Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:4]=1)#[N:2].[CH2:19]([NH2:21])[CH3:20]>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:21][CH2:19][CH3:20])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[N:4]=1)#[N:2]
Reactant: N#Cc1nc(Cl)c(-c2cccc(F)c2)nc1C#N
Reactant: CCN
Solvent: Cc1ccccc1
Product: CCNc1nc(C#N)c(C#N)nc1-c1cccc(F)c1
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
2,3-Dicyano-5-chloro-6-(m-fluorophenyl)pyrazine (1.00 g; 0.0039 mole) was dissolved in 30 ml of toluene. The solution was cooled to -5° C., and 0.65 g of a 70% aqueous solution of ethylamine was added dropwise. The mixture was stirred at -5° to 0° C. for 30 minutes. The reaction mixture was worked up in the same way as in Example 13, and recrystallized from ethanol to afford 0.63 g (yield 61%) of 2,3-dicyano-5-ethylamino-6-(m-fluorophenyl)pyrazine.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29]Br)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:31]#[N:32].[Na+].[I-].[Na+].O>CN(C=O)C>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][CH2:28][CH2:29][C:31]#[N:32])[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(CCCBr)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: [C-]#N
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCCc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Temperature: 25 °C
Yield: 67.4 %

Procedure:
A solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(3-bromopropyl)pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (80 mg, 0.173 mmol), sodium cyanide (17 mg, 0.35 mmol, 2.0 eq.), and sodium iodide (2.6 mg, 0.017 mmol, 0.1 eq.) in anhydrous DMF (1.7 mL) was stirred at 100° C. for 16 h. The reaction mixture was cooled to rt and poured into water. The aqueous layer was extracted with 3×25 mL of EtOAc and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude was purified via preparative HPLC. The product containing fractions were collected, and the TFA from the eluent was removed via filtration through an acidic resin followed by washing with acetonitrile. The product was then eluted with 2M NH3 in MeOH. The filtrate was concentrated and the residue was crystallized from DCM-ether to provide the title compound (47.5 mg, 67%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8.54 (s, 1H), 7.91 (s, 1H), 7.80 (d, 1H), 7.59 (s, 1H), 7.36 to 7.30 (m, 5H), 7.15 (dd, 1H), 6.65 (s, 1H), 5.65 (s, 2H), 3.00 (t, 2H), 2.59 (t, 2H), 2.04 to 1.96 (m, 2H); ES-MS m/z 408.3 [M+H]+, RT (min) 2.95.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:16]=[C:15]3[NH:40][C:41](=[O:51])[C:42]2[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][CH:43]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[N:74]1([CH:79]2[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]2)[CH2:78][CH2:77][CH2:76][CH2:75]1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:16]=[C:15]3[NH:40][C:41](=[O:51])[C:42]2[CH:50]=[CH:49][C:45]([C:46]([N:82]3[CH2:83][CH2:84][CH:79]([N:74]4[CH2:78][CH2:77][CH2:76][CH2:75]4)[CH2:80][CH2:81]3)=[O:47])=[CH:44][CH:43]=2)(=[O:10])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1ccc(C(=O)Nc2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(S(=O)(=O)c4cc(F)cc(F)c4)cc23)cc1
Reactant: C1CCN(C2CCNCC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(S(=O)(=O)c3cc(F)cc(F)c3)cc12)c1ccc(C(=O)N2CCC(N3CCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude N-[5-(3,5-difluoro-benzenesulfonyl)-1-trityl-1H-indazol-3-yl]-terephthalamic acid (0.56 mmol) was treated with dichloromethane (8 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (140 mg, 1.3 eq), 1-hydroxybenzotriazole (98 mg, 1.3 eq) and 4-pyrrolidin-1-yl-piperidine (113 mg, 1.3 eq). The reaction mixture was stirred at room temperature overnight, diluted with dichloromethane, washed with brine and with a saturated solution of sodium hydrogenocarbonate, dried over sodium sulfate and evaporated to dryness affording the crude title compound that was used as such for the next step without further purification.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[N:38]=[C:39]([N:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]2=[O:48])[S:40][CH:41]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[N:38]=[C:39]([N:42]4[CH:47]=[CH:46][CH:45]=[CH:44][C:43]4=[O:48])[S:40][CH:41]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: O=c1ccccn1-c1nc(Br)cs1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2csc(-n3ccccc3=O)n2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethyl}-1,3-oxazinan-2-one and 1-(4-bromothiazol-2-yl)pyridin-2(1H)-one following a procedure analogous to that described in Example 31. LC (method 5): tR=1.73 min; Mass spectrum (ESI+): m/z=472, 530 [M+H]+; 1H NMR (CDCl3) δ 1.10 (s, 3H), 1.20 (s, 3H), 1.57 (d, 3H), 2.20-2.30 (m, 4H), 2.39 (m, 1H), 2.91 (m, 1H), 5.72 (q, 1H), 6.52 (t, 1H), 6.83 (d, 1H), 7.05 (d, 2H), 7.20-7.40 (m, 6H), 7.50 (m, 1H), 7.70 (d, 2H), 8.98 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=[O:13])[CH:8]=2)[CH:3]=1.[F:15][C:16]([F:26])([F:25])[CH:17](O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C(Cl)Cl.S(=O)(=O)(O)O>[OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:16]([F:15])([F:25])[F:26])=[O:13])[CH:6]=[CH:5]2
Reactant: CCCCCCC(O)C(F)(F)F
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCCCCCC(OC(=O)c1ccc2cc(O)ccc2c1)C(F)(F)F
Reaction time: 48 h

