Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([C:17]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[NH:19]2)=[CH:15][CH:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:36]([O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:37].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([C:17]([C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:19]2[C:36]([O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:37])=[CH:15][CH:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)COC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COC(=O)n1c(-c2ccc(F)cc2)c(-c2ccncc2)c2ccc(NC(=O)CNC(=O)OC(C)(C)C)nc21
Temperature: 23 °C

Procedure:
6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (29) (50 mg, 0.108 mmol), isobutyl chloroformate (42 ml, 0.325 mmol) N-methylmorpholine (119 ml, 1.08 mmol), potassium carbonate (74.9 mg, 0.542 mmol), and DMF (4 mL) were warmed at 80° C. for 16 h. After cooling to 23° C., the reaction was diluted with water (20 mL), extracted with ethyl acetate (2×20 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by preparative plate chromatography to afford 6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutoxycarbonyl-7-aza-indole (142). Compound (104) was converted to 6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutoxycarbonyl-7-aza-indole (143) in the manner of example 6: Mass Spectrum (CI) 462 (MH+).
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[F:25][C:26]([F:38])([F:37])[C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>O1CCCC1>[C:13]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:11][CH2:10][N:9]([S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([C:26]([F:25])([F:37])[F:38])[CH:28]=3)(=[O:35])=[O:34])[C:8]2=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: O=C1NCCC1(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1N(S(=O)(=O)c2cccc(C(F)(F)F)c2)CCC1(c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
To a solution of 3,3-diphenylpyrrolidin-2-one (Example 1A, 0.237 g, 1.0 mmol) dissolved in tetrahydrofuran (10 mL) was added potassium t-butoxide (1.0 M in tetrahydrofuran, 1.5 mL, 1.5 mmol) under nitrogen. The reaction mixture was stirred for 15 minutes, and then 3-(trifluoromethyl)benzene-1-sulfonyl chloride (0.294 g, 1.2 mmol) was added. The reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was concentrated and then diluted with ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (Analogix®, Burlington, Wis.) eluting with ethyl acetate/hexane (40:60) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.26-8.12 (m, 3H), 7.87 (t, J=7.8, 1H), 7.28-7.16 (m, 6H), 7.08-6.98 (m, 4H), 3.82 (t, J=6.4, 2H), 2.90 (t, J=6.4, 2H); MS (DCI) m/z 446.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:14]2[CH2:16][CH2:15]2)[CH:9](OC)[O:10][CH3:11])=[CH:4][CH:3]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:14]2[CH2:16][CH2:15]2)=[CH:9][O:10][CH3:11])=[CH:6][CH:7]=1
Reactant: COC(OC)C(c1ccc(Cl)cc1)C1CC1
Solvent: Cc1ccccc1
Product: COC=C(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Yield: 95.8 %

Procedure:
Water is azeotropically removed from a solution of p-toluenesulfonic acid monohydrate in toluene (150 g) until the distillate is clear. A solution of 1-[1-(p-chlorophenyl)-2,2-dimethoxyethyl]cyclopropane (24.7 g, 0.1 mol) in toluene is then added to the dried solution at 100° C. The resultant reaction mixture is refluxed for one hour, distilled to remove about 80 g of toluene/methanol, cooled to room temperature, treated with sodium carbonate (1 g), and poured into a saturated bicarbonate solution (100 mL). The organic phase is separated, washed with water, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product (20 g, 96% yield).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[CH:5][C:4]=1F.[F:15]C1C=C(CO)C=C(OC)C=1[N+]([O-])=O>>[Cl:1][CH2:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([N+:11]([O-:13])=[O:12])=[C:5]([F:15])[CH:4]=1
Reactant: COc1cc(CO)cc(F)c1[N+](=O)[O-]
Reactant: COc1cc(CCl)c(F)cc1[N+](=O)[O-]
Product: COc1cc(CCl)cc(F)c1[N+](=O)[O-]

