Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:8][C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)N=C=NC(C)C.[CH3:42][C:43]([CH3:47])([CH3:46])[CH2:44][NH2:45]>C1COCC1>[CH3:42][C:43]([CH3:47])([CH3:46])[CH2:44][NH:45][C:30]([C:28]1[CH:27]=[CH:26][C:12]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:23])[F:24])=[CH:17][CH:16]=3)[C:9]([CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[N:10][C:11]=2[CH:29]=1)=[O:31]
Reactant: O=C(O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)CN
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)CNC(=O)c1ccc2c(c1)nc(COc1ccccc1)n2Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.16 mmol of 2-phenoxymethyl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole-5-carboxylic acid were dissolved in 1 ml THF with 1 eq. DIC. After 15 min 1.5 eq of 2,2-dimethylpropylamine were added and the reaction stirred at room temperature for 16 h. The crude material was purified via reversed phase preparative HPLC. MS(ISP): 512.3 (M+H)+.
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:18]([O:20]CC)=[O:19])[CH:16]=[CH:17][C:12]=2[S:11][C@H:10]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:9]1=[O:34])(C)(C)C.BrC1C=C(C(OCC)=O)C=CC=1S[C@@H](CCCC1C=CC(OC)=CC=1)C(O)=O.CC1(C)C23[C@@]4([O:79][N:74]4S(=O)(=O)C2)C(Cl)(Cl)[C@H]1CC3>C(OCC)(=O)C>[OH:79][NH:74][C:6](=[O:5])[CH2:7][N:8]1[C:13]2[CH:14]=[C:15]([C:18]([OH:20])=[O:19])[CH:16]=[CH:17][C:12]=2[S:11][CH:10]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:9]1=[O:34]
Reactant: CCOC(=O)c1ccc2c(c1)N(CC(=O)OC(C)(C)C)C(=O)[C@@H](CCCc1ccc(OC)cc1)S2
Reactant: CC1(C)[C@@H]2CCC13CS(=O)(=O)N1O[C@]13C2(Cl)Cl
Agent: CCOC(=O)c1ccc(S[C@@H](CCCc2ccc(OC)cc2)C(=O)O)c(Br)c1
Solvent: CCOC(C)=O
Product: COc1ccc(CCCC2Sc3ccc(C(=O)O)cc3N(CC(=O)NO)C2=O)cc1

Procedure:
The compound of Example 14 (25% and 90% e.e.) was obtained by the same process as described in Reference Example 14, except for using the compound of Example 8, (+)-(8,8-dichlorocamphorylsulfonyl)oxaziridine and ethyl acetate as solvent. The optical purity was determined by the method described in Example 14.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].C([NH2:22])C1C=CC=CC=1.CS(O)(=O)=O>>[NH2:22][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12]
Reactant: NCc1ccccc1
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: CS(=O)(=O)O
Product: Nc1ccc(N)c(S(N)(=O)=O)c1

Procedure:
The 2-chloro-5-nitro-benzenesulfonamide intermediate (prepared as described in scheme 14) can be treated with a benzylic amine, such as benzylamine, to displace the chloro moiety. Hydrogenation under standard conditions in the presence of an acid (e.g., methanesulfonic acid) can be used to remove the benzylic group and to reduce the nitro group at the same time to afford the 2,5-diamino-benzenesulfonamide intermediate as a salt. Alternatively, the 2,5-diamino-benzenesulfonamide salt can be prepared by reduction of the 2-amino-5-nitro-benzenesulfonamide (prepared as described in schemes 14 and 15) under standard hydrogenation conditions in the presence of an acid (e.g., methanesulfonic acid). Subsequent reaction with methanesulfonyl chloride affords the desired 2-amino-5-methanesulfonylamino-benzenesulfonamide intermediate.
Reaction SMILES: [CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].N1CCCCC1>CCO>[CH3:1][C:2]1([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[C:22]2[S:18][C:19](=[O:24])[NH:20][C:21]2=[O:23])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C1CSC(=O)N1
Reactant: CC1(COc2cccc(C=O)c2)CCCCC1
Solvent: C1CCNCC1
Solvent: CCO
Product: CC1(COc2cccc(C=C3SC(=O)NC3=O)c2)CCCCC1
Yield: 67 %