Procedure:
To a solution of 2-hydroxy-6-carboxynaphthalene (1 g) and optically active 1,1,1-trifluoro-2-octanol (1.1 g) in methylene chloride (50 ml) was added a few drops of conc. sulfuric acid and the mixture was refluxed under stirring for about two days.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:10](O)=[O:11])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2].B.C1COCC1>C1COCC1>[CH2:1]([O:3][C:4]1[C:5]([CH2:10][OH:11])=[N:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccnc1C(=O)O
Agent: B
Solvent: C1CCOC1
Product: CCOc1cccnc1CO
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 124.6 %

Procedure:
To a solution of 3-ethoxypicolinic acid (0.202 g, 1.21 mmol) in dry THF (1 mL) was added BH3.THF (1.0 M in THF, 5.0 mL, 5.0 mmol) and the reaction mixture stirred at room temperature for 2.5 hours. The mixture was then quenched with methanol (20 mL), stirred at reflux for 4 hours and concentrated under reduced pressure. The resultant crude product was dissolved in methanol (3×15 mL) and concentrated to give the desired crude alcohol (0.231 g) as an orange solid. 1H NMR (CDCl3): δ 1.46 (t, 3H, J=7.0 Hz), 4.07 (q, 2H, J=7.0 Hz), 4.74 (s, 2H), 7.09-7.20 (m, 2H), 8.14 (d, 1H, J=4.5 Hz).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:35])[CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]3[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[NH:27][C:26]3=[O:34])[CH2:19][CH2:18]2)=[CH:11][CH:10]=1.CC1C=CC=CC=1.[OH-].[NH4+]>O>[C:1]([N:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:25]([CH2:24][CH2:23][N:20]2[CH2:19][CH2:18][CH:17]([CH2:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=3)=[O:35])[CH2:22][CH2:21]2)[C:26]1=[O:34])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CC1CCN(CCn2c(=O)[nH]c3ccccc32)CC1)c1ccc(F)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)n1c(=O)n(CCN2CCC(CC(=O)c3ccc(F)cc3)CC2)c2ccccc21
Yield: 40 %

Procedure:
A mixture of 3.1 parts of acetic acid anhydride, 5 parts of 1-[2-[4-[2-(4-fluorophenyl)-2-oxoethyl]-1-piperidinyl]ethyl]-1,3-dihydro-2H-benzimidazol-2-one and 56 parts of methylbenzene is stirred and refluxed for 4 hours. The reaction mixture is cooled and water and ammonium hydroxide are added. Upon stirring, the product is crystallized. It is filtered off, washed with water and dried in vacuo, yielding 2.2 parts (40%) of 1-acetyl-3-[2-[4-[2-(4-fluorophenyl)-2-oxoethyl]-1-piperidinyl]ethyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 149.2° C.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[BrH:20]>C(O)(=O)C>[Br:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Reactant: Br
Solvent: CC(=O)O
Product: O=C(O)CCCCCCCCCCCCCCCBr
Yield: 99 %

