Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]3[CH:24]=[CH:25][CH:26]=[C:20]3[CH:19]=2)=[CH:8]1)(C)(C)C.Cl[CH2:28][CH2:29][O:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[N:33]1[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH2:29][CH2:28][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:18]2[N:23]=[CH:22][N:21]4[CH:24]=[CH:25][CH:26]=[C:20]4[CH:19]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH:32]=1
Reactant: ClCCOc1cccnc1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCOc3cccnc3)cc12

Procedure:
6-[2-(Pyridin-3-yloxy)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime was prepared in 16% overall yield using the method described in example 147, starting from 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) and 3-(2-Chloro-ethoxy)-pyridine.
Reaction SMILES: [ClH:1].O[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].Cl.[NH2:11][CH2:12][CH2:13][SH:14]>Cl.C(O)(C)C>[ClH:1].[ClH:1].[CH3:9][C:8]1[N:7]=[CH:6][NH:5][C:4]=1[CH2:3][S:14][CH2:13][CH2:12][NH2:11]
Reactant: NCCS
Reactant: Cc1[nH]cnc1CO
Agent: Cl
Solvent: CC(C)O
Product: Cc1nc[nH]c1CSCCN
Yield: 164.7 %

Procedure:
A solution of 4-hydroxymethyl-5-methylimidazole hydrochloride (30.0 g.) and cysteamine hydrochloride (23.0 g.) in concentrated aqueous hydrochloric acid (450 ml.) was heated under reflux for 17 hours. Concentration followed by re-evaporation with water afforded a residue which was dissolved in isopropyl alcohol, concentrated to low bulk and cooled to afford 4-methyl-5-[(2-aminoethyl)thiomethyl]-imidazole dihydrochloride (40.6 g.), m.p. 185°-191°.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1)C.[OH-].[K+]>O>[NH:15]1[CH:16]=[CH:17][N:18]=[C:14]1[CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:19])=[O:3]
Reactant: CCOC(=O)COc1ccccc1Cc1ncc[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccccc1Cc1ncc[nH]1
Reaction time: 18 h
Yield: 29.1 %

Procedure:
2-(1-Imidazolylmethyl)phenoxyacetic acid ethyl ester (1 g) was heated on a steam bath for 30 minutes in a solution of potassium hydroxide (0.5 g) in water (10 ml) and the solution was allowed to stand at room temperature for 18 hours. The solution was then evaporated to small volume and acidified to pH 5 with acetic acid. The solid was collected by filtration and crystallised from water to give 2-(1-imidazolylmethyl)phenoxyacetic acid (0.26 g), m.p. 213°-214° C. Found: C, 61.83, H, 5.24, N, 12.34. C12H12N2O3 requires: C, 62.05, H, 5.21, N, 12.06%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH3:13])[CH3:12].[H-].[Na+].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:20][C:19]1[CH:22]=[CH:23][CH:24]=[C:17]([F:16])[CH:18]=1)[C:8](=[O:11])[C:7]2([CH3:13])[CH3:12]
Reactant: Fc1cccc(CBr)c1
Reactant: CC1(C)C(=O)Nc2c(F)cccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(Cc2cccc(F)c2)c2c(F)cccc21
Reaction time: 0.5 h
Yield: 81.1 %