Procedure:
The title compound was prepared using the procedure from Compound 130C (1-(chloromethyl)-2-fluoro-5-methoxy-4-nitrobenzene) with (3-fluoro-5-methoxy-4-nitrophenyl)methanol (Compound 146D). 1H NMR (CDCl3, 400 MHz): δ=3.96 (s, 3 H), 4.55 (s, 2 H), 6.87-6.90 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)/[C:8]([OH:10])=O)[N:6]=1.[NH2:17][C@@H:18]1[C:36](=[O:37])[N:20]2[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][O:26][C:27](=[O:32])[CH2:28][C:29](=[O:31])[CH3:30])[CH2:23][S:24][C@H:19]12>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)/[C:8]([NH:17][C@@H:18]2[C:36](=[O:37])[N:20]3[C:21]([C:33]([OH:35])=[O:34])=[C:22]([CH2:25][O:26][C:27](=[O:32])[CH2:28][C:29](=[O:31])[CH3:30])[CH2:23][S:24][C@H:19]23)=[O:10])[N:6]=1
Reactant: Nc1nc(/C(=N/OCC2CC2)C(=O)O)cs1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)/C(=N\OCC3CC3)c3csc(N)n3)[C@H]2SC1

Procedure:
Starting from 2-(2-aminothiazol-4-yl)-2(Z)-cyclopropylmethoxyiminoacetic acid and 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid, the titled compound is obtained by the procedure of Reference Example 3.
Reaction SMILES: Br[CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[CH3:18][N:19]([CH2:21][CH2:22][SH:23])[CH3:20].[OH-].[Na+]>CN(C)C=O.Cl.O>[CH3:18][N:19]([CH3:20])[CH2:21][CH2:22][S:23][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CBr)C2
Reactant: CN(C)CCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CSCCN(C)C)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.5 %

Procedure:
To a suspension of 2-bromomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (1. 765 g) in dimethylformamide (60 ml), hydrochloric acid salt of 2 (dimethylamino)ethylmercaptan (4.25 g) and caustic soda (2.40 g) in water (20 ml) were added and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure. The residue was combined with water, and extracted with chloroform. The extract was washed with NaCl solution twice and dried and condensed. The residue was crystallized from chloroform--n-hexane to obtain 1.741 g of the title compound as white powder (mp.: 163°-165° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:12][C:11]=2[CH3:22])=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.[C:30](O)(=[O:33])[CH2:31][OH:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:23])[C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:21][CH2:20][N:19]([C:31](=[O:32])[CH2:30][OH:33])[CH2:18][CH2:17]3)=[N:12][C:11]=2[CH3:22])=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=C(O)CO
Reactant: Cc1nc(N2CCNCC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1
Product: Cc1nc(N2CCN(C(=O)CO)CC2)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
100 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(piperazin-1-yl)nicotinamide was coupled to glycolic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-(2-hydroxyacetyl)piperazin-1-yl)-2-methylnicotinamide. MS (Q1) 466.3 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:15]=[C:16]([NH:24][C@@H:25]4[CH2:29][CH2:28][NH:27][CH2:26]4)[C:17]4[S:22](=[O:23])[CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[O:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[C:35](O)=[O:36]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:15]=[C:16]([NH:24][C@@H:25]4[CH2:29][CH2:28][N:27]([C:35]([C@H:31]5[CH2:32][CH2:33][CH2:34][O:30]5)=[O:36])[CH2:26]4)[C:17]4[S:22](=[O:23])[CH2:21][CH2:20][C:18]=4[N:19]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: O=S1CCc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc(N[C@@H]3CCNC3)c21
Product: O=C([C@H]1CCCO1)N1CC[C@@H](Nc2nc(N3CCN(c4ccc(Cl)cc4)CC3)nc3c2S(=O)CC3)C1

Procedure:
Starting from {2-[4-(4-chloro-phenyl)-piperazin-1-yl]-5-oxo-6,7-dihydro-5H-5λ4-thieno[3,2-d]pyrimidin-4-yl}-(R)-pyrrolidin-3-yl-amine Diastereomer 1 (Example 171) (see scheme 3, 3.22) and (R)-(+)-tetrahydrofuran-2-carboxylic acid, Example 196 is prepared as described in Example 231 (see scheme 7). The product is purified by preparative HPLC (method B). Analytical HPLC-MS (method D): RT=1.18 min.
Reaction SMILES: [OH:1][C:2]([CH3:23])([CH3:22])[CH:3]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)=[CH:10][CH:9]=1)[S:4]([NH2:7])(=[O:6])=[O:5].[C:24](OC)(OC)(OC)[O:25][CH3:26]>C(O)(=O)C>[CH3:24][O:25][C:26]1[O:1][C:2]([CH3:23])([CH3:22])[CH:3]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:10][CH:9]=2)[S:4](=[O:5])(=[O:6])[N:7]=1
Reactant: COC(OC)(OC)OC
Reactant: CC(C)(O)C(c1ccc(CCN2CCOCC2)cc1)S(N)(=O)=O
Solvent: CC(=O)O
Product: COC1=NS(=O)(=O)C(c2ccc(CCN3CCOCC3)cc2)C(C)(C)O1