Procedure:
16-Bromohexadecanoic acid was prepared by refluxing for 48 hrs 5.0 gr (18.35 mmole) of 16-hydroxyhexadecanoic acid in 24 ml of 1:1 v/v mixture of HBr (48% aqueous solution) and glacial acetic acid. Upon cooling, crude product was solidified inside the reaction vessel. It was filtered out and washed with 3×100 ml of cold water. Material was purified by recrystalization from n-hexane, filtered out and dried on high vacuum. 6.1 gr (99% yield) of the desired product were obtained.
Reaction SMILES: [CH2:1]([N:8]1CCC(N)C1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:21]C1(OC)C=CC(C(O)=O)=CC1OC)C1C=CC=CC=1.C(NC(C)C)(C)C.C[NH3+].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([NH2:8])(=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCN(Cc2ccccc2)C1
Reactant: COC1C=C(C(=O)O)C=CC1(OC)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[NH3+]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)NC(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
1-benzylpyrrolidine-3-amine represented by Formula 102 (180 mg, 1.02 mmol) was slowly added to a solution of 4-benzyloxy-3,4-dimethoxybenzoic acid represented by Formula 89 (323.88 mg, 1.12 mmol) prepared in Preparative Example 1 as well as diisopropylamine (0.71 mL, 4.09 mmol) in DMF (7 mL) at room temperature. The reaction mixture was cooled to 0° C. and, after adding 2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate methanaminium (HATU, 388.29 mg, 1.02 mmol) thereto, the mixture was agitated at room temperature for 24 hours. After removing the reaction solvent under reduced pressure, chloroform (20 mL) was added to the remaining concentrate to form a solution, the solution was washed with a potassium carbonate solution, followed by separation to form an organic layer. The organic layer was dried with sodium sulfate (Na2SO4) and the solvent was removed again under reduced pressure. The obtained vacuum-concentrated mixture was subjected to separation and purification through column chromatography (ethyl acetate/hexane/triethylamine, 2:1:0.1, v/v/v) using silica gel (SiO2), resulting in a benzamide compound represented by Formula 12 as a desired product (VVZ-013; 392.9 mg, 86% yield).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.O>[C:16]([O:15][C:13]([NH:1][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([O:12][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:11])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 95.8 %

Procedure:
To a stirred solution of Boc-Phe-OH (10 g, 37.7 mmoL) in DMF (50 mL) was added potassium carbonate (7.81 g, 56.5 mmol) followed by benzyl chloride (4.55 mL, 39.6 mmol) and the resulting suspension was stirred at 60° C. for 3 d. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (75 mL, 2×25 mL). The combined organics were washed with brine (200 mL), water (3×100 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated then chromatographed on silica gel eluting with 0%-20% ethyl acetate in hexanes. The product-containing fractions were concentrated in vacuo giving the title compound (12.84 g, 95%) as a white solid.
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)=[N+:2]=[N-:3].S(Cl)(Cl)=O.[Cl:18][C:19]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:20]=1[NH2:21]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[N:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([NH:21][C:20]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=1[Cl:18])=[O:8])=[N+:2]=[N-:3]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: [N-]=[N+]=Nc1cc(Cl)ccc1C(=O)O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: [N-]=[N+]=Nc1cc(Cl)ccc1C(=O)Nc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
2-Azido-4-chlorobenzoic acid (130 g) was stirred with thionyl chloride (52 ml) in dry toluene at room temperature for 24 hours. The solution was evaporated to give crude 2-azido-4-chlorobenzoyl chloride. This product (14.2 g) was added to a solution of 2,4-dichloroaniline (10.65 g) in dry pyridine (70 ml) and the mixture stirred for 25 mins. It was then poured into ice-water and the precipitate filtered off, washed with water, sucked dry, heated in boiling ethanol and the residue filtered off, washed with ethanol and air-dried to give 2-azido-4-chloro-N-(2,4-dichlorophenyl)benzamide, m.p. 169.5° C. (dec.)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].C1([O:20][C:21](=O)[NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([OH:33])[CH:31]=3)[CH:26]=[CH:25][CH:24]=2)C=CC=CC=1>CS(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:21]([NH:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([OH:33])[CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[O:20])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13]
Reactant: NCc1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C(Nc1cccc2ccc(O)cc12)Oc1ccccc1
Solvent: CS(C)=O
Product: O=C(NCc1ccc(Cl)c(C(F)(F)F)c1)Nc1cccc2ccc(O)cc12
Yield: 77.1 %