Procedure:
7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (1.3 g, 7.3 mmol) was dissolved in dimethylformamide (14 mL) and NaH (0.30 g, 8 mmol) was added and the mixture was stirred 30 minutes then 3-fluorobenzyl bromide (1.5 g, 8.0 mmol) was added. The mixture was stirred 4 hours then quenched with saturated aqueous ammonium chloride, diluted with ether, washed with water, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was purified via Isco chromatography (Redisep, silica, gradient 0-20% ethyl acetate in hexane) to afford 1.7 g (81%) of 7-fluoro-1-(3-fluorobenzyl)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one.
Reaction SMILES: C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[CH2:11]([O:18][C:19](=[O:36])[C:20]([CH3:35])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C@@H:29]2[CH2:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH:24]=1)[CH3:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+].Cl[C:43]([O:45][CH3:46])=[O:44].Cl>C(Cl)Cl.O>[CH3:46][O:45][C:43]([N:31]1[CH2:32][CH2:33][CH2:34][C@@H:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([O:22][C:20]([C:19]([O:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:36])([CH3:21])[CH3:35])[CH:24]=2)[CH2:30]1)=[O:44]
Reactant: CC(C)(Oc1cccc([C@@H]2CCCNC2)c1)C(=O)OCc1ccccc1
Reactant: COC(=O)Cl
Agent: Cl
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: O
Product: COC(=O)N1CCC[C@@H](c2cccc(OC(C)(C)C(=O)OCc3ccccc3)c2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
(S)-2-methyl-2-(3-piperidin-3-yl-phenoxy)-propionic acid benzyl ester-L-(+)-tartrate salt (Preparation 3, Method F; 119 mg, 0.24 mmol) was dissolved in 2 mL methlyene chloride and 1 mL water. Sodium bicarbonate (79 mg, 0.95 mmol) and methyl chloroformate (37 mL, 0.47 mmol) were added, and the biphasic mixture and resulting mixture stirred at ambient temperature for 2 h. The mixture was diluted with water (50 mL), acidified with 1N aqueous hydrochloric acid and extracted with diethyl ether (2×50 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide 90 mg (93%) of (S)-3-[3-(1-Benzyloxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid methyl ester as a clear oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14])=[CH:5][CH:4]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>>[CH3:15][S:16]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1)(=[O:18])=[O:17]
Reactant: CSc1ccc(CCOCCO)cc1
Reactant: CS(=O)(=O)Cl
Product: CSc1ccc(CCOCCOS(C)(=O)=O)cc1
Yield: 90 %

Procedure:
The 2-[2-(4-methylthiophenyl)ethoxy]ethanol obtained according to the preceding paragraph was sulfonylated with methanesulfonyl chloride in a manner analogous to that described in Example 1(c) to give 2.41 g (90%) of 2-[2-(4-methylthiophenyl)ethoxy]ethyl methanesulfonate in the form of an oil which was homogeneous according to chromatography.
Reaction SMILES: C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1.[OH-].[Na+].[N+:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]=[N:27][C:28]1[CH:33]=[C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=1[OH:38])([O-])=[O:18].N(C1C=CC=CC=1)=NC1C=CC=CC=1>O.C(O)(CC)C>[OH:38][C:29]1[CH:30]=[CH:31][C:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:33][C:28]=1[N:27]1[N+:17]([O-:18])=[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]2=[N:26]1
Reactant: CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: O=C1c2ccccc2-c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCC(C)O
Product: CC(C)(C)c1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Temperature: 80 °C

Procedure:
9-fluorenone 2.5 g was added to a mixture of secondary butanol 80 g, water 14 g and 97% sodium hydroxide 22.4 g, and 2-nitro-2'-hydroxy-5'-t-butylazobenzene 19.9 g was added to the resultant mixture for one hour while stirring at 80° C. The mixture was further stirred at 90°~97° C. for 4 hours, thus almost all of the azobenzene having disappeared to produce 2-(2-hydroxy-5-t-butylphenyl)benzotriazole-N-oxide. Thus, the reaction of Process (b) was completed. The resultant reaction liquor was further stirred for 4 hours, thus the N-oxide having disappeared to finish the reaction of Process (c).
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:32])([CH3:31])[CH2:4][C:5]1[N:6]=[C:7]([CH:16]([OH:30])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[N:8](S(N(C)C)(=O)=O)[CH:9]=1>O1CCCC1>[CH3:2][C:3]([CH3:32])([CH3:31])[CH2:4][C:5]1[N:6]=[C:7]([CH:16]([OH:30])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[NH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(O)Cc1ccc(-c2ccccn2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(C)Cc1c[nH]c(C(O)Cc2ccc(-c3ccccn3)cc2)n1
Temperature: 70 °C

