Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+].[Cl:3][C:4]1[CH:39]=[CH:38][CH:37]=[CH:36][C:5]=1[C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH3:14])[S:10][C:9]=1[N:15]1[C:19]([CH3:20])=[N:18][N:17]=[C:16]1[CH2:21][NH:22][C:23](=[O:35])/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N+:32]([O-])=O)=[O:7]>C(O)C.O.[Fe]>[Cl:3][C:4]1[CH:39]=[CH:38][CH:37]=[CH:36][C:5]=1[C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH3:14])[S:10][C:9]=1[N:15]1[C:19]([CH3:20])=[N:18][N:17]=[C:16]1[CH2:21][NH:22][C:23](=[O:35])/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32])=[O:7]
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)/C=C/c2ccccc2[N+](=O)[O-])s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)/C=C/c2ccccc2N)s1
Yield: 59.4 %

Procedure:
Ammonium chloride (118 mg) and iron powder (1.0 g) were dissolved in a mixed solvent of ethanol (15 ml) and water (5 ml). trans-N-(4-(3-(2-Chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3-(2-nitrophenyl)propenamide (1.07 g) was carefully added under reflux to the reaction mixture, and the mixture was refluxed for 1 hour. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was concentrated under reduced pressure. The obtained solid was recrystallized from ethyl acetate to give 0.60 g of trans-N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)-3-(2-aminophenyl)propenamide.
Reaction SMILES: [NH2:1]CCCCCCN.[C:9](O)(=O)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]>>[NH2:1][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=C(O)CCCCC(=O)O
Reactant: NCCCCCCN
Product: NCCCCCC(=O)O

Procedure:
from 5% to 35% by weight of units derived from equimolar quantities of hexamethylene diamine and adipic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH:7][C@@H:8]([CH3:14])[C:9](OCC)=[O:10].C[O-].[Na+].O.O.O.C(O)(=O)C(O)=O>C(O)C>[OH:7][C@@H:8]([CH3:14])[C:9]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)=[O:10]
Reactant: C1CNCCN1
Reactant: CCOC(=O)[C@H](C)O
Agent: C[O-]
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H](O)C(=O)N1CCNCC1
Temperature: 10 °C
Reaction time: 16 h

Procedure:
A flask charged with piperazine (10.0 g, 116 mmol) and (S)-ethyl 2-hydroxypropanoate 7 (17.84 g, 151 mmol, 1.30 equiv) was cooled to 10° C. Sodium methoxide (25 wt % in MeOH) (12.55 g, 58.1 mmol, 0.50 equiv) was slowly added while maintaining the temperature below 20° C. The cold water bath was removed and the reaction mixture was allowed to warm to ambient temperature and aged for 19 h. Water (6.23 g, 346 mmol, 3.0 equiv) was added and the mixture was aged for 16 h. The mixture was diluted with ethanol (40 mL) and concentrated under reduced pressure. The residue was diluted with ethanol (40 mL) and treated with a solution of oxalic acid dihydrate (6.58 g, 52.2 mmol) in ethanol (30 mL) to adjust the pH to 7.5. The suspension was cooled to <10° C., filtered through a pad of CELITE® and washed with ethanol (2×60 mL). The filtrate and washes were combined and concentrated to 50 mL. The solution was cooled to 10° C. and a solution of oxalic acid dihydrate (16.1 g, 128 mmol) in ethanol (60 mL) was slowly added. The suspension was allowed to warm to ambient temperature and stirred for 1 h. The suspension was cooled to 10° C. and the solid was collected by filtration, washed with cold ethanol (2×18 mL) and dried under reduced pressure at 50° C. for 24 h to afford the oxalate salt of (S)-2-hydroxy-1-(piperazin-1-yl)propan-1-one V as a white solid (15.2 g, 53%). 1H NMR (300 MHz, D2O) δ 4.73-4.51 (m, 1H), 3.93-3.59 (m, 4H), 3.26 (dd, J=8.8, 4.0 Hz, 4H), 1.27 (d, J=6.7 Hz, 3H).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH3:30])[CH:25]=4)[N:20]=3)=[CH:16][C:3]1=2.[SH:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35]>>[C:34]([CH2:33][CH2:32][S:31][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH3:30])[CH:25]=4)[N:20]=3)=[CH:16][C:3]1=2)([OH:36])=[O:35]
Reactant: COc1ccc2nc(COc3ccc4c(c3)C(O)c3ccccc3CO4)ccc2c1
Reactant: O=C(O)CCS
Product: COc1ccc2nc(COc3ccc4c(c3)C(SCCC(=O)O)c3ccccc3CO4)ccc2c1