Procedure:
4-Chloro-3-trifluoromethyl-benzylamine (150 mg, 0.71 mmol) and (7-hydroxy-naphthalen-1-yl)-carbamic acid phenyl ester (200 mg, 0.7 mmol) were combined and stirred at ambient temperature in DMSO (3 mL) overnight. The product was purified by directly injecting the crude reaction onto a reverse phase prep-HPLC (90–10% water:acetonitrile gradient). The appropriate fractions were lyophilized to yield 1-(4-Chloro-3-trifluoromethyl-benzyl)-3-(7-hydroxy-naphthalen-1-yl)-urea (212.7 mg, 0.54 mmol). MS (MH+) 394.9; 1H NMR (CD3OD) δ 4.41 (s, 2H), 7.09 (dd, 1H, J=2.4 Hz), 7.21–7.26 (m, 2H), 7.46 (d, 1H, J=7.3 Hz), 7.54 (d, 2H, J=1.0 Hz), 7.62 (d, 1H, J=8.2 Hz), 7.71–7.75 (m, 2H). HPLC Rt=4.4 min (90–10% water:acetonitrile gradient, 100% pure).
Reaction SMILES: CC1C=CC(S(NCC(N2[C@H](C(N[C@H](C(NC3C=CC([N+]([O-])=O)=CC=3)=O)CCCN=C(N)N)=O)CCC2)=O)(=O)=O)=CC=1.Cl.[CH3:44][C:45]1[CH:50]=[CH:49][C:48]([S:51]([NH:54][CH2:55][C:56]([N:58]2[CH:62]([C:63]([NH:65][CH:66]([C:72]([NH:74][C:75]3[CH:80]=[CH:79][C:78]([N+:81]([O-:83])=[O:82])=[CH:77][CH:76]=3)=[O:73])[CH2:67][CH2:68][CH2:69][CH2:70][NH2:71])=[O:64])[CH2:61][CH2:60][CH2:59]2)=[O:57])(=[O:53])=[O:52])=[CH:47][CH:46]=1>>[NH:54]([S:51]([C:48]1[CH:47]=[CH:46][C:45]([CH3:44])=[CH:50][CH:49]=1)(=[O:53])=[O:52])[CH2:55][C:56]([N:58]1[CH2:59][CH2:60][CH2:61][C@H:62]1[C:63]([NH:65][C@H:66]([C:72]([NH:74][C:75]1[CH:80]=[CH:79][C:78]([N+:81]([O-:83])=[O:82])=[CH:77][CH:76]=1)=[O:73])[CH2:67][CH2:68][CH2:69][CH2:70][NH2:71])=[O:64])=[O:57]
Reactant: Cc1ccc(S(=O)(=O)NCC(=O)N2CCCC2C(=O)NC(CCCCN)C(=O)Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cc1ccc(S(=O)(=O)NCC(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCN=C(N)N)C(=O)Nc2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)NCC(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCCN)C(=O)Nc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
The activity of two samples treated in parallel according to Example 1 was determined with Chromozym TH and with an equimolar amount of Chromozym PL. With Chromozym PL, there was found ΔE/h=0.052 and with Chromozym TH ΔE/h=0.048.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:14][C:15]1[C:16]([N:27]2[CH2:31][CH2:30][CH2:29][C@@H:28]2[C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][C:39](O)=[O:40])[CH2:34][CH2:33]2)=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([F:25])=[C:20]([F:26])[CH:19]=2)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[NH4+].[Cl-].Cl.C([N:56]=C=NCCCN(C)C)C.ON1C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O.C(N(CC)CC)C>[F:48][C:45]([F:47])([F:46])[C:43]1[CH:42]=[C:5]([CH:4]=[C:3]([C:2]([F:50])([F:49])[F:1])[CH:44]=1)[CH2:6][N:7]([CH2:14][C:15]1[C:16]([N:27]2[CH2:31][CH2:30][CH2:29][C@@H:28]2[C@H:32]2[CH2:37][CH2:36][C@H:35]([CH2:38][C:39]([NH2:56])=[O:40])[CH2:34][CH2:33]2)=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][C:21]([F:25])=[C:20]([F:26])[CH:19]=2)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc3cc(F)c(F)cc3nc2N2CCC[C@@H]2[C@H]2CC[C@H](CC(=O)O)CC2)n1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc3cc(F)c(F)cc3nc2N2CCC[C@@H]2[C@H]2CC[C@H](CC(N)=O)CC2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of trans-(4-{(R)-1-[3-({N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino}methyl)-6,7-difluoroquinolin-2-yl]pyrrolidin-2-yl}cyclohexyl)acetic acid (85 mg, 0.12 mmol) in DMF (3 mL) is added NH4Cl (10 mg, 0.18 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl 41 mg, 0.18 mmol), 1-hydroxy-7-azabenzotriazole (HOAt, 24 mg, 0.18 mmol), and small amount of triethylamine. After stirring for 2 hours at room temperature, the reaction mixture is diluted with EtOAc, washed successively with water and brine, and dried over magnesium sulfate. Evaporation of the solvent and purification by silica gel column using ethyl acetate-hexane affords trans-(4-{(R)-1-[3-({N-[3,5-bis(trifluoromethyl)benzyl]-N-(2-methyl-2H-tetrazol-5-yl)amino}methyl)-6,7-difluoroquinolin-2-yl]pyrrolidin-2-yl}cyclohexyl)acetic acid amide.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:20])[NH:18][NH2:19].CCN=C=NCCCN(C)C>C(#N)C>[C:1]([NH:8][C@H:9]([C:14]([NH:19][NH:18][C:17]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[CH2:10][CH2:11][S:12][CH3:13])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of Boc-L-methionine (9.972 g) [Boc:tert-butoxycarbonyl] and tert-butyl carbazate (5.29 g) in acetonitrile (100 ml) was combined with WSC (9.202 g) and stirred at room temperature for 5 hours. The reaction mixture was concentrated and the resultant residue was combined with ethyl acetate and water, and the organic phase was washed with water, aqueous sodium bicarbonate and brine, dried and concentrated to obtain tert-butyl 2-(Boc-L-methionyl)-1-hydrazine carboxylate as a colorless oil.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)CC)C.S=[C:21]1[CH2:25][S:24][C:23](=[O:26])[NH:22]1>C(O)C>[CH3:12][N:3]([CH3:2])[C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:9])[CH3:10])[NH:6][C:21]1[CH2:25][S:24][C:23](=[O:26])[N:22]=1
Reactant: O=C1NC(=S)CS1
Reactant: CC(C)C[C@H](N)C(=O)N(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)C[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.4 %