Procedure:
1.5 N Hydrochloric acid (1 mL) was added to an ambient temperature solution of 4-(2,2-dimethylpropyl)-2-[1-hydroxy-2-(4-pyridin-2-ylphenyl)ethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide (7 mg, 0.02 mmol) in tetrahydrofuran (1 mL). After heating in a sealed tube at 70° C. until no further reaction (LCMS), the reaction mixture was cooled to 0° C., quenched with 10% aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Preparative plate chromatography eluting with 15% methanol/ethyl acetate afforded the title compound. High pressure liquid chromatography (Chiralcel OD column) eluting with 20% isopropanol/heptane afforded the two pure enantiomers. (M+H) found: 336.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.O.O.O.O.O.[OH-].C[N+](C)(C)C.Br[CH2:34][CH2:35][CH2:36][OH:37].Cl>CN(C=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:21][CH2:34][CH2:35][CH2:36][OH:37])=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: OCCCBr
Reactant: Oc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Agent: C[N+](C)(C)C
Agent: Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: OCCCOc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Yield: 144.5 %

Procedure:
To 4-(6-chloro-2,3-dihydro-indol-1-yl)-quinazolin-7-ol (125 mg, 0.42 mmol; from Example 65) in DMF (2 mL) was added H2O (50 μL), K2 CO3 (s) (116 mg, 0.84 mmol) and tetramethylammonium hydroxide pentahydrate (15 mg, 0.08 mmol) followed by 3-bromopropanol (43 μL, 0.46 mmol). The mixture was stirred at 50° C. under N2(g) for 24 hours before another aliquot (11 μL) of 3-bromopropanol was added. After heating another 24 hours, extractive workup and chromatography analogous to that described in Example 1 followed by conversion to the HCl salt as outlined for Example 2 afforded 119 mg (70%) of product. (M.P. 211°-223° C. (dec); LC-MS: 356 (MH+); anal. RP18-HPLC RT: 4.40 min.; M.P. of free-base: 137°-138° C.).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:19][CH2:20][O:21][C:22]([CH2:24][CH:25]1[C:30](=O)[CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:23]>>[Br:16][C:13]1[CH:12]=[C:11]2[C:10](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]1[CH:17]=[CH:18][C:3]([Cl:2])=[CH:4][CH:5]=1)[C:26]1[CH:25]([CH2:24][C:22]([O:21][CH2:20][CH3:19])=[O:23])[CH2:30][CH2:29][CH2:28][C:27]2=1
Reactant: NN(Cc1ccc(Cl)cc1)c1ccc(Br)cc1
Reactant: CCOC(=O)CC1CCCCC1=O
Agent: Cl
Product: CCOC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1ccc(Br)cc21

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-bromophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound is prepared.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([NH:12][CH3:13])=[O:11].[C:14]([OH:20])(=O)[CH2:15][C:16]([OH:18])=O.C(OC(=O)C)(=O)C.C(Cl)(=O)C>CCCCCC.O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14](=[O:20])[CH2:15][C:16](=[O:18])[N:12]([CH3:13])[C:10]1=[O:11]
Reactant: O=C(O)CC(=O)O
Reactant: CNC(=O)Nc1ccc(I)cc1F
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C(=O)CC(=O)N(c2ccc(I)cc2F)C1=O
Temperature: 65 °C
Reaction time: 3 h
Yield: 69.6 %

Procedure:
Under a nitrogen atmosphere, to 1-(2-fluoro-4-iodophenyl)-3-methylurea 63 (87.9 g) obtained in Step 1 and malonic acid 4 (31.1 g) were added acetic anhydride (264 ml) and acetyl chloride (42.5 ml), and the mixture was stirred at 65° C. for 3 hrs. After allowing to cool to room temperature, the reaction mixture was added dropwise to water-toluene [2:1 (volume ratio), 800 ml] with stirring, and hexane (132 ml) was successively added. The precipitated crystals were collected by filtration and dried to give 1-(2-fluoro-4-iodophenyl)-3-methylpyrimidine-2,4,6-trione 64 (75.3 g, yield 69.5%) as pale-yellow crystals.
Reaction SMILES: [Na].Cl[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:24][CH2:25][CH2:26][CH3:27])=[C:8]([C:10]2[NH:11][C:12](=[O:23])[C:13]3[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=3[N:15]=2)[CH:9]=1.[CH2:28]([OH:30])[CH3:29]>>[CH2:28]([O:30][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:24][CH2:25][CH2:26][CH3:27])=[C:8]([C:10]2[NH:11][C:12](=[O:23])[C:13]3[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=3[N:15]=2)[CH:9]=1)[CH3:29]
Reactant: CCO
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Agent: [Na]
Product: CCCOc1ccc(COCC)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1