Procedure:
A mixture consisting of compound v (0.5 mmol), 2,4-thiazolidinedione (0.6 mmol) and catalytic amounts of piperidine was refluxed in EtOH (5 mL) for 24 h and then concentrated. The oily product was dissolved in ethyl acetate, poured into water and acidified with AcOH. The solution was extracted with ethyl acetate, dried and concentrated. The residue was purified by silica gel chromatography, providing compound 1 in 67% yield. 1H NMR (300 MHz, CDCl3) δ 1.04 (s, 3H), 1.46-1.56 (m, 10H), 3.69 (s, 2H), 6.78-7.28 (m, 2H), 7.08 (d, J=8.40 Hz, 1H), 7.39 (dt, J=2.10, 8.40 Hz, 1H), 7.84 (s, 1H), 8.21-8.78 (br, 1H); HRMS exact mass of (M+Na)+, 354.1140 amu; observed mass of (M+Na)+, 354.113 amu.
Reaction SMILES: [OH:1][CH:2]([CH:6]([S:21][CH2:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([NH2:5])=[O:4].[C:31](Cl)(=[O:33])[CH3:32]>C(Cl)Cl.N1C=CC=CC=1.O>[C:31]([O:1][CH:2]([CH:6]([S:21][CH2:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[C:3]([NH2:5])=[O:4])(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: COc1ccc(-c2ccccc2C(SCC(=O)c2ccccc2)C(O)C(N)=O)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(-c2ccccc2C(SCC(=O)c2ccccc2)C(OC(C)=O)C(N)=O)cc1
Reaction time: 1 h

Procedure:
To a solution of 3.5 g (0.01 mol) of rac.-(R,*S*)α-(hydroxy)-4-methoxyphenyl-β-[(2-oxo -2-phenYlethYl)thio]benzenepropanamide in 130 mL of methylene chloride and 4.4 mL of pyridine was added dropwise at ice-bath temperature a solution of 1.1 g (0.014 mol) of acetyl chloride in 25 mL of methylene chloride. The mixture was stirred at this temperature for one hour then at room temperature for 17 hrs and diluted with water. The aqueous suspension was extracted with methylene chloride and the combined organic solutions were washed with water and dried (MgSO4). Removal of the solvent gave the crude ester, which after crystallization from ethyl acetate afforded 2.9 g (74%) of rac.-(S,*R*)-α-(acetyloxy)-4-methoxyphenyl -β-[(2-oxo-2-phenylethyl) thio]benzenepropanamide, mp 122°-123°.
Reaction SMILES: N/[C:2](/[CH3:6])=[CH:3]\[C:4]#[N:5].Cl.[CH:8]1([NH:12][NH2:13])[CH2:11][CH2:10][CH2:9]1>C(O)C>[CH:8]1([N:12]2[C:4]([NH2:5])=[CH:3][C:2]([CH3:6])=[N:13]2)[CH2:11][CH2:10][CH2:9]1
Reactant: C/C(N)=C/C#N
Reactant: NNC1CCC1
Agent: Cl
Solvent: CCO
Product: Cc1cc(N)n(C2CCC2)n1
Temperature: 75 °C
Reaction time: 0.17 h