Procedure:
11-Hydroxy-2-(6-methoxyquinolin-2-yl)methoxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][C:8]1=[O:20])=[O:6])[CH3:3].C(=O)(O)[O-].[Na+].[CH3:26][CH2:27]OC(C)=O>>[CH2:2]([O:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:9]([CH2:26][CH3:27])[C:8]1=[O:20])=[O:6])[CH3:3]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)C1CCN(Cc2ccccc2)C(CC)C1=O
Reaction time: 2 h

Procedure:
To a stirred suspension of 1-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester hydrochloride salt (25 g) in EtOAc (500 mL) was added saturated sodium bicarbonate solution (200 mL) and continued stirring for 2 h. The organic layer was separated, dried over Na2SO4, filtered and concentrated to provide ethyl 1-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester (22.00 g). To a solution of ethyl 1-benzyl-3-oxo-piperidine-4-carboxylic acid ethyl ester (22 g, 84.18 mmol) in EtOAc (75 mL) was added (Boc)2O (20.21 g, 92.59 mmol) followed by 10% Pd—C (2.4 g) and the resultant reaction mixture was subjected to hydrogenation at 50 psi of hydrogen for 14 h. The catalyst was filtered by passing through a pad of celite, washed the celite pad with EtOAc (200 mL) and the combined filtrate was concentrated. The residue was purified by flash silica gel column chromatography by eluting with 0.5% ethyl acetate in hexanes to provide ethyl 3-oxo-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (34 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH3:23][NH:24][CH3:25].C(O)C>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[N:15]=[C:16]([N:24]([CH3:25])[CH3:23])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Clc1ccc2c(n1)C(c1ccccc1Cl)=NCc1nncn1-2
Reactant: CNC
Solvent: CO
Solvent: CCO
Product: CN(C)c1ccc2c(n1)C(c1ccccc1Cl)=NCc1nncn1-2

Procedure:
This compound was obtained in an analogous manner to that given in Example 10a from 15 grams of 6-(o-chloro-phenyl)-8-chloro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine and 55 grams of dimethylamine in 500 ml. of ethanol by heating for 5 hours at 120° C. M.P. 240°-242° C. (from methanol); Yield 8.5 grams.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[CH:7][C:6]=1F)[CH3:2].[CH:27]([NH2:30])([CH3:29])[CH3:28]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:26])[C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]2)=[CH:7][C:6]=1[NH:30][CH:27]([CH3:29])[CH3:28])[CH3:2]
Reactant: CC(C)N
Reactant: CCOC(=O)c1cc(F)c(N2CCC(NC(=O)OC(C)(C)C)C2)cc1F
Solvent: CS(C)=O
Product: CCOC(=O)c1cc(F)c(N2CCC(NC(=O)OC(C)(C)C)C2)cc1NC(C)C
Yield: 28.1 %

