 7.16 (s, 1H), 7.01 (m, 3H), 6.90 (s, 1H), 6.45 (s, 1H), 5.56 (s, 1H), 4.89 (q, J=3.0 Hz, 1H), 3.61 (s, 2H), 3.56-3.53 (m, 1H), 3.44-3.39 (m, 1H), 3.33 (m, obscured by H2O peak, 1H), 3.23-3.16 (m, 3H), 2.44 (s, 2H), 1.93 (m, 1.97-1.90, 2H), 1.78-1.71 (m, 2H), 1.65-1.62 (m, 2H), 1.56-1.45 (m, 2H).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.NC(N)=O.[N+:16]([O-])([OH:18])=[O:17]>O>[CH3:6][C:7]1[NH:8][CH:9]=[C:10]([N+:16]([O-:18])=[O:17])[N:11]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ncc[nH]1
Agent: NC(N)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1nc([N+](=O)[O-])c[nH]1
Reaction time: 6.5 h
Yield: 89 %

Procedure:
A mixture of 330 parts of sulfuric acid (36 percent by weight), 100 parts of 2-methylimidazole, 50 parts of urea, 283 parts of nitric acid (31 percent by weight) and 153 parts of water is kept for 6.5 hours in a distillation vessel, equipped with a stirrer, at from 123° to 130° C. During the reaction, 20 parts of 30 percent strength by weight nitric acid distill off. The reaction mixture is then diluted with a 3.5-fold volume of water whilst cooling and is neutralized to pH 3-4 with ammonia solution. The 2-methyl-4-nitroimidazole which separates out is centrifuged off, washed, dried and recrystallized from water. 138 parts of 2-methyl-4-nitroimidazole (89.0% of theory) of melting point 145°-146° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[N-:14]=[N+]=[N-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:13])[NH:14][C:11]=2[CH:12]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Product: COc1ccc2c(c1)NC(=O)CCC2
Temperature: 55 °C
Reaction time: 8 h

Procedure:
Combined 7-Methoxy-1-tetralone (5.0 g, 0.028 mol) with Polyphosphoric acid (80 g, 0.7 mol) in 2-neck 500 ml Flask fit with overhead mechanical stirrer and septa under nitrogen flow. Sodium azide (2.2 g, 0.034 mol) added portionwise over 5 min and the reaction was heated to 55° C. Continue stirring overnight. The mixture was poured into water and a white precipitate ensued. The mixture was filtered and washed with water then hexane and dried over 60 h. 8-Methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one obtained as a white solid (3.34 g, 62%). MP: 103-104° C.; 1H-NMR (CDCl3, 400 MHz) δ 7.45 (broad s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.72-6.69 (m, 1H), 6.54 (d, J=2.1 Hz, 1H), 3.81 (s, 3H), 2.76 (t, J=7.2 Hz, 2H), 2.38 (t, J=7.3 Hz, 2H), 2.25-2.18 (m, 2H); LC/MS: 192.07 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13]O)=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:18])=O>>[Cl:18][CH2:13][C:12]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][O:10][C:11]=1[CH3:15]
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1CO
Reactant: O=S(Cl)Cl
Product: Cc1onc(-c2ccc(Cl)cc2)c1CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 3-(4-chlorophenyl)-5-methyl-4-isoxazolylmethanol (2.23 g) and thionyl chloride (5.0 ml) was stirred at 0° C. for 30 min. The reaction mixture was concentrated, saturated aqueous sodium hydrogencarbonate was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were filtrated to give 4-chloromethyl-3-(4-chlorophenyl)-5-methylisoxazole (2.20 g, yield 91%). The crystals were recrystallized from diisopropyl ether. melting point: 91–92° C.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:14]([F:19])([F:18])C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:18][CH:14]([F:19])[O:12][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(F)c1O
Reactant: O=C(O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(F)c1OC(F)F
Yield: 41.3 %

Procedure:
A mixture of methyl 3-fluoro-2-hydroxy-benzoate (1.5 g, 8.8 mmol), 2-chloro-2,2-difluoro-acetic acid (1.62 g, 1.05 mL, 10.6 mmol) and potassium carbonate (1.46 g, 10.6 mmol) were heated in DMF (5 mL) at 120° C. for 5 hours. The reaction mixture was diluted with water (20 mL) and extracted with ether (2×10 mL). The organics were separated and washed sequentially with water (5 mL) and brine solution (5 mL). The organics were dried (MgSO4) and concentrated in vacuo to give residue which was purified by silica gel column chromatography using 0-30% EtOAc/hexanes as eluent to give methyl 2-(difluoromethoxy)-3-fluorobenzoate (0.8 g, 39%). To methyl 2-(difluoromethoxy)-3-fluorobenzoate (0.8 g, 3.64 mmol) was added 12% aq. NaOH (3 mL) and the reaction mixture was heated at 50° C. for 1 hour. The aqueous layer was extracted with 1:1 ether/hexane (2×5 mL). The aqueous layer was acidified to pH 1 with 6 N HCl solution to give a suspension. The solid was filtered and washed with water, then dried in vacuo to give 2-(difluoromethoxy)-3-fluoro-benzoic acid (555 mg, 31%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=7.8 Hz, 1H), 7.43 (dd, J=13.1, 4.8 Hz, 1H), 7.35 (td, J=8.1, 4.9 Hz, 1H), 6.68 (t, J=74.4 Hz, 1H).