Procedure:
(2Z)-3-Amino-2-butenenitrile (1.339 g, 16.31 mmol) and cyclobutylhydrazine HCl (2 g, 16.31 mmol) were added to ethanol (20 mL) and heated at 75° C. for 16 h. After cooling to room temperature, the solvent was removed under reduced pressure. The crude residue was suspended in saturated NaHCO3 (30 mL) and EtOAc (50 mL), and stirred for 10 min. The phases were separated and the aq. phase extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified via silica gel chromatography (eluent: 0 to 5% EtOAc:DCM, then gradient to 100% EtOAc). The final product was collected as 0.4 g (16%). LCMS E-S (M+H)=:152.0. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.67-2.00 (m, 2 H) 2.21 (s, 3 H) 2.32-2.43 (m, 2 H) 2.69 (ddd, J=10.55, 9.41, 2.53 Hz, 2 H) 3.26-3.55 (br s, 2 H) 4.48-4.59 (m, 1 H) 5.36 (s, 1 H)
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:11])[CH2:8][C:9]#[N:10].C(N(CC)CC)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([N:25]=[C:26]=[O:27])[CH:20]=1>C1(C)C=CC=CC=1>[O:11]=[C:7]([C:3]1[N:2]([CH3:1])[CH:6]=[CH:5][CH:4]=1)[CH:8]([C:26](=[O:27])[NH:25][C:21]1[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=1)[C:9]#[N:10]
Reactant: O=C=Nc1cccnc1
Reactant: Cn1cccc1C(=O)CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cn1cccc1C(=O)C(C#N)C(=O)Nc1cccnc1
Reaction time: 8 h

Procedure:
To the suspension of 12.9 g of 1-methyl-β-oxo-2-pyrrolepropionitrile (U.S. Pat. No. 4,256,759) in 150 ml of dry toluene and 10.1 g of anhydrous triethylamine are added 10.8 g of 3-pyridyl isocyanate while stirring. After all solids are dissolved, the solution is allowed to stand at room temperature overnight. The mixture is evaporated to dryness, the residue taken up in methanol and the solution is neutralized to pH ca. 6 with 3 N hydrochloric acid and diluted with 600 ml of water. The resulting precipitate is collected, washed with water, and dried to yield the β-oxo-α-(3-pyridylcarbamoyl)-β-(1-methyl-2-pyrrolyl)propionitrile.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27]([O:29]C)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.CC(C)([O-])C.[K+]>CO>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27]([OH:29])=[O:28])[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: COC(=O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)C1CC(c2ccc(CC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 733 mg (1.71 mmol) of the compound from Example 57A in methanol (32 ml) were added, at RT, 1.92 g (17.1 mmol) of potassium tert-butoxide. The mixture was stirred at 60° C. for 5 h. For workup, the methanol was removed under reduced pressure, and the residue was admixed with water and acidified (pH=1) with aqueous 1 N hydrochloric acid solution. The mixture was extracted with ethyl acetate, and the organic phase was dried with magnesium sulphate, filtered and concentrated under reduced pressure. Yield: 735 mg (99% of theory)
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[C:6]([O:16]CC)(=O)[CH:7]([CH2:9][C:10]([O:12]CC)=O)[OH:8]>>[CH2:1]([NH:5][C:6](=[O:16])[CH:7]([CH2:9][C:10]([NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:12])[OH:8])[CH:2]([CH3:4])[CH3:3]
Reactant: CCOC(=O)CC(O)C(=O)OCC
Reactant: CC(C)CN
Product: CC(C)CNC(=O)CC(O)C(=O)NCC(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 29 %

Procedure:
N,N′-Di-iso-butyl DL-malamide was prepared by the reaction of iso-butylamine with diethyl DL-malate. To a round-bottomed flask were added diethyl DL-malate (5.229 g, 1 eq) and iso-butylamine (14.058 g, 7 eq). The clear light yellow solution was stirred for 24 hours at room temperature, after which point a white solid had precipitated from solution. The solid was filtered, washed with hexane (3×25 mL), and dried under vacuum (1.96 g, 29% yield). The product was >99% pure as determined by NMR analyses.
Reaction SMILES: [Li+].[OH-].C1COCC1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[C:34]3[CH:35]=[CH:36][C:37]([C:40]([NH:42][CH2:43][CH2:44][C:45]([O:47]CC)=[O:46])=[O:41])=[N:38][CH:39]=3)=[O:23])=[CH:17][CH:16]=2)=[C:11]([CH3:50])[CH:10]=1.Cl>CCOC(C)=O.O.CO>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:31])[F:33])=[CH:26][C:25]=3[C:34]3[CH:35]=[CH:36][C:37]([C:40]([NH:42][CH2:43][CH2:44][C:45]([OH:47])=[O:46])=[O:41])=[N:38][CH:39]=3)=[O:23])=[CH:17][CH:16]=2)=[C:11]([CH3:50])[CH:10]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C(=O)Nc2ccc(-c3ccc(Cl)cc3C)cc2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Cl)ccc1-c1ccc(NC(=O)c2ccc(C(F)(F)F)cc2-c2ccc(C(=O)NCCC(=O)O)nc2)cc1
Temperature: 25 °C