Procedure:
4-[3-(tert-Butoxycarbonylamino)-pyrrolidin-1-yl]-2,5-difluorobenzoic acid ethyl ester (Example 2j, 5.4 g, 13.9 mmol), isopropylamine (40 mL, 469 mmol), and dimethyl sulfoxide (25 mL) are heated at 100° C. for 4 days in a sealed glass tube. The excess amine is removed by blowing in compressed air. The residue is filtered and concentrated under vacuum to a thick oil. Purification by column chromatography (1:1:7 ethyl acetate/chloroform/hexanes) to provide the title compound as a solid (1.6 g). MS: m/z 410 (MH+).
Reaction SMILES: [CH2:1]1[N:5]2[C:6]3[C:11]([NH:12][CH2:13][CH:4]2[CH2:3][CH2:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(N(CC)CC)C.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[C:24]=1[C:25](Cl)=[O:26]>CC(C)=O>[CH3:33][O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:23]([O:22][CH3:21])[C:24]=1[C:25]([N:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH2:1][CH2:2][CH2:3][CH:4]2[CH2:13]1)=[O:26]
Reactant: c1ccc2c(c1)NCC1CCCN21
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1cccc(OC)c1C(=O)N1CC2CCCN2c2ccccc21
Reaction time: 3 h
Yield: 79 %

Procedure:
To a stirred solution of the 1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinoxaline 1.7 g. (0.009 mole) and 4 ml. of dry triethylamine in 50 ml. of dry acetone was added 2.5 g. (0.01 mole) of 2,6-dimethoxybenzoyl chloride. The reaction mixture was stirred for three hours and filtered, and the acetone was evaporated under vacuo. The residue was washed with water, dried and recrystallized from aqueous ethanol to afford 2.4 g. (79% yield) of the title compound, m.p. 140°-142° C.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([Cl:22])[CH:5](C)[CH2:6][C:7]1[C:15]2([CH3:16])[CH:10]([CH:11]([O:17][C:18](=[O:20])[CH3:19])[CH2:12][CH2:13][CH2:14]2)[CH2:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCC[CH2:31]1>>[C:18]([O:17][CH:11]1[CH:10]2[C:15]([CH3:16])([C:7]([CH:6]([CH3:31])[CH2:5][CH:4]([Cl:22])[CH2:3][OH:2])=[CH:8][CH2:9]2)[CH2:14][CH2:13][CH2:12]1)(=[O:20])[CH3:19]
Reactant: C1CCOC1
Reactant: COC(=O)C(Cl)C(C)CC1=CCC2C(OC(C)=O)CCCC12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(=O)OC1CCCC2(C)C(C(C)CC(Cl)CO)=CCC12
Temperature: 0 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of 1.01 g (2.95 mmol) of [3aS-[3(αS*, γR*),3aα,7β,7aβ]-7-(acetyloxy)-α-chloro-3a,4,5,6,7,7a-hexahydro-β,3a-dimethyl-1H-indene-3-butanoic acid methyl ester in 25 mL of anhydrous tetrahydrofuran was cooled at 0° C. and treated under argon with 1.47 mL (1.47 mmol) of a 1M solution of lithium aluminum hydride in tetrahydrofuran. After stirring for 2 hours at 0° C., additional 0.20 mL of lithium aluminum hydride solution was added and the reaction allowed to proceed for 1 additional hour. It was then quenched by careful addition of 8 mL of a 2N aqueous Rochelle salt solution, then 0.5 mL of 2N hydrochloric acid. After dilution with water, it was extracted with ethyl acetate. The combined extracts were washed with 2N aqueous Rochelle salt solution, then brine, dried and evaporated to dryness to give 0.90 g (93% yield) of the title compound as a colorless, thick oil: [α]23D -30.1° (c 0.6, EtOH); 1H NMR (200 MHz, CDCl3) δ0.93 (s,3H),1.07 (d, J=7.2 Hz, 3H), 2.04 (s, 3H), 2.52 (br m, 1H), 3.73 (m, 2H), 4.00 (m, 1H), 4.97 (td, J=12.0, 4.4 Hz, 1H), 5.27 (br s, 1H) ppm.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Br[CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[N:10]>[OH-].[Na+]>[CH3:1][N:2]([CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[N:10]
Reactant: N#CCCCCBr
Reactant: CNC
Agent: [Na+]
Agent: [OH-]
Product: CN(C)CCCCC#N
Reaction time: 24 h