Procedure:
To a solution of the crude product containing N,N-dimethyl-L-leucinamide hydrochloride (11.7 g) obtained in B) and triethylamine (18.2 g) in ethanol (150 mL) was added 4-thioxothiazolidin-2-one (8.00 g) at room temperature. The reaction mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the obtained solid was suspended in THF. The suspension was filtered through celite pad and silica gel pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/petroleum ether) to give the title compound (8.1 g).
Reaction SMILES: [F:1][C:2]([F:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6]>CO.[Pd]>[F:1][C:2]([F:16])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)/C=C/C(F)(F)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCC(F)(F)c1ccccc1

Procedure:
A solution of Intermediate 20 (1 g, 4.42 mmol) in methanol (20 mL) was hydrogenated in the presence of palladium on charcoal (10 mg, 10%) for 3 hours. The mixture was then filtered over Celite and the solvent removed under reduced pressure. The residue (0.91 g) was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[C:7]([NH:18][CH2:19][C:20]3[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=3)[N:8]=[C:9]([NH:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:10]=2[N:11]=1.[CH3:30][S:31]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O>[CH3:30][S:31]([C:34]1[CH:39]=[C:38]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]=[C:7]([NH:18][CH2:19][C:20]4[CH:21]=[C:22]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=4)[N:8]=[C:9]([NH:12][CH2:13][C:14]([F:17])([F:15])[F:16])[C:10]=3[N:11]=2)[CH:37]=[CH:36][CH:35]=1)(=[O:33])=[O:32]
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Reactant: NS(=O)(=O)c1cccc(CNc2nc(NCC(F)(F)F)c3nc(Cl)ccc3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CS(=O)(=O)c1cccc(-c2ccc3nc(NCc4cccc(S(N)(=O)=O)c4)nc(NCC(F)(F)F)c3n2)c1
Temperature: 120 °C
Yield: 49.2 %

Procedure:
3-{[6-Chloro-4-(2,2,2-trifluoro-ethylamino)-pyrido[3,2-d]pyrimidin-2-ylamino]-methyl}-benzenesulfonamide (0.077 g) was combined with 3-methylsulfonyl-phenylboronic acid (0.067 g), palladium tetrakistriphenylphosphine (0.006 g) and potassium carbonate (0.121 g). The mixture was suspended in DME (1.6 mL) and water (0.8 mL), sealed and heated by microwave to 120° C. for 3 min. Crude product was precipitated by the addition of water. The precipitate was filtered and purified by reverse phase HPLC (5-100% ACN/H2O+0.1% TFA) to give 0.048 g (41% yield) of the title compound, which was characterized by its NMR and mass spectrum as follows: 1H NMR (d6-DMSO): d 3.34 (s, 3H), 4.40-4.46 (m, 2H), 4.73-4.82 (m, 2H), 7.35 (s, 2H), 7.52-7.7.64 (m, 2H), 7.73-7.75 (m, 1H), 7.83-7.87 (m, 2H), 8.03-8.06 (m, 2H), 8.58-8.62 (m, 1H), 8.68 (s, 1H), 8.80 (d, 1H), 9.10 (bs, 1H), 9.98 (bs, 1H); MS (m/z): 567.1 ([M+H]+, 100).