Procedure:
Sodium (0.15 g, 0.0013 mol) was added portionwise to ethanol (40 ml) over 1 hour. 5-(5-Chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]-pyrimidin-7-one (0.5 g, 0.0013 mol) was then added to the solution and, after 3 days at room temperature, the solvent was removed by evaporation under vacuum. The residual solid was suspended in water (50 ml) and the suspension extracted with ethyl acetate (3×30 ml). The extracts were then combined, dried (Na2SO4) and evaporated under vacuum to give a green solid. Chromatography on silica gel (6 g) using a methanol in dichloromethane elution gradient gave, after crystallisation of the required product from a hexane-ethyl acetate mixture, the title compound as a white solid (0.2 g, 39%) m.p. 89°-90° C. Found C,65,87; H,7.57; N,14.66. C21H28N4O3 requires C,65.60; H,7.34; H,7.34; N,14.57%
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.[I:13]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[C:5]2[N:6]([N:8]=[CH:9][C:10]=2[I:13])[CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(Br)cn2nccc12
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(Br)cn2ncc(I)c12
Reaction time: 1 h

Procedure:
6-bromo-4-methoxypyrazolo[1,5-a]pyridine (50.0 mg, 0.220 mmol) was dissolved in acetonitrile (2 ml). N-iodosuccinimide (49.5 mg, 0.220 mmol) was added and the mixture was stirred for 1 h, at which time LCMS indicated about 60% conversion. Additional N-iodosuccinimide (9.9 mg, 0.044 mmol) was added and the mixture was stirred for 30 minutes, at which time LCMS indicated about 80% conversion. Additional N-iodosuccinimide (9.9 mg, 0.044 mmol) was added and the mixture was stirred for 30 minutes, at which time LCMS indicated about 80% conversion. Additional N-iodosuccinimide (14.9 mg, 0.066 mmol) was added and the mixture was stirred for 30 minutes, at which time LCMS indicated complete conversion. The reaction mixture was diluted in ethyl acetate, washed with 1N aqueous sodium hydroxide and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/isohexane gradient) to give 6-bromo-3-iodo-4-methoxypyrazolo[1,5-a]pyridine as a colorless solid (faster eluting), along with recovered starting material 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (slower eluting). 1H NMR (600 MHz, CDCl3) δ 8.25 (d, 1H); 7.80 (s, 1H); 6.47 (s, 1H); 3.93 (s, 3H). LRMS (ESI) calculated for C8H779BrIN2O [M+H]+, 352.9; found 352.8.
Reaction SMILES: [S:1]1CS[C:2]1=[C:5]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)[C:6]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])=O.O.[NH2:23][NH2:24]>C(O)C>[SH:1][C:2]1[NH:24][N:23]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])[C:5]=1[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1
Reactant: N#Cc1cccc(C(=O)C(=C2SCS2)c2ccncc2)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: N#Cc1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
3-(2-[1,3]Dithietan-2-ylidene-2-pyridin-4-yl-acetyl)-benzonitrile (5 g, 16.1 mmol) was suspended in absolute ethanol (50 mL) and heated to 60° C. Hydrazine monohydrate (3.13 mL, 64.4 mmol, 4 eq) was added dropwise and the mixture was stirred at 60° C. for 2 hours. The suspension was concentrated to about ¼ of the original volume, diluted with THF (50 mL) and stirred for 5 minutes. The yellow solid was filtered, washed with THF and dried at 50° C. for 1 hours. The crude product (4.59 g) was used in the following step without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[N:12][C:11]([NH2:14])=[C:10]([N:15]3[CH2:20][CH2:19][CH:18]([CH3:21])[CH2:17][CH2:16]3)[N:9]=2)[CH2:4][CH2:3]1.[C:22]([C:24]1[O:28][C:27]([C:29](Cl)=[O:30])=[CH:26][CH:25]=1)#[N:23].CCN(C(C)C)C(C)C>>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[N:12][C:11]([NH:14][C:29]([C:27]3[O:28][C:24]([C:22]#[N:23])=[CH:25][CH:26]=3)=[O:30])=[C:10]([N:15]3[CH2:16][CH2:17][CH:18]([CH3:21])[CH2:19][CH2:20]3)[N:9]=2)[CH2:6][CH2:7]1
Reactant: N#Cc1ccc(C(=O)Cl)o1
Reactant: CC1CCN(c2nc(N3CCN(C)CC3)cnc2N)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCN(c2nc(N3CCN(C)CC3)cnc2NC(=O)c2ccc(C#N)o2)CC1
Yield: 24.4 %