Procedure:
A mixture of dimethylamine (4 mL, 40% in water) and 5-bromo-pentanenitrile (2.3 mL, 20 mmol) is stirred for 24 h. The resulting reaction mixture is diluted with sodium hydroxide solution (10 mL, 5M) and extracted with ether. The ether extract is dried over K2CO3 and concentrated under reduced pressure to give an oil (1.5 g) which is used without further purification.
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:5]=2[NH:4][CH2:3]1.[Br:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][CH:2]1[O:7][C:6]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:5]=2[N:4]([CH2:16][CH2:15][CH2:14][Br:13])[CH2:3]1
Reactant: CC1CNc2ccc(F)cc2O1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CN(CCCBr)c2ccc(F)cc2O1
Temperature: 70 °C
Yield: 47.2 %

Procedure:
A mixture of 2-methyl-7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazine (4.3 g, 1 eq, 25.74 mmol) obtained in step (iii) above, 1,3-dibromo propane (26.1 ml, 10 eq, 257 mmol) and anhydrous sodium carbonate (8.2 g, 3 eq, 77.2 mmol) in dry DMF (260 ml) was heated at 70° C. for 16 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The residue was chromatographed using ethyl acetate and hexane to afford the title compound (3.5 g, yield 48%) as viscous oil.
Reaction SMILES: [C:1](=[O:43])(SCC)[O:2][CH2:3][O:4][C:5](=[O:39])[CH2:6][CH2:7][C:8](=[O:38])[NH:9][C:10]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].S(Cl)([Cl:47])(=O)=O>>[Cl:47][C:1]([O:2][CH2:3][O:4][C:5](=[O:39])[CH2:6][CH2:7][C:8](=[O:38])[NH:9][C:10]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:43]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCSC(=O)OCOC(=O)CCC(=O)NC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)CCC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)CCC(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)NC(=O)CCC(=O)OCOC(=O)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of carbonothioate 74 (351 mg, 0.55 mmol) in ice-cold CH2Cl2 (3 mL) was added sulfuryl chloride (67 μL, 0.83 mmol) and the mixture was stirred at 0° C. for 3 h, after which the mixture was concentrated to dryness, providing chloroformate 75 as a colorless gum (334 mg, quant.) which was used directly in the next step: 1H NMR (400 MHz, CDCl3) δ 1.44 (s, 27H), 1.94-1.98 (m, 6H), 2.21-2.24 (m, 6H), 2.46 (t, J=6.6 Hz, 2H), 2.74 (t, J=6.6 Hz, 2H), 5.83 (s, 2H), 6.15 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:19])[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH3:11][N:12]([CH3:19])[CH:13]1[CH2:18][CH2:17][N:16]([C:6]([C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)=[O:7])[CH2:15][CH2:14]1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: CN(C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C1CCN(C(=O)c2ccc(I)cc2)CC1
Reaction time: 2.5 h
Yield: 97.7 %

Procedure:
A solution of 4-iodo-benzoyl chloride (4.72 g, 17.71 mmol) in DCM (70 mL) at 0° C. was treated with dimethyl-piperidin-4-yl-amine (2.27 g, 17.71 mmol). The resultant suspension was warmed to room temperature and stirred for 2.5 hours. The reaction mixture was diluted with 1M aqueous Na2CO3 solution and the phases separated. The aqueous phase was extracted twice with DCM and the combined organic phase was dried (Na2SO4) and evaporated to afford (4-dimethylamino-piperidin-1-yl)-(4-iodo-phenyl)-methanone as a white solid (6.2 g, 98%). LCMS (Method 3) [M+H]+=359.2, RT=1.82 min.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][C:20]=1[CH3:28]>>[F:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[C:20]([CH3:28])[CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: Cc1cc(B(O)O)ccc1F
Product: Cc1cc(-c2cc(F)cc3c(C)c4n(c23)CCNC4=O)ccc1F