Procedure:
2-Hydroxy-2-methyl-1-[4-(2-morpholin-4-ylethyl)phenyl]propane-1-sulfonamide (44 mg) was stirred with tetramethyl orthocarbonate (1 ml) and glacial acetic acid (0.2 ml) at 80° C. for 17 hours. The solvents were removed under reduced pressure. This gave the crude product with a molecular weight of 382.5 g/mol (C18H26N2O5S), which was used without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]1[O:31][N:30]=[C:29]([C:32](OCC)=O)[N:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH:37]/N=C(\N)/C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:10]([O:17][N:18]1[C:24](=[O:25])[N:23]2[CH2:26][C@H:19]1[CH2:20][CH2:21][C@H:22]2[C:27]([NH:28]/[C:29](=[N:30]\[OH:37])/[CH3:32])=[O:31])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C/C(N)=N/O
Reactant: CCOC(=O)c1noc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C/C(=N/O)NC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 99.7 %

Procedure:
DIPEA (0.137 mL, 0.787 mmol) was added to a solution of ethyl 5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octan-2-yl)-1,2,4-oxadiazole-3-carboxylate (145 mg, 0.525 mmol) and (Z)—N′-hydroxyacetimidamide (38.9 mg, 0.525 mmol) in DCM (2.6 mL), followed by addition of HATU (239 mg, 0.630 mmol). The reaction mixture was stirred at rt for 45 minutes and then concentrated to provide (2S,5R)-6-(benzyloxy)-N—((Z)-1-(hydroxyimino)ethyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxamide (174 mg, 100%), which was used directly in the next step. ESI-MS (EI+, m/z): 333.5.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].C(=O)([O-])[O-].[K+].[K+].[C:18]([O:22][C:23](=[O:26])[CH2:24]Br)([CH3:21])([CH3:20])[CH3:19].O>CN(C=O)C>[C:18]([O:22][C:23](=[O:26])[CH2:24][N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1Nc2ccccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)C(=O)c2ccccc21

Procedure:
44.1 g (0.3 mol) of isatin, 62.5 g (0.45 mol) of potassium carbonate and 66.2 g (0.34 mol) of bromoacetic acid tert-butyl ester (from Aldrich) are stirred in 100 ml of N,N′-dimethylformamide at room temperature for 24 hours. The mixture is then poured into 800 ml of water, and the precipitate formed is filtered off, washed with water and dried at 60° C. After recrystallising once from toluene-hexane (1:1), 608 g (78% of theory) of product having a melting point of 119-121° C. are obtained.
Reaction SMILES: [CH:1]1([C:7]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]=2[OH:18])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1>FC(F)(F)C(O)=O>[Cl:17][C:15]1[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]2[O:18][C@@H:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]3[C:7]=2[CH:16]=1
Reactant: COC(=O)c1cc(Cl)cc(C2CC=CCC2)c1O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Cl)cc2c1O[C@@H]1CCCC[C@@H]21
Temperature: 70 °C

Procedure:
A mixture of 9 g of methyl 3-(3-cyclohexenyl)-5-chlorosalicylate and 20 ml trifluoroacetic acid is heated at 70° C. overnight. The cooled reaction mixture is diluted with hexanes, washed three times with water, dried and evaporated to dryness. The residue is purified with flash chromatography using 10% ethyl acetate/hexane to give four fractions. First fraction 2.29 of material (mixture of at least two materials); second fraction 2.29 cis isomer; third fraction 1.69 mixture of cis and trans isomers; and fourth fraction 19 trans isomer.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([C:19]#[N:20])([CH3:18])[CH3:17])[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH:22](O)=[O:23].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1>[C:19]([C:16]([C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[C:9]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][CH:22]=[O:23])[CH:3]=1)=[O:21])([CH3:18])[CH3:17])#[N:20]
Reactant: O=CO
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(N)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(NC=O)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of the above-mentioned crude product of N-(3-aminophenyl)-3-(1-cyano-1-methylethyl)benzamide in tetrahydrofuran (15 mL) was added a mixture of formic acid (1 mL) and acetic anhydride (2 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and the fractions containing the object product were concentrated under reduced pressure to give the title compound (407 mg, 83%) as a colorless amorphous solid.
Reaction SMILES: ClC12[O:8]C1CCC(Cl)(F)C2.[CH:11]([C:13]1(O)[C:18]([Cl:20])([Cl:19])[CH2:17][CH2:16][CH2:15][C:14]1([Cl:22])Cl)=[CH2:12].[OH-].[Na+]>O>[Cl:22][C:14]12[O:8][CH:15]1[CH2:16][CH2:17][C:18]([Cl:20])([Cl:19])[CH:13]2[CH:11]=[CH2:12]
Reactant: C=CC1(O)C(Cl)(Cl)CCCC1(Cl)Cl
Reactant: FC1(Cl)CCC2OC2(Cl)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CC1C(Cl)(Cl)CCC2OC21Cl
Reaction time: 0.25 h
Yield: 90 %