Procedure:
A 1M aqueous solution of LiOH (1.0 mL, 1.0 mmol) was added to a THF (2.0 mL) and MeOH (0.5 mL) solution of ethyl 3-(5-(2-((4′-chloro-2′-methyl-[1,1′-biphenyl]-4-yl)carbamoyl)-5-(trifluoromethyl)phenyl)picolinamido)propanoate (85 mg, 0.14 mmol) and the resulting mixture was stirred at room temperature. After 1 h the resulting mixture was neutralized with 2M aqueous HCl, diluted with EtOAc and water and the layers were separated. The aqueous layer was extracted with EtOAc and the combined extracts were dried (Na2SO4), and concentrated. The title compound was re-solidified from CH2Cl2/heptane (ca. 1/19) and dried in vacuo.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].CN(C)C=O.[H-].[Na+].Br[C:20]1[CH:24]=[CH:23][S:22][CH:21]=1>O>[NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:20]2[CH:24]=[CH:23][S:22][CH:21]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: Brc1ccsc1
Reactant: Nc1cc(S)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1cc(Sc2ccsc2)ccc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
3.4 G. of 2-amino-4-mercapto-1-nitrobenzene is dissolved in 40 ml. of dimethylformamide under nitrogen and treated at 20°-25° C with 0.5 g. of 100% sodium hydride. After 1 hour, 2.8 g. of cuprous oxide and 4.0 g. of 3-bromothiophene are added. The mixture is heated in an oil bath for 5 hours at 140°-150° C, cooled, diluted with water, and extracted with chloroform. The chloroform solution is passed through a silica gel column and the eluate evaporated to yield 2-amino-4-(3-thienylthio)-1-nitrobenzene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:23]=[CH:24][C:25](Cl)=[N:26][CH:27]=2)=[O:21])=[CH:5][CH:4]=1.[Na].CCO[C:33]([CH3:35])=[O:34]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[C:20]([C:22]2[CH:23]=[CH:24][C:25]([O:34][CH2:33][CH2:35][N:26]3[CH2:27][CH2:22][CH2:23][CH2:24][CH2:25]3)=[N:26][CH:27]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: CCOC(C)=O
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(Cl)nc2)cc1
Agent: [Na]
Solvent: c1ccccc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)nc2)cc1
Temperature: 70 °C