Procedure:
The title compound, light yellow solid (69 mg, 85%), MS (ISP) m/z=327.5 [(M+H)+], mp 236° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available 4-fluoro-3-methyl-phenylboronic acid (50.0 mg, 0.325 mmol).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[C:7]([F:13])[CH:6]=1)[CH:2]=[CH2:3].[CH3:14][C:15]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[CH2:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([N+:22]([O-:24])=[O:23])[C:15]=2[CH3:14])=[C:7]([F:13])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Reactant: C=CCOc1ccc(C=O)c(F)c1
Product: C=CCOc1ccc(CNc2cccc([N+](=O)[O-])c2C)c(F)c1

Procedure:
The product from Example 53B and 2-methyl-3-nitroaniline were processed as described in Example 6A to provide the title compound. MS (ESI−) m/z 315 (M−H)−.
Reaction SMILES: C1C2C(COC([N:18]3[CH2:23][C@H:22]([NH:24][C:25]([O:27]C(C)(C)C)=O)[CH2:21][C@H:20]([C:32]([OH:34])=O)[CH2:19]3)=O)C3C(=CC=CC=3)C=2C=CC=1.[CH2:35]([NH:37][C:38]1[CH:39]=[CH:40][C:41]2[O:46][CH2:45][C:44](=[O:47])[N:43]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:42]=2[CH:53]=1)[CH3:36]>>[CH2:35]([N:37]([C:38]1[CH:39]=[CH:40][C:41]2[O:46][CH2:45][C:44](=[O:47])[N:43]([CH2:48][CH2:49][CH2:50][O:51][CH3:52])[C:42]=2[CH:53]=1)[C:32]([C@H:20]1[CH2:21][C@@H:22]([NH:24][C:25](=[O:27])[C:20]([CH3:32])([CH3:21])[CH3:19])[CH2:23][NH:18][CH2:19]1)=[O:34])[CH3:36]
Reactant: CCNc1ccc2c(c1)N(CCCOC)C(=O)CO2
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)CN(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Product: CCN(C(=O)[C@@H]1CNC[C@H](NC(=O)C(C)(C)C)C1)c1ccc2c(c1)N(CCCOC)C(=O)CO2

Procedure:
The title compound is prepared analogously as described in Example 92A. using (3S*,5R*)-5-tert-butoxycarbonylamino-piperidine-1,3-dicarboxylic acid 1-(9H-fluoren-9-ylmethyl) ester and 6-ethylamino-4-(3-methoxy-propyl)-4H-benzo[1,4]oxazin-3-one. The product is purified by preparative HPLC (YMC Pack Pro C18, 10-100% CH3CN+0.1% TFA/H2O+0.1% TFA, 20 min, flow 20 ml/min); tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 5.47 min.
Reaction SMILES: CO[C:3]([C:5]1[C:10](=[O:11])[N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)[N:8]2[CH:23]=[CH:24][CH:25]=[C:7]2[C:6]=1[OH:26])=[O:4].[NH2:27][C@H:28]([C:30]([OH:32])=[O:31])[CH3:29].C[O-].[Na+]>>[OH:26][C:6]1[C:7]2[N:8]([CH:23]=[CH:24][CH:25]=2)[N:9]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[C:10](=[O:11])[C:5]=1[C:3]([NH:27][C@@H:28]([CH3:29])[C:30]([OH:32])=[O:31])=[O:4]
Reactant: COC(=O)c1c(O)c2cccn2n(Cc2ccc(C(F)(F)F)cc2)c1=O
Reactant: C[C@H](N)C(=O)O
Agent: C[O-]
Agent: [Na+]
Product: C[C@H](NC(=O)c1c(O)c2cccn2n(Cc2ccc(C(F)(F)F)cc2)c1=O)C(=O)O