Procedure:
Using a procedure similar to Example 23, step (a) 4-methyl-6′-(4-methyl-piperidin-1-yl)-5′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (37 mg, 0.11 mmol) was stirred with 20 mg 5% Pd—C in 5 mL MeOH under H2 to afford 32 mg (100%) of the title compound as an oil, which was used immediately without further purification. Using a procedure similar to Example 4, step (c), 4-methyl-6′-(4-methyl-piperidin-1-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-5′-ylamine (32 mg, 0.10 mmol)) was allowed to react with 5-cyano-furan-2-carbonyl chloride (44.6 mg, 0.28 mmol) in the presence of DIEA (107 μL, 0.610 mmol) to afford 10 mg (25%) of the title compound as a dark semi-solid. 1H-NMR (CDCl3; 400 MHz): δ 8.29 (s, 1H), 7.57 (s, 1H), 7.32 (d, 1H, J=3.6 Hz), 7.24-7.23 (d, 1H, J=3.6 Hz), 3.60-3.57 (m, 6H), 2.87-2.81 (m, 2H), 2.57-2.54 (m, 4H), 2.39 (s, 3H), 1.77-1.73 (m, 2H), 1.66-1.55 (m, 1H), 1.40-1.32 (m, 2H), 1.02 (d, 3H, J=6.5 Hz); Mass spectrum (ESI, m/z): Calcd. for C21H27N7O2, 410.2 (M+H), found 410.2.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:8]([F:12])=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1C(O)=O.CN1C(=O)CCC1>O>[F:12][C:8]1[CH:9]=[C:10]([F:11])[C:2]([F:1])=[CH:3][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1c(F)cc(F)c(F)c1C(=O)O
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.8 %

Procedure:
A 250 mL single-neck flask equipped with a condenser and a magnetic stirrer was charged with 30.00 g of 3,4,6-trifluorophthalic acid, and 200 mL of NMP. The reaction mixture was then heated with stirring for 18 hr. at a bath temperature of 140° C., followed by 55 hr. at a bath temperature of 150° C. The flask was then allowed to cool to room temperature and the contents were poured into 500 mL of water, and extracted with 4×200 mL of ethyl acetate. The combined organic extracts were washed with water (2×200 mL), dried over magnesium sulfate, filtered, and the solvent removed on a rotary evaporator followed by drying at the pump overnight. The crude product (24.25 g) was then dissolved in 25 mL of ethyl acetate and introduced at the top of a silica column (4.5 cm ID×56 cm, flushed with hexane). The product was then eluted with 90:10 hexane:ethyl acetate under a slight nitrogen pressure, and the fractions (500 mL each) were monitored by gas chromatography. The fractions containing the product were combined, the solvent removed on a rotary evaporator, and then dried at the pump overnight to give 2,4,5-trifluorobenzoic acid as a light yellow solid (21.06 g, 98.97% pure, 87.8% yield). Recrystallization of the product from toluene (50 mL, ca. 60° C.) gave a white product (71.1% overall yield) mp 101°-102° C.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][O:15][C:16]1[CH:24]=[C:23]([NH:25][C:26]2[S:27][C:28]3[CH2:34][CH2:33][CH2:32][CH:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]=3[N:30]=2)[CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=O.N1C=CC=CC=1>O1CCOCC1>[CH3:14][O:15][C:16]1[CH:24]=[C:23]([NH:25][C:26]2[S:27][C:28]3[CH2:34][CH2:33][CH2:32][CH:31]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]=3[N:30]=2)[CH:22]=[CH:21][C:17]=1[C:18]#[N:20]
Reactant: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1C(N)=O
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1C#N
Reaction time: 0.5 h
Yield: 39.6 %