Procedure:
[2-(4-Methoxyphenyl)-6-methoxybenzo[b]thien-3-yl][2-chloropyridin-5-yl]methanone (1 g, 2.44 mmol) was dissolved in 10 mL of benzene and 950 mg (7.32 mmol) of 2-hydroxyethyl-1-piperidine was added. To the reaction mixture was added 85 mg (3.7 mmol) of sodium and the reaction was stirred at ambient temperature under a nitrogen atmosphere until all the sodium dissolved. The reaction was heated to 70° C. for two and half hours, then allowed to cool. To the reaction solution was added 150 mL of EtOAc and the solution was washed three times with saturated aqueous Na2CO3. The organic layer was separated and evaporated to dryness. The crude product was chromatographed on a silica gel column eluted with a linear gradient beginning with CHCl3 and ending with CHCl3 -MeOH (19:1). The desired fraction were determined by tlc, combined, and evaporated to dryness. This yielded the title compound as a yellow, amorphous solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22]([O:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:23])[CH2:18][CH2:17]3)[CH:11]=2)[N:6]=1)=O.[NH3:30]>C1(C)C=CC=CC=1>[C:3]([C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:17][CH2:18][N:19]([C:22]([O:24][CH2:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:23])[CH2:20][CH2:21]3)[CH:11]=2)[N:6]=1)(=[O:2])[NH2:30]
Reactant: N
Reactant: COC(=O)c1nc(-c2ccnc(N3CCN(C(=O)OCC(C)(C)C)CC3)c2)no1
Solvent: Cc1ccccc1
Product: CC(C)(C)COC(=O)N1CCN(c2cc(-c3noc(C(N)=O)n3)ccn2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,2-Dimethylpropyl 4-{4-[5-(methoxycarbonyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}-1-piperazinecarboxylate (86.5 mg) obtained in Example 31 was dissolved in toluene (1 mL), and aqueous ammonia (0.3 mL) was added thereto and stirred at room temperature for 4 hours. Then, the solvent was evaporated away, and the resulting residue was isolated and purified through thin-layer silica gel chromatography (chloroform/methanol=97/3) to obtain 40 mg of the entitled compound as a colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([N:19]2[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]3[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:20]2=3)=[O:18])[CH2:13][CH2:12]1>CN(C=O)C.C(N(CC)CC)C>[Cl:34][C:31]1[CH:32]=[CH:33][C:20]2[N:19]([C:17]([CH:14]3[CH2:13][CH2:12][CH:11]([CH2:10][NH:9][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:16][CH2:15]3)=[O:18])[CH2:28][C:27]3[CH:26]=[N:25][N:24]([CH3:29])[C:23]=3[NH:22][C:21]=2[CH:30]=1
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)C1CCC(CN)CC1)C2
Reactant: CCCCCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCCNCC1CCC(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-bromohexane (0.83 mg, 0.005 mmol) in DMF (0.05 ml) was added to a solution of (4-Aminomethyl-cyclohexyl)-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone hydrochloride from Example E10.2 (2.05 mg, 0.005 mmol) in DMF (0.05 ml) and triethylamine (0.0021 ml). The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=458.4
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C@@H:23]([C:37]([OH:39])=O)[CH2:24][C:25]4[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[C:28]([NH2:35])=[C:27]([Cl:36])[CH:26]=4)=[O:21])[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:40]=1.[CH2:41]([O:43][C:44](=[O:58])[CH2:45][N:46]1[CH2:51][CH2:50][CH:49]([CH:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH2:48][CH2:47]1)[CH3:42]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C@H:23]([CH2:24][C:25]4[CH:30]=[C:29]([C:31]([F:32])([F:33])[F:34])[C:28]([NH2:35])=[C:27]([Cl:36])[CH:26]=4)[C:37]([N:55]4[CH2:54][CH2:53][CH:52]([CH:49]5[CH2:48][CH2:47][N:46]([CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:58])[CH2:51][CH2:50]5)[CH2:57][CH2:56]4)=[O:39])=[O:21])[CH2:18][CH2:19]3)[CH2:9][CH2:8][C:7]=2[CH:40]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(C(=O)O[C@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)C(=O)O)CC1)C(=O)N2
Reactant: CCOC(=O)CN1CCC(C2CCNCC2)CC1
Product: CCOC(=O)CN1CCC(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5cc(OC)ccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 9 from 100 mg (0.17 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate and 48 mg (0.19 mmol) ethyl[4,4′]bipiperidinyl-1-yl-acetate.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[NH2:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([NH2:23])=[CH:9][CH:8]=1>C(O)(=O)C>[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][NH:6][C:7]1[C:20]2[C:19](=[O:21])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:22])[C:11]=2[C:10]([NH:23][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2])=[CH:9][CH:8]=1
Reactant: Nc1ccc(N)c2c1C(=O)c1ccccc1C2=O
Reactant: ClCC1CO1
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)c2c(NCC(O)CCl)ccc(NCC(O)CCl)c21
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
Epichlorohydrin (84.5 mL, 1.08 mol) was added to a solution of 1,4 - diaminoanthraquinone (Aldrich Chemical Company, Milwaukee, Wis.) (10 g, 42 mmol) in glacial acetic acid (200 mL) at room temperature. The solution was stirred for 30 minutes at 90° C. and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, CH2Cl2 :MeOH/25:1) and recrystallized from CH2Cl2 -Ether-Hexanes to give a pure blue solid of the title compound (12.46 g, 70%), mp 167°-169° C.: 1H NMR (CDCl3) δ 3.21 (broad, 2H, OH), 3.5-3.6 (m, 6H, CHCH2), 3.75 (d, J=3Hz, 4H, CH2), 4.19 (broad, 2H, NH), 7.03 (d, J=3.2 Hz, 2H, ArH (2, 3)), 7.69 (m, 2H, ArH (6, 7)), 8.27 (m, 2H, ArH (5, 8)). Anal. Calcd for C20H20O4N2Cl2 ×0.25 H2O: C, 56.15; H, 4.83; N, 6.55. Found: C, 56.18; H, 4.76; N, 6.29.
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.C[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1CCN>>[C:34]1([CH3:35])[CH:33]=[CH:32][CH:37]=[CH:36][C:12]=1[CH2:11][CH2:10][NH:13][C:14]([C:16]1[S:17][CH:18]=[CH:19][C:20]=1[NH:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[NH:28][CH:29]=[CH:30][C:23]=12)=[O:15]
Reactant: Cc1ccccc1CCN
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: Cc1ccccc1CCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 2-(2-methylphenyl)ethylamine instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 377 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.97 (1H, br. s.) 10.45 (1H, s) 8.28 (1H, t, J=5.66 Hz) 8.06 (1H, d, J=6.25 Hz) 7.84 (1H, d, J=5.47 Hz) 7.36-7.43 (2H, m) 7.01-7.15 (4H, m) 6.78 (1H, d, J=6.25 Hz) 6.59 (1H, d, J=3.51 Hz) 3.39 (2H, td, J=7.52, 6.05 Hz) 2.77 (2H, d, J=7.81 Hz) 2.29 (3H, s)
Reaction SMILES: [F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:16]=[CH:15][C:14](=O)[C:13]([C:18](=[O:24])/[CH:19]=[CH:20]/N(C)C)=[N:12]3)[C:4]=2[O:3]1.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1)[NH2:27]>>[F:1][C:2]1([F:25])[O:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]3[CH:20]=[CH:19][C:18](=[O:24])[C:13]([C:14]4[N:26]([C:28]5[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=5)[N:27]=[CH:16][CH:15]=4)=[N:12]3)[C:4]=2[O:3]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc3c2OC(F)(F)O3)ccc1=O
Reactant: Cc1cc(NN)ccn1
Product: Cc1cc(-n2nccc2-c2nn(-c3cccc4c3OC(F)(F)O4)ccc2=O)ccn1