Procedure:
The same procedure was employed as for the preparation of 2e in Example 17: it was performed with 1.14 g (4.32 mmol) of pure alcohol 1k, 12 cm3 of distilled water and 0.5 g (12.5 mmol) of sodium hydroxide; reaction time was 1 h 15 min; ether extraction (4×25 cm3); the crude product was employed as such (crude yld=90.5%) or purified by flash chromatography on silica (eluent: ether/petroleum ether=3/97): 0.88 g of epoxide 2i were obtained, that was a 90% yield (macrobore GC purity>98.6%)
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].CCN(C(C)C)C(C)C.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[F:13][C:9]1[CH:8]=[C:7]([CH:2]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(Br)c1cccc(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(Nc1ccccc1)c1cccc(F)c1
Temperature: 100 °C
Yield: 73 %

Procedure:
Methyl 2-bromo-2-(3-fluorophenyl)acetate (I15) (300 mg, 1.21 mmol), DIPEA (0.32 ml, 1.82 mmol), and aniline (0.17 ml, 1.82 mmol) were dissolved in acetonitrile (4 ml) and heated under microwave irradiation at 100° C. for 1 hour. Acetonitrile was evaporated, and the residue was purified by flash chromatography (Petroleum ether/EtOAc=95/5) to obtain intermediate I16 (229 mg, 73% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=O)[C:5]2=1.C(=O)(O)O.[NH2:20][NH:21][C:22]([NH2:24])=[NH:23]>C(O)(C)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[N:20][NH:21][C:22](=[NH:23])[NH2:24])[C:5]2=1
Reactant: N=C(N)NN
Reactant: O=C1CCCc2[nH]c3ccc(Cl)cc3c21
Agent: Cl
Agent: O=C(O)O
Solvent: CC(C)O
Product: N=C(N)NN=C1CCCc2[nH]c3ccc(Cl)cc3c21
Temperature: 80 °C
Yield: 49 %

Procedure:
A suspension of 6-chloro-4-oxo-1,2,3,4-tetrahydrocarbazole (21.9 mg, 0.1 mmol) in isopropanol and concentrated HCl (50 μL) is treated with aminoguanidine bicarbonate (20.4 μg, 0.15 mmol), heated at 80° C. for 4 h, cooled to room temperature and concentrated in vacuo. The resultant residue is purified by HPLC to give the title compound, 15.8 mg (49% yield), identified by mass spectral and HPLC analyses, (M+H) 276; retention time 3.72 min.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:10]=[C:11]1[N:16]2[CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:15]2[CH2:14][NH:13][CH2:12]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]1([C:7]([N:13]2[CH2:12][C:11](=[S:10])[N:16]3[CH2:17][CH2:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[CH:15]3[CH2:14]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: S=C1CNCC2c3ccccc3CCCN12
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(C1CCCCC1)N1CC(=S)N2CCCc3ccccc3C2C1
Reaction time: 5 h
Yield: 15.5 %