Procedure:
Trifluoroacetic acid anhydride (257 uL, 1.83 mmol) was added slowly to a cooled suspension of 2-methoxy-4-(4-phenyl-4,5,6,7-tetrahydro-benzothiazol-2-ylamino)-benzamide (625 mg, 1.65 mmol) in dioxane (2 mL) and pyridine (292 uL, 3.6 mmol). The white suspension was stirred for 30 minutes under cooling and then for 2 hours at 50° C. and for 3 hours at 80° C. Additional trifluoroacetic acid anhydride (300 uL), pyridine (400 uL) and dioxane (5 mL) were added and the reaction was stirred at 80° C. for 2 hours resulting in a clear brown solution. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was washed twice with saturated aqueous sodium hydrogen carbonate, brine, dried over magnesium sulfate, filtered and the solvent was removed under reduced pressure. The residue was purified on silica gel using dichloromethane with 4% methanol as eluent to yield the title compound (236 mg, 40%) as a beige foam. MS ISP (m/e): 362.3 (100) [(M+H)+].
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3].O=[C:19]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:20]([NH2:22])=[O:21].C([BH3-])#N.[Na+]>>[NH2:22][C:20]([CH:19]([NH:1][C@H:2]([C:4]([N:6]1[CH:14]2[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C@H:7]1[C:15]([OH:17])=[O:16])=[O:5])[CH3:3])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21]
Reactant: NC(=O)C(=O)CCc1ccccc1
Reactant: C[C@H](N)C(=O)N1C2CCCCC2C[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NC(CCc1ccccc1)C(N)=O)C(=O)N1C2CCCCC2C[C@H]1C(=O)O

Procedure:
React 1-[(S)-alanyl]octahydroindole-2(S)-carboxylic acid (preparable as described in Example 1) and 2-oxo-4-phenylbutyramide and sodium cyanoborohydride to obtain the title compound as described in Example 5.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[C:10]([F:23])[CH:9]=1)=[O:6].[OH-].[NH4+:26]>>[F:23][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:26])=[O:2])[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)c(F)c1
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)c(F)c1

Procedure:
The title compound is prepared in analogy to example 3 from N-[3-fluoro-4-(3-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Light yellow solid. MS: m/e=321.2 (M++H).
Reaction SMILES: C(O[C:4]([C:6]1[NH:10][C:9]2[S:11][C:12]([Cl:14])=[CH:13][C:8]=2[CH:7]=1)=[O:5])C.[CH2:15]1[NH:20][CH2:19][CH2:18][N:17]2[CH2:21][CH2:22][CH2:23][CH:16]12>>[Cl:14][C:12]1[S:11][C:9]2[NH:10][C:6]([C:4]([N:20]3[CH2:19][CH2:18][N:17]4[CH2:21][CH2:22][CH2:23][CH:16]4[CH2:15]3)=[O:5])=[CH:7][C:8]=2[CH:13]=1
Reactant: CCOC(=O)c1cc2cc(Cl)sc2[nH]1
Reactant: C1CC2CNCCN2C1
Product: O=C(c1cc2cc(Cl)sc2[nH]1)N1CCN2CCCC2C1
Yield: 78 %

Procedure:
2-Chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid ethyl ester (102 mg, 0.45 mmol) was hydrolyzed (Procedure B) and then coupled with octahydro-pyrrolo[1,2-a]pyrazine (Procedure D) to provide the title compound (108 mg, 78% for two steps) as an off-white solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.35. MS (electrospray): exact mass calculated for C14H16ClN3OS, 309.07; m/z found, 310.1 [M+H]+. 1H NMR (CDCl3, 400 MHz): 11.1 (br s, 1H), 6.86 (s, 1H), 6.62 (s, 1H), 4.79 (d, J=11.8 Hz, 1H), 4.67 (d, J=11.8 Hz, 1H), 3.30-2.90 (m, 4H), 2.30-1.40 (m, 7H).