Procedure:
The product was obtained starting from 1-(2,2-Difluoro-benzo[1,3]dioxol-4-yl)-3-((E)-3-dimethylamino-acryloyl)-1H-pyridazin-4-one (A-15) and 4-hydrazino-2-methylpyridine according to the method described for example 91. MS: M=410.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][NH:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][OH:14])=[O:7].[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1)[CH3:20]>C1COCC1>[CH2:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:29])[O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[C:6](=[O:7])[NH:5][CH2:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:23][CH:22]=1)[CH3:20]
Reactant: O=C(NCc1ccccc1Cl)N1CCC[C@H]1CO
Reactant: CCc1ccc(N=C=O)cc1
Solvent: C1CCOC1
Product: CCc1ccc(NC(=O)OC[C@@H]2CCCN2C(=O)NCc2ccccc2Cl)cc1
Reaction time: 1 h
Yield: 10.1 %

Procedure:
To a solution of (S)—N-(2-chlorobenzyl)-2-(hydroxymethyl)pyrrolidine-1-carboxamide (268 mg, 1.0 mmol) in THF (2.0 mL) was added 4-ethyl-phenyl-isocyanate (220 mg, 1.5 mmol). The reaction mixture was stirred for 1 h. LC/MS indicated the reaction was complete. The reaction was concentrated and the resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O to give (S)-(1-(2-chlorobenzylcarbamoyl)pyrrolidin-2-yl)methyl 4-ethylphenylcarbamate (42 mg, 10% for two steps). LRMS (M+H+) m/z 416.0.