Procedure:
Cyclohexanoyl chloride (0.16 g) was added to a mixture of 4-thioxo-1,2,3,4,6,7,8,12b-octahydropyrazino[2,1-a][2]benzazepine (0.24 g) and triethylamine (0.25 ml) in chloroform (20 ml, ethanol-free) at 0°. The mixture was maintained at 0° for 30 min then at room temperature for 5 hr. The solution was washed with, first, dilute hydrochloric acid, and secondly with sodium bicarbonate solution. The chloroform solution was dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, Et2O) and recrystallised from dichloromethane/40°-60° C. petroleum ether to give white crystals of the title compound (55 mg, 16%) m.p. 150°-151° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([NH:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[C:26]([F:54])=[C:27]([C@@H:31]2[C@:35]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=3[F:45])([C:36]#[N:37])[C@H:34]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[NH:33][C@H:32]2[C:51](O)=[O:52])[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH3:13][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:51]([C@@H:32]2[C@@H:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[C:26]=3[F:54])[C@@:35]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:39]=3[F:45])([C:36]#[N:37])[C@@H:34]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[NH:33]2)=[O:52])=[CH:7][CH:6]=1)([C:9](=[O:10])[NH:11][CH3:12])[CH3:14]
Reactant: CNC(=O)C(C)(C)c1ccc(N)cc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)C(C)(C)c1ccc(NC(=O)[C@H]2N[C@H](CC(C)(C)C)[C@@](C#N)(c3ccc(Cl)cc3F)[C@@H]2c2cccc(Cl)c2F)cc1
Temperature: 25 °C
Yield: 40.8 %

Procedure:
Reagent 2-(4-amino-phenyl)-N-methyl-isobutyramide (130 mg, 0.676 mmol) was dissolved in dichloromethane (4 mL) then iPr2NEt (0.375 mL, 2.15 mmol) was added and stirred at 25° C. In three portions chiral (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-carboxylic acid (100 mg, 0.214 mmol) and 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 106 mg, 0.278 mmol) was added in 30 min intervals. The reaction mixture was stirred at 25° C. for 5 hours, complete by LCMS. The mixture was then diluted with CH2Cl2 and washed with water. The organic phase was separated, then concentrated under reduced pressure. The compound was purified by RP-HPLC (30-95% acetonitrile/water) to afford chiral (2S,3R,4S,5R)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [4-(1-methyl-1-methylcarbamoyl-ethyl)-phenyl]-amide as an off-white solid (56 mg, 40.8%) HRMS (ES+) m/z Calcd for C34H36Cl2F2N4O2+H [(M+H)+]: 641.2256. found: 641.2256.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO.[BH4-].[Na+]>CCO>[CH2:9]([NH:1][CH2:2][CH2:3][C:4]1[NH:8][CH:7]=[N:6][CH:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCCc1c[nH]cn1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: c1ccc(CNCCc2cnc[nH]2)cc1

Procedure:
Compound XIIIA is prepared by treatment of a mixture of compound XIIA, histamine, and benzaldehyde in a solvent such as MeOH or EtOH, with a reducing agent such as NaBH4 to provide N-benzyl-2-(1H-imidazol-5-yl)ethanamine (compound not shown). To this compound in water at 0° C., is added KOH followed by acetaldehyde. After approximately six hours at 80° C. followed by treatment with acid, compound XIIIA, PG=Bn, is isolated. Trifluoromethyl derivative XIVA is also prepared from compound XIIA. To a solution of compound XIIA in a solvent such as water at a temperature of about 0° C., is added a base such as KOH along with trifluoroacetaldehyde. After heating at a temperature of approximately 80° C. for approximately 6 hours and acidification, compound XIVA is isolated.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:5]([C:21]([O:23]C)=[O:22])=[N:6][C:7]([N:14]([CH3:20])[S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2.Cl>O1CCOCC1.O>[OH:3][C:4]1[C:5]([C:21]([OH:23])=[O:22])=[N:6][C:7]([N:14]([CH3:20])[S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: CCS(=O)(=O)N(C)c1nc(C(=O)OC)c(O)c2ncccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)N(C)c1nc(C(=O)O)c(O)c2ncccc12
Temperature: 55 °C

Procedure:
Sodium hydroxide (6.73 mL, 6.73 mmol, 1N solution) was added to a suspension of methyl 8-hydroxy-5-[methyl(ethylsulfonyl)amino]-1,6-naphthyridine-7-carboxylate (730 mg, 2.24 mmol) in a 2:1 solution of dioxane/water (20 mL) and the resulting mixture was heated overnight at 55° C. overnight. The opaque solution was acidified to a pH=7 using 1N HCl solution. The reaction was cooled and the solids that had precipitated out of solution were collected by vacuum filtration to give the desired product as an off-white solid.