Procedure:
Prepared according to the reaction condition used in Example 19 step a) from 4-hydroxy-2-oxo-1-(4-trifluoromethyl-benzyl)-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid methyl ester, L-alanine and NaOMe. ESI (m/z): 424 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:11]([OH:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[F:20][C:21]([F:36])([C:32]([F:35])([F:34])[F:33])[C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[S:24](Cl)(=[O:26])=[O:25]>C(#N)C>[Cl:1][C:2]1[C:11]([O:12][S:24]([C:23]([F:28])([F:29])[C:22]([F:30])([F:31])[C:21]([F:20])([F:36])[C:32]([F:35])([F:34])[F:33])(=[O:26])=[O:25])=[C:10]([Cl:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=S(=O)(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)c(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(Cl)c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.2 %

Procedure:
9.5 g (43.0 mmol) of methyl 2,4-dichloro-3-hydroxybenzoate in 240 ml of acetonitrile were admixed with 8.6 g (62.2 mmol) of potassium carbonate and then with 9.5 ml (52.8 mmol) of nonafluoro-n-butanesulfonyl chloride. The reaction mixture was stirred at room temperature (RT) for 16 h. For workup, the contents were poured onto ice-water and the mixture was extracted with ethyl acetate. The organic phase was dried and the filtrate was freed of the solvent on a rotary evaporator. The residue was purified by chromatography, which gave 3.5 g of clean product.
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.[C-:21]#[N:22].[K+].O>CS(C)=O>[C:21]([CH2:6][C@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@@H:8]1[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])#[N:22]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1COS(C)(=O)=O
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCCC[C@@H]1CC#N
Temperature: 90 °C

Procedure:
A solution of tert-butyl N-[(1S,2S)-2-(methylsulfonyloxymethyl)cyclohexyl]carbamate (1.8 g) in dry DMSO was added with potassium cyanide (0.52 g, 7.76 mL) and the mixture was then heated at 90° C. under N2 for 4 hours. The mixture was cooled and then poured on to water (50 mL) and extracted with ether (3×30 mL). The combined organic phases were washed with brine and concentrated in vacuo to provide the title compound.
Reaction SMILES: F[B-](F)(F)F.[O:6]=[N+:7]=[O:8].[OH:9][C:10]1[C:18]2[S:17][C:16]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[N:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>C(#N)C.C(OCC)C>[OH:9][C:10]1[C:18]2[S:17][C:16]([NH:19][C:20]([NH:22][CH2:23][CH3:24])=[O:21])=[N:15][C:14]=2[CH:13]=[CH:12][C:11]=1[N+:7]([O-:8])=[O:6]
Reactant: CCNC(=O)Nc1nc2cccc(O)c2s1
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: CCOCC
Solvent: CC#N
Product: CCNC(=O)Nc1nc2ccc([N+](=O)[O-])c(O)c2s1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 10.4 %

Procedure:
To a solution of 2-methylpyridone (0.020 mL, 0.20 mmol, 1.2 eq) in anhydrous acetonitrile (0.5 mL), nitronium tetrafluoroborate (0.045 g, 0.32 mmol, 1.9 eq) was added. The suspension was stirred at about 20° C. for about 5 minutes to get an orange solution. The solution was then transferred to a suspension of 1-(7-hydroxy-2-benzothiazolyl)-3-ethyl-urea 8 (0.040 g, 0.17 mmol) in acetonitrile (0.5 mL). The reaction mixture was stirred at about 20° C. for about 15 minutes, then taken up in diethyl ether (8 mL), and neutralized by washing with saturated sodium bicarbonate solution (1.5 mL). The organic extract was concentrated and dissolved in methanol (2 mL). LC/MS purification was followed by flash chromatography purification on silica (methylene chloride/methanol=40/1) to afford 0.005 g (10%) of the desired compound 17. 1H NMR (DMSO) δ 11.20 (br s, 1H, NH), 8.02 (d, 1H, J=9.0 Hz, ArH), 7.23 (d, 1H, J=7.5 Hz, ArH), 6.78 (br s, 1H, NH), 3.20 (m, 2H, CH2), 1.10 (t, 3H, J=7.2 Hz, CH3). LC/MS 283 (MH+); RP-HPLC RT 2.74 minutes.